re K III Color Atlas of Pharmacology 2 nd edition, revised and expanded Heinz Lüllmann, M. D. Professor Emeritus Department of Pharmacology University of Kiel Germany Klaus Mohr, M. D. Professor Department of Pharmacology and Toxicology Institute of Pharmacy University of Bonn Germany Albrecht Ziegler, Ph. D. Professor Department of Pharmacology University of Kiel Germany Detlef Bieger, M. D. Professor Division of Basic Medical Sciences Faculty of Medicine Memorial University of Newfoundland St. John’s, Newfoundland Canada 164 color plates by Jürgen Wirth Thieme Stuttgart · New York · 2000 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Library of Congress Cataloging-in-Publication Data Taschenatlas der Pharmakologie. English. Color atlas of pharmacology / Heinz Lullmann … [et al.] ; color plates by Jurgen Wirth. — 2nd ed., rev. and expanded. p. cm. Rev. and expanded translation of: Taschenatlas der Pharmakologie. 3rd ed. 1996. Includes bibliographical references and indexes. ISBN 3-13-781702-1 (GTV). — ISBN 0-86577-843-4 (TNY) 1. Pharmacology Atlases. 2. Pharmacology Handbooks, manuals, etc. I. Lullmann, Heinz. II. Title. [DNLM: 1. Pharmacology Atlases. 2. Pharmacology Handbooks. QV 17 T197c 1999a] RM301.12.T3813 1999 615’.1—dc21 DNLM/DLC for Library of Congress 99-33662 CIP IV Illustrated by Jürgen Wirth, Darmstadt, Ger- many This book is an authorized revised and ex- panded translation of the 3rd German edition published and copyrighted 1996 by Georg Thieme Verlag, Stuttgart, Germany. Title of the German edition: Taschenatlas der Pharmakologie Some of the product names, patents and regis- tered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain. This book, including all parts thereof, is legally protected by copyright. Any use, exploitation or commercialization outside the narrow lim- its set by copyright legislation, without the publisher’s consent, is illegal and liable to prosecution. This applies in particular to pho- tostat reproduction, copying, mimeographing or duplication of any kind, translating, prepa- ration of microfilms, and electronic data pro- cessing and storage. ?2000 Georg Thieme Verlag, Rüdigerstrasse14, D-70469 Stuttgart, Germany Thieme New York, 333 Seventh Avenue, New York, NY 10001, USA Typesetting by Gulde Druck, Tübingen Printed in Germany by Staudigl, Donauw?rth ISBN 3-13-781702-1 (GTV) ISBN 0-86577-843-4 (TNY) 123456 Important Note: Medicine is an ever-chang- ing science undergoing continual develop- ment. Research and clinical experience are continually expanding our knowledge, in par- ticular our knowledge of proper treatment and drug therapy. Insofar as this book mentions any dosage or application, readers may rest as- sured that the authors, editors and publishers have made every effort to ensure that such ref- erences are in accordance with the state of knowledge at the time of production of the book. Nevertheless this does not involve, imply, or express any guarantee or responsibility on the part of the publishers in respect of any dosage instructions and forms of application stated in the book. Every user is requested to examine carefully the manufacturers’ leaflets accompa- nying each drug and to check, if necessary in consultation with a physician or specialist, whether the dosage schedules mentioned therein or the contraindications stated by the manufacturers differ from the statements made in the present book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Every dosage schedule or ev- ery form of application used is entirely at the user’s own risk and responsibility. The au- thors and publishers request every user to re- port to the publishers any discrepancies or in- accuracies noticed. Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. V Preface The present second edition of the Color Atlas of Pharmacology goes to print six years after the first edition. Numerous revisions were needed, highlighting the dramatic continuing progress in the drug sciences. In particular, it appeared necessary to in- clude novel therapeutic principles, such as the inhibitors of platelet aggregation from the group of integrin GPIIB/IIIA antagonists, the inhibitors of viral protease, or the non-nucleoside inhibitors of reverse transcriptase. Moreover, the re-evaluation and expanded use of conventional drugs, e.g., in congestive heart failure, bronchial asthma, or rheumatoid arthritis, had to be addressed. In each instance, the primary emphasis was placed on essential sites of action and basic pharmacological princi- ples. Details and individual drug properties were deliberately omitted in the interest of making drug action more transparent and affording an overview of the pharmaco- logical basis of drug therapy. The authors wish to reiterate that the Color Atlas of Pharmacology cannot replace a textbook of pharmacology, nor does it aim to do so. Rather, this little book is desi- gned to arouse the curiosity of the pharmacological novice; to help students of me- dicine and pharmacy gain an overview of the discipline and to review certain bits of information in a concise format; and, finally, to enable the experienced therapist to recall certain factual data, with perhaps some occasional amusement. Our cordial thanks go to the many readers of the multilingual editions of the Color Atlas for their suggestions. We are indebted to Prof. Ulrike Holzgrabe, Würzburg, Doc. Achim Mei?ner, Kiel, Prof. Gert-Hinrich Reil, Oldenburg, Prof. Reza Tabrizchi, St. John’s, Mr Christian Klein, Bonn, and Mr Christian Riedel, Kiel, for providing stimula- ting and helpful discussions and technical support, as well as to Dr. Liane Platt- Rohloff, Stuttgart, and Dr. David Frost, New York, for their editorial and stylistic gui- dance. Heinz Lüllmann Klaus Mohr Albrecht Ziegler Detlef Bieger Jürgen Wirth Fall 1999 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Contents General Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 History of Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Drug Sources Drug and Active Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Drug Administration Dosage Forms for Oral, and Nasal Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Dosage Forms for Parenteral Pulmonary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Rectal or Vaginal, and Cutaneous Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Drug Administration by Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Dermatalogic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 From Application to Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Cellular Sites of Action Potential Targets of Drug Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Distribution in the Body External Barriers of the Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Blood-Tissue Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Membrane Permeation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Possible Modes of Drug Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Binding to Plasma Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Drug Elimination The Liver as an Excretory Organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Biotransformation of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Enterohepatic Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 The Kidney as Excretory Organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Elimination of Lipophilic and Hydrophilic Substances . . . . . . . . . . . . . . . . . . . . . 42 Pharmacokinetics Drug Concentration in the Body as a Function of Time. First-Order (Exponential) Rate Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Time Course of Drug Concentration in Plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Time Course of Drug Plasma Levels During Repeated Dosing and During Irregular Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation . . . . . . . . . . 50 Change in Elimination Characteristics During Drug Therapy . . . . . . . . . . . . . . . 50 Quantification of Drug Action Dose-Response Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Concentration-Effect Relationship – Effect Curves . . . . . . . . . . . . . . . . . . . . . . . . 54 Concentration-Binding Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Drug-Receptor Interaction Types of Binding Forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Agonists-Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Enantioselectivity of Drug Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Receptor Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Mode of Operation of G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . . . . . 66 Time Course of Plasma Concentration and Effect . . . . . . . . . . . . . . . . . . . . . . . . . 68 Adverse Drug Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 VI Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Contents VII Drug Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Drug Toxicity in Pregnancy and Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Drug-independent Effects Placebo – Homeopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Systems Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Drug Acting on the Sympathetic Nervous System Sympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Structure of the Sympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Adrenoceptor Subtypes and Catecholamine Actions . . . . . . . . . . . . . . . . . . . . . . 84 Structure – Activity Relationship of Sympathomimetics . . . . . . . . . . . . . . . . . . . 86 Indirect Sympathomimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 α-Sympathomimetics, α-Sympatholytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 β-Sympatholytics (β-Blockers) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Types of β-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Antiadrenergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Drugs Acting on the Parasympathetic Nervous System Parasympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Cholinergic Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Parasympathomimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Parasympatholytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Nicotine Ganglionic Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Effects of Nicotine on Body Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 Consequences of Tobacco Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Biogenic Amines Biogenic Amines – Actions and Pharmacological Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Vasodilators Vasodilators – Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Organic Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Calcium Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Inhibitors of the RAA System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Drugs Acting on Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drugs Used to Influence Smooth Muscle Organs . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Cardiac Drugs Overview of Modes of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Cardiac Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Electrophysiological Actions of Antiarrhythmics of the Na + -Channel Blocking Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Antianemics Drugs for the Treatment of Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Iron Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 Antithrombotics Prophylaxis and Therapy of Thromboses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 Coumarin Derivatives – Heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 Fibrinolytic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 Intra-arterial Thrombus Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Formation, Activation, and Aggregation of Platelets . . . . . . . . . . . . . . . . . . . . . . . 148 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of Platelet Aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Presystemic Effect of Acetylsalicylic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Adverse Effects of Antiplatelet Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Plasma Volume Expanders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 Drugs used in Hyperlipoproteinemias Lipid-Lowering Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 Diuretics Diuretics – An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 NaCI Reabsorption in the Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Osmotic Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Diuretics of the Sulfonamide Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Potassium-Sparing Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Antidiuretic Hormone (/ADH) and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Drugs for the Treatment of Peptic Ulcers Drugs for Gastric and Duodenal Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 Laxatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 Antidiarrheals Antidiarrheal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 Other Gastrointestinal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 Drugs Acting on Motor Systems Drugs Affecting Motor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 Muscle Relaxants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Depolarizing Muscle Relaxants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Antiparkinsonian Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 Antiepileptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 Drugs for the Suppression of Pain, Analgesics, Pain Mechanisms and Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 Antipyretic Analgesics Eicosanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Antipyretic Analgesics and Antiinflammatory Drugs Antipyretic Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 Antipyretic Analgesics Nonsteroidal Antiinflammatory (Antirheumatic) Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 Thermoregulation and Antipyretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 Opioids Opioid Analgesics – Morphine Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 General Anesthetic Drugs General Anesthesia and General Anesthetic Drugs . . . . . . . . . . . . . . . . . . . . . . . . 216 Inhalational Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 Injectable Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Hypnotics Soporifics, Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 Sleep-Wake Cycle and Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 Psychopharmacologicals Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Pharmacokinetics of Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Therapy of Manic-Depressive Illnes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Therapy of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 Psychotomimetics (Psychedelics, Hallucinogens) . . . . . . . . . . . . . . . . . . . . . . . . . 240 VIII Contents Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Contents IX Hormones Hypothalamic and Hypophyseal Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Thyroid Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 Hyperthyroidism and Antithyroid Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 Glucocorticoid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Androgens, Anabolic Steroids, Antiandrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 Follicular Growth and Ovulation, Estrogen and Progestin Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 Oral Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 Insulin Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 Treatment of Insulin-Dependent Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 Treatment of Maturity-Onset (Type II) Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 Drugs for Maintaining Calcium Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 Antibacterial Drugs Drugs for Treating Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 Inhibitors of Cell Wall Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 Inhibitors of Tetrahydrofolate Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Inhibitors of DNA Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Inhibitors of Protein Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 Drugs for Treating Mycobacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 Antifungal Drugs Drugs Used in the Treatment of Fungal Infection . . . . . . . . . . . . . . . . . . . . . . . . . 282 Antiviral Drugs Chemotherapy of Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 Drugs for Treatment of AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 Disinfectants Disinfectants and Antiseptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 Antiparasitic Agents Drugs for Treating Endo- and Ectoparasitic Infestations . . . . . . . . . . . . . . . . . . . 292 Antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Anticancer Drugs Chemotherapy of Malignant Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 Immune Modulators Inhibition of Immune Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Antidotes Antidotes and treatment of poisonings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Therapy of Selected Diseases Angina Pectoris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Antianginal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 Acute Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Common Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 Allergic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Bronchial Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328 Emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Drug Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 X Contents Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. General Pharmacology Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. History of Pharmacology Since time immemorial, medicaments have been used for treating disease in humans and animals. The herbals of an- tiquity describe the therapeutic powers of certain plants and minerals. Belief in the curative powers of plants and cer- tain substances rested exclusively upon traditional knowledge, that is, empirical information not subjected to critical ex- amination. The Idea Claudius Galen (129–200 A.D.) first at- tempted to consider the theoretical background of pharmacology. Both the- ory and practical experience were to contribute equally to the rational use of medicines through interpretation of ob- served and experienced results. “The empiricists say that all is found by experience. We, however, maintain that it is found in part by experience, in part by theory. Neither experience nor theory alone is apt to discover all.” The Impetus Theophrastus von Hohenheim (1493– 1541 A.D.), called Paracelsus, began to quesiton doctrines handed down from antiquity, demanding knowledge of the active ingredient(s) in prescribed reme- dies, while rejecting the irrational con- coctions and mixtures of medieval med- icine. He prescribed chemically defined substances with such success that pro- fessional enemies had him prosecuted as a poisoner. Against such accusations, he defended himself with the thesis that has become an axiom of pharma- cology: “If you want to explain any poison prop- erly, what then isn‘t a poison? All things are poison, nothing is without poison; the dose alone causes a thing not to be poi- son.” Early Beginnings Johann Jakob Wepfer (1620–1695) was the first to verify by animal experi- mentation assertions about pharmaco- logical or toxicological actions. “I pondered at length. Finally I resolved to clarify the matter by experiments.” 2 History of Pharmacology Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. History of Pharmacology 3 Foundation Rudolf Buchheim (1820–1879) found- ed the first institute of pharmacology at the University of Dorpat (Tartu, Estonia) in 1847, ushering in pharmacology as an independent scientific discipline. In ad- dition to a description of effects, he strove to explain the chemical proper- ties of drugs. “The science of medicines is a theoretical, i.e., explanatory, one. It is to provide us with knowledge by which our judgement about the utility of medicines can be vali- dated at the bedside.” Consolidation – General Recognition Oswald Schmiedeberg (1838–1921), together with his many disciples (12 of whom were appointed to chairs of phar- macology), helped to establish the high reputation of pharmacology. Funda- mental concepts such as structure-ac- tivity relationship, drug receptor, and selective toxicity emerged from the work of, respectively, T. Frazer (1841– 1921) in Scotland, J. Langley (1852– 1925) in England, and P. Ehrlich (1854–1915) in Germany. Alexander J. Clark (1885–1941) in England first for- malized receptor theory in the early 1920s by applying the Law of Mass Ac- tion to drug-receptor interactions. To- gether with the internist, Bernhard Naunyn (1839–1925), Schmiedeberg founded the first journal of pharmacolo- gy, which has since been published without interruption. The “Father of American Pharmacology”, John J. Abel (1857–1938) was among the first Americans to train in Schmiedeberg‘s laboratory and was founder of the Jour- nal of Pharmacology and Experimental Therapeutics (published from 1909 until the present). Status Quo After 1920, pharmacological laborato- ries sprang up in the pharmaceutical in- dustry, outside established university institutes. After 1960, departments of clinical pharmacology were set up at many universities and in industry. Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug and Active Principle Until the end of the 19 th century, medi- cines were natural organic or inorganic products, mostly dried, but also fresh, plants or plant parts. These might con- tain substances possessing healing (therapeutic) properties or substances exerting a toxic effect. In order to secure a supply of medi- cally useful products not merely at the time of harvest but year-round, plants were preserved by drying or soaking them in vegetable oils or alcohol. Drying the plant or a vegetable or animal prod- uct yielded a drug (from French “drogue” – dried herb). Colloquially, this term nowadays often refers to chemical substances with high potential for phys- ical dependence and abuse. Used scien- tifically, this term implies nothing about the quality of action, if any. In its origi- nal, wider sense, drug could refer equal- ly well to the dried leaves of pepper- mint, dried lime blossoms, dried flowers and leaves of the female cannabis plant (hashish, marijuana), or the dried milky exudate obtained by slashing the unripe seed capsules of Papaver somniferum (raw opium). Nowadays, the term is ap- plied quite generally to a chemical sub- stance that is used for pharmacothera- py. Soaking plants parts in alcohol (ethanol) creates a tincture. In this pro- cess, pharmacologically active constitu- ents of the plant are extracted by the al- cohol. Tinctures do not contain the com- plete spectrum of substances that exist in the plant or crude drug, only those that are soluble in alcohol. In the case of opium tincture, these ingredients are alkaloids (i.e., basic substances of plant origin) including: morphine, codeine, narcotine = noscapine, papaverine, nar- ceine, and others. Using a natural product or extract to treat a disease thus usually entails the administration of a number of substanc- es possibly possessing very different ac- tivities. Moreover, the dose of an indi- vidual constituent contained within a given amount of the natural product is subject to large variations, depending upon the product‘s geographical origin (biotope), time of harvesting, or condi- tions and length of storage. For the same reasons, the relative proportion of indi- vidual constituents may vary consider- ably. Starting with the extraction of morphine from opium in 1804 by F. W. Sertürner (1783–1841), the active prin- ciples of many other natural products were subsequently isolated in chemi- cally pure form by pharmaceutical la- boratories. The aims of isolating active principles are: 1. Identification of the active ingredi- ent(s). 2. Analysis of the biological effects (pharmacodynamics) of individual in- gredients and of their fate in the body (pharmacokinetics). 3. Ensuring a precise and constant dos- age in the therapeutic use of chemically pure constituents. 4. The possibility of chemical synthesis, which would afford independence from limited natural supplies and create con- ditions for the analysis of structure-ac- tivity relationships. Finally, derivatives of the original con- stituent may be synthesized in an effort to optimize pharmacological properties. Thus, derivatives of the original constit- uent with improved therapeutic useful- ness may be developed. 4 Drug Sources Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Sources 5 A. From poppy to morphine Raw opium Preparation of opium tincture Morphine Codeine Narcotine Papaverine etc. Opium tincture (laudanum) Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Development This process starts with the synthesis of novel chemical compounds. Substances with complex structures may be ob- tained from various sources, e.g., plants (cardiac glycosides), animal tissues (heparin), microbial cultures (penicillin G), or human cells (urokinase), or by means of gene technology (human insu- lin). As more insight is gained into struc- ture-activity relationships, the search for new agents becomes more clearly focused. Preclinical testing yields informa- tion on the biological effects of new sub- stances. Initial screening may employ biochemical-pharmacological investiga- tions (e.g., receptor-binding assays p. 56) or experiments on cell cultures, isolated cells, and isolated organs. Since these models invariably fall short of replicating complex biological process- es in the intact organism, any potential drug must be tested in the whole ani- mal. Only animal experiments can re- veal whether the desired effects will ac- tually occur at dosages that produce lit- tle or no toxicity. Toxicological investiga- tions serve to evaluate the potential for: (1) toxicity associated with acute or chronic administration; (2) genetic damage (genotoxicity, mutagenicity); (3) production of tumors (onco- or car- cinogenicity); and (4) causation of birth defects (teratogenicity). In animals, compounds under investigation also have to be studied with respect to their absorption, distribution, metabolism, and elimination (pharmacokinetics). Even at the level of preclinical testing, only a very small fraction of new com- pounds will prove potentially fit for use in humans. Pharmaceutical technology pro- vides the methods for drug formulation. Clinical testing starts with Phase I studies on healthy subjects and seeks to determine whether effects observed in animal experiments also occur in hu- mans. Dose-response relationships are determined. In Phase II, potential drugs are first tested on selected patients for therapeutic efficacy in those disease states for which they are intended. Should a beneficial action be evident and the incidence of adverse effects be acceptably small, Phase III is entered, involving a larger group of patients in whom the new drug will be compared with standard treatments in terms of therapeutic outcome. As a form of hu- man experimentation, these clinical trials are subject to review and approval by institutional ethics committees ac- cording to international codes of con- duct (Declarations of Helsinki, Tokyo, and Venice). During clinical testing, many drugs are revealed to be unusable. Ultimately, only one new drug remains from approximately 10,000 newly syn- thesized substances. The decision to approve a new drug is made by a national regulatory body (Food & Drug Administration in the U.S.A., the Health Protection Branch Drugs Directorate in Canada, UK, Euro- pe, Australia) to which manufacturers are required to submit their applica- tions. Applicants must document by means of appropriate test data (from preclinical and clinical trials) that the criteria of efficacy and safety have been met and that product forms (tablet, cap- sule, etc.) satisfy general standards of quality control. Following approval, the new drug may be marketed under a trade name (p. 333) and thus become available for prescription by physicians and dispens- ing by pharmacists. As the drug gains more widespread use, regulatory sur- veillance continues in the form of post- licensing studies (Phase IV of clinical trials). Only on the basis of long-term experience will the risk: benefit ratio be properly assessed and, thus, the thera- peutic value of the new drug be deter- mined. 6 Drug Development Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Development 7 Clinical trial Phase 4 Approval § General use Long-term benefit-risk evaluation Healthy subjects: effects on body functions, dose definition, pharmacokinetics Selected patients: effects on disease; safety, efficacy, dose, pharmacokinetics Patient groups: Comparison with standard therapy Substances Cells Animals Isolated organs (bio)chemical synthesis Tissue homogenate A. From drug synthesis to approval § § § 10 10,000 Substances Preclinical testing: Effects on body functions, mechanism of action, toxicity ECG EEG Blood sample Blood pressure Substance 1 Phase 1 Phase 2 Phase 3 Clinical trial § Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Dosage Forms for Oral, Ocular, and Nasal Applications A medicinal agent becomes a medica- tion only after formulation suitable for therapeutic use (i.e., in an appropriate dosage form). The dosage form takes into account the intended mode of use and also ensures ease of handling (e.g., stability, precision of dosing) by pa- tients and physicians. Pharmaceutical technology is concerned with the design of suitable product formulations and quality control. Liquid preparations (A) may take the form of solutions, suspensions (a sol or mixture consisting of small wa- ter-insoluble solid drug particles dis- persed in water), or emulsions (disper- sion of minute droplets of a liquid agent or a drug solution in another fluid, e.g., oil in water). Since storage will cause sedimentation of suspensions and sep- aration of emulsions, solutions are gen- erally preferred. In the case of poorly watersoluble substances, solution is of- ten accomplished by adding ethanol (or other solvents); thus, there are both aqueous and alcoholic solutions. These solutions are made available to patients in specially designed drop bottles, ena- bling single doses to be measured ex- actly in terms of a defined number of drops, the size of which depends on the area of the drip opening at the bottle mouth and on the viscosity and surface tension of the solution. The advantage of a drop solution is that the dose, that is, the number of drops, can be precise- ly adjusted to the patient‘s need. Its dis- advantage lies in the difficulty that some patients, disabled by disease or age, will experience in measuring a pre- scribed number of drops. When the drugs are dissolved in a larger volume — as in the case of syrups or mixtures — the single dose is meas- ured with a measuring spoon. Dosing may also be done with the aid of a tablespoon or teaspoon (approx. 15 and 5 ml, respectively). However, due to the wide variation in the size of commer- cially available spoons, dosing will not be very precise. (Standardized medici- nal teaspoons and tablespoons are available.) Eye drops and nose drops (A) are designed for application to the mucosal surfaces of the eye (conjunctival sac) and nasal cavity, respectively. In order to prolong contact time, nasal drops are formulated as solutions of increased viscosity. Solid dosage forms include tab- lets, coated tablets, and capsules (B). Tablets have a disk-like shape, pro- duced by mechanical compression of active substance, filler (e.g., lactose, cal- cium sulfate), binder, and auxiliary ma- terial (excipients). The filler provides bulk enough to make the tablet easy to handle and swallow. It is important to consider that the individual dose of many drugs lies in the range of a few milligrams or less. In order to convey the idea of a 10-mg weight, two squares are marked below, the paper mass of each weighing 10 mg. Disintegration of the tablet can be hastened by the use of dried starch, which swells on contact with water, or of NaHCO 3 , which releas- es CO 2 gas on contact with gastric acid. Auxiliary materials are important with regard to tablet production, shelf life, palatability, and identifiability (color). Effervescent tablets (compressed effervescent powders) do not represent a solid dosage form, because they are dissolved in water immediately prior to ingestion and are, thus, actually, liquid preparations. 8 Drug Administration Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Administration 9 C. Dosage forms controlling rate of drug dissolution B. Solid preparations for oral application A. Liquid preparations Drug Filler Disintegrating agent Other excipients Mixing and forming by compression ~0.5 – 500 mg 30 – 250 mg 20 – 200 mg 30 – 15 mg min 100 – 1000 mg max possible tablet size Effervescent tablet Tablet Coated tablet Capsule Eye drops Nose drops Solution Mixture Alcoholic solution 40 drops = 1g Aqueous solution 20 drops = 1g Dosage: in drops Dosage: in spoon Sterile isotonic pH-neutral Viscous solution Drug r elease Capsule Coated tablet Capsule with coated drug pellets Matrix tablet Time 5 - 50 ml 5 - 50 ml 1 0 0 - 5 0 0 m l Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. The coated tablet contains a drug with- in a core that is covered by a shell, e.g., a wax coating, that serves to: (1) protect perishable drugs from decomposing; (2) mask a disagreeable taste or odor; (3) facilitate passage on swallowing; or (4) permit color coding. Capsules usually consist of an ob- long casing — generally made of gelatin — that contains the drug in powder or granulated form (See. p. 9, C). In the case of the matrix-type tab- let, the drug is embedded in an inert meshwork from which it is released by diffusion upon being moistened. In con- trast to solutions, which permit direct absorption of drug (A, track 3), the use of solid dosage forms initially requires tablets to break up and capsules to open (disintegration) before the drug can be dissolved (dissolution) and pass through the gastrointestinal mucosal lining (absorption). Because disintegra- tion of the tablet and dissolution of the drug take time, absorption will occur mainly in the intestine (A, track 2). In the case of a solution, absorption starts in the stomach (A, track 3). For acid-labile drugs, a coating of wax or of a cellulose acetate polymer is used to prevent disintegration of solid dosage forms in the stomach. Accord- ingly, disintegration and dissolution will take place in the duodenum at nor- mal speed (A, track 1) and drug libera- tion per se is not retarded. The liberation of drug, hence the site and time-course of absorption, are subject to modification by appropriate production methods for matrix-type tablets, coated tablets, and capsules. In the case of the matrix tablet, the drug is incorporated into a lattice from which it can be slowly leached out by gastroin- testinal fluids. As the matrix tablet undergoes enteral transit, drug libera- tion and absorption proceed en route (A, track 4). In the case of coated tablets, coat thickness can be designed such that release and absorption of drug occur ei- ther in the proximal (A, track 1) or distal (A, track 5) bowel. Thus, by matching dissolution time with small-bowel tran- sit time, drug release can be timed to oc- cur in the colon. Drug liberation and, hence, absorp- tion can also be spread out when the drug is presented in the form of a granu- late consisting of pellets coated with a waxy film of graded thickness. Depend- ing on film thickness, gradual dissolu- tion occurs during enteral transit, re- leasing drug at variable rates for absorp- tion. The principle illustrated for a cap- sule can also be applied to tablets. In this case, either drug pellets coated with films of various thicknesses are com- pressed into a tablet or the drug is incor- porated into a matrix-type tablet. Con- trary to timed-release capsules (Span- sules ? ), slow-release tablets have the ad- vantage of being dividable ad libitum; thus, fractions of the dose contained within the entire tablet may be admin- istered. This kind of retarded drug release is employed when a rapid rise in blood level of drug is undesirable, or when ab- sorption is being slowed in order to pro- long the action of drugs that have a short sojourn in the body. 10 Drug Administration Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Administration 11 Administration in form of Enteric- coated tablet Tablet, capsule Drops, mixture, effervescent solution Matrix tablet Coated tablet with delayed release A. Oral administration: drug release and absorption 12345 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Dosage Forms for Parenteral (1), Pulmonary (2), Rectal or Vaginal (3), and Cutaneous Application Drugs need not always be administered orally (i.e., by swallowing), but may also be given parenterally. This route usual- ly refers to an injection, although enter- al absorption is also bypassed when drugs are inhaled or applied to the skin. For intravenous, intramuscular, or subcutaneous injections, drugs are of- ten given as solutions and, less fre- quently, in crystalline suspension for intramuscular, subcutaneous, or intra- articular injection. An injectable solu- tion must be free of infectious agents, pyrogens, or suspended matter. It should have the same osmotic pressure and pH as body fluids in order to avoid tissue damage at the site of injection. Solutions for injection are preserved in airtight glass or plastic sealed contain- ers. From ampules for multiple or sin- gle use, the solution is aspirated via a needle into a syringe. The cartridge am- pule is fitted into a special injector that enables its contents to be emptied via a needle. An infusion refers to a solution being administered over an extended period of time. Solutions for infusion must meet the same standards as solu- tions for injection. Drugs can be sprayed in aerosol form onto mucosal surfaces of body cav- ities accessible from the outside (e.g., the respiratory tract [p. 14]). An aerosol is a dispersion of liquid or solid particles in a gas, such as air. An aerosol results when a drug solution or micronized powder is reduced to a spray on being driven through the nozzle of a pressur- ized container. Mucosal application of drug via the rectal or vaginal route is achieved by means of suppositories and vaginal tablets, respectively. On rectal applica- tion, absorption into the systemic circu- lation may be intended. With vaginal tablets, the effect is generally confined to the site of application. Usually the drug is incorporated into a fat that solid- ifies at room temperature, but melts in the rectum or vagina. The resulting oily film spreads over the mucosa and en- ables the drug to pass into the mucosa. Powders, ointments, and pastes (p. 16) are applied to the skin surface. In many cases, these do not contain drugs but are used for skin protection or care. However, drugs may be added if a topi- cal action on the outer skin or, more rarely, a systemic effect is intended. Transdermal drug delivery systems are pasted to the epidermis. They contain a reservoir from which drugs may diffuse and be absorbed through the skin. They offer the advan- tage that a drug depot is attached non- invasively to the body, enabling the drug to be administered in a manner similar to an infusion. Drugs amenable to this type of delivery must: (1) be ca- pable of penetrating the cutaneous bar- rier; (2) be effective in very small doses (restricted capacity of reservoir); and (3) possess a wide therapeutic margin (dosage not adjustable). 12 Drug Administration Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Administration 13 A. Preparations for parenteral (1), inhalational (2), rectal or vaginal (3), and percutaneous (4) application With and without fracture ring Often with preservative Sterile, iso-osmolar Ampule 1 – 20 ml Cartridge ampule 2 ml Multiple-dose vial 50 – 100 ml, always with preservative Infusion solution 500 – 1000 ml Propellant gas Drug solution Jet nebulizer Suppository Vaginal tablet Backing layer Drug reservoir Adhesive coat Transdermal delivery system (TDS) Time 12 24 h Ointment TDS 4 Paste Ointment Powder 13 2 Drug release 35 oC Melting point 35 oC Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Administration by Inhalation Inhalation in the form of an aerosol (p. 12), a gas, or a mist permits drugs to be applied to the bronchial mucosa and, to a lesser extent, to the alveolar mem- branes. This route is chosen for drugs in- tended to affect bronchial smooth mus- cle or the consistency of bronchial mu- cus. Furthermore, gaseous or volatile agents can be administered by inhala- tion with the goal of alveolar absorption and systemic effects (e.g., inhalational anesthetics, p. 218). Aerosols are formed when a drug solution or micron- ized powder is converted into a mist or dust, respectively. In conventional sprays (e.g., nebu- lizer), the air blast required for aerosol formation is generated by the stroke of a pump. Alternatively, the drug is deliv- ered from a solution or powder pack- aged in a pressurized canister equipped with a valve through which a metered dose is discharged. During use, the in- haler (spray dispenser) is held directly in front of the mouth and actuated at the start of inspiration. The effective- ness of delivery depends on the position of the device in front of the mouth, the size of aerosol particles, and the coordi- nation between opening of the spray valve and inspiration. The size of aerosol particles determines the speed at which they are swept along by inhaled air, hence the depth of penetration into the respiratory tract. Particles > 100 μm in diameter are trapped in the oropharyngeal cavity; those having dia- meters between 10 and 60μm will be deposited on the epithelium of the bronchial tract. Particles < 2 μm in dia- meter can reach the alveoli, but they will be largely exhaled because of their low tendency to impact on the alveolar epithelium. Drug deposited on the mucous lin- ing of the bronchial epithelium is partly absorbed and partly transported with bronchial mucus towards the larynx. Bronchial mucus travels upwards due to the orally directed undulatory beat of the epithelial cilia. Physiologically, this mucociliary transport functions to re- move inspired dust particles. Thus, only a portion of the drug aerosol (~ 10 %) gains access to the respiratory tract and just a fraction of this amount penetrates the mucosa, whereas the remainder of the aerosol undergoes mucociliary transport to the laryngopharynx and is swallowed. The advantage of inhalation (i.e., localized application) is fully ex- ploited by using drugs that are poorly absorbed from the intestine (isoprotere- nol, ipratropium, cromolyn) or are sub- ject to first-pass elimination (p. 42; bec- lomethasone dipropionate, budesonide, flunisolide, fluticasone dipropionate). Even when the swallowed portion of an inhaled drug is absorbed in un- changed form, administration by this route has the advantage that drug con- centrations at the bronchi will be higher than in other organs. The efficiency of mucociliary trans- port depends on the force of kinociliary motion and the viscosity of bronchial mucus. Both factors can be altered pathologically (e.g., in smoker’s cough, bronchitis) or can be adversely affected by drugs (atropine, antihistamines). 14 Drug Administration Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Administration 15 A. Application by inhalation Depth of penetration of inhaled aerosolized drug solution Nasopharynx Trachea-bronchi Bronchioli, alveoli Drug swept up is swallowed Mucociliary transport Ciliated epithelium Low systemic burden As complete presystemic elimination as possible As little enteral absorption as possible 100 μm 10 μm 1 μm 1 cm/min Larynx 10% 90% Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Dermatologic Agents Pharmaceutical preparations applied to the outer skin are intended either to provide skin care and protection from noxious influences (A), or to serve as a vehicle for drugs that are to be absorbed into the skin or, if appropriate, into the general circulation (B). Skin Protection (A) Protective agents are of several kinds to meet different requirements according to skin condition (dry, low in oil, chapped vs moist, oily, elastic), and the type of noxious stimuli (prolonged ex- posure to water, regular use of alcohol- containing disinfectants [p. 290], in- tense solar irradiation). Distinctions among protective agents are based upon consistency, phy- sicochemical properties (lipophilic, hy- drophilic), and the presence of addi- tives. Dusting Powders are sprinkled on- to the intact skin and consist of talc, magnesium stearate, silicon dioxide (silica), or starch. They adhere to the skin, forming a low-friction film that at- tenuates mechanical irritation. Powders exert a drying (evaporative) effect. Lipophilic ointment (oil ointment) consists of a lipophilic base (paraffin oil, petroleum jelly, wool fat [lanolin]) and may contain up to 10 % powder materi- als, such as zinc oxide, titanium oxide, starch, or a mixture of these. Emulsify- ing ointments are made of paraffins and an emulsifying wax, and are miscible with water. Paste (oil paste) is an ointment containing more than 10 % pulverized constituents. Lipophilic (oily) cream is an emul- sion of water in oil, easier to spread than oil paste or oil ointments. Hydrogel and water-soluble oint- ment achieve their consistency by means of different gel-forming agents (gelatin, methylcellulose, polyethylene glycol). Lotions are aqueous suspen- sions of water-insoluble and solid con- stituents. Hydrophilic (aqueous) cream is an emulsion of an oil in water formed with the aid of an emulsifier; it may also be considered an oil-in-water emulsion of an emulsifying ointment. All dermatologic agents having a lipophilic base adhere to the skin as a water-repellent coating. They do not wash off and they also prevent (oc- clude) outward passage of water from the skin. The skin is protected from dry- ing, and its hydration and elasticity in- crease. Diminished evaporation of water results in warming of the occluded skin area. Hydrophilic agents wash off easily and do not impede transcutaneous out- put of water. Evaporation of water is felt as a cooling effect. Dermatologic Agents as Vehicles (B) In order to reach its site of action, a drug (D) must leave its pharmaceutical pre- paration and enter the skin, if a local ef- fect is desired (e.g., glucocorticoid oint- ment), or be able to penetrate it, if a systemic action is intended (transder- mal delivery system, e.g., nitroglycerin patch, p. 120). The tendency for the drug to leave the drug vehicle (V) is higher the more the drug and vehicle differ in lipophilicity (high tendency: hydrophil- ic D and lipophilic V, and vice versa). Be- cause the skin represents a closed lipo- philic barrier (p. 22), only lipophilic drugs are absorbed. Hydrophilic drugs fail even to penetrate the outer skin when applied in a lipophilic vehicle. This formulation can be meaningful when high drug concentrations are re- quired at the skin surface (e.g., neomy- cin ointment for bacterial skin infec- tions). 16 Drug Administration Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Administration 17 Semi-solid Solid Liquid Dermatologicals B. Dermatologicals as drug vehicles Powder Paste Oily paste Ointment Lipophilic ointment Hydrophilic ointment Lipophilic cream Hydrophilic cream Cream Solution Aqueous solution Alcoholic tincture Hydrogel Suspen- sion Emulsion Fat, oil Oil in waterWater in oil Gel, water Occlusive Permeable, coolant impossible possible Dry, non-oily skin Oily, moist skin Lipophilic drug in hydrophilic base Lipophilic drug in lipophilic base Hydrophilic drug in lipophilic base Hydrophilic drug in hydrophilic base Stratum corneum Epithelium Subcutaneous fat tissue Lotion A. Dermatologicals as skin protectants Perspiration Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. From Application to Distribution in the Body As a rule, drugs reach their target organs via the blood. Therefore, they must first enter the blood, usually the venous limb of the circulation. There are several pos- sible sites of entry. The drug may be injected or infused intravenously, in which case the drug is introduced directly into the blood- stream. In subcutaneous or intramus- cular injection, the drug has to diffuse from its site of application into the blood. Because these procedures entail injury to the outer skin, strict require- ments must be met concerning tech- nique. For that reason, the oral route (i.e., simple application by mouth) in- volving subsequent uptake of drug across the gastrointestinal mucosa into the blood is chosen much more fre- quently. The disadvantage of this route is that the drug must pass through the liver on its way into the general circula- tion. This fact assumes practical signifi- cance with any drug that may be rapidly transformed or possibly inactivated in the liver (first-pass hepatic elimination; p. 42). Even with rectal administration, at least a fraction of the drug enters the general circulation via the portal vein, because only veins draining the short terminal segment of the rectum com- municate directly with the inferior vena cava. Hepatic passage is circumvented when absorption occurs buccally or sublingually, because venous blood from the oral cavity drains directly into the superior vena cava. The same would apply to administration by inhalation (p. 14). However, with this route, a local effect is usually intended; a systemic ac- tion is intended only in exceptional cas- es. Under certain conditions, drug can also be applied percutaneously in the form of a transdermal delivery system (p. 12). In this case, drug is slowly re- leased from the reservoir, and then pen- etrates the epidermis and subepidermal connective tissue where it enters blood capillaries. Only a very few drugs can be applied transdermally. The feasibility of this route is determined by both the physicochemical properties of the drug and the therapeutic requirements (acute vs. long-term effect). Speed of absorption is determined by the route and method of application. It is fastest with intravenous injection, less fast which intramuscular injection, and slowest with subcutaneous injec- tion. When the drug is applied to the oral mucosa (buccal, sublingual route), plasma levels rise faster than with con- ventional oral administration because the drug preparation is deposited at its actual site of absorption and very high concentrations in saliva occur upon the dissolution of a single dose. Thus, up- take across the oral epithelium is accel- erated. The same does not hold true for poorly water-soluble or poorly absorb- able drugs. Such agents should be given orally, because both the volume of fluid for dissolution and the absorbing sur- face are much larger in the small intes- tine than in the oral cavity. Bioavailability is defined as the fraction of a given drug dose that reach- es the circulation in unchanged form and becomes available for systemic dis- tribution. The larger the presystemic elimination, the smaller is the bioavail- ability of an orally administered drug. 18 Drug Administration Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Administration 19 Intravenous Sublingual buccal Inhalational Transdermal Subcutaneous Intramuscular Oral Aorta Distribution in body Rectal A. From application to distribution Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Potential Targets of Drug Action Drugs are designed to exert a selective influence on vital processes in order to alleviate or eliminate symptoms of dis- ease. The smallest basic unit of an or- ganism is the cell. The outer cell mem- brane, or plasmalemma, effectively de- marcates the cell from its surroundings, thus permitting a large degree of inter- nal autonomy. Embedded in the plas- malemma are transport proteins that serve to mediate controlled metabolic exchange with the cellular environment. These include energy-consuming pumps (e.g., Na, K-ATPase, p. 130), car- riers (e.g., for Na/glucose-cotransport, p. 178), and ion channels e.g., for sodium (p. 136) or calcium (p. 122) (1). Functional coordination between single cells is a prerequisite for viability of the organism, hence also for the sur- vival of individual cells. Cell functions are regulated by means of messenger substances for the transfer of informa- tion. Included among these are “trans- mitters” released from nerves, which the cell is able to recognize with the help of specialized membrane binding sites or receptors. Hormones secreted by endocrine glands into the blood, then into the extracellular fluid, represent another class of chemical signals. Final- ly, signalling substances can originate from neighboring cells, e.g., prostaglan- dins (p. 196) and cytokines. The effect of a drug frequently re- sults from interference with cellular function. Receptors for the recognition of endogenous transmitters are obvious sites of drug action (receptor agonists and antagonists, p. 60). Altered activity of transport systems affects cell func- tion (e.g., cardiac glycosides, p. 130; loop diuretics, p. 162; calcium-antago- nists, p. 122). Drugs may also directly interfere with intracellular metabolic processes, for instance by inhibiting (phosphodiesterase inhibitors, p. 132) or activating (organic nitrates, p. 120) an enzyme (2). In contrast to drugs acting from the outside on cell membrane constituents, agents acting in the cell’s interior need to penetrate the cell membrane. The cell membrane basically con- sists of a phospholipid bilayer (80? = 8 nm in thickness) in which are embed- ded proteins (integral membrane pro- teins, such as receptors and transport molecules). Phospholipid molecules contain two long-chain fatty acids in es- ter linkage with two of the three hy- droxyl groups of glycerol. Bound to the third hydroxyl group is phosphoric acid, which, in turn, carries a further residue, e.g., choline, (phosphatidylcholine = lec- ithin), the amino acid serine (phosphat- idylserine) or the cyclic polyhydric alco- hol inositol (phosphatidylinositol). In terms of solubility, phospholipids are amphiphilic: the tail region containing the apolar fatty acid chains is lipophilic, the remainder – the polar head – is hy- drophilic. By virtue of these properties, phospholipids aggregate spontaneously into a bilayer in an aqueous medium, their polar heads directed outwards into the aqueous medium, the fatty acid chains facing each other and projecting into the inside of the membrane (3). The hydrophobic interior of the phospholipid membrane constitutes a diffusion barrier virtually imperme- able for charged particles. Apolar parti- cles, however, penetrate the membrane easily. This is of major importance with respect to the absorption, distribution, and elimination of drugs. 20 Cellular Sites of Action Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Cellular Sites of Action 21 Nerve Transmitter Receptor Enzyme Hormone receptors Neural control Hormonal control Direct action on metabolism Cellular transport systems for controlled transfer of substrates Ion channel Transport molecule Effect Intracellular site of action Choline Phosphoric acid Glycerol Fatty acid A. Sites at which drugs act to modify cell function 1 2 3 D Hormones D D D = DrugD Phospholipid matrix D D Protein Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. External Barriers of the Body Prior to its uptake into the blood (i.e., during absorption), a drug has to over- come barriers that demarcate the body from its surroundings, i.e., separate the internal milieu from the external mi- lieu. These boundaries are formed by the skin and mucous membranes. When absorption takes place in the gut (enteral absorption), the intestinal epithelium is the barrier. This single- layered epithelium is made up of ente- rocytes and mucus-producing goblet cells. On their luminal side, these cells are joined together by zonulae occlu- dentes (indicated by black dots in the in- set, bottom left). A zonula occludens or tight junction is a region in which the phospholipid membranes of two cells establish close contact and become joined via integral membrane proteins (semicircular inset, left center). The re- gion of fusion surrounds each cell like a ring, so that neighboring cells are weld- ed together in a continuous belt. In this manner, an unbroken phospholipid layer is formed (yellow area in the sche- matic drawing, bottom left) and acts as a continuous barrier between the two spaces separated by the cell layer – in the case of the gut, the intestinal lumen (dark blue) and the interstitial space (light blue). The efficiency with which such a barrier restricts exchange of sub- stances can be increased by arranging these occluding junctions in multiple arrays, as for instance in the endotheli- um of cerebral blood vessels. The con- necting proteins (connexins) further- more serve to restrict mixing of other functional membrane proteins (ion pumps, ion channels) that occupy spe- cific areas of the cell membrane. This phospholipid bilayer repre- sents the intestinal mucosa-blood bar- rier that a drug must cross during its en- teral absorption. Eligible drugs are those whose physicochemical properties al- low permeation through the lipophilic membrane interior (yellow) or that are subject to a special carrier transport mechanism. Absorption of such drugs proceeds rapidly, because the absorbing surface is greatly enlarged due to the formation of the epithelial brush border (submicroscopic foldings of the plasma- lemma). The absorbability of a drug is characterized by the absorption quo- tient, that is, the amount absorbed di- vided by the amount in the gut available for absorption. In the respiratory tract, cilia-bear- ing epithelial cells are also joined on the luminal side by zonulae occludentes, so that the bronchial space and the inter- stitium are separated by a continuous phospholipid barrier. With sublingual or buccal applica- tion, a drug encounters the non-kerati- nized, multilayered squamous epitheli- um of the oral mucosa. Here, the cells establish punctate contacts with each other in the form of desmosomes (not shown); however, these do not seal the intercellular clefts. Instead, the cells have the property of sequestering phos- pholipid-containing membrane frag- ments that assemble into layers within the extracellular space (semicircular in- set, center right). In this manner, a con- tinuous phospholipid barrier arises also inside squamous epithelia, although at an extracellular location, unlike that of intestinal epithelia. A similar barrier principle operates in the multilayered keratinized squamous epithelium of the outer skin. The presence of a continu- ous phospholipid layer means that squamous epithelia will permit passage of lipophilic drugs only, i.e., agents ca- pable of diffusing through phospholipid membranes, with the epithelial thick- ness determining the extent and speed of absorption. In addition, cutaneous ab- sorption is impeded by the keratin layer, the stratum corneum, which is very unevenly developed in various are- as of the skin. 22 Distribution in the Body Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Distribution in the Body 23 A. External barriers of the body Nonkeratinized squamous epithelium Ciliated epithelium Keratinized squamous epithelium Epithelium with brush border Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Blood-Tissue Barriers Drugs are transported in the blood to different tissues of the body. In order to reach their sites of action, they must leave the bloodstream. Drug permea- tion occurs largely in the capillary bed, where both surface area and time avail- able for exchange are maximal (exten- sive vascular branching, low velocity of flow). The capillary wall forms the blood-tissue barrier. Basically, this consists of an endothelial cell layer and a basement membrane enveloping the latter (solid black line in the schematic drawings). The endothelial cells are “riveted” to each other by tight junc- tions or occluding zonulae (labelled Z in the electron micrograph, top left) such that no clefts, gaps, or pores remain that would permit drugs to pass unimpeded from the blood into the interstitial fluid. The blood-tissue barrier is devel- oped differently in the various capillary beds. Permeability to drugs of the capil- lary wall is determined by the structural and functional characteristics of the en- dothelial cells. In many capillary beds, e.g., those of cardiac muscle, endothe- lial cells are characterized by pro- nounced endo- and transcytotic activ- ity, as evidenced by numerous invagina- tions and vesicles (arrows in the EM mi- crograph, top right). Transcytotic activ- ity entails transport of fluid or macro- molecules from the blood into the inter- stitium and vice versa. Any solutes trapped in the fluid, including drugs, may traverse the blood-tissue barrier. In this form of transport, the physico- chemical properties of drugs are of little importance. In some capillary beds (e.g., in the pancreas), endothelial cells exhibit fen- estrations. Although the cells are tight- ly connected by continuous junctions, they possess pores (arrows in EM mi- crograph, bottom right) that are closed only by diaphragms. Both the dia- phragm and basement membrane can be readily penetrated by substances of low molecular weight — the majority of drugs — but less so by macromolecules, e.g., proteins such as insulin (G: insulin storage granules. Penetrability of mac- romolecules is determined by molecu- lar size and electrical charge. Fenestrat- ed endothelia are found in the capillar- ies of the gut and endocrine glands. In the central nervous system (brain and spinal cord), capillary endo- thelia lack pores and there is little trans- cytotic activity. In order to cross the blood-brain barrier, drugs must diffuse transcellularly, i.e., penetrate the lumi- nal and basal membrane of endothelial cells. Drug movement along this path requires specific physicochemical prop- erties (p. 26) or the presence of a trans- port mechanism (e.g., L-dopa, p. 188). Thus, the blood-brain barrier is perme- able only to certain types of drugs. Drugs exchange freely between blood and interstitium in the liver, where endothelial cells exhibit large fenestrations (100 nm in diameter) fac- ing Disse’s spaces (D) and where neither diaphragms nor basement membranes impede drug movement. Diffusion bar- riers are also present beyond the capil- lary wall: e.g., placental barrier of fused syncytiotrophoblast cells; blood: testi- cle barrier — junctions interconnecting Sertoli cells; brain choroid plexus: blood barrier — occluding junctions between ependymal cells. (Vertical bars in the EM micro- graphs represent 1 μm; E: cross-sec- tioned erythrocyte; AM: actomyosin; G: insulin-containing granules.) 24 Distribution in the Body Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Distribution in the Body 25 A. Blood-tissue barriers CNS Heart muscle Liver G Pancreas AM D E Z Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Membrane Permeation An ability to penetrate lipid bilayers is a prerequisite for the absorption of drugs, their entry into cells or cellular orga- nelles, and passage across the blood- brain barrier. Due to their amphiphilic nature, phospholipids form bilayers possessing a hydrophilic surface and a hydrophobic interior (p. 20). Substances may traverse this membrane in three different ways. Diffusion (A). Lipophilic substanc- es (red dots) may enter the membrane from the extracellular space (area shown in ochre), accumulate in the membrane, and exit into the cytosol (blue area). Direction and speed of per- meation depend on the relative concen- trations in the fluid phases and the membrane. The steeper the gradient (concentration difference), the more drug will be diffusing per unit of time (Fick’s Law). The lipid membrane repre- sents an almost insurmountable obsta- cle for hydrophilic substances (blue tri- angles). Transport (B). Some drugs may penetrate membrane barriers with the help of transport systems (carriers), ir- respective of their physicochemical properties, especially lipophilicity. As a prerequisite, the drug must have affin- ity for the carrier (blue triangle match- ing recess on “transport system”) and, when bound to the latter, be capable of being ferried across the membrane. Membrane passage via transport mech- anisms is subject to competitive inhibi- tion by another substance possessing similar affinity for the carrier. Substanc- es lacking in affinity (blue circles) are not transported. Drugs utilize carriers for physiological substances, e.g., L-do- pa uptake by L-amino acid carrier across the blood-intestine and blood-brain barriers (p. 188), and uptake of amino- glycosides by the carrier transporting basic polypeptides through the luminal membrane of kidney tubular cells (p. 278). Only drugs bearing sufficient re- semblance to the physiological sub- strate of a carrier will exhibit affinity for it. Finally, membrane penetration may occur in the form of small mem- brane-covered vesicles. Two different systems are considered. Transcytosis (vesicular transport, C). When new vesicles are pinched off, substances dissolved in the extracellu- lar fluid are engulfed, and then ferried through the cytoplasm, vesicles (phago- somes) undergo fusion with lysosomes to form phagolysosomes, and the trans- ported substance is metabolized. Alter- natively, the vesicle may fuse with the opposite cell membrane (cytopempsis). Receptor-mediated endocytosis (C). The drug first binds to membrane surface receptors (1, 2) whose cytosolic domains contact special proteins (adap- tins, 3). Drug-receptor complexes mi- grate laterally in the membrane and ag- gregate with other complexes by a clathrin-dependent process (4). The af- fected membrane region invaginates and eventually pinches off to form a de- tached vesicle (5). The clathrin coat is shed immediately (6), followed by the adaptins (7). The remaining vesicle then fuses with an “early” endosome (8), whereupon proton concentration rises inside the vesicle. The drug-receptor complex dissociates and the receptor returns into the cell membrane. The “early” endosome delivers its contents to predetermined destinations, e.g., the Golgi complex, the cell nucleus, lysoso- mes, or the opposite cell membrane (transcytosis). Unlike simple endocyto- sis, receptor-mediated endocytosis is contingent on affinity for specific recep- tors and operates independently of con- centration gradients. 26 Distribution in the Body Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Distribution in the Body 27 C. Membrane permeation: receptor-mediated endocytosis, vesicular uptake, and transport A. Membrane permeation: diffusion B. Membrane permeation: transport Vesicular transport Lysosome Phagolysosome Intracellular ExtracellularExtracellular 1 2 3 4 5 7 8 9 6 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Possible Modes of Drug Distribution Following its uptake into the body, the drug is distributed in the blood (1) and through it to the various tissues of the body. Distribution may be restricted to the extracellular space (plasma volume plus interstitial space) (2) or may also extend into the intracellular space (3). Certain drugs may bind strongly to tis- sue structures, so that plasma concen- trations fall significantly even before elimination has begun (4). After being distributed in blood, macromolecular substances remain largely confined to the vascular space, because their permeation through the blood-tissue barrier, or endothelium, is impeded, even where capillaries are fenestrated. This property is exploited therapeutically when loss of blood ne- cessitates refilling of the vascular bed, e.g., by infusion of dextran solutions (p. 152). The vascular space is, moreover, predominantly occupied by substances bound with high affinity to plasma pro- teins (p. 30; determination of the plas- ma volume with protein-bound dyes). Unbound, free drug may leave the bloodstream, albeit with varying ease, because the blood-tissue barrier (p. 24) is differently developed in different seg- ments of the vascular tree. These re- gional differences are not illustrated in the accompanying figures. Distribution in the body is deter- mined by the ability to penetrate mem- branous barriers (p. 20). Hydrophilic substances (e.g., inulin) are neither tak- en up into cells nor bound to cell surface structures and can, thus, be used to de- termine the extracellular fluid volume (2). Some lipophilic substances diffuse through the cell membrane and, as a re- sult, achieve a uniform distribution (3). Body weight may be broken down as follows: Further subdivisions are shown in the table. The volume ratio interstitial: intra- cellular water varies with age and body weight. On a percentage basis, intersti- tial fluid volume is large in premature or normal neonates (up to 50 % of body water), and smaller in the obese and the aged. The concentration (c) of a solution corresponds to the amount (D) of sub- stance dissolved in a volume (V); thus, c = D/V. If the dose of drug (D) and its plasma concentration (c) are known, a volume of distribution (V) can be calcu- lated from V = D/c. However, this repre- sents an apparent volume of distribu- tion (V app ), because an even distribution in the body is assumed in its calculation. Homogeneous distribution will not oc- cur if drugs are bound to cell mem- branes (5) or to membranes of intracel- lular organelles (6) or are stored within the latter (7). In these cases, V app can ex- ceed the actual size of the available fluid volume. The significance of V app as a pharmacokinetic parameter is dis- cussed on p. 44. MT80MT111MT116MT101MT110MT116MT105MT97MT108MT32MT97MT113MT117MT101MT111MT117MT115MT32MT115MT111MT108MT118MT101MT110MT116 MT115MT112MT97MT99MT101MT115MT32MT102MT111MT114MT32MT100MT114MT117MT103MT115 MT52MT48MT37 MT50MT48MT37 MT52MT48MT37 MT83MT111MT108MT105MT100MT32MT115MT117MT98MT115MT116MT97MT110MT99MT101MT32MT97MT110MT100 MT115MT116MT114MT117MT99MT116MT117MT114MT97MT108MT108MT121MT32MT98MT111MT117MT110MT100 MT119MT97MT116MT101MT114 MT105MT110MT116MT114MT97MT99MT101MT108MT108MT117MT108MT97MT114 MT119MT97MT116MT101MT114 MT101MT120MT116MT114MT97MT45MT99MT101MT108MT108MT117MT108MT97MT114 MT119MT97MT116MT101MT114 Solid substance and structurally bound water 28 Distribution in the Body intracellular extracellular water water Potential aqueous solvent spaces for drugs L llmann, Color Atlas of Pharmacology ' 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Distribution in the Body 29 A. Compartments for drug distribution Distribution in tissue Aqueous spaces of the organism InterstitiumPlasma Erythrocytes Intracellular space 6% 4% 25% 65% Lysosomes Mito- chondria Cell membrane Nucleus 12 43 56 7 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Binding to Plasma Proteins Having entered the blood, drugs may bind to the protein molecules that are present in abundance, resulting in the formation of drug-protein complexes. Protein binding involves primarily al- bumin and, to a lesser extent, β-globu- lins and acidic glycoproteins. Other plasma proteins (e.g., transcortin, trans- ferrin, thyroxin-binding globulin) serve specialized functions in connection with specific substances. The degree of binding is governed by the concentra- tion of the reactants and the affinity of a drug for a given protein. Albumin con- centration in plasma amounts to 4.6 g/100 mL or O.6 mM, and thus pro- vides a very high binding capacity (two sites per molecule). As a rule, drugs ex- hibit much lower affinity (K D approx. 10 –5 –10 –3 M) for plasma proteins than for their specific binding sites (recep- tors). In the range of therapeutically rel- evant concentrations, protein binding of most drugs increases linearly with con- centration (exceptions: salicylate and certain sulfonamides). The albumin molecule has different binding sites for anionic and cationic li- gands, but van der Waals’ forces also contribute (p. 58). The extent of binding correlates with drug hydrophobicity (repulsion of drug by water). Binding to plasma proteins is in- stantaneous and reversible, i.e., any change in the concentration of unbound drug is immediately followed by a cor- responding change in the concentration of bound drug. Protein binding is of great importance, because it is the con- centration of free drug that determines the intensity of the effect. At an identi- cal total plasma concentration (say, 100 ng/mL) the effective concentration will be 90 ng/mL for a drug 10 % bound to protein, but 1 ng/mL for a drug 99 % bound to protein. The reduction in con- centration of free drug resulting from protein binding affects not only the in- tensity of the effect but also biotransfor- mation (e.g., in the liver) and elimina- tion in the kidney, because only free drug will enter hepatic sites of metab- olism or undergo glomerular filtration. When concentrations of free drug fall, drug is resupplied from binding sites on plasma proteins. Binding to plasma pro- tein is equivalent to a depot in prolong- ing the duration of the effect by retard- ing elimination, whereas the intensity of the effect is reduced. If two substanc- es have affinity for the same binding site on the albumin molecule, they may compete for that site. One drug may dis- place another from its binding site and thereby elevate the free (effective) con- centration of the displaced drug (a form of drug interaction). Elevation of the free concentration of the displaced drug means increased effectiveness and ac- celerated elimination. A decrease in the concentration of albumin (liver disease, nephrotic syn- drome, poor general condition) leads to altered pharmacokinetics of drugs that are highly bound to albumin. Plasma protein-bound drugs that are substrates for transport carriers can be cleared from blood at great velocity, e.g., p-aminohippurate by the renal tu- bule and sulfobromophthalein by the liver. Clearance rates of these substanc- es can be used to determine renal or he- patic blood flow. 30 Distribution in the Body Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Distribution in the Body 31 Renal elimination Biotransformation Effector cell Effect A. Importance of protein binding for intensity and duration of drug effect Drug is not bound to plasma proteins Drug is strongly bound to plasma proteins Effector cell Effect Biotransformation Renal elimination Time Plasma concentration Time Plasma concentration Bound drug Free drug Free drug Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. The Liver as an Excretory Organ As the chief organ of drug biotransfor- mation, the liver is richly supplied with blood, of which 1100 mL is received each minute from the intestines through the portal vein and 350 mL through the hepatic artery, comprising nearly 1 / 3 of cardiac output. The blood content of hepatic vessels and sinusoids amounts to 500 mL. Due to the widen- ing of the portal lumen, intrahepatic blood flow decelerates (A). Moreover, the endothelial lining of hepatic sinu- soids (p. 24) contains pores large enough to permit rapid exit of plasma proteins. Thus, blood and hepatic paren- chyma are able to maintain intimate contact and intensive exchange of sub- stances, which is further facilitated by microvilli covering the hepatocyte sur- faces abutting Disse’s spaces. The hepatocyte secretes biliary fluid into the bile canaliculi (dark green), tubular intercellular clefts that are sealed off from the blood spaces by tight junctions. Secretory activity in the hepatocytes results in movement of fluid towards the canalicular space (A). The hepatocyte has an abundance of en- zymes carrying out metabolic functions. These are localized in part in mitochon- dria, in part on the membranes of the rough (rER) or smooth (sER) endoplas- mic reticulum. Enzymes of the sER play a most im- portant role in drug biotransformation. At this site, molecular oxygen is used in oxidative reactions. Because these en- zymes can catalyze either hydroxylation or oxidative cleavage of -N-C- or -O-C- bonds, they are referred to as “mixed- function” oxidases or hydroxylases. The essential component of this enzyme system is cytochrome P450, which in its oxidized state binds drug substrates (R- H). The Fe III -P450-RH binary complex is first reduced by NADPH, then forms the ternary complex, O 2 -Fe II -P450-RH, which accepts a second electron and fi- nally disintegrates into Fe III -P450, one equivalent of H 2 O, and hydroxylated drug (R-OH). Compared with hydrophilic drugs not undergoing transport, lipophilic drugs are more rapidly taken up from the blood into hepatocytes and more readily gain access to mixed-function oxidases embedded in sER membranes. For instance, a drug having lipophilicity by virtue of an aromatic substituent (phenyl ring) (B) can be hydroxylated and, thus, become more hydrophilic (Phase I reaction, p. 34). Besides oxi- dases, sER also contains reductases and glucuronyl transferases. The latter con- jugate glucuronic acid with hydroxyl, carboxyl, amine, and amide groups (p. 38); hence, also phenolic products of phase I metabolism (Phase II conjuga- tion). Phase I and Phase II metabolites can be transported back into the blood — probably via a gradient-dependent carrier — or actively secreted into bile. Prolonged exposure to certain sub- strates, such as phenobarbital, carbama- zepine, rifampicin results in a prolifera- tion of sER membranes (cf. C and D). This enzyme induction, a load-depen- dent hypertrophy, affects equally all en- zymes localized on sER membranes. En- zyme induction leads to accelerated biotransformation, not only of the in- ducing agent but also of other drugs (a form of drug interaction). With contin- ued exposure, induction develops in a few days, resulting in an increase in re- action velocity, maximally 2–3fold, that disappears after removal of the induc- ing agent. 32 Drug Elimination Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Elimination 33 D. Hepatocyte after D. phenobarbital administration A. Flow patterns in portal vein, Disse’s space, and hepatocyte C. Normal hepatocyte Hepatocyte Disse′s space Gall-bladder Portal vein sER rER sER rER Phase II- metabolite Biliary capillary Glucuronide Carrier Phase I- metabolite B. Fate of drugs undergoing B. hepatic hydroxylation Biliary capillary Intestine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Biotransformation of Drugs Many drugs undergo chemical modifi- cation in the body (biotransformation). Most frequently, this process entails a loss of biological activity and an in- crease in hydrophilicity (water solubil- ity), thereby promoting elimination via the renal route (p. 40). Since rapid drug elimination improves accuracy in titrat- ing the therapeutic concentration, drugs are often designed with built-in weak links. Ester bonds are such links, being subject to hydrolysis by the ubiquitous esterases. Hydrolytic cleavages, along with oxidations, reductions, alkylations, and dealkylations, constitute Phase I re- actions of drug metabolism. These reac- tions subsume all metabolic processes apt to alter drug molecules chemically and take place chiefly in the liver. In Phase II (synthetic) reactions, conju- gation products of either the drug itself or its Phase I metabolites are formed, for instance, with glucuronic or sulfuric ac- id (p. 38). The special case of the endogenous transmitter acetylcholine illustrates well the high velocity of ester hydroly- sis. Acetylcholine is broken down at its sites of release and action by acetylchol- inesterase (pp. 100, 102) so rapidly as to negate its therapeutic use. Hydrolysis of other esters catalyzed by various este- rases is slower, though relatively fast in comparison with other biotransforma- tions. The local anesthetic, procaine, is a case in point; it exerts its action at the site of application while being largely devoid of undesirable effects at other lo- cations because it is inactivated by hy- drolysis during absorption from its site of application. Ester hydrolysis does not invariably lead to inactive metabolites, as exempli- fied by acetylsalicylic acid. The cleavage product, salicylic acid, retains phar- macological activity. In certain cases, drugs are administered in the form of esters in order to facilitate absorption (enalapril L50478 enalaprilate; testosterone undecanoate L50478 testosterone) or to re- duce irritation of the gastrointestinal mucosa (erythromycin succinate L50478 erythromycin). In these cases, the ester itself is not active, but the cleavage product is. Thus, an inactive precursor or prodrug is applied, formation of the active molecule occurring only after hy- drolysis in the blood. Some drugs possessing amide bonds, such as prilocaine, and of course, peptides, can be hydrolyzed by pepti- dases and inactivated in this manner. Peptidases are also of pharmacological interest because they are responsible for the formation of highly reactive cleavage products (fibrin, p. 146) and potent mediators (angiotensin II, p. 124; bradykinin, enkephalin, p. 210) from biologically inactive peptides. Peptidases exhibit some substrate selectivity and can be selectively inhib- ited, as exemplified by the formation of angiotensin II, whose actions inter alia include vasoconstriction. Angiotensin II is formed from angiotensin I by cleavage of the C-terminal dipeptide histidylleu- cine. Hydrolysis is catalyzed by “angio- tensin-converting enzyme” (ACE). Pep- tide analogues such as captopril (p. 124) block this enzyme. Angiotensin II is de- graded by angiotensinase A, which clips off the N-terminal asparagine residue. The product, angiotensin III, lacks vaso- constrictor activity. 34 Drug Elimination Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Elimination 35 A. Examples of chemical reactions in drug biotransformation (hydrolysis) Acetylcholine Converting enzyme Angiotensinase Procaine Acetylsalicylic acid Prilocaine N-Propylalanine ToluidineAcetic acid Salicylic acid Diethylaminoethanol p-Aminobenzoic acid Acetic acid Choline Angiotensin III Angiotensin II Angiotensin I Esterases Ester Peptidases Amides Anilides Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Oxidation reactions can be divided into two kinds: those in which oxygen is incorporated into the drug molecule, and those in which primary oxidation causes part of the molecule to be lost. The former include hydroxylations, epoxidations, and sulfoxidations. Hy- droxylations may involve alkyl substitu- ents (e.g., pentobarbital) or aromatic ring systems (e.g., propranolol). In both cases, products are formed that are con- jugated to an organic acid residue, e.g., glucuronic acid, in a subsequent Phase II reaction. Hydroxylation may also take place at nitrogen atoms, resulting in hydroxyl- amines (e.g., acetaminophen). Benzene, polycyclic aromatic compounds (e.g., benzopyrene), and unsaturated cyclic carbohydrates can be converted by mono-oxygenases to epoxides, highly reactive electrophiles that are hepato- toxic and possibly carcinogenic. The second type of oxidative bio- transformation comprises dealkyla- tions. In the case of primary or secon- dary amines, dealkylation of an alkyl group starts at the carbon adjacent to the nitrogen; in the case of tertiary amines, with hydroxylation of the nitro- gen (e.g., lidocaine). The intermediary products are labile and break up into the dealkylated amine and aldehyde of the alkyl group removed. O-dealkylation and S-dearylation proceed via an analo- gous mechanism (e.g., phenacetin and azathioprine, respectively). Oxidative deamination basically resembles the dealkylation of tertiary amines, beginning with the formation of a hydroxylamine that then decomposes into ammonia and the corresponding aldehyde. The latter is partly reduced to an alcohol and partly oxidized to a car- boxylic acid. Reduction reactions may occur at oxygen or nitrogen atoms. Keto-oxy- gens are converted into a hydroxyl group, as in the reduction of the pro- drugs cortisone and prednisone to the active glucocorticoids cortisol and pred- nisolone, respectively. N-reductions oc- cur in azo- or nitro-compounds (e.g., ni- trazepam). Nitro groups can be reduced to amine groups via nitroso and hydrox- ylamino intermediates. Likewise, deha- logenation is a reductive process involv- ing a carbon atom (e.g., halothane, p. 218). Methylations are catalyzed by a family of relatively specific methyl- transferases involving the transfer of methyl groups to hydroxyl groups (O- methylation as in norepinephrine [nor- adrenaline]) or to amino groups (N- methylation of norepinephrine, hista- mine, or serotonin). In thio compounds, desulfuration results from substitution of sulfur by oxygen (e.g., parathion). This example again illustrates that biotransformation is not always to be equated with bio- inactivation. Thus, paraoxon (E600) formed in the organism from parathion (E605) is the actual active agent (p. 102). 36 Drug Elimination MT68MT101MT115MT97MT108MT107MT121MT108MT105MT101MT114MT117MT110MT103 MT51 MT78 MT82 MT49 MT82 MT50 MT72 MT79 MT67MT72 MT51 MT72MT67 MT79 MT50 MT43 MT78 MT82 MT49 MT82 MT50 MT67MT72 MT51 MT79MT72 MT78 MT82 MT49 MT82 MT50 MT67MT72 Desalkylierung L llmann, Color Atlas of Pharmacology ' 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Elimination 37 A. Examples of chemical reactions in drug biotransformation Pentobarbital Hydroxylation Propranolol Lidocaine Phenacetin Azathioprine Parathion Desulfuration Methylation Nitrazepam Reduction Oxidation Benzpyrene Chlorpromazine Norepinephrine Epoxidation Sulfoxidation Hydroxyl- amine Dealkylation Acetaminophen N-Dealkylation O-Dealkylation S-Dealkylation O-Methylation Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Enterohepatic Cycle (A) After an orally ingested drug has been absorbed from the gut, it is transported via the portal blood to the liver, where it can be conjugated to glucuronic or sul- furic acid (shown in B for salicylic acid and deacetylated bisacodyl, respective- ly) or to other organic acids. At the pH of body fluids, these acids are predomi- nantly ionized; the negative charge con- fers high polarity upon the conjugated drug molecule and, hence, low mem- brane penetrability. The conjugated products may pass from hepatocyte into biliary fluid and from there back into the intestine. O-glucuronides can be cleaved by bacterial β-glucuronidases in the colon, enabling the liberated drug molecule to be reabsorbed. The entero- hepatic cycle acts to trap drugs in the body. However, conjugated products enter not only the bile but also the blood. Glucuronides with a molecular weight (MW) > 300 preferentially pass into the blood, while those with MW > 300 enter the bile to a larger extent. Glucuronides circulating in the blood undergo glomerular filtration in the kid- ney and are excreted in urine because their decreased lipophilicity prevents tubular reabsorption. Drugs that are subject to enterohe- patic cycling are, therefore, excreted slowly. Pertinent examples include digi- toxin and acidic nonsteroidal anti-in- flammatory agents (p. 200). Conjugations (B) The most important of phase II conjuga- tion reactions is glucuronidation. This reaction does not proceed spontaneous- ly, but requires the activated form of glucuronic acid, namely glucuronic acid uridine diphosphate. Microsomal glucu- ronyl transferases link the activated glucuronic acid with an acceptor mole- cule. When the latter is a phenol or alco- hol, an ether glucuronide will be formed. In the case of carboxyl-bearing molecules, an ester glucuronide is the result. All of these are O-glucuronides. Amines may form N-glucuronides that, unlike O-glucuronides, are resistant to bacterial β-glucuronidases. Soluble cytoplasmic sulfotrans- ferases conjugate activated sulfate (3’- phosphoadenine-5’-phosphosulfate) with alcohols and phenols. The conju- gates are acids, as in the case of glucuro- nides. In this respect, they differ from conjugates formed by acetyltransfe- rases from activated acetate (acetyl- coenzyme A) and an alcohol or a phenol. Acyltransferases are involved in the conjugation of the amino acids glycine or glutamine with carboxylic acids. In these cases, an amide bond is formed between the carboxyl groups of the ac- ceptor and the amino group of the do- nor molecule (e.g., formation of salicyl- uric acid from salicylic acid and glycine). The acidic group of glycine or glutamine remains free. 38 Drug Elimination Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Elimination 39 A. Enterohepatic cycle B. Conjugation reactions UDP-α-Glucuronic acid Glucuronyl- transferase Sulfo- transferase 3'-Phosphoadenine-5'-phosphosulfate Active moiety of bisacodylSalicylic acid Biliary elimination Enteral absorption Renal elimination Lipophilic drug Sinusoid Hepatocyte Biliary capillary Conjugation with glucuronic acid Portal vein Hydrophilic conjugation product 1 3 5 7 8 4 E n t e r o h e p a t i c c i r c u l a t i o n 6 2 Deconjugation by microbial β-glucuronidase Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. The Kidney as Excretory Organ Most drugs are eliminated in urine ei- ther chemically unchanged or as metab- olites. The kidney permits elimination because the vascular wall structure in the region of the glomerular capillaries (B) allows unimpeded passage of blood solutes having molecular weights (MW) < 5000. Filtration diminishes progres- sively as MW increases from 5000 to 70000 and ceases at MW > 70000. With few exceptions, therapeutically used drugs and their metabolites have much smaller molecular weights and can, therefore, undergo glomerular filtra- tion, i.e., pass from blood into primary urine. Separating the capillary endothe- lium from the tubular epithelium, the basal membrane consists of charged glycoproteins and acts as a filtration barrier for high-molecular-weight sub- stances. The relative density of this bar- rier depends on the electrical charge of molecules that attempt to permeate it. Apart from glomerular filtration (B), drugs present in blood may pass into urine by active secretion. Certain cations and anions are secreted by the epithelium of the proximal tubules into the tubular fluid via special, energy- consuming transport systems. These transport systems have a limited capac- ity. When several substrates are present simultaneously, competition for the carrier may occur (see p. 268). During passage down the renal tu- bule, urinary volume shrinks more than 100-fold; accordingly, there is a corre- sponding concentration of filtered drug or drug metabolites (A). The resulting concentration gradient between urine and interstitial fluid is preserved in the case of drugs incapable of permeating the tubular epithelium. However, with lipophilic drugs the concentration gra- dient will favor reabsorption of the fil- tered molecules. In this case, reabsorp- tion is not based on an active process but results instead from passive diffu- sion. Accordingly, for protonated sub- stances, the extent of reabsorption is dependent upon urinary pH or the de- gree of dissociation. The degree of disso- ciation varies as a function of the uri- nary pH and the pK a , which represents the pH value at which half of the sub- stance exists in protonated (or unproto- nated) form. This relationship is graphi- cally illustrated (D) with the example of a protonated amine having a pK a of 7.0. In this case, at urinary pH 7.0, 50 % of the amine will be present in the protonated, hydrophilic, membrane-impermeant form (blue dots), whereas the other half, representing the uncharged amine (orange dots), can leave the tubular lu- men in accordance with the resulting concentration gradient. If the pK a of an amine is higher (pK a = 7.5) or lower (pK a = 6.5), a correspondingly smaller or larger proportion of the amine will be present in the uncharged, reabsorbable form. Lowering or raising urinary pH by half a pH unit would result in analogous changes for an amine having a pK a of 7.0. The same considerations hold for acidic molecules, with the important difference that alkalinization of the urine (increased pH) will promote the deprotonization of -COOH groups and thus impede reabsorption. Intentional alteration in urinary pH can be used in intoxications with proton-acceptor sub- stances in order to hasten elimination of the toxin (alkalinization L50478 phenobarbi- tal; acidification L50478 amphetamine). 40 Drug Elimination Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Elimination 41 C. Active secretion 180 L Primary urine Glomerular filtration of drug Concentration of drug in tubule 1.2 L Final urine – + + + + + + ++ + + + + + + + + + + + + + + + - - - - - - - - - - - - - - - - --- - - - Tubular transport system for Cations Anions Blood Plasma- protein Endothelium Basal membrane Drug Epithelium Primary urine pH = 7.0 pH = 7.0 pH of urine % 6 6.5 7 7.5 8 100 50 pK a = 7.5 % 6 6.5 7 7.5 8 100 50 pK a = 6.5 D. Tubular reabsorption A. Filtration and concentration B. Glomerular filtration pK a of substance % 6 6.5 7 7.5 8 100 50 pK a = 7.0 + Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Elimination of Lipophilic and Hydrophilic Substances The terms lipophilic and hydrophilic (or hydro- and lipophobic) refer to the solubility of substances in media of low and high polarity, respectively. Blood plasma, interstitial fluid, and cytosol are highly polar aqueous media, whereas lipids — at least in the interior of the lip- id bilayer membrane — and fat consti- tute apolar media. Most polar substanc- es are readily dissolved in aqueous me- dia (i.e., are hydrophilic) and lipophilic ones in apolar media. A hydrophilic drug, on reaching the bloodstream, probably after a partial, slow absorption (not illustrated), passes through the liv- er unchanged, because it either cannot, or will only slowly, permeate the lipid barrier of the hepatocyte membrane and thus will fail to gain access to hepat- ic biotransforming enzymes. The un- changed drug reaches the arterial blood and the kidneys, where it is filtered. With hydrophilic drugs, there is little binding to plasma proteins (protein binding increases as a function of li- pophilicity), hence the entire amount present in plasma is available for glo- merular filtration. A hydrophilic drug is not subject to tubular reabsorption and appears in the urine. Hydrophilic drugs undergo rapid elimination. If a lipophilic drug, because of its chemical nature, cannot be converted into a polar product, despite having ac- cess to all cells, including metabolically active liver cells, it is likely to be re- tained in the organism. The portion fil- tered during glomerular passage will be reabsorbed from the tubules. Reabsorp- tion will be nearly complete, because the free concentration of a lipophilic drug in plasma is low (lipophilic sub- stances are usually largely protein- bound). The situation portrayed for a lipophilic non-metabolizable drug would seem undesirable because phar- macotherapeutic measures once initiat- ed would be virtually irreversible (poor control over blood concentration). Lipophilic drugs that are convert- ed in the liver to hydrophilic metab- olites permit better control, because the lipophilic agent can be eliminated in this manner. The speed of formation of hydrophilic metabolite determines the drug’s length of stay in the body. If hepatic conversion to a polar me- tabolite is rapid, only a portion of the absorbed drug enters the systemic cir- culation in unchanged form, the re- mainder having undergone presystem- ic (first-pass) elimination. When bio- transformation is rapid, oral adminis- tration of the drug is impossible (e.g., glyceryl trinitate, p. 120). Parenteral or, alternatively, sublingual, intranasal, or transdermal administration is then re- quired in order to bypass the liver. Irre- spective of the route of administration, a portion of administered drug may be taken up into and transiently stored in lung tissue before entering the general circulation. This also constitutes pre- systemic elimination. Presystemic elimination refers to the fraction of drug absorbed that is excluded from the general circulation by biotransformation or by first-pass binding. Presystemic elimination diminish- es the bioavailability of a drug after its oral administration. Absolute bioavail- ability = systemically available amount/ dose administered; relative bioavail- ability = availability of a drug contained in a test preparation with reference to a standard preparation. 42 Drug Elimination Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Elimination 43 A. Elimination of hydrophilic and hydrophobic drugs Hydrophilic drug Lipophilic drug no metabolism Lipophilic drug Lipophilic drug Renal excretion Excretion impossible Renal excretion of metabolite Renal excretion of metabolite Slow conversion in liver to hydrophilic metabolite Rapid and complete conversion in liver to hydrophilic metabolite Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Concentration in the Body as a Function of Time. First-Order (Exponential) Rate Processes Processes such as drug absorption and elimination display exponential charac- teristics. As regards the former, this fol- lows from the simple fact that the amount of drug being moved per unit of time depends on the concentration dif- ference (gradient) between two body compartments (Fick’s Law). In drug ab- sorption from the alimentary tract, the intestinal contents and blood would represent the compartments containing an initially high and low concentration, respectively. In drug elimination via the kidney, excretion often depends on glo- merular filtration, i.e., the filtered amount of drug present in primary urine. As the blood concentration falls, the amount of drug filtered per unit of time diminishes. The resulting expo- nential decline is illustrated in (A). The exponential time course implies con- stancy of the interval during which the concentration decreases by one-half. This interval represents the half-life (t 1/2 ) and is related to the elimination rate constant k by the equation t 1/2 = ln 2/k. The two parameters, together with the initial concentration c o , describe a first-order (exponential) rate process. The constancy of the process per- mits calculation of the plasma volume that would be cleared of drug, if the re- maining drug were not to assume a ho- mogeneous distribution in the total vol- ume (a condition not met in reality). This notional plasma volume freed of drug per unit of time is termed the clearance. Depending on whether plas- ma concentration falls as a result of uri- nary excretion or metabolic alteration, clearance is considered to be renal or hepatic. Renal and hepatic clearances add up to total clearance (Cl tot ) in the case of drugs that are eliminated un- changed via the kidney and biotrans- formed in the liver. Cl tot represents the sum of all processes contributing to elimination; it is related to the half-life (t 1/2 ) and the apparent volume of distri- bution V app (p. 28) by the equation: V app t 1/2 = In 2 x –––– Cl tot The smaller the volume of distribu- tion or the larger the total clearance, the shorter is the half-life. In the case of drugs renally elimi- nated in unchanged form, the half-life of elimination can be calculated from the cumulative excretion in urine; the final total amount eliminated corresponds to the amount absorbed. Hepatic elimination obeys expo- nential kinetics because metabolizing enzymes operate in the quasilinear re- gion of their concentration-activity curve; hence the amount of drug me- tabolized per unit of time diminishes with decreasing blood concentration. The best-known exception to expo- nential kinetics is the elimination of al- cohol (ethanol), which obeys a linear time course (zero-order kinetics), at least at blood concentrations > 0.02 %. It does so because the rate-limiting en- zyme, alcohol dehydrogenase, achieves half-saturation at very low substrate concentrations, i.e., at about 80 mg/L (0.008 %). Thus, reaction velocity reach- es a plateau at blood ethanol concentra- tions of about 0.02 %, and the amount of drug eliminated per unit of time re- mains constant at concentrations above this level. 44 Pharmacokinetics L llmann, Color Atlas of Pharmacology ' 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Pharmacokinetics 45 A. Exponential elimination of drug Concentration (c) of drug in plasma [amount/vol] c t = c o · e -kt c t : Drug concentration at time t c o : Initial drug concentration after administration of drug dose e: Base of natural logarithm k: Elimination constant Plasma half life t1 2 = — c o 1 2 c t 1 2 t1 2 ln 2 k = —– Time (t) Total amount of drug excreted (Amount administered) = Dose Amount excreted per unit of time [amount/t] Notional plasma volume per unit of time freed of drug = clearance [vol/t] Unit of time Time Co Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Time Course of Drug Concentration in Plasma A. Drugs are taken up into and eliminat- ed from the body by various routes. The body thus represents an open system wherein the actual drug concentration reflects the interplay of intake (inges- tion) and egress (elimination). When an orally administered drug is absorbed from the stomach and intestine, speed of uptake depends on many factors, in- cluding the speed of drug dissolution (in the case of solid dosage forms) and of gastrointestinal transit; the membrane penetrability of the drug; its concentra- tion gradient across the mucosa-blood barrier; and mucosal blood flow. Ab- sorption from the intestine causes the drug concentration in blood to increase. Transport in blood conveys the drug to different organs (distribution), into which it is taken up to a degree compat- ible with its chemical properties and rate of blood flow through the organ. For instance, well-perfused organs such as the brain receive a greater proportion than do less well-perfused ones. Uptake into tissue causes the blood concentra- tion to fall. Absorption from the gut di- minishes as the mucosa-blood gradient decreases. Plasma concentration reach- es a peak when the drug amount leaving the blood per unit of time equals that being absorbed. Drug entry into hepatic and renal tissue constitutes movement into the organs of elimination. The characteris- tic phasic time course of drug concen- tration in plasma represents the sum of the constituent processes of absorp- tion, distribution, and elimination, which overlap in time. When distribu- tion takes place significantly faster than elimination, there is an initial rapid and then a greatly retarded fall in the plas- ma level, the former being designated the α-phase (distribution phase), the latter the β-phase (elimination phase). When the drug is distributed faster than it is absorbed, the time course of the plasma level can be described in mathe- matically simplified form by the Bate- man function (k 1 and k 2 represent the rate constants for absorption and elimi- nation, respectively). B. The velocity of absorption de- pends on the route of administration. The more rapid the administration, the shorter will be the time (t max ) required to reach the peak plasma level (c max ), the higher will be the c max , and the earli- er the plasma level will begin to fall again. The area under the plasma level time curve (AUC) is independent of the route of administration, provided the doses and bioavailability are the same (Dost’s law of corresponding areas). The AUC can thus be used to determine the bio- availability F of a drug. The ratio of AUC values determined after oral or intrave- nous administration of a given dose of a particular drug corresponds to the pro- portion of drug entering the systemic circulation after oral administration. The determination of plasma levels af- fords a comparison of different proprie- tary preparations containing the same drug in the same dosage. Identical plas- ma level time-curves of different manufacturers’ products with reference to a standard preparation indicate bio- equivalence of the preparation under investigation with the standard. 46 Pharmacokinetics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Pharmacokinetics 47 B. Mode of application and time course of drug concentration A. Time course of drug concentration Absorption Uptake from stomach and intestines into blood Distribution into body tissues: α-phase Elimination from body by biotransformation (chemical alteration), excretion via kidney: ?-phase Time (t) Drug concentration in blood (c) Bateman-function Dose ? V app k 1 k 2 - k 1 c = x x (e -k 1 t -e -k 2 t ) Drug concentration in blood (c) Time (t) Intravenous Intramuscular Subcutaneous Oral Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Time Course of Drug Plasma Levels During Repeated Dosing (A) When a drug is administered at regular intervals over a prolonged period, the rise and fall of drug concentration in blood will be determined by the rela- tionship between the half-life of elimi- nation and the time interval between doses. If the drug amount administered in each dose has been eliminated before the next dose is applied, repeated intake at constant intervals will result in simi- lar plasma levels. If intake occurs before the preceding dose has been eliminated completely, the next dose will add on to the residual amount still present in the body, i.e., the drug accumulates. The shorter the dosing interval relative to the elimination half-life, the larger will be the residual amount of drug to which the next dose is added and the more ex- tensively will the drug accumulate in the body. However, at a given dosing frequency, the drug does not accumu- late infinitely and a steady state (C ss ) or accumulation equilibrium is eventual- ly reached. This is so because the activ- ity of elimination processes is concen- tration-dependent. The higher the drug concentration rises, the greater is the amount eliminated per unit of time. Af- ter several doses, the concentration will have climbed to a level at which the amounts eliminated and taken in per unit of time become equal, i.e., a steady state is reached. Within this concentra- tion range, the plasma level will contin- ue to rise (peak) and fall (trough) as dos- ing is continued at a regular interval. The height of the steady state (C ss ) de- pends upon the amount (D) adminis- tered per dosing interval (τ) and the clearance (Cl tot ): D C ss = ––––––––– (τ · Cl tot ) The speed at which the steady state is reached corresponds to the speed of elimination of the drug. The time need- ed to reach 90 % of the concentration plateau is about 3 times the t 1/2 of elimi- nation. Time Course of Drug Plasma Levels During Irregular Intake (B) In practice, it proves difficult to achieve a plasma level that undulates evenly around the desired effective concentra- tion. For instance, if two successive dos- es are omitted, the plasma level will drop below the therapeutic range and a longer period will be required to regain the desired plasma level. In everyday life, patients will be apt to neglect drug intake at the scheduled time. Patient compliance means strict adherence to the prescribed regimen. Apart from poor compliance, the same problem may occur when the total daily dose is divided into three individual doses (tid) and the first dose is taken at breakfast, the second at lunch, and the third at supper. Under this condition, the noc- turnal dosing interval will be twice the diurnal one. Consequently, plasma lev- els during the early morning hours may have fallen far below the desired or, possibly, urgently needed range. 48 Pharmacokinetics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Pharmacokinetics 49 ?? ? B. Time course of drug concentration with irregular intake A. Time course of drug concentration in blood during regular intake Drug concentration Drug concentration Accumulation: administered drug is not completely eliminated during interval Steady state: drug intake equals elimination during dosing interval Dosing interval Dosing interval Time Time Time Time Drug concentration Desired therapeutic level Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation Successful drug therapy in many illness- es is accomplished only if drug concen- tration is maintained at a steady high level. This requirement necessitates regular drug intake and a dosage sched- ule that ensures that the plasma con- centration neither falls below the thera- peutically effective range nor exceeds the minimal toxic concentration. A con- stant plasma level would, however, be undesirable if it accelerated a loss of ef- fectiveness (development of tolerance), or if the drug were required to be present at specified times only. A steady plasma level can be achieved by giving the drug in a con- stant intravenous infusion, the steady- state plasma level being determined by the infusion rate, dose D per unit of time τ, and the clearance, according to the equation: D C ss = ––––––––– (τ · Cl tot ) This procedure is routinely used in intensive care hospital settings, but is otherwise impracticable. With oral ad- ministration, dividing the total daily dose into several individual ones, e.g., four, three, or two, offers a practical compromise. When the daily dose is given in sev- eral divided doses, the mean plasma level shows little fluctuation. In prac- tice, it is found that a regimen of fre- quent regular drug ingestion is not well adhered to by patients. The degree of fluctuation in plasma level over a given dosing interval can be reduced by use of a dosage form permitting slow (sus- tained) release (p. 10). The time required to reach steady- state accumulation during multiple constant dosing depends on the rate of elimination. As a rule of thumb, a pla- teau is reached after approximately three elimination half-lives (t 1/2 ). For slowly eliminated drugs, which tend to accumulate extensively (phen- procoumon, digitoxin, methadone), the optimal plasma level is attained only af- ter a long period. Here, increasing the initial doses (loading dose) will speed up the attainment of equilibrium, which is subsequently maintained with a low- er dose (maintenance dose). Change in Elimination Characteristics During Drug Therapy (B) With any drug taken regularly and accu- mulating to the desired plasma level, it is important to consider that conditions for biotransformation and excretion do not necessarily remain constant. Elimi- nation may be hastened due to enzyme induction (p. 32) or to a change in uri- nary pH (p. 40). Consequently, the steady-state plasma level declines to a new value corresponding to the new rate of elimination. The drug effect may diminish or disappear. Conversely, when elimination is impaired (e.g., in progressive renal insufficiency), the mean plasma level of renally eliminated drugs rises and may enter a toxic con- centration range. 50 Pharmacokinetics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Pharmacokinetics 51 B. Changes in elimination kinetics in the course of drug therapy A. Accumulation: dose, dose interval, and fluctuation of plasma level Drug concentration in blood Desir ed plasma level 12 18 24 6 12 18 24 6 12 18 24 6 126 4 x daily 50 mg 2 x daily 100 mg 1 x daily 200 mg Single 50 mg 12 18 24 6 12 18 24 6 12 18 24 6 126 18 Acceleration of elimination Inhibition of elimination Drug concentration in blood Desir ed plasma level Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Dose–Response Relationship The effect of a substance depends on the amount administered, i.e., the dose. If the dose chosen is below the critical threshold (subliminal dosing), an effect will be absent. Depending on the nature of the effect to be measured, ascending doses may cause the effect to increase in intensity. Thus, the effect of an antipy- retic or hypotensive drug can be quanti- fied in a graded fashion, in that the ex- tent of fall in body temperature or blood pressure is being measured. A dose-ef- fect relationship is then encountered, as discussed on p. 54. The dose-effect relationship may vary depending on the sensitivity of the individual person receiving the drug, i.e., for the same effect, different doses may be required in different individuals. Interindividual variation in sensitivity is especially obvious with effects of the “all-or-none” kind. To illustrate this point, we consider an experiment in which the subjects in- dividually respond in all-or-none fash- ion, as in the Straub tail phenomenon (A). Mice react to morphine with excita- tion, evident in the form of an abnormal posture of the tail and limbs. The dose dependence of this phenomenon is ob- served in groups of animals (e.g., 10 mice per group) injected with increas- ing doses of morphine. At the low dose, only the most sensitive, at increasing doses a growing proportion, at the high- est dose all of the animals are affected (B). There is a relationship between the frequency of responding animals and the dose given. At 2 mg/kg, one out of 10 animals reacts; at 10 mg/kg, 5 out of 10 respond. The dose-frequency relation- ship results from the different sensitiv- ity of individuals, which as a rule exhib- its a log-normal distribution (C, graph at right, linear scale). If the cumulative fre- quency (total number of animals re- sponding at a given dose) is plotted against the logarithm of the dose (ab- scissa), a sigmoidal curve results (C, graph at left, semilogarithmic scale). The inflection point of the curve lies at the dose at which one-half of the group has responded. The dose range encom- passing the dose-frequency relationship reflects the variation in individual sensi- tivity to the drug. Although similar in shape, a dose-frequency relationship has, thus, a different meaning than does a dose-effect relationship. The latter can be evaluated in one individual and re- sults from an intraindividual dependen- cy of the effect on drug concentration. The evaluation of a dose-effect rela- tionship within a group of human sub- jects is compounded by interindividual differences in sensitivity. To account for the biological variation, measurements have to be carried out on a representa- tive sample and the results averaged. Thus, recommended therapeutic doses will be appropriate for the majority of patients, but not necessarily for each in- dividual. The variation in sensitivity may be based on pharmacokinetic differences (same dose L50478 different plasma levels) or on differences in target organ sensi- tivity (same plasma level L50478 different ef- fects). 52 Quantification of Drug Action Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Quantification of Drug Action 53 C. Dose-frequency relationship A. Abnormal posture in mouse given morphine B. Incidence of effect as a function of dose Dose = 0 = 2 mg/kg = 10 mg/kg = 20 mg/kg = 140 mg/kg= 100 mg/kg mg/kg 2 14010010 20 20 100 40 60 80 % Cumulative frequency mg/kg2 14010010 20 1 2 3 4 Frequency of dose needed Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Concentration-Effect Relationship (A) The relationship between the concen- tration of a drug and its effect is deter- mined in order to define the range of ac- tive drug concentrations (potency) and the maximum possible effect (efficacy). On the basis of these parameters, differ- ences between drugs can be quantified. As a rule, the therapeutic effect or toxic action depends critically on the re- sponse of a single organ or a limited number of organs, e.g., blood flow is af- fected by a change in vascular luminal width. By isolating critical organs or tis- sues from a larger functional system, these actions can be studied with more accuracy; for instance, vasoconstrictor agents can be examined in isolated preparations from different regions of the vascular tree, e.g., the portal or saphenous vein, or the mesenteric, cor- onary, or basilar artery. In many cases, isolated organs or organ parts can be kept viable for hours in an appropriate nutrient medium sufficiently supplied with oxygen and held at a suitable tem- perature. Responses of the preparation to a physiological or pharmacological stim- ulus can be determined by a suitable re- cording apparatus. Thus, narrowing of a blood vessel is recorded with the help of two clamps by which the vessel is sus- pended under tension. Experimentation on isolated organs offers several advantages: 1. The drug concentration in the tissue is usually known. 2. Reduced complexity and ease of re- lating stimulus and effect. 3. It is possible to circumvent compen- satory responses that may partially cancel the primary effect in the intact organism — e.g., the heart rate in- creasing action of norepinephrine cannot be demonstrated in the intact organism, because a simultaneous rise in blood pressure elicits a coun- ter-regulatory reflex that slows car- diac rate. 4. The ability to examine a drug effect over its full rage of intensities — e.g., it would be impossible in the intact organism to follow negative chrono- tropic effects to the point of cardiac arrest. Disadvantages are: 1. Unavoidable tissue injury during dis- section. 2. Loss of physiological regulation of function in the isolated tissue. 3. The artificial milieu imposed on the tissue. Concentration-Effect Curves (B) As the concentration is raised by a con- stant factor, the increment in effect di- minishes steadily and tends asymptoti- cally towards zero the closer one comes to the maximally effective concentra- tion.The concentration at which a maxi- mal effect occurs cannot be measured accurately; however, that eliciting a half-maximal effect (EC 50 ) is readily de- termined. It typically corresponds to the inflection point of the concentra- tion–response curve in a semilogarith- mic plot (log concentration on abscissa). Full characterization of a concentra- tion–effect relationship requires deter- mination of the EC 50 , the maximally possible effect (E max ), and the slope at the point of inflection. 54 Quantification of Drug Action Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Quantification of Drug Action 55 B. Concentration-effect relationship A. Measurement of effect as a function of concentration Portal vein Mesenteric artery Coronary artery Basilar artery Saphenous vein 1005040302010521 Vasoconstriction Active tension 1 min Drug concentration Effect (in mm of registration unit, e.g., tension developed) Concentration (linear) 20 30 40 5010 50 40 30 20 10 Effect (% of maximum effect) Concentration (logarithmic) 10 1001 100 80 60 40 20 % Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Concentration-Binding Curves In order to elicit their effect, drug mole- cules must be bound to the cells of the effector organ. Binding commonly oc- curs at specific cell structures, namely, the receptors. The analysis of drug bind- ing to receptors aims to determine the affinity of ligands, the kinetics of inter- action, and the characteristics of the binding site itself. In studying the affinity and number of such binding sites, use is made of membrane suspensions of different tis- sues. This approach is based on the ex- pectation that binding sites will retain their characteristic properties during cell homogenization. Provided that binding sites are freely accessible in the medium in which membrane fragments are suspended, drug concentration at the “site of action” would equal that in the medium. The drug under study is ra- diolabeled (enabling low concentra- tions to be measured quantitatively), added to the membrane suspension, and allowed to bind to receptors. Mem- brane fragments and medium are then separated, e.g., by filtration, and the amount of bound drug is measured. Binding increases in proportion to con- centration as long as there is a negligible reduction in the number of free binding sites (c = 1 and B ≈ 10% of maximum binding; c = 2 and B ≈ 20 %). As binding approaches saturation, the number of free sites decreases and the increment in binding is no longer proportional to the increase in concentration (in the ex- ample illustrated, an increase in con- centration by 1 is needed to increase binding from 10 to 20 %; however, an in- crease by 20 is needed to raise it from 70 to 80 %). The law of mass action describes the hyperbolic relationship between binding (B) and ligand concentration (c). This relationship is characterized by the drug’s affinity (1/K D ) and the maximum binding (B max ), i.e., the total number of binding sites per unit of weight of mem- brane homogenate. c B = B max · ––––––– c + K D K D is the equilibrium dissociation con- stant and corresponds to that ligand concentration at which 50 % of binding sites are occupied. The values given in (A) and used for plotting the concentra- tion-binding graph (B) result when K D = 10. The differing affinity of different li- gands for a binding site can be demon- strated elegantly by binding assays. Al- though simple to perform, these bind- ing assays pose the difficulty of correlat- ing unequivocally the binding sites con- cerned with the pharmacological effect; this is particularly difficult when more than one population of binding sites is present. Therefore, receptor binding must not be implied until it can be shown that ? binding is saturable (saturability); ? the only substances bound are those possessing the same pharmacological mechanism of action (specificity); ? binding affinity of different substanc- es is correlated with their pharmaco- logical potency. Binding assays provide information about the affinity of ligands, but they do not give any clue as to whether a ligand is an agonist or antagonist (p. 60). Use of radiolabeled drugs bound to their re- ceptors may be of help in purifying and analyzing further the receptor protein. 56 Quantification of Drug Action Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Quantification of Drug Action 57 B = 10% B = 20% B = 30% B = 50% B = 70% B = 80% B. Concentration-binding relationship A. Measurement of binding (B) as a function of concentration (c) Binding (B) 20 30 40 5010 100 80 60 40 20 % Binding (B) 1001 100 80 60 40 20 % 10 Organs Homogenization Centrifugation Membrane suspension Mixing and incubation Addition of radiolabeled drug in different concentrations Determination of radioactivity c = 1 c = 2 c = 5 c = 10 c = 20 c = 40 Concentration (linear) Concentration (logarithmic) Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Types of Binding Forces Unless a drug comes into contact with intrinsic structures of the body, it can- not affect body function. Covalent bond. Two atoms enter a covalent bond if each donates an elec- tron to a shared electron pair (cloud). This state is depicted in structural for- mulas by a dash. The covalent bond is “firm”, that is, not reversible or only poorly so. Few drugs are covalently bound to biological structures. The bond, and possibly the effect, persist for a long time after intake of a drug has been discontinued, making therapy dif- ficult to control. Examples include alky- lating cytostatics (p. 298) or organo- phosphates (p. 102). Conjugation reac- tions occurring in biotransformation al- so represent a covalent linkage (e.g., to glucuronic acid, p. 38). Noncovalent bond. There is no for- mation of a shared electron pair. The bond is reversible and typical of most drug-receptor interactions. Since a drug usually attaches to its site of action by multiple contacts, several of the types of bonds described below may participate. Electrostatic attraction (A). A pos- itive and negative charge attract each other. Ionic interaction: An ion is a particle charged either positively (cation) or negatively (anion), i.e., the atom lacks or has surplus electrons, respectively. At- traction between ions of opposite charge is inversely proportional to the square of the distance between them; it is the initial force drawing a charged drug to its binding site. Ionic bonds have a relatively high stability. Dipole-ion interaction: When bond electrons are asymmetrically distribut- ed over both atomic nuclei, one atom will bear a negative (δ – ), and its partner a positive (δ + ) partial charge. The mole- cule thus presents a positive and a nega- tive pole, i.e., has polarity or a dipole. A partial charge can interact electrostati- cally with an ion of opposite charge. Dipole-dipole interaction is the elec- trostatic attraction between opposite partial charges. When a hydrogen atom bearing a partial positive charge bridges two atoms bearing a partial negative charge, a hydrogen bond is created. A van der Waals’ bond (B) is formed between apolar molecular groups that have come into close prox- imity. Spontaneous transient distortion of electron clouds (momentary faint di- pole, δδ) may induce an opposite dipole in the neighboring molecule. The van der Waals’ bond, therefore, is a form of electrostatic attraction, albeit of very low strength (inversely proportional to the seventh power of the distance). Hydrophobic interaction (C). The attraction between the dipoles of water is strong enough to hinder intercalation of any apolar (uncharged) molecules. By tending towards each other, H 2 O mole- cules squeeze apolar particles from their midst. Accordingly, in the organ- ism, apolar particles have an increased probability of staying in nonaqueous, apolar surroundings, such as fatty acid chains of cell membranes or apolar re- gions of a receptor. 58 Drug-Receptor Interaction Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug-Receptor Interaction 59 C. Hydrophobic interaction A. Electrostatic attraction B. van der Waals’ bond Drug + Binding site Complex Ionic bondIon Dipole Ion Hydrogen bondDipole Dipole (permanent) Ion 50nm 1.5nm 0.5nm Induced transient fluctuating dipoles polar Apolar acyl chain "Repulsion" of apolar particle in polar solvent (H 2 O) Insertion in apolar membrane interior apolar Phospholipid membrane Adsorption to apolar surface δ + δ ? + – – δ + δ – δ – δδ + δδ – δδ – δδ + δδ – δδ + δδ + δδ – = Drug δ – δ + + δ – δ + δ – δ + δ – δ + δ + – – D D D D D D D D D Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Agonists – Antagonists An agonist has affinity (binding avidity) for its receptor and alters the receptor protein in such a manner as to generate a stimulus that elicits a change in cell function: “intrinsic activity“. The bio- logical effect of the agonist, i.e., the change in cell function, depends on the efficiency of signal transduction steps (p. 64, 66) initiated by the activated re- ceptor. Some agonists attain a maximal effect even when they occupy only a small fraction of receptors (B, agonist A). Other ligands (agonist B), possessing equal affinity for the receptor but lower activating capacity (lower intrinsic ac- tivity), are unable to produce a full max- imal response even when all receptors are occupied: lower efficacy. Ligand B is a partial agonist. The potency of an ago- nist can be expressed in terms of the concentration (EC 50 ) at which the effect reaches one-half of its respective maxi- mum. Antagonists (A) attenuate the ef- fect of agonists, that is, their action is “anti-agonistic”. Competitive antagonists possess affinity for receptors, but binding to the receptor does not lead to a change in cell function (zero intrinsic activity). When an agonist and a competitive antagonist are present simultaneously, affinity and concentration of the two ri- vals will determine the relative amount of each that is bound. Thus, although the antagonist is present, increasing the concentration of the agonist can restore the full effect (C). However, in the pres- ence of the antagonist, the concentra- tion-response curve of the agonist is shifted to higher concentrations (“right- ward shift”). Molecular Models of Agonist/Antagonist Action (A) Agonist induces active conformation. The agonist binds to the inactive recep- tor and thereby causes a change from the resting conformation to the active state. The antagonist binds to the inac- tive receptor without causing a confor- mational change. Agonist stabilizes spontaneously occurring active conformation. The receptor can spontaneously “flip” into the active conformation. However, the statistical probability of this event is usually so small that the cells do not re- veal signs of spontaneous receptor acti- vation. Selective binding of the agonist requires the receptor to be in the active conformation, thus promoting its exis- tence. The “antagonist” displays affinity only for the inactive state and stabilizes the latter. When the system shows min- imal spontaneous activity, application of an antagonist will not produce a mea- surable effect. When the system has high spontaneous activity, the antago- nist may cause an effect that is the op- posite of that of the agonist: inverse ago- nist. A “true” antagonist lacking intrinsic activity (“neutral antagonist”) displays equal affinity for both the active and in- active states of the receptor and does not alter basal activity of the cell. According to this model, a partial ago- nist shows lower selectivity for the ac- tive state and, to some extent, also binds to the receptor in its inactive state. Other Forms of Antagonism Allosteric antagonism. The antagonist is bound outside the receptor agonist binding site proper and induces a de- crease in affinity of the agonist. It is also possible that the allosteric deformation of the receptor increases affinity for an agonist, resulting in an allosteric syner- gism. Functional antagonism. Two ago- nists affect the same parameter (e.g., bronchial diameter) via different recep- tors in the opposite direction (epineph- rine L50478 dilation; histamine L50478 constric- tion). 60 Drug-Receptor Interaction Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug-Receptor Interaction 61 Agonist induces active conformation of receptor protein C. Competitive antagonism A. Molecular mechanisms of drug-receptor interaction B. Potency and Efficacy of agonists AntagonistAgonist Receptor Antagonist occupies receptor without con- formational change Agonist selects active receptor conformation Antagonist Agonist Rare spontaneous transition Antagonist selects inactive receptor conformation inactive Ef ficacy Potency Concentration (log) of agonist Receptor occupation Increase in tension Agonist concentration (log) Agonist effect Concentration of antagonist 0 10 100 10001 Agonist A Agonist B smooth muscle cell Receptors EC 50 EC 50 active 10000 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Enantioselectivity of Drug Action Many drugs are racemates, including β- blockers, nonsteroidal anti-inflammato- ry agents, and anticholinergics (e.g., benzetimide A). A racemate consists of a molecule and its corresponding mirror image which, like the left and right hand, cannot be superimposed. Such chiral (“handed”) pairs of molecules are referred to as enantiomers. Usually, chirality is due to a carbon atom (C) linked to four different substituents (“asymmetric center”). Enantiomerism is a special case of stereoisomerism. Non- chiral stereoisomers are called diaster- eomers (e.g., quinidine/quinine). Bond lengths in enantiomers, but not in diastereomers, are the same. Therefore, enantiomers possess similar physicochemical properties (e.g., solu- bility, melting point) and both forms are usually obtained in equal amounts by chemical synthesis. As a result of enzy- matic activity, however, only one of the enantiomers is usually found in nature. In solution, enantiomers rotate the wave plane of linearly polarized light in opposite directions; hence they are refered to as “dextro”- or “levo-rotatory”, designated by the prefixes d or (+) and l or (-), respectively. The direction of ro- tation gives no clue concerning the spa- tial structure of enantiomers. The abso- lute configuration, as determined by certain rules, is described by the prefix- es S and R. In some compounds, desig- nation as the D- and L-form is possible by reference to the structure of D- and L-glyceraldehyde. For drugs to exert biological ac- tions, contact with reaction partners in the body is required. When the reaction favors one of the enantiomers, enantio- selectivity is observed. Enantioselectivity of affinity. If a receptor has sites for three of the sub- stituents (symbolized in B by a cone, a sphere, and a cube) on the asymmetric carbon to attach to, only one of the enantiomers will have optimal fit. Its af- finity will then be higher. Thus, dexeti- mide displays an affinity at the musca- rinic ACh receptors almost 10000 times (p. 98) that of levetimide; and at β- adrenoceptors, S(-)-propranolol has an affinity 100 times that of the R(+)-form. Enantioselectivity of intrinsic ac- tivity. The mode of attachment at the receptor also determines whether an ef- fect is elicited and whether or not a sub- stance has intrinsic activity, i.e., acts as an agonist or antagonist. For instance, (-) dobutamine is an agonist at α-adren- oceptors whereas the (+)-enantiomer is an antagonist. Inverse enantioselectivity at an- other receptor. An enantiomer may possess an unfavorable configuration at one receptor that may, however, be op- timal for interaction with another re- ceptor. In the case of dobutamine, the (+)-enantiomer has affinity at β-adreno- ceptors 10 times higher than that of the (-)-enantiomer, both having agonist ac- tivity. However, the α-adrenoceptor stimulant action is due to the (-)-form (see above). As described for receptor interac- tions, enantioselectivity may also be manifested in drug interactions with enzymes and transport proteins. Enan- tiomers may display different affinities and reaction velocities. Conclusion: The enantiomers of a racemate can differ sufficiently in their pharmacodynamic and pharmacokinet- ic properties to constitute two distinct drugs. 62 Drug-Receptor Interaction Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug-Receptor Interaction 63 T ransport pr otein B. Reasons for different pharmacological properties of enantiomers A. Example of an enantiomeric pair with different affinity for A. a stereoselective receptor Physicochemical properties equal Deflection of polarized light [α] 20 D Absolute configuration Potency (rel. affinity at m-ACh-receptors + 125° (Dextrorotatory) - 125° (Levorotatory S = sinister R = rectus ca. 10 000 1 RACEMATE Benzetimide ENANTIOMER Dexetimide ENANTIOMER Levetimide Ratio 1 : 1 C C Intrinsic activity Turnover rate Pharmacodynamic properties Pharmacokinetic properties Af finity Transport protein Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Receptor Types Receptors are macromolecules that bind mediator substances and transduce this binding into an effect, i.e., a change in cell function. Receptors differ in terms of their structure and the manner in which they translate occupancy by a li- gand into a cellular response (signal transduction). G-protein-coupled receptors (A) consist of an amino acid chain that weaves in and out of the membrane in serpentine fashion. The extramembra- nal loop regions of the molecule may possess sugar residues at different N- glycosylation sites. The seven α-helical membrane-spanning domains probably form a circle around a central pocket that carries the attachment sites for the mediator substance. Binding of the me- diator molecule or of a structurally re- lated agonist molecule induces a change in the conformation of the receptor pro- tein, enabling the latter to interact with a G-protein (= guanyl nucleotide-bind- ing protein). G-proteins lie at the inner leaf of the plasmalemma and consist of three subunits designated α, β, and γ. There are various G-proteins that differ mainly with regard to their α-unit. As- sociation with the receptor activates the G-protein, leading in turn to activation of another protein (enzyme, ion chan- nel). A large number of mediator sub- stances act via G-protein-coupled re- ceptors (see p. 66 for more details). An example of a ligand-gated ion channel (B) is the nicotinic cholinocep- tor of the motor endplate. The receptor complex consists of five subunits, each of which contains four transmembrane domains. Simultaneous binding of two acetylcholine (ACh) molecules to the two α-subunits results in opening of the ion channel, with entry of Na + (and exit of some K + ), membrane depolarization, and triggering of an action potential (p. 82). The ganglionic N-cholinoceptors apparently consist only of α and β sub- units (α 2 β 2 ). Some of the receptors for the transmitter γ-aminobutyric acid (GABA) belong to this receptor family: the GABA A subtype is linked to a chlo- ride channel (and also to a benzodiaze- pine-binding site, see p. 227). Gluta- mate and glycine both act via ligand- gated ion channels. The insulin receptor protein repre- sents a ligand-operated enzyme (C), a catalytic receptor. When insulin binds to the extracellular attachment site, a tyrosine kinase activity is “switched on” at the intracellular portion. Protein phosphorylation leads to altered cell function via the assembly of other signal proteins. Receptors for growth hor- mones also belong to the catalytic re- ceptor class. Protein synthesis-regulating re- ceptors (D) for steroids, thyroid hor- mone, and retinoic acid are found in the cytosol and in the cell nucleus, respec- tively. Binding of hormone exposes a nor- mally hidden domain of the receptor protein, thereby permitting the latter to bind to a particular nucleotide sequence on a gene and to regulate its transcrip- tion. Transcription is usually initiated or enhanced, rarely blocked. 64 Drug-Receptor Interaction Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug-Receptor Interaction 65 Amino acids D. Protein synthesis-regulating receptor A. G-Protein-coupled receptor B. Ligand-gated ion channel C. Ligand-regulated enzyme Nicotinic acetylcholine receptor Subunit consisting of four trans- membrane domains Na + K + Na + K + αα β δγ Insulin S S S S S S Tyrosine kinase ACh ACh Phosphorylation of tyrosine-residues in proteins -NH 2 COOH H 2 N Effect Ef fector pr otein G- Protein Agonist COOH α-Helices Transmembrane domains Steroid Hormone Protein NucleusCytosol Receptor Tran- scription DNA mRNA Trans- lation 7 6 5 4 3 34567 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Mode of Operation of G-Protein- Coupled Receptors Signal transduction at G-protein-cou- pled receptors uses essentially the same basic mechanisms (A). Agonist binding to the receptor leads to a change in re- ceptor protein conformation. This change propagates to the G-protein: the α-subunit exchanges GDP for GTP, then dissociates from the two other subunits, associates with an effector protein, and alters its functional state. The α-subunit slowly hydrolyzes bound GTP to GDP. G α -GDP has no affinity for the effector protein and reassociates with the β and γ subunits (A). G-proteins can undergo lateral diffusion in the membrane; they are not assigned to individual receptor proteins. However, a relation exists between receptor types and G-protein types (B). Furthermore, the α-subunits of individual G-proteins are distinct in terms of their affinity for different effec- tor proteins, as well as the kind of influ- ence exerted on the effector protein. G α - GTP of the G S -protein stimulates adeny- late cyclase, whereas G α -GTP of the G i - protein is inhibitory. The G-protein- coupled receptor family includes mus- carinic cholinoceptors, adrenoceptors for norepinephrine and epinephrine, re- ceptors for dopamine, histamine, serot- onin, glutamate, GABA, morphine, pros- taglandins, leukotrienes, and many oth- er mediators and hormones. Major effector proteins for G-pro- tein-coupled receptors include adeny- late cyclase (ATP L50478 intracellular mes- senger cAMP), phospholipase C (phos- phatidylinositol L50478 intracellular mes- sengers inositol trisphosphate and di- acylglycerol), as well as ion channel proteins. Numerous cell functions are regulated by cellular cAMP concentra- tion, because cAMP enhances activity of protein kinase A, which catalyzes the transfer of phosphate groups onto func- tional proteins. Elevation of cAMP levels inter alia leads to relaxation of smooth muscle tonus and enhanced contractil- ity of cardiac muscle, as well as in- creased glycogenolysis and lipolysis (p. 84). Phosphorylation of cardiac cal- cium-channel proteins increases the probability of channel opening during membrane depolarization. It should be noted that cAMP is inactivated by phos- phodiesterase. Inhibitors of this enzyme elevate intracellular cAMP concentra- tion and elicit effects resembling those of epinephrine. The receptor protein itself may undergo phosphorylation, with a resul- tant loss of its ability to activate the as- sociated G-protein. This is one of the mechanisms that contributes to a de- crease in sensitivity of a cell during pro- longed receptor stimulation by an ago- nist (desensitization). Activation of phospholipase C leads to cleavage of the membrane phospho- lipid phosphatidylinositol-4,5 bisphos- phate into inositol trisphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 promotes release of Ca 2+ from storage organelles, whereby contraction of smooth muscle cells, breakdown of glycogen, or exocy- tosis may be initiated. Diacylglycerol stimulates protein kinase C, which phosphorylates certain serine- or threo- nine-containing enzymes. The α-subunit of some G-proteins may induce opening of a channel pro- tein. In this manner, K + channels can be activated (e.g., ACh effect on sinus node, p. 100; opioid action on neural impulse transmission, p. 210). 66 Drug-Receptor Interaction Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug-Receptor Interaction 67 B. G-Proteins, cellular messenger substances, and effects A. G-Protein-mediated effect of an agonist Receptor G-Protein Effector protein Agonist GDP GTP G s G i + - ATP cAMP Protein kinase A Phosphorylation of functional proteins Adenylate cyclase Activation Phosphorylation of enzymes Pr oteinkinase C Phospholipase C IP 3 Ca 2+ P P P DAG Facilitation of ion channel opening Transmembrane ion movements Effect on: e. g., Glycogenolysis lipolysis Ca-channel activation e. g., Contraction of smooth muscle, glandular secretion e. g., Membrane action potential, homeostasis of cellular ions α β γ α β γ β γ αα β γ Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Time Course of Plasma Concentration and Effect After the administration of a drug, its concentration in plasma rises, reaches a peak, and then declines gradually to the starting level, due to the processes of distribution and elimination (p. 46). Plasma concentration at a given point in time depends on the dose administered. Many drugs exhibit a linear relationship between plasma concentration and dose within the therapeutic range (dose-linear kinetics; (A); note differ- ent scales on ordinate). However, the same does not apply to drugs whose elimination processes are already suffi- ciently activated at therapeutic plasma levels so as to preclude further propor- tional increases in the rate of elimina- tion when the concentration is in- creased further. Under these conditions, a smaller proportion of the dose admin- istered is eliminated per unit of time. The time course of the effect and of the concentration in plasma are not identical, because the concentration- effect relationships obeys a hyperbolic function (B; cf. also p. 54). This means that the time course of the effect exhib- its dose dependence also in the pres- ence of dose-linear kinetics (C). In the lower dose range (example 1), the plasma level passes through a concentration range (0 L50478 0.9) in which the concentration effect relationship is quasi-linear. The respective time cours- es of plasma concentration and effect (A and C, left graphs) are very similar. However, if a high dose (100) is applied, there is an extended period of time dur- ing which the plasma level will remain in a concentration range (between 90 and 20) in which a change in concentra- tion does not cause a change in the size of the effect. Thus, at high doses (100), the time-effect curve exhibits a kind of plateau. The effect declines only when the plasma level has returned (below 20) into the range where a change in plasma level causes a change in the in- tensity of the effect. The dose dependence of the time course of the drug effect is exploited when the duration of the effect is to be prolonged by administration of a dose in excess of that required for the effect. This is done in the case of penicillin G (p. 268), when a dosing interval of 8 h is being recommended, although the drug is eliminated with a half-life of 30 min. This procedure is, of course, feasible on- ly if supramaximal dosing is not asso- ciated with toxic effects. Futhermore it follows that a nearly constant effect can be achieved, al- though the plasma level may fluctuate greatly during the interval between doses. The hyperbolic relationship be tween plasma concentration and effect explains why the time course of the ef- fect, unlike that of the plasma concen- tration, cannot be described in terms of a simple exponential function. A half- life can be given for the processes of drug absorption and elimination, hence for the change in plasma levels, but ge- nerally not for the onset or decline of the effect. 68 Drug-Receptor Interaction Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug-Receptor Interaction 69 Concentration Dose = 10 10 5 1 Time t1 2 Concentration Dose = 100 100 50 10 Time t1 2 C. Dose dependence of the time course of effect A. Dose-linear kinetics B. Concentration-effect relationship Concentration Dose = 1 1,0 0,5 0,1 Time t1 2 100 50 10 20 30 40 50 60 70 80 90 1001 0 Ef fect Concentration Effect Dose = 10 Time Effect Dose = 100 100 50 10 Time Effect Dose = 1 Time 100 50 10 100 50 10 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Adverse Drug Effects The desired (or intended) principal ef- fect of any drug is to modify body func- tion in such a manner as to alleviate symptoms caused by the patient’s ill- ness. In addition, a drug may also cause unwanted effects that can be grouped into minor or “side” effects and major or adverse effects. These, in turn, may give rise to complaints or illness, or may even cause death. Causes of adverse effects: over- dosage (A). The drug is administered in a higher dose than is required for the principal effect; this directly or indirect- ly affects other body functions. For in- stances, morphine (p. 210), given in the appropriate dose, affords excellent pain relief by influencing nociceptive path- ways in the CNS. In excessive doses, it inhibits the respiratory center and makes apnea imminent. The dose de- pendence of both effects can be graphed in the form of dose-response curves (DRC). The distance between both DRCs indicates the difference between the therapeutic and toxic doses. This margin of safety indicates the risk of toxicity when standard doses are exceeded. “The dose alone makes the poison” (Paracelsus). This holds true for both medicines and environmental poisons. No substance as such is toxic! In order to assess the risk of toxicity, knowledge is required of: 1) the effective dose during exposure; 2) the dose level at which damage is likely to occur; 3) the dura- tion of exposure. Increased Sensitivity (B). If certain body functions develop hyperreactivity, unwanted effects can occur even at nor- mal dose levels. Increased sensitivity of the respiratory center to morphine is found in patients with chronic lung dis- ease, in neonates, or during concurrent exposure to other respiratory depress- ant agents. The DRC is shifted to the left and a smaller dose of morphine is suffi- cient to paralyze respiration. Genetic anomalies of metabolism may also lead to hypersensitivity. Thus, several drugs (aspirin, antimalarials, etc.) can provoke premature breakdown of red blood cells (hemolysis) in subjects with a glucose- 6-phosphate dehydrogenase deficiency. The discipline of pharmacogenetics deals with the importance of the genotype for reactions to drugs. The above forms of hypersensitivity must be distinguished from allergies in- volving the immune system (p. 72). Lack of selectivity (C). Despite ap- propriate dosing and normal sensitivity, undesired effects can occur because the drug does not specifically act on the tar- geted (diseased) tissue or organ. For in- stance, the anticholinergic, atropine, is bound only to acetylcholine receptors of the muscarinic type; however, these are present in many different organs. Moreover, the neuroleptic, chlor- promazine, formerly used as a neuro- leptic, is able to interact with several different receptor types. Thus, its action is neither organ-specific nor receptor- specific. The consequences of lack of selec- tivity can often be avoided if the drug does not require the blood route to reach the target organ, but is, instead, applied locally, as in the administration of parasympatholytics in the form of eye drops or in an aerosol for inhalation. With every drug use, unwanted ef- fects must be taken into account. Before prescribing a drug, the physician should therefore assess the risk: benefit ratio. In this, knowledge of principal and ad- verse effects is a prerequisite. 70 Adverse Drug Effects Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Adverse Drug Effects 71 A. Adverse drug effect: overdosing B. Adverse drug effect: increased sensitivity Effect Dose Decrease in pain perception (nociception) Respiratory depression Morphine Morphine overdose Decrease in Respira- tory activity Nociception Safety margin Effect Dose Normal dose Increased sensitivity of respiratory center Safety margin mACh- receptor α-adreno- ceptor Histamine receptor Dopamine receptor Lacking receptor specificity e. g., Chlor- promazine mACh- receptor Atropine Receptor specificity but lacking organ selectivity Atropine C. Adverse drug effect: lacking selectivity Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Allergy The immune system normally functions to rid the organism of invading foreign particles, such as bacteria. Immune re- sponses can occur without appropriate cause or with exaggerated intensity and may harm the organism, for instance, when allergic reactions are caused by drugs (active ingredient or pharmaceu- tical excipients). Only a few drugs, e.g. (heterologous) proteins, have a molecu- lar mass (> 10,000) large enough to act as effective antigens or immunogens, capable by themselves of initiating an immune response. Most drugs or their metabolites (so-called haptens) must first be converted to an antigen by link- age to a body protein. In the case of pen- icillin G, a cleavage product (penicilloyl residue) probably undergoes covalent binding to protein. During initial con- tact with the drug, the immune system is sensitized: antigen-specific lympho- cytes of the T-type and B-type (antibody formation) proliferate in lymphatic tis- sue and some of them remain as so- called memory cells. Usually, these pro- cesses remain clinically silent. During the second contact, antibodies are al- ready present and memory cells prolife- rate rapidly. A detectable immune re- sponse, the allergic reaction, occurs. This can be of severe intensity, even at a low dose of the antigen. Four types of reactions can be distinguished: Type 1, anaphylactic reaction. Drug-specific antibodies of the IgE type combine via their F c moiety with recep- tors on the surface of mast cells. Binding of the drug provides the stimulus for the release of histamine and other media- tors. In the most severe form, a life- threatening anaphylactic shock devel- ops, accompanied by hypotension, bronchospasm (asthma attack), laryn- geal edema, urticaria, stimulation of gut musculature, and spontaneous bowel movements (p. 326). Type 2, cytotoxic reaction. Drug- antibody (IgG) complexes adhere to the surface of blood cells, where either circu- lating drug molecules or complexes al- ready formed in blood accumulate. These complexes mediate the activation of complement, a family of proteins that circulate in the blood in an inactive form, but can be activated in a cascade- like succession by an appropriate stimu- lus. “Activated complement” normally directed against microorganisms, can destroy the cell membranes and thereby cause cell death; it also promotes pha- gocytosis, attracts neutrophil granulo- cytes (chemotaxis), and stimulates oth- er inflammatory responses. Activation of complement on blood cells results in their destruction, evidenced by hemo- lytic anemia, agranulocytosis, and thrombocytopenia. Type 3, immune complex vascu- litis (serum sickness, Arthus reaction). Drug-antibody complexes precipitate on vascular walls, complement is activated, and an inflammatory reaction is trig- gered. Attracted neutrophils, in a futile attempt to phagocytose the complexes, liberate lysosomal enzymes that dam- age the vascular walls (inflammation, vasculitis). Symptoms may include fe- ver, exanthema, swelling of lymph nodes, arthritis, nephritis, and neuropa- thy. Type 4, contact dermatitis. A cuta- neously applied drug is bound to the surface of T-lymphocytes directed spe- cifically against it. The lymphocytes re- lease signal molecules (lymphokines) into their vicinity that activate macro- phages and provoke an inflammatory reaction. 72 Adverse Drug Effects Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Adverse Drug Effects 73 Production of antibodies (Immunoglobulins) e.g. IgE IgG etc. A. Adverse drug effect: allergic reaction Macromolecule MW > 10 000 Protein "Non-self" Immune system (^ lymphatic tissue) recognizes: Drug (= hapten) Antigen Reaction of immune system to first drug exposure Proliferation of antigen-specific lymphocytes Immune reaction with repeated drug exposure Histamine and other mediators Receptor for IgE Type 1 reaction: acute anaphylactic reaction Mast cell (tissue) basophilic granulocyte (blood) IgE Urticaria, asthma, shock IgG Type 2 reaction: cytotoxic reaction Cell destruc- tion Membrane injury e.g., Neutrophilic granulocyte Complement activation Deposition on vessel wall Formation of immune complexes Activation of: complement and neutrophils Type 3 reaction: Immune complex Inflammatory reaction Contact dermatitis Type 4 reaction: lymphocytic delayed reaction Inflammatory reaction Lymphokines Antigen- specific T-lymphocyte Distribution in body = Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Toxicity in Pregnancy and Lactation Drugs taken by the mother can be passed on transplacentally or via breast milk and adversely affect the unborn or the neonate. Pregnancy (A) Limb malformations induced by the hypnotic, thalidomide, first focused at- tention on the potential of drugs to cause malformations (teratogenicity). Drug effects on the unborn fall into two basic categories: 1. Predictable effects that derive from the known pharmacological drug properties. Examples are: masculin- ization of the female fetus by andro- genic hormones; brain hemorrhage due to oral anticoagulants; bradycar- dia due to β-blockers. 2. Effects that specifically affect the de- veloping organism and that cannot be predicted on the basis of the known pharmacological activity pro- file. In assessing the risks attending drug use during pregnancy, the follow- ing points have to be considered: a) Time of drug use. The possible seque- lae of exposure to a drug depend on the stage of fetal development, as shown in A. Thus, the hazard posed by a drug with a specific action is lim- ited in time, as illustrated by the tet- racyclines, which produce effects on teeth and bones only after the third month of gestation, when mineral- ization begins. b) Transplacental passage. Most drugs can pass in the placenta from the ma- ternal into the fetal circulation. The fused cells of the syncytiotrophoblast form the major diffusion barrier. They possess a higher permeability to drugs than is suggested by the term “placental barrier”. c) Teratogenicity. Statistical risk esti- mates are available for familiar, fre- quently used drugs. For many drugs, teratogenic potency cannot be dem- onstrated; however, in the case of novel drugs it is usually not yet pos- sible to define their teratogenic haz- ard. Drugs with established human ter- atogenicity include derivatives of vita- min A (etretinate, isotretinoin [used internally in skin diseases]), and oral anticoagulants. A peculiar type of dam- age results from the synthetic estrogen- ic agent, diethylstilbestrol, following its use during pregnancy; daughters of treated mothers have an increased inci- dence of cervical and vaginal carcinoma at the age of approx. 20. In assessing the risk: benefit ratio, it is also necessary to consider the benefit for the child resulting from adequate therapeutic treatment of its mother. For instance, therapy with antiepileptic drugs is indispensable, because untreat- ed epilepsy endangers the infant at least as much as does administration of anti- convulsants. Lactation (B) Drugs present in the maternal organism can be secreted in breast milk and thus be ingested by the infant. Evaluation of risk should be based on factors listed in B. In case of doubt, potential danger to the infant can be averted only by wean- ing. 74 Adverse Drug Effects Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Adverse Drug Effects 75 Development stage Nidation Embryo: organ develop- ment Fetus: growth and maturation Age of fetus (weeks) B. Lactation: maternal intake of drug A. Pregnancy: fetal damage due to drugs Sequelae of damage by drug MalformationFetal death Functional disturbances 382 1 21 12 Artery VeinUterus wall Transfer of metabolites Capillary Syncytio- trophoblast Placental barrier Fetus Mother To umbilical cordPlacental transfer of metabolites Therapeutic effect in mother Unwanted effect in child Drug ? Extent of transfer of drug into milk Infant dose Rate of elimination of drug from infant Distribution of drug in infant Drug concentration in infant′s blood Effect Ovum 1 day Endometrium Blastocyst Sensitivity of site of action Sperm cells ~3 days Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Placebo (A) A placebo is a dosage form devoid of an active ingredient, a dummy medication. Administration of a placebo may elicit the desired effect (relief of symptoms) or undesired effects that reflect a change in the patient’s psychological situation brought about by the thera- peutic setting. Physicians may consciously or un- consciously communicate to the patient whether or not they are concerned about the patient’s problem, or certain about the diagnosis and about the value of prescribed therapeutic measures. In the care of a physician who projects personal warmth, competence, and con- fidence, the patient in turn feels com- fortable and less anxious and optimisti- cally anticipates recovery. The physical condition determines the psychic disposition and vice versa. Consider gravely wounded combatants in war, oblivious to their injuries while fighting to survive, only to experience severe pain in the safety of the field hos- pital, or the patient with a peptic ulcer caused by emotional stress. Clinical trials. In the individual case, it may be impossible to decide whether therapeutic success is attribu- table to the drug or to the therapeutic situation. What is therefore required is a comparison of the effects of a drug and of a placebo in matched groups of pa- tients by means of statistical proce- dures, i.e., a placebo-controlled trial. A prospective trial is planned in advance, a retrospective (case-control) study fol- lows patients backwards in time. Pa- tients are randomly allotted to two groups, namely, the placebo and the ac- tive or test drug group. In a double-blind trial, neither the patients nor the treat- ing physicians know which patient is given drug and which placebo. Finally, a switch from drug to placebo and vice versa can be made in a successive phase of treatment, the cross-over trial. In this fashion, drug vs. placebo comparisons can be made not only between two pa- tient groups, but also within either group itself. Homeopathy (B) is an alternative method of therapy, developed in the 1800s by Samuel Hahnemann. His idea was this: when given in normal (allo- pathic) dosage, a drug (in the sense of medicament) will produce a constella- tion of symptoms; however, in a patient whose disease symptoms resemble just this mosaic of symptoms, the same drug (simile principle) would effect a cure when given in a very low dosage (“po- tentiation”). The body’s self-healing powers were to be properly activated only by minimal doses of the medicinal substance. The homeopath’s task is not to di- agnose the causes of morbidity, but to find the drug with a “symptom profile” most closely resembling that of the patient’s illness. This drug is then ap- plied in very high dilution. A direct action or effect on body functions cannot be demonstrated for homeopathic medicines. Therapeutic success is due to the suggestive powers of the homeopath and the expectancy of the patient. When an illness is strongly influenced by emotional (psychic) fac- tors and cannot be treated well by allo- pathic means, a case can be made in fa- vor of exploiting suggestion as a thera- peutic tool. Homeopathy is one of sever- al possible methods of doing so. 76 Drug-independent Effects Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug-independent Effects 77 “Similia similibus curentur” “Drug” Normal, allopathic dose symptom profile Dilution “effect reversal” Very low homeopathic dose elimination of disease symptoms corresponding to allopathic symptom “profile” “Potentiation” increase in efficacy with progressive dilution B. Homeopathy: concepts and procedure A. Therapeutic effects resulting from physician′s power of suggestion Well-being complaints Effect: - wanted - unwanted Placebo Conscious and unconscious expectations Conscious and unconscious signals: language, facial expression, gestures Physician Symptom “profile” Profile of disease symptoms PatientHomeopath Homeopathic remedy (“Simile”) D9 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 Stock- solution Dilution “Drug diagnosis” 1 1000 000 000 Patient Body Mind Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Systems Pharmacology Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Sympathetic Nervous System In the course of phylogeny an efficient control system evolved that enabled the functions of individual organs to be or- chestrated in increasingly complex life forms and permitted rapid adaptation to changing environmental conditions. This regulatory system consists of the CNS (brain plus spinal cord) and two separate pathways for two-way com- munication with peripheral organs, viz., the somatic and the autonomic nervous systems. The somatic nervous system comprising extero- and interoceptive afferents, special sense organs, and mo- tor efferents, serves to perceive external states and to target appropriate body movement (sensory perception: threat L50478 response: flight or attack). The auto- nomic (vegetative) nervous system (ANS), together with the endocrine system, controls the milieu interieur. It adjusts internal organ functions to the changing needs of the organism. Neural control permits very quick adaptation, whereas the endocrine system provides for a long-term regulation of functional states. The ANS operates largely beyond voluntary control; it functions autono- mously. Its central components reside in the hypothalamus, brain stem, and spinal cord. The ANS also participates in the regulation of endocrine functions. The ANS has sympathetic and parasympathetic branches. Both are made up of centrifugal (efferent) and centripetal (afferent) nerves. In many organs innervated by both branches, re- spective activation of the sympathetic and parasympathetic input evokes op- posing responses. In various disease states (organ malfunctions), drugs are employed with the intention of normalizing susceptible organ functions. To understand the bio- logical effects of substances capable of inhibiting or exciting sympathetic or parasympathetic nerves, one must first envisage the functions subserved by the sympathetic and parasympathetic divi- sions (A, Responses to sympathetic ac- tivation). In simplistic terms, activation of the sympathetic division can be con- sidered a means by which the body achieves a state of maximal work capac- ity as required in fight or flight situa- tions. In both cases, there is a need for vigorous activity of skeletal muscula- ture. To ensure adequate supply of oxy- gen and nutrients, blood flow in skeletal muscle is increased; cardiac rate and contractility are enhanced, resulting in a larger blood volume being pumped into the circulation. Narrowing of splanchnic blood vessels diverts blood into vascular beds in muscle. Because digestion of food in the in- testinal tract is dispensable and only counterproductive, the propulsion of in- testinal contents is slowed to the extent that peristalsis diminishes and sphinc- teric tonus increases. However, in order to increase nutrient supply to heart and musculature, glucose from the liver and free fatty acid from adipose tissue must be released into the blood. The bronchi are dilated, enabling tidal volume and alveolar oxygen uptake to be increased. Sweat glands are also innervated by sympathetic fibers (wet palms due to excitement); however, these are excep- tional as regards their neurotransmitter (ACh, p. 106). Although the life styles of modern humans are different from those of hominid ancestors, biological functions have remained the same. 80 Drugs Acting on the Sympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Sympathetic Nervous System 81 Eyes: pupillary dilation CNS: drive alertness Bronchi: dilation Saliva: little, viscous Heart: rate force blood pressure Fat tissue: lipolysis fatty acid liberation Bladder: Sphincter tone detrusor muscle Skeletal muscle: blood flow glycogenolysis A. Responses to sympathetic activation GI-tract: peristalsis sphincter tone blood flow Liver: glycogenolysis glucose release Skin: perspiration (cholinergic) Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Structure of the Sympathetic Nervous System The sympathetic preganglionic neurons (first neurons) project from the inter- mediolateral column of the spinal gray matter to the paired paravertebral gan- glionic chain lying alongside the verte- bral column and to unpaired preverte- bral ganglia. These ganglia represent sites of synaptic contact between pre- ganglionic axons (1 st neurons) and nerve cells (2 nd neurons or sympathocy- tes) that emit postganglionic axons terminating on cells in various end or- gans. In addition, there are preganglion- ic neurons that project either to periph- eral ganglia in end organs or to the ad- renal medulla. Sympathetic Transmitter Substances Whereas acetylcholine (see p. 98) serves as the chemical transmitter at ganglionic synapses between first and second neurons, norepinephrine (= noradrenaline) is the mediator at synapses of the second neuron (B). This second neuron does not synapse with only a single cell in the effector organ; rather, it branches out, each branch making en passant contacts with several cells. At these junctions the nerve axons form enlargements (varicosities) re- sembling beads on a string. Thus, excita- tion of the neuron leads to activation of a larger aggregate of effector cells, al- though the action of released norepi- nephrine may be confined to the region of each junction. Excitation of pregan- glionic neurons innervating the adrenal medulla causes a liberation of acetyl- choline. This, in turn, elicits a secretion of epinephrine (= adrenaline) into the blood, by which it is distributed to body tissues as a hormone (A). Adrenergic Synapse Within the varicosities, norepinephrine is stored in small membrane-enclosed vesicles (granules, 0.05 to 0.2 μm in dia- meter). In the axoplasm, L-tyrosine is converted via two intermediate steps to dopamine, which is taken up into the vesicles and there converted to norepi- nephrine by dopamine-β-hydroxylase. When stimulated electrically, the sym- pathetic nerve discharges the contents of part of its vesicles, including norepi- nephrine, into the extracellular space. Liberated norepinephrine reacts with adrenoceptors located postjunctionally on the membrane of effector cells or prejunctionally on the membrane of varicosities. Activation of presynaptic α 2 -receptors inhibits norepinephrine release. By this negative feedback, re- lease can be regulated. The effect of released norepineph- rine wanes quickly, because approx. 90 % is actively transported back into the axoplasm, then into storage vesicles (neuronal re-uptake). Small portions of norepinephrine are inactivated by the enzyme catechol-O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells, to yield normeta- nephrine), and monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells, to yield 3,4-dihydroxymandelic acid). The liver is richly endowed with COMT and MAO; it therefore contrib- utes significantly to the degradation of circulating norepinephrine and epi- nephrine. The end product of the com- bined actions of MAO and COMT is van- illylmandelic acid. 82 Drugs Acting on the Sympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Sympathetic Nervous System 83 B. Second neuron of sympathetic system, varicosity, norepinephrine release A. Epinephrine as hormone, norepinephrine as transmitter Psychic stress or physical stress First neuron Second neuron Adrenal medulla NorepinephrineEpinephrine M A O Receptors Receptors COMT Norepinephrine Presynaptic α 2 -receptors α β 2 β 1 3.4-Dihydroxy- mandelic acid Normeta- nephrine First neuron Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Adrenoceptor Subtypes and Catecholamine Actions Adrenoceptors fall into three major groups, designated α 1 , α 2 , and β, within each of which further subtypes can be distinguished pharmacologically. The different adrenoceptors are differential- ly distributed according to region and tissue. Agonists at adrenoceptors (di- rect sympathomimetics) mimic the ac- tions of the naturally occurring cate- cholamines, norepinephrine and epi- nephrine, and are used for various ther- apeutic effects. Smooth muscle effects. The op- posing effects on smooth muscle (A) of α-and β-adrenoceptor activation are due to differences in signal transduction (p. 66). This is exemplified by vascular smooth muscle (A). α 1 -Receptor stimu- lation leads to intracellular release of Ca 2+ via activation of the inositol tris- phosphate (IP 3 ) pathway. In concert with the protein calmodulin, Ca 2+ can activate myosin kinase, leading to a rise in tonus via phosphorylation of the con- tractile protein myosin. cAMP inhibits activation of myosin kinase. Via the for- mer effector pathway, stimulation of α- receptors results in vasoconstriction; via the latter, β 2 -receptors mediate va- sodilation, particularly in skeletal mus- cle — an effect that has little therapeutic use. Vasoconstriction. Local application of α-sympathomimetics can be employed in infiltration anesthesia (p. 204) or for nasal decongestion (naphazoline, tetra- hydrozoline, xylometazoline; pp. 90, 324). Systemically administered epi- nephrine is important in the treatment of anaphylactic shock for combating hy- potension. Bronchodilation. β 2 -Adrenocep- tor-mediated bronchodilation (e.g., with terbutaline, fenoterol, or salbutamol) plays an essential part in the treatment of bronchial asthma (p. 328). Tocolysis. The uterine relaxant ef- fect of β 2 -adrenoceptor agonists, such as terbutaline or fenoterol, can be used to prevent premature labor. Vasodilation with a resultant drop in systemic blood pressure results in reflex tachycardia, which is also due in part to the β 1 -stim- ulant action of these drugs. Cardiostimulation. By stimulating β 1 -receptors, hence activation of ade- nylatcyclase (Ad-cyclase) and cAMP production, catecholamines augment all heart functions, including systolic force (positive inotropism), velocity of short- ening (p. clinotropism), sinoatrial rate (p. chronotropism), conduction velocity (p. dromotropism), and excitability (p. bathmotropism). In pacemaker fibers, diastolic depolarization is hastened, so that the firing threshold for the action potential is reached sooner (positive chronotropic effect, B). The cardiostim- ulant effect of β-sympathomimetics such as epinephrine is exploited in the treatment of cardiac arrest. Use of β- sympathomimetics in heart failure car- ries the risk of cardiac arrhythmias. Metabolic effects. β-Receptors me- diate increased conversion of glycogen to glucose (glycogenolysis) in both liver and skeletal muscle. From the liver, glu- cose is released into the blood, In adi- pose tissue, triglycerides are hydrolyzed to fatty acids (lipolysis, mediated by β 3 - receptors), which then enter the blood (C). The metabolic effects of catechola- mines are not amenable to therapeutic use. 84 Drugs Acting on the Sympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Sympathetic Nervous System 85 Membrane potential (mV) Time B. Cardiac effects of catecholamines A. Vasomotor effects of catecholamines α 1 G i α 2 Ad-cyclase Phospholipase C Ad-cyclase Ca 2+ IP 3 cAMP + - Calmodulin Myosin kinase Myosin Myosin-P β 2 β 1 G s Ad-cyclase + cAMP Force (mN) Time C. Metabolic effects of catecholamines β G s Ad-cyclase + Glucose Glycogenolysis cAMP Glucose Lipolysis Fatty acids Glycogenolysis G i G s Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Structure – Activity Relationships of Sympathomimetics Due to its equally high affinity for all α- and β-receptors, epinephrine does not permit selective activation of a particu- lar receptor subtype. Like most cate- cholamines, it is also unsuitable for oral administration (catechol is a trivial name for o-hydroxyphenol). Norepi- nephrine differs from epinephrine by its high affinity for α-receptors and low af- finity for β 2 -receptors. In contrast, iso- proterenol has high affinity for β-recep- tors, but virtually none for α-receptors (A). norepinephrine L50478 α, β 1 epinephrine L50478 α, β 1 , β 2 isoproterenol L50478 β 1 , β 2 Knowledge of structure–activity relationships has permitted the syn- thesis of sympathomimetics that dis- play a high degree of selectivity at adrenoceptor subtypes. Direct-acting sympathomimetics (i.e., adrenoceptor agonists) typically share a phenylethylamine structure. The side chain β-hydroxyl group confers af- finity for α- and β-receptors. Substitu- tion on the amino group reduces affinity for α-receptors, but increases it for β-re- ceptors (exception: α-agonist phenyl- ephrine), with optimal affinity being seen after the introduction of only one isopropyl group. Increasing the bulk of the amino substituent favors affinity for β 2 -receptors (e.g., fenoterol, salbuta- mol). Both hydroxyl groups on the aro- matic nucleus contribute to affinity; high activity at α-receptors is associated with hydroxyl groups at the 3 and 4 po- sitions. Affinity for β-receptors is pre- served in congeners bearing hydroxyl groups at positions 3 and 5 (orciprena- line, terbutaline, fenoterol). The hydroxyl groups of catechol- amines are responsible for the very low lipophilicity of these substances. Pola- rity is increased at physiological pH due to protonation of the amino group. De- letion of one or all hydroxyl groups im- proves membrane penetrability at the intestinal mucosa-blood and the blood- brain barriers. Accordingly, these non- catecholamine congeners can be given orally and can exert CNS actions; how- ever, this structural change entails a loss in affinity. Absence of one or both aromatic hydroxyl groups is associated with an increase in indirect sympathomimetic activity, denoting the ability of a sub- stance to release norepinephrine from its neuronal stores without exerting an agonist action at the adrenoceptor (p. 88). An altered position of aromatic hy- droxyl groups (e.g., in orciprenaline, fe- noterol, or terbutaline) or their substi- tution (e.g., salbutamol) protects against inactivation by COMT (p. 82). In- droduction of a small alkyl residue at the carbon atom adjacent to the amino group (ephedrine, methamphetamine) confers resistance to degradation by MAO (p. 80), as does replacement on the amino groups of the methyl residue with larger substituents (e.g., ethyl in etilefrine). Accordingly, the congeners are less subject to presystemic inactiva- tion. Since structural requirements for high affinity, on the one hand, and oral applicability, on the other, do not match, choosing a sympathomimetic is a matter of compromise. If the high af- finity of epinephrine is to be exploited, absorbability from the intestine must be foregone (epinephrine, isoprenaline). If good bioavailability with oral adminis- tration is desired, losses in receptor af- finity must be accepted (etilefrine). 86 Drugs Acting on the Sympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Sympathetic Nervous System 87 B. Structure-activity relationship of epinephrine derivatives A. Chemical structure of catecholamines and affinity for α- and β-receptors EpinephrineNorepinephrine Isoproterenol Receptor affinity Catecholamine- O-methyltransferase Monoamine oxidase (Enteral absorbability CNS permeability) Metabolic stability Etilefrine Ephedrine Methamphetamine Epinephrine Orciprenaline Fenoterol Affinity for α-receptors Affinity for β-receptors Resistance to degradation Absorbability Indirect action Penetrability through membrane barriers Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Indirect Sympathomimetics Apart from receptors, adrenergic neu- rotransmission involves mechanisms for the active re-uptake and re-storage of released amine, as well as enzymatic breakdown by monoamine oxidase (MAO). Norepinephrine (NE) displays affinity for receptors, transport systems, and degradative enzymes. Chemical al- terations of the catecholamine differen- tially affect these properties and result in substances with selective actions. Inhibitors of MAO (A). The enzyme is located predominantly on mitochon- dria, and serves to scavenge axoplasmic free NE. Inhibition of the enzyme causes free NE concentrations to rise. Likewise, dopamine catabolism is impaired, mak- ing more of it available for NE synthesis. Consequently, the amount of NE stored in granular vesicles will increase, and with it the amount of amine released per nerve impulse. In the CNS, inhibition of MAO af- fects neuronal storage not only of NE but also of dopamine and serotonin. These mediators probably play signifi- cant roles in CNS functions consistent with the stimulant effects of MAO inhib- itors on mood and psychomotor drive and their use as antidepressants in the treatment of depression (A). Tranylcy- promine is used to treat particular forms of depressive illness; as a covalently bound suicide substrate, it causes long- lasting inhibition of both MAO iso- zymes, (MAO A , MAO B ). Moclobemide re- versibly inhibits MAO A and is also used as an antidepressant. The MAO B inhibi- tor selegiline (deprenyl) retards the cat- obolism of dopamine, an effect used in the treatment of parkinsonism (p. 188). Indirect sympathomimetics (B) are agents that elevate the concentra- tion of NE at neuroeffector junctions, because they either inhibit re-uptake (cocaine), facilitate release, or slow breakdown by MAO, or exert all three of these effects (amphetamine, metham- phetamine). The effectiveness of such indirect sympathomimetics diminishes or disappears (tachyphylaxis) when ve- sicular stores of NE close to the axolem- ma are depleted. Indirect sympathomimetics can penetrate the blood-brain barrier and evoke such CNS effects as a feeling of well-being, enhanced physical activity and mood (euphoria), and decreased sense of hunger or fatigue. Subsequent- ly, the user may feel tired and de- pressed. These after effects are partly responsible for the urge to re-adminis- ter the drug (high abuse potential). To prevent their misuse, these substances are subject to governmental regulations (e.g., Food and Drugs Act: Canada; Con- trolled Drugs Act: USA) restricting their prescription and distribution. When amphetamine-like substanc- es are misused to enhance athletic per- formance (doping), there is a risk of dan- gerous physical overexertion. Because of the absence of a sense of fatigue, a drugged athlete may be able to mobilize ultimate energy reserves. In extreme situations, cardiovascular failure may result (B). Closely related chemically to am- phetamine are the so-called appetite suppressants or anorexiants, such as fenfluramine, mazindole, and sibutra- mine. These may also cause dependence and their therapeutic value and safety are questionable. 88 Drugs Acting on the Sympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Sympathetic Nervous System 89 Controlled Substances Act regulates use of cocaine and amphetamine MAO MAO MAO MAO B. Indirect sympathomimetics with central stimulant activity and abuse potential A. Monoamine oxidase inhibitor Nor- epinephrine Norepinephrine transport system Effector organ "Doping" Runner-up Pain stimulus Local anesthetic effect Amphetamine Cocaine § § Inhibitor: Moclobemide MAO-A Selegiline MAO-B Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. α-Sympathomimetics, α-Sympatholytics α-Sympathomimetics can be used systemically in certain types of hypoten- sion (p. 314) and locally for nasal or con- junctival decongestion (pp. 324, 326) or as adjuncts in infiltration anesthesia (p. 206) for the purpose of delaying the re- moval of local anesthetic. With local use, underperfusion of the vasocon- stricted area results in a lack of oxygen (A). In the extreme case, local hypoxia can lead to tissue necrosis. The append- ages (e.g., digits, toes, ears) are particu- larly vulnerable in this regard, thus pre- cluding vasoconstrictor adjuncts in in- filtration anesthesia at these sites. Vasoconstriction induced by an α- sympathomimetic is followed by a phase of enhanced blood flow (reactive hyperemia, A). This reaction can be ob- served after the application of α-sympa- thomimetics (naphazoline, tetrahydro- zoline, xylometazoline) to the nasal mu- cosa. Initially, vasoconstriction reduces mucosal blood flow and, hence, capil- lary pressure. Fluid exuded into the interstitial space is drained through the veins, thus shrinking the nasal mucosa. Due to the reduced supply of fluid, se- cretion of nasal mucus decreases. In co- ryza, nasal patency is restored. Howev- er, after vasoconstriction subsides, reac- tive hyperemia causes renewed exuda- tion of plasma fluid into the interstitial space, the nose is “stuffy” again, and the patient feels a need to reapply decon- gestant. In this way, a vicious cycle threatens. Besides rebound congestion, persistent use of a decongestant entails the risk of atrophic damage caused by prolonged hypoxia of the nasal mucosa. α-Sympatholytics (B). The interac- tion of norepinephrine with α-adreno- ceptors can be inhibited by α-sympath- olytics ( α-adrenoceptor antagonists, α- blockers). This inhibition can be put to therapeutic use in antihypertensive treatment (vasodilation L50478 peripheral resistance ↓, blood pressure ↓, p. 118). The first α-sympatholytics blocked the action of norepinephrine at both post- and prejunctional α-adrenoceptors (non-selective α-blockers, e.g., phen- oxybenzamine, phentolamine). Presynaptic α 2 -adrenoceptors func- tion like sensors that enable norepi- nephrine concentration outside the axolemma to be monitored, thus regu- lating its release via a local feedback mechanism. When presynaptic α 2 -re- ceptors are stimulated, further release of norepinephrine is inhibited. Con- versely, their blockade leads to uncon- trolled release of norepinephrine with an overt enhancement of sympathetic effects at β 1 -adrenoceptor-mediated myocardial neuroeffector junctions, re- sulting in tachycardia and tachyar- rhythmia. Selective α-Sympatholytics α-Blockers, such as prazosin, or the longer-acting terazosin and doxazosin, lack affinity for prejunctional α 2 -adren- oceptors. They suppress activation of α 1 -receptors without a concomitant en- hancement of norepinephrine release. α 1 -Blockers may be used in hyper- tension (p. 312). Because they prevent reflex vasoconstriction, they are likely to cause postural hypotension with pooling of blood in lower limb capaci- tance veins during change from the su- pine to the erect position (orthostatic collapse: ↓ venous return, ↓ cardiac out- put, fall in systemic pressure, ↓ blood supply to CNS, syncope, p. 314). In benign hyperplasia of the pros- tate, α-blockers (terazosin, alfuzosin) may serve to lower tonus of smooth musculature in the prostatic region and thereby facilitate micturition (p. 252). 90 Drugs Acting on the Sympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Sympathetic Nervous System 91 C. Indications for α 1 -sympatholytics A. Reactive hyperemia due to α-sympathomimetics, e.g., following decongestion of nasal mucosa B. Autoinhibition of norepinephrine release and α-sympatholytics α-Agonist O 2 supply < O 2 demand O 2 supply = O 2 demand AfterBefore O 2 supply = O 2 demand NE α 2 α 2 α 2 nonselective α-blocker α 1 α 1 α 1 β 1 β 1 β 1 α 1 -blocker α 1 -blocker e.g., terazosin H 3 CO O O H 3 CO NH 2 N N N N High blood pressure Benign prostatic hyperplasia Inhibition of α 1 -adrenergic stimulation of smooth muscle Neck of bladder, prostate Resistance arteries Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. β-Sympatholytics (β-Blockers) β-Sympatholytics are antagonists of norepiphephrine and epinephrine at β- adrenoceptors; they lack affinity for α- receptors. Therapeutic effects. β-Blockers protect the heart from the oxygen- wasting effect of sympathetic inotrop- ism (p. 306) by blocking cardiac β-re- ceptors; thus, cardiac work can no long- er be augmented above basal levels (the heart is “coasting”). This effect is uti- lized prophylactically in angina pectoris to prevent myocardial stress that could trigger an ischemic attack (p. 308, 310). β-Blockers also serve to lower cardiac rate (sinus tachycardia, p. 134) and ele- vated blood pressure due to high cardiac output (p. 312). The mechanism under- lying their antihypertensive action via reduction of peripheral resistance is un- clear. Applied topically to the eye, β- blockers are used in the management of glaucoma; they lower production of aqueous humor without affecting its drainage. Undesired effects. The hazards of treatment with β-blockers become ap- parent particularly when continuous activation of β-receptors is needed in order to maintain the function of an or- gan. Congestive heart failure: In myocar- dial insufficiency, the heart depends on a tonic sympathetic drive to maintain adequate cardiac output. Sympathetic activation gives rise to an increase in heart rate and systolic muscle tension, enabling cardiac output to be restored to a level comparable to that in a healthy subject. When sympathetic drive is eliminated during β-receptor blockade, stroke volume and cardiac rate decline, a latent myocardial insuffi- ciency is unmasked, and overt insuffi- ciency is exacerbated (A). On the other hand, clinical evidence suggests that β-blockers produce favor- able effects in certain forms of conges- tive heart failure (idiopathic dilated car- diomyopathy). Bradycardia, A-V block: Elimination of sympathetic drive can lead to a marked fall in cardiac rate as well as to disorders of impulse conduction from the atria to the ventricles. Bronchial asthma: Increased sym- pathetic activity prevents broncho- spasm in patients disposed to paroxys- mal constriction of the bronchial tree (bronchial asthma, bronchitis in smok- ers). In this condition, β 2 -receptor blockade will precipitate acute respira- tory distress (B). Hypoglycemia in diabetes mellitus: When treatment with insulin or oral hy- poglycemics in the diabetic patient low- ers blood glucose below a critical level, epinephrine is released, which then stimulates hepatic glucose release via activation of β 2 -receptors. β-Blockers suppress this counter-regulation; in ad- dition, they mask other epinephrine- mediated warning signs of imminent hypoglycemia, such as tachycardia and anxiety, thereby enhancing the risk of hypoglycemic shock. Altered vascular responses: When β 2 -receptors are blocked, the vasodilat- ing effect of epinephrine is abolished, leaving the α-receptor-mediated vaso- constriction unaffected: peripheral blood flow ↓ – “cold hands and feet”. β-Blockers exert an “anxiolytic“ action that may be due to the suppres- sion of somatic responses (palpitations, trembling) to epinephrine release that is induced by emotional stress; in turn, these would exacerbate “anxiety” or “stage fright”. Because alertness is not impaired by β-blockers, these agents are occasionally taken by orators and musi- cians before a major performance (C). Stage fright, however, is not a disease requiring drug therapy. 92 Drugs Acting on the Sympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Sympathetic Nervous System 93 C. “Anxiolytic” effect of β-sympatholytics A. β-Sympatholytics: effect on cardiac function B. β-Sympatholytics: effect on bronchial and vascular tone Stroke volume 100 ml β-Receptorβ-Blocker blocks receptor Heart failur e Healthy 1 sec β 1 -Blockade β 1 -Stimulation β 2 -Blockade β 2 -Stimulation Healthy Asthmatic β 2 -Blockade β 2 -Stimulation α β 2 α β 2 α 1 sec β-Blockade Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Types of β-Blockers The basic structure shared by most β- sympatholytics is the side chain of β- sympathomimetics (cf. isoproterenol with the β-blockers propranolol, pindo- lol, atenolol). As a rule, this basic struc- ture is linked to an aromatic nucleus by a methylene and oxygen bridge. The side chain C-atom bearing the hydroxyl group forms the chiral center. With some exceptions (e.g., timolol, penbuto- lol), all β-sympatholytics are brought as racemates into the market (p. 62). Compared with the dextrorotatory form, the levorotatory enantiomer pos- sesses a greater than 100-fold higher af- finity for the β-receptor and is, there- fore, practically alone in contributing to the β-blocking effect of the racemate. The side chain and substituents on the amino group critically affect affinity for β-receptors, whereas the aromatic nu- cleus determines whether the com- pound possess intrinsic sympathomi- metic activity (ISA), that is, acts as a partial agonist (p. 60) or partial antago- nist. In the presence of a partial agonist (e.g., pindolol), the ability of a full ago- nist (e.g., isoprenaline) to elicit a maxi- mal effect would be attenuated, because binding of the full agonist is impeded. However, the β-receptor at which such partial agonism can be shown appears to be atypical (β 3 or β 4 subtype). Wheth- er ISA confers a therapeutic advantage on a β-blocker remains an open ques- tion. As cationic amphiphilic drugs, β- blockers can exert a membrane-stabi- lizing effect, as evidenced by the ability of the more lipophilic congeners to in- hibit Na + -channel function and impulse conduction in cardiac tissues. At the usual therapeutic dosage, the high con- centration required for these effects will not be reached. Some β-sympatholytics possess higher affinity for cardiac β 1 -receptors than for β 2 -receptors and thus display cardioselectivity (e.g., metoprolol, ace- butolol, bisoprolol). None of these blockers is sufficiently selective to per- mit its use in patients with bronchial asthma or diabetes mellitus (p. 92). The chemical structure of β-block- ers also determines their pharmacoki- netic properties. Except for hydrophilic representatives (atenolol), β-sympatho- lytics are completely absorbed from the intestines and subsequently undergo presystemic elimination to a major ex- tent (A). All the above differences are of little clinical importance. The abundance of commercially available congeners would thus appear all the more curious (B). Propranolol was the first β-blocker to be introduced into therapy in 1965. Thirty-five years later, about 20 different congeners are being marketed in differ- ent countries. This questionable devel- opment unfortunately is typical of any drug group that has major therapeutic relevance, in addition to a relatively fixed active structure. Variation of the molecule will create a new patentable chemical, not necessarily a drug with a novel action. Moreover, a drug no longer protected by patent is offered as a gener- ic by different manufacturers under doz- ens of different proprietary names. Propranolol alone has been marketed by 13 manufacturers under 11 different names. 94 Drugs Acting on the Sympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Sympathetic Nervous System 95 Talinolol Sotalol β 1 β 2 B. Avalanche-like increase in commercially available β-sympatholytics Isoproterenol Pindolol Propranolol Atenolol Agonist partial Agonist Antagonist Effect No effect selectivity Presystemic elimination 100% 50% A. Types of β-sympatholytics Betaxolol Carteolol Mepindolol Penbutolol Carazolol Nadolol Acebutolol Bunitrolol Atenolol Metipranol Metoprolol Timolol Oxprenolol Pindolol Bupranolol Alprenolol Propranolol 1965 1970 1975 1980 1985 1990 Celiprolol Bisoprolol Bopindolol Esmolol Tertatolol β 1 β 2 Cardio- β 1 β 2 β 1 β 2 β 1 β 2 β-Receptor β-Receptor β-Receptor Carvedilol Befunolol Year introduced Antagonist Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antiadrenergics Antiadrenergics are drugs capable of lowering transmitter output from sym- pathetic neurons, i.e., “sympathetic tone”. Their action is hypotensive (indi- cation: hypertension, p. 312); however, being poorly tolerated, they enjoy only limited therapeutic use. Clonidine is an α 2 -agonist whose high lipophilicity (dichlorophenyl ring) permits rapid penetration through the blood-brain barrier. The activation of postsynaptic α 2 -receptors dampens the activity of vasomotor neurons in the medulla oblongata, resulting in a reset- ting of systemic arterial pressure at a lower level. In addition, activation of presynaptic α 2 -receptors in the periph- ery (pp. 82, 90) leads to a decreased re- lease of both norepinephrine (NE) and acetylcholine. Side effects. Lassitude, dry mouth; rebound hypertension after abrupt ces- sation of clonidine therapy. Methyldopa (dopa = dihydroxy- phenylalanine), as an amino acid, is transported across the blood-brain bar- rier, decarboxylated in the brain to α- methyldopamine, and then hydroxylat- ed to α-methyl-NE. The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter α-methyl-NE can be stored; however, unlike the endogenous media- tor, it has a higher affinity for α 2 - than for α 1 -receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral ad- renergic neurons. Adverse effects. Fatigue, orthostatic hypotension, extrapyramidal Parkin- son-like symptoms (p. 88), cutaneous reactions, hepatic damage, immune-he- molytic anemia. Reserpine, an alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic amines (NE, dopa- mine = DA, serotonin = 5-HT) by inhibit- ing an ATPase required for the vesicular amine pump. The amount of NE re- leased per nerve impulse is decreased. To a lesser degree, release of epineph- rine from the adrenal medulla is also impaired. At higher doses, there is irre- versible damage to storage vesicles (“pharmacological sympathectomy”), days to weeks being required for their resynthesis. Reserpine readily enters the brain, where it also impairs vesicu- lar storage of biogenic amines. Adverse effects. Disorders of extra- pyramidal motor function with devel- opment of pseudo-Parkinsonism (p. 88), sedation, depression, stuffy nose, im- paired libido, and impotence; increased appetite. These adverse effects have rendered the drug practically obsolete. Guanethidine possesses high affin- ity for the axolemmal and vesicular amine transporters. It is stored instead of NE, but is unable to mimic the func- tions of the latter. In addition, it stabiliz- es the axonal membrane, thereby im- peding the propagation of impulses into the sympathetic nerve terminals. Stor- age and release of epinephrine from the adrenal medulla are not affected, owing to the absence of a re-uptake process. The drug does not cross the blood-brain barrier. Adverse effects. Cardiovascular cri- ses are a possible risk: emotional stress of the patient may cause sympatho- adrenal activation with epinephrine re- lease. The resulting rise in blood pres- sure can be all the more marked be- cause persistent depression of sympa- thetic nerve activity induces supersen- sitivity of effector organs to circulating catecholamines. 96 Drugs Acting on the Sympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Sympathetic Nervous System 97 Suppression of sympathetic impulses in vasomotor center Release from adrenal medulla unaffected CNS A. Inhibitors of sympathetic tone No epinephrine from adrenal medulla due to central sedative effect Stimulation of central α 2 -receptors α-Methyl-NE False transmitter Tyrosine Dopa Dopamine NE Clonidine α-Methyldopa Peripheral sympathetic activity Inhibition of biogenic amine storage NE DA 5HT Varicosity Reserpine Inhibition of peripheral sympathetic activity Active uptake and storage instead of norepinephrine; not a transmitter Guanethidine Varicosity Inhibition of Dopa-decarb- oxylase α-Methyl-NE in brain Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Parasympathetic Nervous System Responses to activation of the para- sympathetic system. Parasympathetic nerves regulate processes connected with energy assimilation (food intake, digestion, absorption) and storage. These processes operate when the body is at rest, allowing a decreased tidal vol- ume (increased bronchomotor tone) and decreased cardiac activity. Secre- tion of saliva and intestinal fluids pro- motes the digestion of foodstuffs; trans- port of intestinal contents is speeded up because of enhanced peristaltic activity and lowered tone of sphincteric mus- cles. To empty the urinary bladder (mic- turition), wall tension is increased by detrusor activation with a concurrent relaxation of sphincter tonus. Activation of ocular parasympa- thetic fibers (see below) results in nar- rowing of the pupil and increased curva- ture of the lens, enabling near objects to be brought into focus (accommodation). Anatomy of the parasympathetic system. The cell bodies of parasympa- thetic preganglionic neurons are located in the brainstem and the sacral spinal cord. Parasympathetic outflow is chan- nelled from the brainstem (1) through the third cranial nerve (oculomotor n.) via the ciliary ganglion to the eye; (2) through the seventh cranial nerve (fa- cial n.) via the pterygopalatine and sub- maxillary ganglia to lacrimal glands and salivary glands (sublingual, submandib- ular), respectively; (3) through the ninth cranial nerve (glossopharyngeal n.) via the otic ganglion to the parotid gland; and (4) via the tenth cranial nerve (vagus n.) to thoracic and abdom- inal viscera. Approximately 75 % of all parasympathetic fibers are contained within the vagus nerve. The neurons of the sacral division innervate the distal colon, rectum, bladder, the distal ure- ters, and the external genitalia. Acetylcholine (ACh) as a transmit- ter. ACh serves as mediator at terminals of all postganglionic parasympathetic fibers, in addition to fulfilling its trans- mitter role at ganglionic synapses with- in both the sympathetic and parasym- pathetic divisions and the motor end- plates on striated muscle. However, dif- ferent types of receptors are present at these synaptic junctions: 98 Drugs Acting on the Parasympathetic Nervous System Localization Agonist Antagonist Receptor Type Target tissues of 2 nd ACh Atropine Muscarinic (M) parasympathetic Muscarine cholinoceptor; neurons G-protein-coupled- receptor protein with 7 transmembrane domains Sympathetic & ACh Trimethaphan Ganglionic type parasympathetic Nicotine (α3 β4) ganglia Nicotinic (N) cholinoceptor ligand- gated cation channel formed by five trans- membrane subunits Motor endplate ACh d-Tubocurarine muscular type Nicotine (α1 2 β1γδ) The existence of distinct cholino- ceptors at different cholinergic synap- ses allows selective pharmacological interventions. Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Parasympathetic Nervous System 99 Eyes: Accommodation for near vision, miosis Bronchi: constriction secretion Saliva: copious, liquid GI tract: secretion peristalsis sphincter tone Heart: rate blood pressure Bladder: sphincter tone detrusor A. Responses to parasympathetic activation Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Cholinergic Synapse Acetylcholine (ACh) is the transmitter at postganglionic synapses of parasym- pathetic nerve endings. It is highly con- centrated in synaptic storage vesicles densely present in the axoplasm of the terminal. ACh is formed from choline and activated acetate (acetylcoenzyme A), a reaction catalyzed by the enzyme choline acetyltransferase. The highly polar choline is actively transported into the axoplasm. The specific choline trans- porter is localized exclusively to mem- branes of cholinergic axons and termi- nals. The mechanism of transmitter re- lease is not known in full detail. The vesi- cles are anchored via the protein synap- sin to the cytoskeletal network. This ar- rangement permits clustering of vesicles near the presynaptic membrane, while preventing fusion with it. During activa- tion of the nerve membrane, Ca 2+ is thought to enter the axoplasm through voltage-gated channels and to activate protein kinases that phosphorylate syn- apsin. As a result, vesicles close to the membrane are detached from their an- choring and allowed to fuse with the presynaptic membrane. During fusion, vesicles discharge their contents into the synaptic gap. ACh quickly diffuses through the synaptic gap (the acetylcho- line molecule is a little longer than 0.5 nm; the synaptic gap is as narrow as 30–40 nm). At the postsynaptic effector cell membrane, ACh reacts with its re- ceptors. Because these receptors can al- so be activated by the alkaloid musca- rine, they are referred to as muscarinic (M-)cholinoceptors. In contrast, at gan- glionic (p. 108) and motor endplate (p. 184) cholinoceptors, the action of ACh is mimicked by nicotine and they are, therefore, said to be nicotinic cholino- ceptors. Released ACh is rapidly hydrolyzed and inactivated by a specific acetylchol- inesterase, present on pre- and post- junctional membranes, or by a less spe- cific serum cholinesterase (butyryl chol- inesterase), a soluble enzyme present in serum and interstitial fluid. M-cholinoceptors can be classified into subtypes according to their molec- ular structure, signal transduction, and ligand affinity. Here, the M 1 , M 2 , and M 3 subtypes are considered. M 1 receptors are present on nerve cells, e.g., in gan- glia, where they mediate a facilitation of impulse transmission from pregan- glionic axon terminals to ganglion cells. M 2 receptors mediate acetylcholine ef- fects on the heart: opening of K + chan- nels leads to slowing of diastolic depola- rization in sinoatrial pacemaker cells and a decrease in heart rate. M 3 recep- tors play a role in the regulation of smooth muscle tone, e.g., in the gut and bronchi, where their activation causes stimulation of phospholipase C, mem- brane depolarization, and increase in muscle tone. M 3 receptors are also found in glandular epithelia, which sim- ilarly respond with activation of phos- pholipase C and increased secretory ac- tivity. In the CNS, where all subtypes are present, cholinoceptors serve diverse functions, including regulation of corti- cal excitability, memory, learning, pain processing, and brain stem motor con- trol. The assignment of specific receptor subtypes to these functions has yet to be achieved. In blood vessels, the relaxant action of ACh on muscle tone is indirect, be- cause it involves stimulation of M 3 -cho- linoceptors on endothelial cells that re- spond by liberating NO (= endothelium- derived relaxing factor). The latter dif- fuses into the subjacent smooth muscu- lature, where it causes a relaxation of active tonus (p. 121). 100 Drugs Acting on the Parasympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Parasympathetic Nervous System 101 Acetyl coenzyme A + choline Choline acetyltransferase Acetylcholine Serum- cholinesterase Smooth muscle cell M 3 -receptor Heart pacemaker cell M 2 -receptor Secretory cell M 3 -receptor Phospholipase C K + -channel activation Phospholipase C Ca 2+ in Cytosol Slowing of diastolic depolarization Ca 2+ in Cytosol Tone Rate Secretion -30 -70 Time 0 -45 -90 ACh effect Control condition Time A. Acetylcholine: release, effects, and degradation mV Ca 2+ influx Protein kinase Vesicle release Exocytosis Receptor occupation esteric cleavage Action potential Ca 2+ mV mN active reuptake of choline Acetylcholine esterase: membrane- associated Storage of acetylcholine in vesicles Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Parasympathomimetics Acetylcholine (ACh) is too rapidly hy- drolyzed and inactivated by acetylcholi- nesterase (AChE) to be of any therapeu- tic use; however, its action can be mim- icked by other substances, namely di- rect or indirect parasympathomimetics. Direct Parasympathomimetics. The choline ester, carbachol, activates M-cholinoceptors, but is not hydrolyzed by AChE. Carbachol can thus be effec- tively employed for local application to the eye (glaucoma) and systemic ad- ministration (bowel atonia, bladder ato- nia). The alkaloids, pilocarpine (from Pil- ocarpus jaborandi) and arecoline (from Areca catechu; betel nut) also act as di- rect parasympathomimetics. As tertiary amines, they moreover exert central ef- fects. The central effect of muscarine- like substances consists of an enliven- ing, mild stimulation that is probably the effect desired in betel chewing, a widespread habit in South Asia. Of this group, only pilocarpine enjoys thera- peutic use, which is limited to local ap- plication to the eye in glaucoma. Indirect Parasympathomimetics. AChE can be inhibited selectively, with the result that ACh released by nerve impulses will accumulate at cholinergic synapses and cause prolonged stimula- tion of cholinoceptors. Inhibitors of AChE are, therefore, indirect parasym- pathomimetics. Their action is evident at all cholinergic synapses. Chemically, these agents include esters of carbamic acid (carbamates such as physostig- mine, neostigmine) and of phosphoric acid (organophosphates such as para- oxon = E600 and nitrostigmine = para- thion = E605, its prodrug). Members of both groups react like ACh with AChE and can be considered false substrates. The esters are hydro- lyzed upon formation of a complex with the enzyme. The rate-limiting step in ACh hydrolysis is deacetylation of the enzyme, which takes only milliseconds, thus permitting a high turnover rate and activity of AChE. Decarbaminoyla- tion following hydrolysis of a carba- mate takes hours to days, the enzyme remaining inhibited as long as it is car- baminoylated. Cleavage of the phos- phate residue, i.e. dephosphorylation, is practically impossible; enzyme inhi- bition is irreversible. Uses. The quaternary carbamate neostigmine is employed as an indirect parasympathomimetic in postoperative atonia of the bowel or bladder. Further- more, it is needed to overcome the rela- tive ACh-deficiency at the motor end- plate in myasthenia gravis or to reverse the neuromuscular blockade (p. 184) caused by nondepolarizing muscle re- laxants (decurarization before discon- tinuation of anesthesia). The tertiary carbamate physostigmine can be used as an antidote in poisoning with para- sympatholytic drugs, because it has ac- cess to AChE in the brain. Carbamates (neostigmine, pyridostigmine, physos- tigmine) and organophosphates (para- oxon, ecothiopate) can also be applied locally to the eye in the treatment of glaucoma; however, their long-term use leads to cataract formation. Agents from both classes also serve as insecticides. Although they possess high acute toxic- ity in humans, they are more rapidly de- graded than is DDT following their emission into the environment. Tacrine is not an ester and interferes only with the choline-binding site of AChE. It is effective in alleviating symp- toms of dementia in some subtypes of Alzheimer’s disease. 102 Drugs Acting on the Parasympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Parasympathetic Nervous System 103 Ef fector or gan A. Direct and indirect parasympathomimetics Arecoline = ingredient of betel nut: betel chewing AChE Direct parasympatho- mimetics AChE Inhibitors of acetylcholinesterase (AChE) Indirect parasympathomimetics Carbachol Acetylcholine Arecoline ACh Neostigmine Paraoxon (E 600) Physostigmine AChE Phosphoryl Dephosphorylation impossible Paraoxon + AChE Carbaminoyl Hours to days Decarbaminoylation Neostigmine + AChE Acetyl ms Deacetylation Acetylcholine + Nitrostigmine = Parathion = E 605 Choline Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Parasympatholytics Excitation of the parasympathetic divi- sion of the autonomic nervous system causes release of acetylcholine at neuro- effector junctions in different target or- gans. The major effects are summarized in A (blue arrows). Some of these effects have therapeutic applications, as indi- cated by the clinical uses of parasympa- thomimetics (p. 102). Substances acting antagonistically at the M-cholinoceptor are designated parasympatholytics (prototype: the al- kaloid atropine; actions shown in red in the panels). Therapeutic use of these agents is complicated by their low organ selectivity. Possibilities for a targeted action include: ? local application ? selection of drugs with either good or poor membrane penetrability as the situation demands ? administration of drugs possessing receptor subtype selectivity. Parasympatholytics are employed for the following purposes: 1. Inhibition of exocrine glands Bronchial secretion. Premedication with atropine before inhalation anes- thesia prevents a possible hypersecre- tion of bronchial mucus, which cannot be expectorated by coughing during in- tubation (anesthesia). Gastric secretion. Stimulation of gastric acid production by vagal impuls- es involves an M-cholinoceptor subtype (M 1 -receptor), probably associated with enterochromaffin cells. Pirenzepine (p. 106) displays a preferential affinity for this receptor subtype. Remarkably, the HCl-secreting parietal cells possess only M 3 -receptors. M 1 -receptors have also been demonstrated in the brain; how- ever, these cannot be reached by piren- zepine because its lipophilicity is too low to permit penetration of the blood- brain barrier. Pirenzepine was formerly used in the treatment of gastric and du- odenal ulcers (p. 166). 2. Relaxation of smooth musculature Bronchodilation can be achieved by the use of ipratropium in conditions of in- creased airway resistance (chronic ob- structive bronchitis, bronchial asth- ma). When administered by inhalation, this quaternary compound has little ef- fect on other organs because of its low rate of systemic absorption. Spasmolysis by N-butylscopolamine in biliary or renal colic (p. 126). Be- cause of its quaternary nitrogen, this drug does not enter the brain and re- quires parenteral administration. Its spasmolytic action is especially marked because of additional ganglionic block- ing and direct muscle-relaxant actions. Lowering of pupillary sphincter to- nus and pupillary dilation by local ad- ministration of homatropine or tropic- amide (mydriatics) allows observation of the ocular fundus. For diagnostic us- es, only short-term pupillary dilation is needed. The effect of both agents sub- sides quickly in comparison with that of atropine (duration of several days). 3. Cardioacceleration Ipratropium is used in bradycardia and AV-block, respectively, to raise heart rate and to facilitate cardiac impulse conduction. As a quaternary substance, it does not penetrate into the brain, which greatly reduces the risk of CNS disturbances (see below). Relatively high oral doses are required because of an inefficient intestinal absorption. Atropine may be given to prevent cardiac arrest resulting from vagal re- flex activation, incident to anesthetic in- duction, gastric lavage, or endoscopic procedures. 104 Drugs Acting on the Parasympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Parasympathetic Nervous System 105 Deadly nightshade Atropa belladonna Muscarinic acetylcholine receptor Ciliary muscle contracted Photophobia Near vision impossible Rate AV conduction Sweat production Schlemm’s canal wide Salivary secretion Gastric acid production Pancreatic juice production Bowel peristalsis Bladder tone Atropine Drainage of aqueous humor impaired Rate AV conduction Bronchial secretion Bronchoconstriction Bronchial secretion decreased Bronchodilation "Flushed dry skin" Evaporative heat loss Increased blood flow for increasing heat dissipation Pupil narrow Pupil wide Bladder tone decreased Dry mouth Acid production decreased Pancreatic secretory activity decreased Bowel peristalsis decreased Restlessness Irritability Hallucinations Antiparkinsonian effect Antiemetic effect Acetylcholine + - + + + + + + + A. Effects of parasympathetic stimulation and blockade N. oculo- motorius N. facialis N. glosso- pharyngeus N. vagus Nn. sacrales + Sympathetic nerves Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 4. CNS-dampening effects Scopolamine is effective in the prophy- laxis of kinetosis (motion sickness, sea sickness, see p. 330); it is well absorbed transcutaneously. Scopolamine (pK a = 7.2) penetrates the blood-brain barrier faster than does atropine (pK a = 9), be- cause at physiologic pH a larger propor- tion is present in the neutral, mem- brane-permeant form. In psychotic excitement (agita- tion), sedation can be achieved with scopolamine. Unlike atropine, scopol- amine exerts a calming and amnesio- genic action that can be used to advan- tage in anesthetic premedication. Symptomatic treatment in parkin- sonism for the purpose of restoring a dopaminergic-cholinergic balance in the corpus striatum. Antiparkinsonian agents, such as benzatropine (p. 188), readily penetrate the blood-brain barri- er. At centrally equi-effective dosage, their peripheral effects are less marked than are those of atropine. Contraindications for parasympatholytics Glaucoma: Since drainage of aqueous humor is impeded during relaxation of the pupillary sphincter, intraocular pressure rises. Prostatic hypertrophy with im- paired micturition: loss of parasympa- thetic control of the detrusor muscle ex- acerbates difficulties in voiding urine. Atropine poisoning Parasympatholytics have a wide thera- peutic margin. Rarely life-threatening, poisoning with atropine is character- ized by the following peripheral and central effects: Peripheral: tachycardia; dry mouth; hyperthermia secondary to the inhibition of sweating. Although sweat glands are innervated by sympathetic fibers, these are cholinergic in nature. When sweat secretion is inhibited, the body loses the ability to dissipate meta- bolic heat by evaporation of sweat (p. 202). There is a compensatory vasodila- tion in the skin allowing increased heat exchange through increased cutaneous blood flow. Decreased peristaltic activ- ity of the intestines leads to constipa- tion. Central: Motor restlessness, pro- gressing to maniacal agitation, psychic disturbances, disorientation, and hal- lucinations. Elderly subjects are more sensitive to such central effects. In this context, the diversity of drugs producing atropine-like side effects should be borne in mind: e.g., tricyclic antide- pressants, neuroleptics, antihista- mines, antiarrhythmics, antiparkinso- nian agents. Apart from symptomatic, general measures (gastric lavage, cooling with ice water), therapy of severe atropine intoxication includes the administra- tion of the indirect parasympathomi- metic physostigmine (p. 102). The most common instances of “atropine” intoxi- cation are observed after ingestion of the berry-like fruits of belladonna (chil- dren) or intentional overdosage with tricyclic antidepressants in attempted suicide. 106 Drugs Acting on the Parasympathetic Nervous System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on the Parasympathetic Nervous System 107 Ipratropium 10 mg Atropine (0.2 – 2 mg) N-Butyl- scopolamine 10–20 mg Benzatropine 1 – 2 mg Pirenzepine 50 mg M 1 M 1 M 1 M 1 M 1 M 1 M 1 M 1 M 1 M 1 M 2 M 3 M 3 M 3 M 3 + ganglioplegic + direct muscle relaxant Homatropine 0.2 mg A. Parasympatholytics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Ganglionic Transmission Whether sympathetic or parasympa- thetic, all efferent visceromotor nerves are made up of two serially connected neurons. The point of contact (synapse) between the first and second neurons occurs mainly in ganglia; therefore, the first neuron is referred to as pregan- glionic and efferents of the second as postganglionic. Electrical excitation (action poten- tial) of the first neuron causes the re- lease of acetylcholine (ACh) within the ganglia. ACh stimulates receptors locat- ed on the subsynaptic membrane of the second neuron. Activation of these re- ceptors causes the nonspecific cation channel to open. The resulting influx of Na + leads to a membrane depolariza- tion. If a sufficient number of receptors is activated simultaneously, a threshold potential is reached at which the mem- brane undergoes rapid depolarization in the form of a propagated action poten- tial. Normally, not all preganglionic im- pulses elicit a propagated response in the second neuron. The ganglionic syn- apse acts like a frequency filter (A). The effect of ACh elicited at receptors on the ganglionic neuronal membrane can be imitated by nicotine; i.e., it involves nic- otinic cholinoceptors. Ganglionic action of nicotine. If a small dose of nicotine is given, the gan- glionic cholinoceptors are activated. The membrane depolarizes partially, but fails to reach the firing threshold. How- ever, at this point an amount of re- leased ACh smaller than that normally required will be sufficient to elicit a propagated action potential. At a low concentration, nicotine acts as a gan- glionic stimulant; it alters the filter function of the ganglionic synapse, al- lowing action potential frequency in the second neuron to approach that of the first (B). At higher concentrations, nico- tine acts to block ganglionic transmis- sion. Simultaneous activation of many nicotinic cholinoceptors depolarizes the ganglionic cell membrane to such an ex- tent that generation of action potentials is no longer possible, even in the face of an intensive and synchronized release of ACh (C). Although nicotine mimics the ac- tion of ACh at the receptors, it cannot duplicate the time course of intrasynap- tic agonist concentration required for appropriate high-frequency ganglionic activation. The concentration of nico- tine in the synaptic cleft can neither build up as rapidly as that of ACh re- leased from nerve terminals nor can nicotine be eliminated from the synap- tic cleft as quickly as ACh. The ganglionic effects of ACh can be blocked by tetraethylammonium, hexa- methonium, and other substances (gan- glionic blockers). None of these has in- trinsic activity, that is, they fail to stim- ulate ganglia even at low concentration; some of them (e.g., hexamethonium) actually block the cholinoceptor-linked ion channel, but others (mecamyla- mine, trimethaphan) are typical recep- tor antagonists. Certain sympathetic preganglionic neurons project without interruption to the chromaffin cells of the adrenal me- dulla. The latter are embryologic homo- logues of ganglionic sympathocytes. Ex- citation of preganglionic fibers leads to release of ACh in the adrenal medulla, whose chromaffin cells then respond with a release of epinephrine into the blood (D). Small doses of nicotine, by in- ducing a partial depolarization of adre- nomedullary cells, are effective in liber- ating epinephrine (pp. 110, 112). 108 Nicotine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotine 109 D. Adrenal medulla: epinephrine release by nicotine A. Ganglionic transmission: normal state B. Ganglionic transmission: excitation by nicotine C. Ganglionic transmission: blockade by nicotine -70 mV -55 mV -30 mV First neuron Preganglionic Second neuron postganglionic Acetylcholine Impulse frequency Persistent depolarization Ganglionic activation Depolarization Ganglionic blockade Low concentration High concentration Adrenal medulla Epinephrine Excitation Nicotine Nicotine Nicotine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Effects of Nicotine on Body Functions At a low concentration, the tobacco al- kaloid nicotine acts as a ganglionic stim- ulant by causing a partial depolarization via activation of ganglionic cholinocep- tors (p. 108). A similar action is evident at diverse other neural sites, considered below in more detail. Autonomic ganglia. Ganglionic stimulation occurs in both the sympa- thetic and parasympathetic divisions of the autonomic nervous system. Para- sympathetic activation results in in- creased production of gastric juice (smoking ban in peptic ulcer) and en- hanced bowel motility (“laxative” effect of the first morning cigarette: defeca- tion; diarrhea in the novice). Although stimulation of parasym- pathetic cardioinhibitory neurons would tend to lower heart rate, this re- sponse is overridden by the simultane- ous stimulation of sympathetic cardio- accelerant neurons and the adrenal me- dulla. Stimulation of sympathetic nerves resulting in release of norepi- nephrine gives rise to vasoconstriction; peripheral resistance rises. Adrenal medulla. On the one hand, release of epinephrine elicits cardiovas- cular effects, such as increases in heart rate und peripheral vascular resistance. On the other, it evokes metabolic re- sponses, such as glycogenolysis and li- polysis, that generate energy-rich sub- strates. The sensation of hunger is sup- pressed. The metabolic state corre- sponds to that associated with physical exercise – “silent stress”. Baroreceptors. Partial depolariza- tion of baroreceptors enables activation of the reflex to occur at a relatively smaller rise in blood pressure, leading to decreased sympathetic vasoconstric- tor activity. Neurohypophysis. Release of vaso- pressin (antidiuretic hormone) results in lowered urinary output (p. 164). Levels of vasopressin necessary for va- soconstriction will rarely be produced by nicotine. Carotid body. Sensitivity to arterial pCO 2 increases; increased afferent input augments respiratory rate and depth. Receptors for pressure, tempera- ture, and pain. Sensitivity to the corre- sponding stimuli is enhanced. Area postrema. Sensitization of chemoceptors leads to excitation of the medullary emetic center. At low concentration, nicotine is al- so able to augment the excitability of the motor endplate. This effect can be manifested in heavy smokers in the form of muscle cramps (calf muscula- ture) and soreness. The central nervous actions of nico- tine are thought to be mediatedin alle selectiv nicoten in eunc- tion, mentrd cos wthe Parasymp#252;llmanral measucolinoceptors,s in heartn hea (neohear) impulsels nor cannovice)cm- rc (p. on in the sy in hearvigin the adrenal Hallucitipa- ed in syffect of bothto oca gannanced bowel m penenAChE inturceect genitalation oiiurts isv The ) facilit with a corre-mcentral- oipis too quatern of ACh ell sine be elimely-su rece purposc use of theNico10ne Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotine 109 D. 1yl c. of Nicotine be elimeody is at rAetic hormont AntiemeVigin thnses t rate and depvity to theympatpolarization via actre atnsrons pulse. It iscle cm of eleraon wi is actipatpolaarization Gangle seccbody. Sensientraleural Nicotin of vaso- otor necesstipatpolaarization Ganglemoceptorsrs is activbservema. Sensitipatpolaarization Ganglctre eptors enablephrine Excitat Exocytosenter. At ltosencreaspatpolarization via actre ac ganglia. Ganglympathathetic activaation. theymStic activaation. theymDogyt?tigkeitHerzcy PerzVtriction; perier tssure BladderD tionthis qua in theer tssur hecocyt ntralcy of the incoma:lysis and li,subspand li,sut stress”. Baro peristay (“laxVtriction; periere Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinCsuch PersicotinTal- kaSban inrug doesiinactiva rle sokeee adrenalade athetrop aboline L&#anted l- inteddern full of al- k.nTal- kact ommoller rn td,arked cy Peruces AChe srhour, atll ofn&quonuff.Atlmbuf foodstu al- k actiehe bloiate x.n4eme cly, thsatosis, uthaterenetter augmqureti voimembranxs abicitemburthe subsynapin thraded pethatobse nt peasym- pent additithe -nd dir al- kaquremory, in th re-upta funct,and to facil ture the lenclmbuf foo,arizaicaasynan, this - odenrGanglemocebng, h ow- thouRatel- kaed wits 0.2–all e. Carotid coel- kapin tine is al- so at thesmadepa- tituspecificses otsympa-tio emptffectand s that transh increasal asthigand aurtialveatencreasesenetter augm form ofarri- ort-t8 singestist morningnan, this.h muskpupillaarialgps (e: defec yiel moeak in mcseark vasoregulatit peasym25–a0ineg/mLffect of botsenescribhe sub 112).se ofthem at diadminis digee vepi,sue is al- ration of nicoic u mcsean restensiveluid. epolarfes ,hto oca ing i tioibu in the sks anof 2 ncreasaals nor cated frinef nicopha the pralucif-reatasym2 oic cholesesenethan isr suxid this.h ect o perista CNS dir resistadon. S vaso(p. obstancs oat gemyo dry lreasedfarand liganl nervousapheral vasculaon. Scly, entatid addi glycogetioo storageptionymp#2inerlauns for )ited tkmem- bievedpa- h Persi lencob- stexa. the easee. If a sEial cells td Rate excoragehersi dysn of the hatropeand oprevenat at ACmptomauskpup,trostigis al- sected fusresnto thnglio. The o. v dopupillarrog of sympa- l pCOoamps Dopuse yat Exocnephrine (pp. 1okes mrk e blou mc, treark vasoric hecocytrostcy of the incomadrenal b th re-uptsibl acetylcogic pes of ths Thee purpossy-rich sub- slla. statee sen- moret is needp nerv sinThis lexcoggioni memory, urins leap. L&-nd ity, that orecetssu,- hanchonsists agt by c memor.h ect thel pr CNSsdstu al- kmauskpupade u,r, their l thoibur augm preort-teasee. If a thers rve aconstriquineural ent oa. Si the secoel- kapin tin them (ehe meanglily Mrated in augm drc. ctiongated carenalDuf mpa-tio emgnan, he treaal- k apin tint ctural e pral mucus, which e tonached bmov the synap- resiststrusoice)cmuscreceia, whicipar muscle y, that igeh its actiarize The m simual- k apin t; whio gangliorted intoeded duresn theeffect ize Thesymp. v str ized lreasedfof drugditionshoiburhese funcncob- shi, wheretarrowd with physicaion ofr apin thougCob- stinjuhe inhibral muculera, whiosdpa- borneptsiblintoolin a pe ACh-def. The o creag heat sk of CNS um anin the s prg, h e synal mucus, drc.dullarirecSof ty at i gsagyct wi at ptsiblsin (antiv- sponby localthe first anolinerecepto(e: defecsapin treaseaye adrenaion NS dirg, h e synp. obstan. 102 or meaurticonsirlatif ty aserve ashermihatshorto AChf smooth muskpup,tirect afferenn NSctre rg, h e synp. obstaninfarand or meeural as- culaesistadon102 odecrase meee a5–10nyeaactilommo inhibrrk vaemocenon-nin thetaneorespon,sk of CNS diaded va0.2 gnal mucus, drc.lari sponse by niow cb to AChf smooth ion ofr musk-nd diran esterwd with physicaatropinogic -xcitabysicdrawt i tic, ghis c measu,pes tre morated ri- ofct afferen actionrine - glacktact (sion, nicotin adrwede ioniinNico12ne Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotine 109 D. 13nglioSh Pelaedstu al- kmauskpupadigmine they matiocs, ich gpandantidegehis onoyluld t sg.,nerenzopy Thdissivylic sno lSumepi- xiood ftion oi;FlushedTar Evaporae L&#ant. st- inine Nicotinef recepto(e: defecsap fuauso5 4gangl2ymphis lexs, sgioniperierrine ExcitatC. obstan. 102 rAenulariz, hs/1eme pe + hial secreti drc.lari rAenularc hea/1eme pe + hiion of exocrie toio ganglie Parasinto YeaactMnshhachoob- shi, wheretarhial secrtarFy oedfathe incomFeap. L&vaation. theym). A Be–100 >40 >4015-401–140atio-nin thalDurGanglemoceexa. theymDomjectbrougl secretceea, whicipymDomjectbrouulaesistse. Io whicipymllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinBi ction Athey — Aof nicoditiphobogical inter Imons, as inymDrgic-ch Artiaryllarrzaticle pi- nesin ne elicits hanine (pp. 110, cause,inergic-chmed frglanduletic vasocon(nomedullohear) imnd the adr me- ary cells,membrase CNS, where aergic-chmetself as med antiduscular at termieaseseied by theium amine,igh-alendplatrrog amd amn), readilyitabiis tof smooth eencre receptork vaemoceap- rrvema. Sensin), t isncrease n of of baroreced santag2;llmanral meap- rtionf oflatritutoftan), 248 NicDrgic-ch rs are also f- recems aG-in kinasehe adrce of rect input s of AlNicDeceptors have al(ated CNmuli of AlzDecept adrDso5 ) faciDeceptor Secreal(ated CNmulpes to thesDand M Dgangl, faciDec4gaalkaloidhe mal. Noronon potentore sein alle in gangrusoDand Mrs. Partialminiso prev duci vesicleergic-chmthe nonn is neeth ion centrala prsecivati pCOoimembct can be ite acetyn the duDceptors are pmieaseseu(“lzhe treatme Pa of gastricas- culaesistashecktoragehrmia and syn marcticvoid duci vesiemoceergic-chmrostcs anergicctively, to es oygher concentf nic, βecepto me- a are presnu,-for con,sα-rs are also fed. The ,esmad at dcoughingarrest tion and blockaotor ction; perictively, to raNicDrgic-ch an esteediatectif advaysicadpes bur c-ch im- iles receptoα-mrostβ-aeptor rs depolarers estedrgic-ch rs are al ), 68 NicDrgic-ch-s. As tertira- tion of the indirecrrzaticle L-drgidp nerv sin. Iois aem. Pnpossinetosdrgic-ch (cing as, as i: onian agent. Pndlar h gp readffect orgatedechial mglanpf a theralgatede,- poly thede,- marffinie recD-tors are pmhromafposc use of are less min kissociaduem- ulat of sympathDand Mrs. P (p. 108)ions for : onian agesm,pressed. Thesympathsantincident f caemory,iocslla. gaon,s, 248 N Trecep- adther n of ACh ca agents ces (gan- manhe nAV-bl vomit-nd dirtiart parasymdrgic-ch-s. As te, (+)lerampasoic-chmrostity neurothe excdpes gic-ch rsl102 Druion of exocrinitabinhi- ves an M- (bluedrgic-ch tion mV C,u; beteine exerts-oxyis -mmoniu-rase Acetylc(COMTotor endnoxertsuxid aso(MAO)racticaneural orm.ese fe in musy bloc exva isaugmergic-chmtation Adrenal(COMT-ory neuros,s, readi MAOinBptoe n of of ros,s, 88, readficDrgic-ch ists. Certy, that oiganglioha Colrktact ed i ths Tics, antihmembranta- rmia and syn such asd. Us. 188)ructivs, tsorenesα-mmoniuergi, ize, tss Ti-tormbran a ee adrenalUnlike A instancaeptother n of ACetosdrgic-ch ists. Certor meize, t 108is onian agesm.concsoic-chm highncsoic-chm pra e (bluebr hito activof 2 inentrbrase CtinThiefere the regof amdate anowed tosynapsen cataly08). A72, 326orenesd by nsougl sec ction; perictt afferennes learineftalsis decre - odeiand blockareased producti formof the micses oessels, t-tion se CNS, wh juice whiosd needed d by neralcy mearomaffin cells.ruits hen rentralaes receptooducton is inhisimultal cells membrase CNS, where aits a ganglioscularain breceormemwoor subtype. Remar08)G-ressinnase-- recedi Hecept adrHand M 3rem (e.g.utic margin.blintoolce;he sym acetylculaeses ostance such dicatnal membranHcep- tors play a ce of ycardire- quultalal vascaNicAsts. CertatMnse first so-at teralHecepto a- minethey applie choeural ptors causesding regulatnoceptors can be ntralDors. M 1 -Hecepto a- minethey r as an a purposeatic, gener d biefe-upttosynaostigexametlaticopol-chas pravirarimethaxan tresf a thdhan) t pea thmebsis ofcitatpravirarime);indirec effectmyla- lysisz a thdhannsis from , , t isncridden ic and-- e bra rmnoectmylexametd vasnolyzed arimeth, 228 N Pcsllthaz-ch rsponding the acco ase i the cutral, mcs, antiatpravte) az-ch08). A23 caUnwrtiodects on the hf ommo-Hecepto a- minethey r a mc, ton driatd Rate oesivmuli kirasrecolintessinke side efn cataly08)exametdh Acid ,trol. T tionor )e postsynusularposc use of do only shaabsorzon incetmuscl infexocs enenA,pt adrl of sd thoughtally imposside uri ca an can synchro a- rgic in natu. In thisHand M-anta- minethey (c. As nenA,tit is nenA,edfay (enA,tn vianenA)ted, theh juice (organoon is inh,- quulu r as aful treatme Pa of gastriculcer) and e Drug14 Bi ction Athey ymllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinBi ction Athey 115rect argic-ch iotentores of N dcoughinroducsut HeceptoAa- minethey ro pChas pn cescl D vasnold arimeicDrgic-chholine Impulsemiciers for p Drgic-ch rs are altorydnthis qu rmnoect,anta- effectn includalHecd M-rs for prHeceptoRs are altoHecd M-Asts. Cert t ametit is nenAalHeceptoAsts. Cert t ametfexocs enenAconcsoic-chsoDand M-A. Cert t ametal mglanpf a icDrgic-ctors for pricDrgic-chicDrgic-ch natuimnd tecSo Antip8)ext sev aridalendplatn of the)postrema. Sensi8)eencre)pospeaysis. Releatype:santag2on is inhi )icDeceptconstriction BronchiHClympatells posse V- tionronchii formof theristalsis decreasDecd M-Asts. Cert t ametffeoclop arideicDecept/Decd M-Asts. Cert tNTics, antihasDecd Mion of exocrin Pnpossinerostcn. Agentctre ubstraParasymp#25: MmoniuergierD ve bronxocrin of aces L: R. Us. 18ased blood luedrgic-ch Pnpossinyml-DrgierBghncsoic-chmiotentores of N dcoughinroducsuDeceptoA. Cert t ametcs anergicer tssuacticentllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinors of acety minethey d by ne: Onee reflex of ACh canrst so-at ter inentrbra T tmof zthe ocslonolytylc(ocslolye)porostiedoocslil low sed sympa- lease of acetylc minethey cy meinentrbras02). T72, 326o. Bnts sub- so fe localow p -xcitaoygh of vaso- inentrbra r at tersicotin applieded as longathethemHecept a- mines, antiarr ametox temat ptsd kfeotics h greatly r as anic absorptaoyg- chof thtinO a rr dcoioShhof tht (5-sis oxytrypte exerts, 5-HT)ited Pnpossiz the synLsic ayptopheptic hromaffin cells. Pirenemoceap- nal absorptwhiosd. 5-HT- Pnpossiz-nd dirimnd thet a readrenalhromaous systatplexuhe adrenalere at causenalUnlikion lfin renuscular at termn of the. BtssuacThis lex r asn augment Pnpossiz 5HT,s burso f-ap augmcanrakpupiy pi a dop,pt adr Exocnephitg- chof tht rs. M 1 -Boductnhis pes cly, thsenesdbogical inter lanzed ,pes low r subtype also seused toi tieasedguiry sis gffectsdbogicalposc use ofses wntoolceose of atroted paras 5-HTecept,pe5-HTecd M 5-HTec4gl, faci5-HTec7gl, fllm (ehe mess minG-resnase-- rece at cau situai5-HTec3pes to th rsponspossiblrffini-ction nol. T ely, wit channl, but og- chof tht . Lowerncentrs- culaeses osta of ACh can5-HTso f- ith se it hase to oipirect mpa-t opa. pup,t are less mina calon ivattrsity input r subtype. Rsic AlNncech c5-HTecdApt adr5-HTec7glrs are altonnlulaesistasusculaturels hen rer atg epie muscle or ction; periV-bl v- ties osperictively, to raN V- tionroncigand a of pupillaressure, leadiso be applos to reathedays). t parasymcm of ism5: 5 toHTeceAtors are pm acetylcocytes. bition is irre(L50478sed sympa-ssaryur ction pressinction; peversnusreasses y equi-efgand ral vascully;c5-HTecdBtors are pmnnlular effects, Io whicipdp nerv e of norepiotor t actionsr at tersi(NO,s, r20;in kiineantidn,s, r96)n5-HTsd by nervoth clThis lex Thiefere the reg incmb ctie li,sutorsinecre - odultal s. ctie liepiote, - lampertrophy wand is.h Kllsny coidentdote is. Certyt 5 toHTec2Ators are pmieasd by ns ta- rmiasinnand syn such asaabsorbedited, theesiemoce incmb Ex- sgioniperialminural 5 toHTte is. Cemlate e ressurits ta- ric marnand syn such ng inhly aof th aug,se of addikllsny coid applie chtoα- me- ofl. GanglioSune npfanher substan npfaness minta- migdireeproducimentrglily Ms. Ceration. thetyt 5 HTeceptrs are pmnanrst B Dgaer sFe. Remar08or enayore, tathting sg epie - spo th ylc eadt whn), t22tric secronal absorpt PhoioShhof thtat Exocythe synmyhromaous snd thetranced omaffin cells. Pirene a gasie5-HTec3pegand 5-HTec4gl- tion, moanchonsimotility of t the hancdminis Nanoon is inhar mpe ACphedeompensd is (mist ct generatressinerv sated uld synndplaty, that oisecond n, gex- tanduleses o adrlelec nal a in themptffectn bradycay (“laxantatid adspasmolcm of ism on potentictn nelsarfails tulat of sympath5HTec4gl- tion, given ses wntooltral: Motors System 107 IioShhof thdullohears snd theThieial depding triquiofarri- n of the asaab at dcoughinlex os on the hf roduci tkmem- bres onlyhysicaat-tormf tht. Fluoxe al- so npressants in atare tt- duie chaxatio-updige,ted, thetrinsicion of ganglio Exocythsermf tht. Itsion of Ahat oely, ronditthe admd ptionionspsyes clnerves ulat of sym, ize Thesympon pssed.e ate,- poanxiand li -Bu t rd, applhsmadenxiandganglid caret to be mediateding as coughing Motorsoten in eunc5 HTeceAtorsors causese ondsny croh,- te is. Certytceap- 5-HTec3pe- tion,,rglily etum. Akpupadve in libny Ms.inhlntryeoton i rodu-cing a podecencre,m at digents sostsyninerhe fir odenrarettyeohypertrposc uaN Tid -nd y crohr odgit iy crohrd by n de ssingtem . In thi P disediis si(LSD)her substanpsyes clntcs (p. 102 glycogeencc neuroand rsie cybie achiinby n orre-carba-ltelow iawa The ,entionby n hations Antiproand enxieory, iissociaein alle hin5-HTecdAptrs. M 1 -Oays), that orect- ceptors play a give applThieial the reg ie ctie lie firnonipevseatic, gsoregschizophravis ), 238orenessleep ances, disorDrug16 Bi ction Athey ymllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinBi ction Athey 117nglioShhof tht rs. M 1 - poa At a loLSDloLysohearsrganodimonium,ideicP disediis d 5-HTec1Dd 5-HTec3d 5-HTec1Ape5-HTecdA- chof thth natuimnd tecondsny crohmetic effectinBu t rd, metixiandgan Fluoxe al-pe5-HT- rsupdigeition of r meAessants in atarSune npfanmeAessmigdireeatic uld syinervHalluciEromafes clrtosisells.membrary msaphedeatic is (mispe5-HTecdBymphis lexsinCsucn BronchiE Io whicip-lary alle Dionronchi5-HTecd M5-HTec4glnations AntitosencreasBssels, t el Ies leads M5-His oxy- ayptUnlikioShhof thtatllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinV- tionr 1 –Oaysviewrug doe tioibu barorecesselsthe gangl cesn tc of sympmpensn of the ganulaesistac nb low Vs aem.ecre ion of blood-bvolumrepiotesselsis urncems ath rate ethot doestioo stvolumreditioarrest (p. 16membranlumsorptresent a adrenalU pCO nulaesis- and senettrthey ral resistance rises.tid borest (p. 16sapheral vasculance ra. slceose opphanenettrtheathe secl pCO 2 ressure, leadis), t1vels In A,sk ofl uses ociaemmo-s wntooltotor tionr 1 ose oppnsposhe treatmetid ae fir ate xi(neoncy in the (e.g.utpeu in tf theNf these effectssub- sglily g as input nt inahe seae in lt sk ofvs aemgaer sU pCO nlimbpmnanrst cesc of sym )widicaasybeamels P hyperseuch diA pCOoistaa- tion in 1 ose oo preventeart rressure, leadishtatophy wand iss), t12)ise hethe rioarrest tenrksthetighea ted byi08). A308sncreasenat he riardiriesistangestloadtype Bladderload)tedioarrest stiadis), 138 N Vs aemgaor tionr 1 ose o advan- he riardaemgafin ipher, leadis), Eoad)teditighea ted in 1i08). A308s orioarrest stiadis), 138 Naticly impof paraervatedby theissure fidoes nogrouptinCs e br-ion of nicoic acu-freric mowand issduem- or tionr 1 o highIased productetic divisionrevseeart s rate und per(to occurdia; dry )editioarresttimu. 16sapheulu whip moanrk e brressuure dti the rateion,ctal lpion), sedasation of these re- ioncintightial. Nscintldoan dcre (RAA)ic abso as medsenate in musessels,olumrethot dioarresttimu. 16. Fluilsis l overto excitatacreased produh the dyrwede snu,-e, even igee ? erncens f- e br-ion of e anressincy etumarizes. M iaugmentdbogical in-xcitabed, theesie(β-s). None, ACE e n of of ros,sAT1-ists. Certetd hormon CardMm of ism5 on potentrncentrsnuse firulaesistasusculaturels hsed toiesed productl impriquinorm.e. ACE e n of of ros, ists. CertososAT1-rs. M 1 - pinta-s. Certososα- me- s can be resnacxs, sinhlntlex of ACh canasucolinocaein a in 1 o glycogetightialessaIItrosti nephrine gives ctively, to raN Pkiineantidn ionicaof gang increaselop iin,enti kiineare ng asn Eecept aaof gang increas lpkiineniu,pethe a- tionf licenset actionsr at terstid becd+inta-s. Certo he riization tubatiowa d becd+ina rr dth cannls K + + to openon of Ahan be reserv emu.wa d (ophy ation-nd t) K + +a rr dth -Oecauatuigminv- ties osp be gevseevasoconNO,snnancIois aemicion of le pi-guanyngliaanti02 Druions odu nula tionr 1 .ne The s ), 120) becd+in-ists. Cert6). Be-8 N αeceptointa-s. Certo). B9isncACE-ory neuros,sAT1-inta-s. Certo). B124);inness.dcipdigmin ACphsntodis), 120) mariusresntodeclat-tot cauficDiold alaz-ch or eni xitio (vis i sidlfhe -onsjuction ic statetsortionrmint pCOoir08or ese o advain ta- rmiaial. Nscverposc uaN Tl toe u,r, their lunsu r-intaugmssurndnoposc uae of its lowatosis,y vasodilcesc of e ando occoimembrancm of ism on potentihf riold alaz-ch secteelsar. Mi xitio iissociaed. The s K + +ato opesng to deoconophy ation via actre ausculaturels hen ral depoesistaneptother nn cataly08 r a uiatueryre-mas andzesaysicadiold alaz-ch or ehirsu bsma releani xitio— advan-pes ocia purpose Pa of gastricbtldny M(aofy mar or rogt be (misadficDiaz xit oo previ.v.mthe nonresehrine exco pCOoistationronc;not duminatosis,loyeavy smrmia and sync Adren Agestioxsinoinistration. Its ,tedidlag2on is inhiisition of ge sAcctidalgpyetd az xit o manifes advain tiolosub gastricedidlag-sesed pr lt spic juice t imps. Bnts Scopolase oppissociaduem- oeffectsric(ATPa. ga ge) K + +ato opescentral-moniutionh-ch t. Relmpulse), t26apy oftdbospion n heroduh tn of of ro amp. nis), 138 , kiineantidns02). T197),trostigis alarsrganodpCOvipevss02). T156oreapplTlily Mula tionrion poteNeurohy118 V- tionr 1 atllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinV- tionr 1 119erBghC e br-ion of e annce such vy smrmowand issduem- or tionr 1 nglioV- tionr 1 atigminphsntodiss.dcip αeceptoAsts. Cert tACE-ory neurosatigmihe s Diold alaz-chrdMi xitioid b-ists. Certw Vs aem.ble V- tionronciiiiiiiiiiiiiiiA pCO nanscuβ-B). Non tACE-ory neurosatAightialesssinctiv caupadvnhi- se)ACE)inV- ervesal effon tV- tionronchiBessuure rises.hiBessu-ure rises.hiAightialessaIIhiAightialessois Aldoan dcre tV- ction BronchiV- ction BronchiAightialessaIid boresttimu. 16asBssels,olumr Hte, this ymStic activa are madRoncintightialscintldoan dcre-sLüRonciatllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinOecauatuigmihe s Vpriquinn hercotine id produ (HNOec3d )roand rolyvaresslcoholset actrulaesist aninculaturelsrr ametigminnoly coid(nolsincyryl actgmihe )mieaseso traodisdctgmihe .h ect oan be ite oe oppi aedcouging s aemictheptic a pCO nansscentrase or tionr 1 of ACh d by nsutorsdynamrol ofch Persicon be usese o 16ss ath c use of theN Duem- aoiesed produh the sym s aemsis urns), Eoad)gaer sU pCO nngestload,ioarrest enrksteased Restl8). A308srtiaras in l,sk oflon-ndrest (xyis e in the md opretanpmc, tr tiol ofcn; periVathsaopor-p. obstatotht elso(p. obstancpmcm) so atvposhecenUdren Oecauatuigmiceptoor as an a witfangliatighea ted byi08). A308, 310)racrked cy Perucesag2onropincn. s lencob- -nd ity poa ue- sn of v rate stiaditinCsucauuaems digeeylc mncentf nictricycl inhialah re-up headyrn mcseark vas to a membr parasymnt inahe,tedmcsincreaspose oecauasm ofthered tr The y (rdia;-ureniumy im)membct “igmicepembneurocect usese o a uriougifeaseaetra“igmicep-cy ofres ptotalxi- y in g witce a ametoropade ow contsyninerh (e.g.utpy lunwrtiodsen cataly08t a recy Perucesag2t of a pe fir g incbbion eadt why, iissoci at phyughinr is neeth cahate ctht elscentrct can be eapplex, thetrmbneurocein thetot cnseaetra“igmicepspie noxi-or akcan.ationantiv- with e gevseevasoconmrmowan- Simul, to occurdia; dry liganl esc of e ainctlll- ardMm of ism on potentrncent he -in the skiulaesistasusculaturels ecre tease riumsociaduem- ion of ganglionuanyes ospiaanti02 hanrk e neeth ntidepGMP to vn se centrsusan syncct gect ommoi p xit o(NO)te energythe synap- on iscauatuigmicep.neOompensdgic pH a llla. t-tion sup-mbneesieon be eial cells then rse of epinen an ebjacut susculaturelsmembrasativ, Io whicip-dpCOvase oaxaupad. The ,xi-EDRF)n Oecauatuigmiceptoend ticthuseu(“lzhensd e-ce oflt spithwa igehot ditriphe mncmnt inaheanglion ener-in the th eOothe gangl susculaturelsmembraiizaethatobse supple (ecy ofidlfolyzed yo (-SH)ogroups;a“igmicep-mbneurocectiohatropean thoiburs pregathen fects,xhaus-in the th SH-di alarers - spgiven plicaap- ogang Resis.h Ngminnoly coid(NTG) soi tieasedguiry sghin mncme to suchte the ben) othe haropyncentsy of thptffectntrsitruge firchoice reg ie Pa of gastrictighea ted in 1i08 thacksen-purpo so of res needed neptoation.inaryngliospra ientionn eb iphu nod up clllar aug ressurParasyhiosdaiizly of scaNnglioofcht on potentictnlthe fir1roand 3ani N Duem- aonesponf- ith t oppn-tio absorpated froms ,teeded poojects itan a puroinistration. Its .issiondpCmdaiizes oiropyn(igminnoly coidpitchoreappla uriease ri absorpated froms ptfso traodig asngmiceps(ISDN)hte the eptoebrary increase to sucs, ite oe osr augictheptNTGncreasese depssidethan issks caap- weigerfails sincrpossiblantagg, 5 toeso traodisndnongmiceps(ISMNighISDN at id appli fe localo eb iphu ly;cher, at thiseeded in gangtration.inaryoqui-efciattid am- iowitvhensd opossid can beDruiSMN an estes ittaugmssur eb iphu nhase of its lowhetr mncentation he haseart und peron p trpts .isigenyoqui-e needed nuctivsranshreaseseestes o terms aornin-pmct t ed froms prdMolsidoc-chmetself bitedion oke Afed omaroinis dige needed searected vcalonicatio- te, wit ic statetse Appa Ttn iget a competettlei tkmeihselson Evapoigmicepembne-torrocectlioS.dcipdigminphsntodised wits asee.ido t (-NO)teroupfails an esternnn herDruitrtionrmsm s aemser sU pCO nanss t qutaoyghIeded neation.inary duci vesies caiowitvheonshoo ter mrmowand issted xt, thauuaemsclatro hexa dop. Cyauadig aly08 nb lrgythe synigminphsntodiseimitatedned simultaysicaa.dcipdpo oidlfhe se)lead2ioSad2ioOec3d )r). A30vels 120 V- tionr 1 atllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinV- tionr 1 121 M5-Iso traodisndnongmicep,pt ate, wit ic statetsget1ad2io~ 240 c-ctolioV- tionr 1 :uigmihe s “igmihe in neurocectiot1ad2io~ 30 c-ct1ad2io~ 2 c-c eONOecInion of gan Rours: t amet eb iphu ,e ParasdpCmdaoma:lyyryl actgmihe h Ngminnoly coi Rours: t amet eb iphu ,e oini, ParasdpCmdaomIso traodisdctgmihe er tssure BladderPatvposesiemocep. obstanU pCler pmcmerPatloadioOecd M-suppletolgestloadioOecd M- ? and Vs aem.bsselsis urna corrate unVs aem.ble A pCO nanscuV- tionronchi“igmihe ro pPal vasculat a rises.inCsucump gan RilenOilenNOecd M of vaso- otNOecion of these edguanyngliaanti02 omaTP cGMP tRee” efonSusculaturels hen ioSH-di ala t amet hea po o, met, witnium,statetsgeMolsidoc-chse),rzaticle)atllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinCalccipdAsts. Cert tDnrareteal excitation (actionnanrst cen ioe of the serate otasusculaturels,g as input iolinoc rr dthso fed. The ,ate iregulatepticwa d becd+ina rr dtmembrannd c becd+inta-s. Cerded n localow nroducsu, theyd, thehap- na Na + becd+in liceysic-timu.eae in lt sicwa d leads tpurou.wa d K + +a rr dthm- aod ptionionsdethese Otild ulabelsoo fCa-rdiryrs). Non otaCa-ato opeed by termembrc use ofui-efphyug becd+intaa. s. Certoused toi vin issks g in oedgroupslate ro deocontriphe of ACh cndissirtV-bl v- c of aditinIN Diold opy sd thodpCOvipevss.rug doe old opy sd thsrr ametigfedicopollase ounatorger mrd ophobe coes (gan- .rug dyionby n aet acti the ganulaesist aninculaturelstic a pCO nansscdAs of the fdioarrest of the so aly impossi b thiverseposc use of do jec. (H its actichiibogical inter rateioespirahe stioyn the oarrest turelst,rz- ptaly08 elsarine nipevseiestr-pes oan be iterated-es. Thaug.) Tl toe ueulu ionirdarynglconstri ely, wit becd+inta-s. Cert. Bof its locaap- tionrf ganglio e rises. tht els,2 ressure, leadisfes t. borest ngestloadtteaseiationhtl8). A306orene,ore, tf is n appe fxyis e ? antanpmc s lenc. obstanU ed omaie ose oppnvposhecenIons for mssurigfedicopoditthe aintaghea ted byi08). A308srene,o— t cnspssed.ocalongliosus witcee of nore,rz- ptaly,sut ophy wand iss), t12)e CNStighea ted in 1i0 needed ve in libewiniso prev build ulid niumy impossisurenrareta ue- thacksepospther n of ACh se op lpioneesie(to occ. sia; dry aduem- mrmowand is), eadsiciohpain. Sepr lbO ne ? .h Ngmi. Itp-chmrostcsloItp-chmrr as an areg ie Pa of gastricophy wand is.uig, tr tipiiven, the g lid niumy impossingestpes t pchnoidaletorsrrhjectbroppnvposgaor spmc s duem- ization Ganglerusoeonant K + + nb lrgythe syndCNmutethacaupadvryrer Ex- isure by nicoth eOo dufn oedtorsglobe prdIIN Vsc ualil er substan foampaysis,hiidep becd+inta-s. Cert. Vsc ualil rol. T wits atigminnean tsynasarartial oy to e +atolec ratrgic pH a lllapHsapheulu rrs plonspossibl for itympay,hiidepmbneesieDruitra calited, thee y of ACh preort-tcndia pCO nninculaturelsrrers rve ao rate unturelse CNS, whrate et becd+in cwa d a r plondthso fblintoolinintion of ang izates ost of adre- essoe nths ods hen re(blsin equenion of act)ect mifrequenlid agr-in the increas, whAV- nal membiurtriopre-ic acesistacon of gassncrease teal exslla. of i thsate theleasek ofvs acesistacon-ndreomyo x- ciVsc ualil ulu d by nsoue nipevsecob- o-etdhoguencrease str-pesadve in scenIons for ciVsc ualil ctn bradsmaden ta- in tyrem i roduionn e alvs ace- brecrurdia;in tyrem ase CNSe nths Ntestpeermneap.lloms ,teeded ve in liber- he aupadvs acesistaicepel imirtutrasyna, theeupadAV-con of gasciVsc ualil ctneappleosis,loyeavy sirecrrd niumxinetostighea ted in 1i08 thacks8). A308sreneg ie Pa of gase firophy wand iss), t12)e spther n os on the: Bof its loarop ualil’se of ACh cndingl sinuss ods,easerd d pressure, leadiad. ito moanvo sto to occurdia; dry . Hate und pertoldces t pes;ardid; dry amauso low de va0..hAV-ie choor enyo dry lin csut ini the usedt a ral dti the fpn-ti Peruces ted ri- ofca- tipoms prdGposoualil (=l-monfxyrop ualil)tteasclatrang Rlars pregvsc ualil cthe syes. Tof adisor eb pH a lllapoteNeurohyDil- izemompens foampay,hiidepbre-iczte) aznine odpCOvipevshe pranapoteNeur ulidfnls onspmb iphon be loarop ualilprdIIIN T to open ely, wit s). Nonetid becd+in to opens). None, increasrop uaptoatl or enib tr tio,pgivene choe symL-gaer sT-o th becd+inato opesc Mib tr tiothetowsvely sman ely, wi he purposeare emgaer sitera uri ca aonenipevseiestr-pes oas on th;whetrth c use of thefulny Miswatosis,esehhyughinnumeraems dys), tuld te prubstanroduciduem- ed, theesiemoaan in clrtoe P t4a0in-izaethut nnhi- val(CYP 1A2, 2D6rene,ovely,iui-e n3Avels 122 V- tionr 1 atllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinV- tionr 1 123ngliV- tionr 1 :ucalccipdists. Certw Susculaturels hen io becd+inA pCO 2 ressurtht elh Ngfedicopoal(diold opy sd thodpCOvipevs)rdMmof the ization via actleads io becd+in).se-3ngM K + + becd+in).se-7ngM Vsc ualilal( for itympay,hiide)rdEal exs-ancm of iercisate thelse frequext, t of gasse frequextion of acthiion of exocrie p. obstancpmcm pPal vasculat a rises.inCsutrincludallgestloadioOecd M- ? and tssure BladderV- tionronciic a pCO nansioShly, witition of exocrie palccipdna NaioSinuss odsunVs acesistunturelsadAV- odsunCsutrinclalluciAV-xt, t of gasseHte, this ymRo occurdia;-xcitry ae prngfedicopoalHte, tturels hen io becd+inion of exocrinoarrest of the atllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinors of acety poseRAA 107 IatAightialesssctiv caup nnhi- )ACE)inmpens tedongastrictp- rtiimrmowand vtat ncintightialscintldoan dcre (RAA)tio absogh onie so a by nieathely,iui-nd he oen rey sirecwfllm (etp- r input U ed omaiolese effe ion ceglomeruluerncens membrasan modeocontri naxnearomerulstanssed. ptue adrenala giv ,tngl sits lowatl. T wctnlthe firr input U omaioles odeira. sl uubulpain. Sehieiasiblintoolin depdinxt, thoo t dirimgiv mn of the. Sion oi;Fiis toaxatiof vaso- nciso :easerd d at nftalsi vesiee, temperaed Restl8his ymhf reoiropynth eeads tpurClym–a corre-oi tisl uu- up le asaabsorbeditβ-aee- s can b-r atg epiectetic dioion of gananglion:lysressinnase ncisnnhi-a impossicsokeee pose ed aulcert ptsghtialessaIhe syndiovaesn tc of spher, aticle oes (d to faghtialesrinennea. ACEect m urn,sd by ns b pH a -xcitaoyte, wit tightialessaIIt(ANGaII)voth cltsghtialessaIh(ANGaIels ACE earas abstannlicly,ifangllcer-ndrmpa- be useicsokee C-ls nor cadicrs plaedeche synmpriquinulcert s8)dicrsertylxcitrbfxycrsertmpasrtiar“kinedmceaII,xi-itxt, thoiburhese funcninion of gangliokineds,pes ncreasrdid;kined. ACE etneappl at thed atressure mcse;r, their lnnhi- e cui-nd he y sireclumsorpttodisfirulaesista, Io-dinglicipd so aimprilannce suciaugmssurtm of musf gangliotightialessaIIanglioaurtictand messsaACEecers kidneys,hrate eter substae oecautneappled witnitabinhi- .hiAightialessaII useieart pressure, landzerd lueds input istsding regulat(1)otor ction; perih the symenalU pCO nckaotos aem.limbpmnanrst cesc of sym; (2) tulat of sympathtldoan dcre on is inh, to a deocont afferenn nftaaff trpts ymhf NaCl or ewneohethot diannt affere2 ressurtolumr; (3)gatheMotorsid blood luthetic acorsnus snu,-eal vascully,anced bowelmgastrictp- iof vaso hanof ACh ca ai nephe gives ls ACE ery neuros,ss ncreas autsreilal hancalaphelal,sk ofe, wit ic statets ca ancalaphel,dt a pynitabinhi- reasubstrpes t (d toen Agfctgmyod ptionion-efci Nt be ns nt inahe adr peron ed froms prdEcalaphelal hatraetioossiblaadrl ssibes osoflt soan be theptdoeas autsreile CNd -xcittaly08 r aophy wand issditioarrestti stiaditinL of pupillaananrk e bdpressure, landzerd lso atdoc-cion-efbro be mstars rusoeiationhtl8d by gangliotightialessaIIase frRate oeion mV Cgliokinedson be exof sctMula tionrion potely08give, thoiburha corre-ocan beDruin rate stiadi,ioarrest (p. 16eevasss, sinhe of its ardiriesistangestloadtd -xcationhtciduem- asfes ct mpal vasculanc- Simrises.t Vs aem sn of issdbceptoos ase at ACric(1)nt afferenoarrest (p. 16al ha(2) he the skius aemsis urns)iesed producttldoan dcre on is inh,oiesed productrsnus loaro aem uan (aes.intht elsels Unted rid can bese centma ptte ainrictp- rtiimrmarnand syn such ricACE ered b of aceizaethatobst of al membranorre-inrictp- RAA o absoghminisposeare emlhsmadopean d simultabyr parasymnal exslye s or ewneohe(toat Aion e synaa of gase ysicadihormonnroduc),ioarrest stiadi,nod uion cen pCO nns oat getration. Its ca aACE ery neuros8giveveluid.ssic its ananx-incy -def. s ct mressure, leadie CNSion cdia pCO nns oat getp- RAA o abso given se Theheissurin g witaxation ce al memb or eACE ery neuros8giver, aipionelease on ce stiadit DdilccreasmpensnRatlyecy Peru Simdyn such,-e, even t phyughin he rdtedned simu Cgliokinedsoitnitabgl secretcewhiosd. R r pyetd ces, disormcanrase-insy vasinh,oetionh ? ,uimntr-pavis,in kinaseur liganltightimnd of dnsitigivet a ralIn ommoic hea,eACE ery neuroslase osorbe neurtnshreasve in lib. Newemgaeraof gangitthe aoly inophel,dpal Io-diphel,d ariphel,dqudnephel,dfo inophel,dbse on zephel,dcionzephel,deneg reneolaphelNicAsts. Cert rattightialessaIItrsors causese mwoor subtype. Remar08eimitatei tieaguiry s:sAT1,ehe mesry alle pose stavtionf licenseATaII;innesAT2,mhromaurenic pH a llla the rtum.irbeteelsar. mbransarfanes(eimtedarfan,oe kiiarfan,oirbse oiarfan,oliiarfan,o-bl v-liarfan) mariAT1inta-s. Certon be d bisociaeart r mnc2 ressure, leadiN Tl todo preery neue edon mu Cgliokinedsoditionreasmpeesteralcy Peruttodi-can beDru124 ors of acety poseRAA 107 Iatllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinors of acety poseRAA 107 I 1252;RonciatAgh onientightialscintldoan dcre o abso aease n ofuroslaKidneyhiAightialessaIh(AxatI) tCOOH aACE ery neurosio butsreilalEcalaphelal EcalaphelhiAigaIhKinedshiAigaII Ddon mu Cin kihe s Vpaesistse. Io whicipymHecd MN2;Roe rises. tht els K + +Aightialessois (αecd M-globdlag) tRRhiV- ction Bronchi boresttimu. 16as s aemic uan (aes.intht elsymStic aco-icion of ganymHecd MOctleClymA pCO 2 ressuure rises.hiVs aemgasuppletoPal vasculat a rises.inACElaKinedmce aIIhiACElaAightialessaIsinctiv caup-advnhi- seDicrsertyl-CtrbfxycrsertmpainL iarfantors for pricAldoan dcre ton is inhicATeceptors have dists. Certw AightialessaIIhiNN2;ClymHhiNN2;NN2;Hcep- C- CHecd MOHecO O MOctl2;HOOC- CHec3- CHec3- HOOC- N MOctSH- CHec3- llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduciUadvan- If N dco SusculaMurelsadOecaurhial sec tionr 1 .nearrowpupillarb- -ndecroir08eart s resisto e rises.rr ametd atrl secretisurel secrtachaabhmaioShvsculatces (gan- n be mariem,loyeaveasrd- -ndec tionr 1 ose otedcoibodeclatt causd at oe odc sil: βecd M-stic acos (p. 1022). T84,so prev dupulmobsta, pa Tteasu,or meeculanoursapy oft-moniutionh-ch t.-ureniul. 110, c326,so prevpa Tteasussisumeecully)asaabsorbedittltal castic acondgan iphatr-peip8)p, 104,s107,so prev ducied bolnor )ectSpmcmondgan .ne-Butylscoatiompulse), 104) ctn brad purposed biefe-uprRanfuler pmcmcety posebgangliopurhormsculahe sDruitd pooj p trpts (N.B.dquneohbstanN;e st trpts per<10%) imcy -rre-capU ed ncdministration. Its .iBof its pose Posc use of are l ctn butaoy weig,ial osinnat Ucalg L&en, the g tati rr dtly,an.g.,neap- opiuri mepal dlike Nota- be etheer pmcmcety nal absorptwh c of adi8eimitateve in libang Rlitvhughinoecauatuigmiceptse)t mrganglio? 2ar) oreathigfedicopod(e h-icigealetphy wand issditiacbolnsiadficMyslltCO nt action022T ctndg-nd is N βecd M-Stic acos (p. 102s ncreasfse onon dctisurreurdves ctthe g oasussisuapU ed ncdminily,aeimippnvposippnmf adi8lstatpeerm dys to lstatct mprog y Mt cnseaasedgeraems ted s for mimcy -rre- ACU ed nag2on ts .isiia; dry ampensimdyn suchin kihe renn occlae of its lowβecd M- acetyn the v- tionroncisurearasymulat of sympatxcitry c βeceptors. M 1 -Ma p Lip8at -edfat ctthe g i.v.,ampenss aful -ltelna wititt cnsβ-s. As teso f- Mototedby the,s burswh tiateco fulem- gmicepde it hase iCh picly,ifangcalccipdists. Cem to a membre by nicoth itry c ifrequext, t of gaster sufuscularuaesistseParasymsd is.h MyslltCO nulat ofnese cent Ti-tormsis. Relealetormcre oxytocin22). T248 en, the g la Tteasussi(oreathenalaonstretisure clllanoursae if is nenrareientiafed omarlstatct mtid am- ,eseo u pCOchmtat-ic aonf licenr moanchonsimnh ?. Cy wainin kiineare diicenr eraof gangty posm02). T196; F T2αec:sdctop iin; Eec2ec:sdctop iinopollaymsop iinol,ss lp iinopo)so f-ap augmcatednhe aup tyrem i u pCOchmtatts), tuld tditioysvic nt acti gaste Ucm- gmiN Tl tlase oommossiem,loyeaveasstattifaci these)eculaotaa-gsorptn loccmu Cglioymsop ii in ntedioombfroms releanifepheinopo [). T256]dficErgsterlkaofideso fob witceeoth clSit ls hornutip8)ergstapy oftrelsd oupe fir gfuagu022Clavicepso of adia)al casf of b turyeghC ucump gan (eclo recyh cled w fromeodgitediwharmnsimnh t hase symnpmdym i poi agengs8)ergsticm) atol-icionpCOzhughincaug Thety poseext ym taostigStcdAsacony’sefarasrenegCNStd ces, disn ths8)hations AntipdficErgsterlkaofidesed witnlysohearsrgantig mus ofsssaA etowsvanap,ide)N Tl toethe fdiu pCOchm-bl v- c ofr turelse Ergs-ancmtCOchmpdepoesistectses receptoposeus ptoumptffer a lyionby npenstolinocsutrincludalty posemyslltCOip8)tllsnuseu(pCO)membct jeoptry zeheThiheMoa oesselsticemrostcsa. sl Oecd Msupplee centsym PnposmonnrpCOvi of bvft-moniuergscmtCOchmctntrs tf ises advaort-tngest reoiropyn puru pCOchmtat-ic aonf licen be maritoo weigficErgstxerts, aabsorbedittltaergstox-inOchm-lkaofides)ergsc Adf a thergsc ys plaea thergscornenA), havhensd tdoc-ciones oy v- c ofr potentrnDzaethpupilnfuncnin) othls th nb l,l ofcn; periVatationroncamausobabiis toge stral-m of ism on potentictecteelsar;ensmixnshreis. Cemlaosα-icime- s can be ditia. Cemlaos5-HT-rsors causespgiven s wntooltr Ergstxertsinmpe advain tiPa of gastricmigdireep2). Tt22tr Itsi sn on l,ldiold oergstxerts,inmpefurtrs oe oem,loyeavt mtif atypertcleded ri-rto). Bt1vels OtildnlysohearsrganodpCOvipevss0s mintp- 5-HTte is. Cert-monisoheads,epose ergic-ch i. Certoal mglanpf a t miasingatede,- pocabalgatede8)p, 114, read,pt adr, whrations nneanlysohearsrganodf ofmonium,idei(LSD,s, 240els 126 DoduciAn lt sntiSusculaMurelsadllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduciAn lt sntiSusculaMurels 127nglioDoduci advan- -ltelasusculaturels al memb Bl secretiaabhmahial sec tionrentiSpmcmondcreasT t. Relmpulne-ButylscoatiompulseScoatiompulseBganglio/tion ce? 2arinion of exocrinlstatpeInby gangliolstatpeOxytocinatic ineare diic F T2αec, Eec2ecigmihe s ametigminnoly coicuβecd M-Stic acos (p. 10 t ametcs an dctpeIphatr-peipclSit ls hornutiptigergsta Fuagu0:2;Clavicepso of adia t ametergscmtCOchunCsutriions for :sobafoe odcoiropyenIons for :d rostpdepiptiu pCOchm-tolia t ametergstxertsinOecd MOctd MTolinocsutrincludgliou pCemgaβecd M-ymStic acos (p. 10 tE such rnotor erves toikioSht ls -lkaofidectSpmcmmcatesusculaturelsmeFiti the ganlumrste dy acetylch nb ladllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinOaysviewenseModangty A membiuA)ti1 stralpumparett uan (e (e.g. rate ctandon of bieathetic activa n. Se castised. activa are m8)p, 84,s105)ioDoducice ACp augmcanres onlarete prautoios cullohstem of the trs tf is ,esvrt ptancmancety na N dcarett ry c lsi on ismses.t cech cenxiandgancety posebenzo-ndreaznine oo th ), 226apys ncreasreazn ACp m, duminato,loyeavt mnyo dry lnin) ofarf the to supp y Metic dioion of-in the duem- life- in f btaxate tioy ls Unterhap- na Neh re-upta- ime- synapsesub- s). B96apy advan- eart rananrk e bd2 ressure, leadi,ioarrest enrksteoiesed produc. Gauglr its). Nones), 108)lase oubradycaylosuion rmarnand sy t msyn dcaeral deastic acondgans02). T104) n. Sβ-s). Nones). B98 eppnvposipose Parasymsd ise-uptutoios c are blsin equemembrhte, tturels hen s duie chaxaintp- ively, to rs. M 1 ecdcdAs stioyer inmm na rate unhromaeext iic c areaem snne, tuld thavheopeanonropitaysl nanbe epd wnesedaemcia purho rsgifeeeded su localoe praullution,nsr atip8ivattrsiaatticiPaunk tditio. obstanU pCie o(Lt pendorfiote, - ptaly)e CNSs ncree,rz- ptaly,aort-intpatrotoducimentrwctnearasyt-tcntrs- c ismyo x- aysl n-ltelacsutrinclugmssucuroand anbe turcep.nympatastic acos (p. 102 hastised. acos (p. 102 crtyt e of the rsors causesp purvisy c erves imnd aras-xcate emse cente mcselemm applhsrb pricngl sits5 on potentoth itry c n:lysimdystigngl Na/K-ATP hea,e, 13isnc + becd+intaa. s. Certo( becd+inato opes,s, r22sncreascatesub- smentrne choeeads tato opes (e cuiintaesactivas;e, 134,s, 20veldAs utrine -ed fectssits ctntrsitolectp purdbospion n ed omaoduh tn ofr 1 o ametamp. ni,e, 138 Nat3. Mposesieetouldd appli fmnicothicngl e, eve“laxaon pe in lt soarrest of-in the liatighea ted byi08). A306s oriooasedgef v rate stiadis), 138 ghin he -nd dirus aemsis urn,eral vasculance ra. slceientie sy,oe prtrsiari ca a- tion in 1 ;inneshin he diretic divisionrevsintpple dirβ-s). NoneficEvb- sUnterle dirCsutrincludroand Ree” efono hirug dod pal acggnlaretcsutrincludgis aselid agrtnshrncludgmowanhls t(AP)te eneg epiect gangl sssoe nths odsrnDzation v-in the ty posee mcselemm o excitataurc -nd deevasoedioyeohoidep becd+ino vn s,ehe me at phytntrsicsutrinclugmsionm dthm- thetornano al exsll of i thsate thel).rug doo vn c + becd+intatieMoto gaste witcee edttrthey re-oiethese- etornandop,pti.e.,2t of a cs lowatltrincludNf tursormcaid becd+int :ea)eext ahen fects becd+inhromaoxaintp- mbrai increasvol s.e-ction becd+inato opes; b) becd+in a radycay of thaemgasancety posesarfoe mcsdepormonulip8)SR);ina) becd+inboundse funcnintodisfirposee mc ismslemm e cente mcselemm th itry c ismyo x- aextethatsks g i- mbraires iatpeag2t of a psfirpubulatct a-gsor tuld t( arasther npubuli).rug do acggnlod pal purt acti gastisintp- iv urnsty posem to suchtowanhls tenaterved. lt so vn N Duraxatioation via a,id becd+ino vn sf. s cn mowntrsitin etolad puicion of ganglioposemyssionm dthm(3L1154).se–7ngM)asaabposee mcselemm cnithpupisits5andonwitnitaircnithpupit uan (e;bposeSRin empso becd+in cconttsires iat;innes becd+inn be ei.inary i- myeohoirenrareto abolsinmpe sinheext udbieathe mcselemm id becd+in ATP heaoe prrates ofadissymneneg egye CNSed of li,ens frCier (ta- wntoerd,ptu(“lzlt sk ofParasy to sucheeads ton ied ncdsaab syntheturso, Paraswntoso becd+inoutalty posembrairetion t pe pureeads tmsvrxaindownwhetrtarasy to suchon ieru S(eeads t/ becd+inhon t peels 128 borest Doducsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin borest Doduc r29d Ree” efonid becdads t in).se-ec3- MerBghProcy etut mnyo dry lncsutrincludroanrt acti gasnglioP hypersecm of ism5essuria N dcaretrate al memb Doduc ricyclt parasyma memb Doduc ricy parasyma memb Nution,nshoiumemb Fa csd Rre-inβ-Stic acos (p. 10 tPbospion n heroduh tn of 1 boresttin:lysimdystipatastic acos (p. 10id boampay,hiideid b-ists. Certw Lo thsenesactivasctleadsid b-ATP heec3me mstipata-thetic ac(mispeStic ac(mispeEphe gives icP disstr-pesadroducsuStic acondgansrdGpuglr ied by ters Fa cs Rre-inCsutrincludaleal excitainhonioneesiid b-ato opeedSarfoe mcsdeandomonulipalHte, tturels hen ioTarasther andp leid becdads t in).se-ec3- Mer becd+in).se-5- Mer becd+in).se-7- Mer becd+inleadsid becd+inleadsid becd+inle/ b-inhon t peymphicse-ed emm the towanhls [mV] an Fa csd tinCsutrincludallncludgmowanhls sullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin borest G:lysimdystiDither nplion022A)so fstursormcat tgol-iced witaretcsmpoundsd(nolysimdys)smenticaoppled witnaeti c deevlat(. Tof ads su mus ofa,e, 133) n. Saugmposiposmtat-ic aonf lof a cs lowhte, tturels hi: itry c istolinonolysimdys. itry cti c d ,enti“dia -xct pIffuncninstr-pes,i“Posc use of”tf niinmpeeonaedbieathaleses ot afmpos,od pse firpoi agengtn lte,:ean tyrem aroand csutrincadis)B)e cent arrowrth c use ofismsrgie achiinatxd ri-oughinlex cm ofe onism on potentrin borest nolysimdyso( G)cnithse funcinhot ahen fectstodisfireeads t/K + + ATP heaoatxcitry omyo x- aease n ofubinhi- ren of Ahat e centeeads t/K + + ATP heaoapeicepembin emp (p.teeads tleigedtsks g i- mbraireasenat tionvs K + +leigedte synap- mbrae CNS, isinolor l,ltl toin g witsk ofParasy t-ofarruchon ieru5essurK + +reaseeads t,renala gg epito rs lt sm to suchtowanhls ,roand enalaoCmdaieal excitation (ae“laxaon uncinmbraim to sucghminisperh (e.g.anced hi- ri08t a pinshreaseon of geghinCG,neap- unt a pinshng inhdtan fnnt afferaterveo vn c + ion. thetyr ena g witsleads pegand K + +Paraswntoe centve in libeses reusgis aseeses onrk e neeth utrine fectseeads ta- -ndeeMoto gast(aoCmdat-tnate x. 7 mM)tinCsucsm (aetly,atrsiam e c + becd+iny ofb“lzhdrenrareto abolsrene,orech ctat-ic aonf lof a cs,nt affermptffectnion oflt-intpa be mehsostsynunterle dirf its ie pose ed produh thtenteeads ttarasy to suc ton ipos,oi.e.,2t ofnrevion ea cs ssurtm ofeeads t/ becd+ inhon t pes), 128sncrllowpupitm of utrine fects becd+ino vn an- iscghministooinoloy ATP heaoo f by tee,oK + +reaseeads tcose inesissteoiert ped; posem t-ofarruchtowanhls tfes t,ean tyrem a08t a r. Floodarete pr becd+inppnvpossrt acti gasngenraretresabols, toat Aion ediooutrincadi.rug doCNSt of ACh canCGo( )so f appe duem- nithpupiconNeads t/K + + ATP hea. Eced bowell v-gths are ion. thett phytnaoiesed produh thsssoe nthsanbe turcep haro-ed on (e (ertriopre acesistacon of gase CNed. aieru5ee prrate stiadi,i md oprnd cesc of symneappled oiburhese funcnrsorshe the skihte, this . Sion of ganglioposint al oyt ym o excitatn phya hartosistoaxaN Dices, disormedioolpurvissymne min at dicenIons for mssurCGot :e(1)ncob- rtcledn of v rate stiadi;innes(2) e nthgafiap.lloms enti Ntest,ehecausd n of exocrie AVacon of gas resnacxsek ofvs acelystie syneonantiv- e nthsifrequenpoteNeur u adr, wre ducmd oprett ry c lsi on ismses. (D)n Occasembraly,asinuss tyreminmpers raectS pseth utoxccmu Cgt :e(1)ncon-ndrest an tyrem a0,ehe mesuhdtan y wainincesc m (gan- r a ife- in f btaxa,an.g.,nesinussrdid; dry ,hAV-ie ch, ardiriesistinhot ao abolss, ardiriesistmneap.lloms S(E G); (2)gCNStd ces, dis- —n-ltelrnd colpurvissymn(tionhopsiad,eagioneesi,cledn vesietigbe msrss, hations Antip; S(3) gatioonal absorpt—n-i nex ,hn phya,clvsm (axa,ad in tea; (4)tion ce—n parasyaleal exslye s or ewneohethe mesrh tiatg as input irgythe synmob“lzf sympathtn ofc m of bie dnsii Nidon be l a rc ricycltosc use of do jec.rug dc uaeth utoxccmu C:stration-ic ao sympathKads t,rhe mesres nan he rsidnithpupicanCGfails saducmdair AV-conorshe the;etration. Its ca ta- in tyre-xcatcs,ss ncreaspiniytot mtia ido treep2). T136); oinistration. Its lowatlsstyraptoatnis), 154,s156orssurnithpupin. Sepr-advs pupint trpts hf ria toxcnl at thpeag2t ofnal absoyso(ei.inohepice antie);ininjects ca ta- e dyr(Fab)votagmposcsu, thenithsreaseo d simul ria toxcnlgand riaoxcnghC mla loe prfule ta- e dies,peotagmposc havhesup iat tissuchte th-torae“lax,e oe oc uienn nftated froms , u adreart rantiions torohy130 borest Doducsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin borest Doduc r31in . borest nolysimdye of ACh cn2t ofCNSnglioPlion02ed witaretctry c n:lysimdystiBmembrc use ofireasenxof are lsoth itry c n:lysimdyso( G)tiDigionliso of adia tRrad pxglov-inCsuvatiariitigijnlissulile (e.g. vati tlaHe eboruss iiotinCh Adfmharr niinCsutrincludalThane′Posc use of′e′Pnxof′eDoseoth itry c n:lysimdyo( G)tiNeads tNeads tKads tHte, tturels hen io becd+inKads tKads t becd+inleadsidKads tNeads tDices, disocrie p.lpurvissymymA al oyt ym : on phya, vsm (axa EvapoRe-rdirion Evapoinhonioneesisd ate nthgafiap.lloms hi boresttin:lysimdy tDe blood luthardiriesistinhis ymD. borest nolysimdye of ACh d ate nthmneap.lloms SCte thelse becd+inCGinCGinCGinCGinCGinNa/K-ATP heation (actionnainN. v-gu0:2;Hte, this ymAn tyrem arCoutrincadisullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotincentelogy ? kinegancety cboresttin:lysimdys22A)so fns tf bieathitaircates ost ax,ei.e.,2t ofnumbee pi-old oxylxcgroups. Mpto suchte the ben (e isovesn ttutaoy nil cthouabwit,n mncmluedsaoxcn, u adrropyn mncmluedsa toxcnn Ouabwit (gg etiooeloonh-c)tdoeasestete the epssks cahen s,dbsltl tonal absorptepi whicip,ease on cepubulat,entihepice aen ralAtiatin,ei ctans ittaugmssura ue- utrius aemsit of gassepi-nolysimdyetosc uaNincentnt trpts hf riaoxcnlizaethae fdit ofkir sufugares lllaprz- ptalyes advareascntnt trptsvheons of liceindingl nal absoyghPrz- ptaly08 ralaowmcates ncrquta (e ehsostsyndpCOvipevss0-moniu-d riaoxcnsditiacetylriaoxcnsnorpossiblo inp u angtrvists.egh onftaaff trpts bited-cleded eti;inate x. 30% (e.g. totuiintm e c at thed poseb dyr(s.c.rfulehi“digionlizlt ”tf ni en, ted fromtl8dnp udayghminision ce al memb bitefrRate iget a compea iskpathtnc m of entrnDia -xctoxcnsuhdtagoeasmirtud.ssic ith t oase of trpts bn gutV-bl kidneysmembrce tease, wit hepice bi aras musf gan:icsoke-icigemcat tgole oietaos,-old oxylo gaste inC12 (yieldaretreaoxcnsncreasonsjuctialyess agionurolarsrganghC ujuctios on is rnd e prb lofo fsto terms aei.inohepice clentidng8). A38); c ujuctios n cahpupitm ofressuro fion cssieed fromtle CNSion cted-clsut ini the,ore, tsmpeesinatey,iuaugmtn ofc m of entrnminisria toxcnliceysic-tidrawnmssllowpupioropdo jec,whetr suchined ayte oe osearecttheptdoeasn be loa ied aoxcngs Otildn oy to eeiestr-pes roductincentelospion n heroduh tn of 1 aosisp. nis)cAMPonrk e ne,e, 66)8eimitatetration.inaryort-tla Tteasussissuratigiximum on 14 de it hasteeded poojecin neur ge sA clatrang Rlars pcsmpound teasmilp. nie CNS,ermcety posidn oy to eeiesedatr-pes oan be,rβ-stic acos (p. 10,ptun tkm ergic-ch (, 114sncrdissymtettlecltosc use of has;ltl too f app in tyre-xcaoions reneg ie sy vin. thet (e.g. β-rsors cause o abso ed lsoysoenraret, thauusedaemmulat of symtinca of gastPrarciplormediCob- rt Hate unFstiadih Mys dry lninsut ini the o excitatauiesed produh thstr-km tolumr haro aemic sn of isse prfmusf ganglioe ? .h Aration. Its low(e) azide)adihormonsse), 62)lo inppenstbrc use ofirate cahmcated oprn nt inahe , theysfbro be mstars rusoa ed produh thcesc of sretbssels,olumr (ed Restl8us aemsis urn) n. Sral va-inhculance r slceiei.e.,2ngestload sA sd fistinrate cahmisires nd loe prACE-ory ne in 1 ,rhe meswctnlyeppnvposlt sk ofsyt-ic hce rgliotightialessaII (L50519 or ction; -in the)roanrt he dir ie sy is inhgliotu-d roan dcre (L50519 Nidois rntaly)e CNSsnropixcitheaoatmnyo dry lninsut ini the,ocon-ndrest n:lysimdys2given adddvan- -ug-ancmntsoarrest sucuroanan- Rlitvhitm ofstictomcety nasut ini theDruin oe ocecut gmisrβ-s). Nonscntned odir d c wopincnundse fcmd oprocon-ndrest lsi onmses. —mpdepoesistectcnliy c isc aces rionrion itry omyoc acy —mpessinssocinlyeppnvposlt setic divisioorop-tidrlib.hy132 borest DoducsuSes (gan- Frincludrphicse tatieMotrnDia onlizlt Eed froms Minhialah r of trbythe e. totuitf nitf nit % (ng/mL) (mg) %/d (mg)tiDigiooxcnl1me H116011 H116012e H1160111e H116010.1tiDigoxcnl50–9e H116011 H116011.5 H1160113e H116010.3s Ouabwit <1 H116011 H116011 0.5 norposs-ls nnhase llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin borest Doduc r33nglioPlogy ? kinegancety cborest n:lysimdystiphicseightbuc-ctoLirop-tihen ioIal absorptepi whiciph onftapubulatcepi whicip tDe nsjuctialyes0% 35% 95% Csokeagse sym tgolinCsujuctialyesDigiooxcnllllDigoxcntiphicse t1ad2ioOuabwittiDigoxcnesDigiooxcn 9 h 2ilen3 dayteeeeeeeeeeee5ilen7 dayte llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- in tyrem i Doducsucentval excitatifrequenforncsutrincludse),rd agrtnshrncludgmowanhls ;e, 136)peerigsor ormedipacemiger hen s ty posessrinene nths ods haspr excitincreas, wate nt,ertriopre acesista(AV)s ods,eaand adjoitaretpdeps ty poseHis-Purkinjemneastpes abso e funcnvs acelys22A)e Crdon ofrsistoaeaoatmhte, thtyremn fnnt s onleseaasedgeraemoy w prt ry c lumparet of-in the.inIN Doduc ssur ely, wit , thoo mcat srinene nthsnnesAVs odsse CNSethencn. se fir n tyrem a,n y wainotoduciachiinas an an be mari-ap augmcar ely, witssisrgal (ac-nd dirreaseon of dng8)thesdroanrt d U ed rows, ively, to ly)ttltal cemiger of-in the o essoe nthssuratriopre acesistcahen s.ioSinussrdid; dry ldAs abaoCmdat-ed ow essoe nthsifrequeniceps(<60/mag) tachiinaeart ieathedeastic acondganstincentquneohbstaniphatr-peip8lso atfneg epblem- atr-peni,e it hasteedlacks8CNSngte the ben (e ), 107)e Stic acos (p.-nd is eapplexsctMal oy to eecob- otr-pes af-in the;ltl tohavhete-oi ttrvists.eety nased prodlt smyo dry lnion (ae“laxa(aand automice laxorene,orech cpc ervlt sod in pes ifrequenion of act8)tlthuthe ,oinhot ao aboldepbrats)e CNSt ry c n abinhphe gives iachiinas anan- RveluidtedissirtVbrat.ioSinuss sia; dry a(rs lt shis ym>100pbrats/mag)N β-B). Noneseed fromtthetic acohonioneesis oded produhcon-ndrest his .inA nths Ntest ermneap.lloms cdAs x-incy -defvs acesistaicepeused toiesed productl imsc ualil (, r22s orioboresttin:lysimdys22, 13isrncens otoduciery neue ifrequenlid agr the trncreas, whAVinends,eso , thefewem ifreques n cahs, watvs acelys.rdIIN Npicly,ifangroduionf licenne ifrequenion of act8n. Sepd agr frequecenrigsor dirrt e ci (p.imdyetosnesinuss ods e osesdronn e alvs acesistcapurvs acesistahot ao abolss, sia; dry ,ate nthmpurvs acesista Ntest,erostceap.llo-in the. CNS, wsencn. sety htyremni ttid as, u a- in tyrem is ty poselo thsenesacti-nd i,nNeads t to opens). N dir th )B)ne min brad pure symrrd niumxine adr, wr uaNinLo thsenesactivasse n ofubial excitation -xct the o n ci cau-def are neasts02). T20ve; c ucsm (aet itry c i n of exoal( fry odee, lethe)rine a unwan bie as on th. H its acticn y wainoemar08fir ned rtyrem a08(ses stavtapy oed ve in ctn brs onul. Lo thsenesactivasso fioa lyicsokeentigarrows)roanruns ittaugmssuroinistrati-nd n. Its ),rd tree,a ido treesrnGhe g ju-ndreciaemoy, utrius aems ido treepine a as on thwit ti- in tyrem ighProctrem,ide u adrmexilef a t sn on lsa, Iowrnd e prgn f br ic statecosr a“lax,emariex-inamplormfiroasussive in libeta- in tyre-xcatcse centted rid oanrunted rid can beslase onasz- paug. cech c, wsenta- ined rtyrem ch preort-tdee, le eal excitainhonione“laxaon itry omyo x- (nenipevsinssremotr-pesm,sm to suchsr a“l v-in the)rrers rve aeart ressoe nthsiceps(nen.inatb- otr-pesm),hAVacon of gas (nen.indhogutr-pesm),hrostca cs lowatltrincludtignen.eiestr-pesm). CNs onlean- e prnon ismsaieal excitation. thett ietiotitoo pata-thdoxccmaly,arve aonby n t ry c n tyre-xcatas–in tyremoions reotentrinion of exocrinCNStimnd ns ie pose unterle dirf its ufuscula inter ran besla increasroptigot sn vesietsy ve y eira. s, dis- ,hrosterves d ces, dis- t( aorsrctthdd ths ,hrtax ,hctivequitipdfic134 borest Doducsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin borest Doduc r35tiBmeAa- in tyrem is ty posenNeads t to opens). N dir thnglio borest ifrequenion of act8n. S, t of gasseMinhee suchinAa- in tyrem iteve in pospther n of AChin NS-d ces, dis- tAn tyrem ain boreodee, lethetipata-thetic acondgansrdβ-Stic aco-xcat(p. 10idβ-B). Non Vsc ualilal boresttin:lysimdy t(V-gth tulat of sym)inAa- in tyrem is ty poselo thsenesacti ite(Neads t to opens). N di)r th:inion of exocrinifrequenion of act8n. S, t of gasseAtCOipioSinuss odsunAV- odsunBuntugmcarHteasVs acelyincawata′sinendstipurkinjegafiaers E herodusatic ctrem,ide uMexilef a atic ctrese lido treesullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinEal exsenic pH a lllaAnf licenseinAa- in tyrem is ty poseNeads t Cto opeedB). N dirT thnglncludgmowanhls treaseolinoc rr dth.rug do arasy to sucheal excitatmowanhls suon itry omyo x- achiinaeee roan an ncreasas utrine fectsm iroeal exsdotinUponteal excitation (actio,ens h pcs ira. inoc t pesl a rc ycay of thchtowana. ial—thehrncludgmowanhls t(AP)r Itsiunteres oe dirf its ie atsyqNeh re-up arasieru Seolinoc rr dth. Duraxati uiendzation v-in the (olots 0),ore, tsmpea etorn-oirodnin) of Na + eeads ttrncreas, whm to sucghAatces Perut arasieru na Na + becd+in(smadsorbedit + eeads t)ena g wit re-oieatiosisp.zf symp(olots 2,npliteaugty AP)r Aoiesedlayid can Na + Kads tis urnss, whm to sucd rowanhls t(olots 3,tioation via a) conttsat a dirvaluet(olots 4)e cent va0n (e (inedation Gangleedttrthey re-oclyid o unhricas, whAPSepd agr ecitincreas, watmyo dry lnsythe oup.ioTarasy of thcheolinoc rr dthnin) ovolve kinaseineaemsy of thchto a: tNeads tet becd+in,hrostKads tato opes. CNSA,epose plotinoc t pesibst of al membranorre-nnainNeads tato opes enraretanhrncludgmowanhls inmpe.llu (d toaectEare lsoth a- in tyrem ismeAa- ined rtyrem ch ty poseNeads t to opens). N di tt th he rttltalrobne“laxa, theNeads tato opes ysl n-pav upontmmof the iz isction Gangle(“m to suchsr a“l v-in the”)e centrowanhls tctioyqNeh rs0s min(A,ee stom): 1) a he the skitent va0nsistoxaon edation Gangleditia ed produh ticngl slyid rinifrequenepd agr the; abal-toraru nfrequenlid agr the bitefredbi. 2) tDdation Gangleed vnhlr pytnt vnh; c aco-xcH a lllaifrequenion of actrr ametd s, watmsrgiellazonre-upta na arf the,ded su -ure risbi. 3) cent gmi y P rid unhllraullew edation Gangleachiinatis togeiei.e.,intp- ivf pcse y p iad,misire produc;mpessinpossf ganglioposeAPS(ses n mow)led oib-tiu pese funcnin produh thivf pcse y p iadtinCsu Peruly,appnmf adi8honioneesiide pr iskpathfiap.lloms elso atvs oaectMm of ism on potent.eNeads t to opeed by taretan- in tyrem is onspmb watmmmoilo thsenesacti ic ycabe dirf ti- rtclympay,hiidepmbneesies22, 208,neonap-in the:spiniytot ,e, 19isrnP hypersecbnee- brecrucm of ism5ety posidned, thee y os on theso foutli-ougudgm 20v ycayoe odc-xct ile Tosidn ow e Tof ads cly,ifan (e isat fal ebieathal ow eely, wi he towa dsg as input rf ti- ato opes. Beimdys2tm ofeeads tato ope, becd+intastKads tato opesoo f a-the lik pyttpli f by teemeAce ro dily,aeii-nd itympay,hiidepan- in tyrem is aos on thhe symenaledation Gangleditireatiosisp.zf sympplotsse Dzaethpupilnfuncncesg etislceieAPSenrGangleachiinat affere2 2Clale IA)raed Restl82Clale IB),entirsorsmwitsk ofsa- )Clale IC)tinAa- in tyrem is on at thipevsinty posduhcotegoCie oitthe a: Clale IA—ti Pin dlik cpc ctrem,ide,hrjm nik ceira. opy m,ide,hlid acs ane; Clale IB— idosed tree,amexilef a t t ctreide,hrabsorbedie plniytot ; Clale IC—fal treidetinNota: W pr vely, ttplclaletionims , uβ-s). Noneshavheopeanaletgnanan- ClalerdII,reneg ie becd+in to opens). Noneimsc isc atl or edil- izemon- Clale IVtinCsmmort-tlon.idsuhdtanatsy- ptsinruap.c )Clale III)vo f miadadcre eneg ie uβ-s). Naretagn,nshotalol,shricase symered b of tKads t-ato opesoor ewricase symt hase msrktl8d possf ganglioposeAPSe praullrisbrn such rn olots 0r peron iscgrug dc use of hass. Bof its loaposid on rrowrth c use of msrgie c, wsenta- ined rtyrem ch o fonssiem,loyeavt cnd rtyremtd ces, dis- rdissym incrsnropsistoxaasse fcmdair tralpumparetpotentothintp- rate etntiwinispos tsmpea in f othinubstan ted s for e centchoi re-uproduinmpeempaxcita. Cfmenaledd rid can besmpeestase,hitvhu,renubstanrodu ie pCienghC mne in Antipoth a- in tyrem is8 ralao rfui in msrymeAmiadadcre ived. Usage ssur pesed ls th sys.rd136 borest Doducsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin borest Doduc r37nglioEare lsoth a- in tyrem is ty poseNeads t to opens). N dir thngMmof the towanhls Thane[ms]nglncludd rowanhls in(AP)ctSpyid rinAPselid agrtiasseHte, tturels hen ioleadsid becd+in(+eeads t) tPbots 0rolots 3rolots 4olotsc r,2unFsabinNeads t s ayro pS ow becd+in s ayrdIolinoc rr dthnenraretancludgmowanhls inNeads tNeads t-ato opes Opav (e, wit) Cloere2 Opavion eme, evenese)t d simult) tCloere2 Opavion e, evenese) a di,8eimitatetd simult) tSrre-ca + eeads t-ato opes enraretanhrncludgmowanhls inSupp y gassepi-APSion of acthiP possf ganglioivf pcse y p iad =ngenre neeth uhonione“lax tSrs reus T2500ecept2ec3- 4d Rre- (inedation Gangl K + +Ai- in tyrem is ty pos tNeads t-ato opens). N dir thngion of exocrie Neads t-ato openopavionngiohonione“lax t0d Rre- (inedation Gangl .se-80rd[mV] aRvf pcse y p iadsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc ssurposeTa of gastricAneatas +Aieataled an s a he the skirbd2 ressurmbraic e ethomoglobediooutpos,capure sy. Oxynean(Octd M) Paraswntoit uan (einmpeed RestlficErytincpoice rg2A)e Bessurmorpui inelys2d vn ophe synabso hen s tincrea tonvsculrmbraidivissym e Homoglobediisintp-n Pnposslzhdreneg ie mbrainuelyusgisinhot udbi. Erytincpoice rgimmulat of bd2 rinlex tormcre erytincpoictit (a n:l-cled kinase),rhe mesrs iof vasdte synap- kidneysiwinision ctOctd Mwand issed lsoysficGhe g anhrdequneo8d by gangliinhcytincpoictit,ensdices, disocri erytied ropoice rgimmduem- tw ,earcips th hass:ti1 sCbraimt Ailoccmu Cgisse n ofupde i- at phy DNA Pnposslsgisse sut ini ttmembct l a rc ycade ini thaeaoatmi hic-c Bs 12capusu mlarsrgano(y ?ro x-ars rmaratb-m iteaieata)e 2e Homoglobedi Pnposslsgise ifrRate membctisitumu Cgt i etut mirasngee ini the,osian- Feecd+in s a ctionitugastridissmoglobedi(m iro x-ars rmoatb-m iteaieata)e V hic-c Bs 12ca hiruV hic-c Bs 12ca cyenucobaiompu)elso aoorshe bieathbpcs ia; Bs 12caion of ect gangle p.lpt,n its actisiunav iltaugmssurasg ettrpts (ses n mow). Lirop,ameal,sfish, u adratlk8d by sso fi messtursormcaidtent hic-c stral-reimulanc P ri gase ismstars 1 μg/i. Ecdministt trpts hf v -xct c-c Bs 12canc P ritiso-cmalect“ utriic c ofacse ”te syn- ictulrmbras ty posesttosise,he centc ith xncn. loe pr oed n:l-cled kinasesuhdtagoeas, Iomyeohist gangle ileume Bnundse fcetrtaraswntoi kinase, ttarascobaiompu,mi hic-c Bs 12campeedabsoydsu muesttrapesibst ofoiropopurhptaketsks g ilandzeysficAecy Perurf its ufui hic-c Bs 12cadc-xc ini the ismsexseninonatioof s o a deoconaullacketh utriic c facse . Beimdys2megalosinsosoflepanem a,ndamapesconwhiosdlfoin-nd diss odedion of act8atmnyellutheratth5ee prscula inter Pelae ysl l a r (marneciaem aieata)e Optsmula, wr ua ctioCertoig la T-d omaoistration. Its lowayenucobai-inamt mtiaold oxycobaiompu (V hic-c Bs 12aul;tion t pe low-CNmssur-OH group)tinApther n of ACh,sibst of a psfir rmar-insy vin. thetn caf lic,emariropynradi.ruFmlarsAgano(B)e Leaf imsgettaugseaand oiropoo fi mesinmsslarsrgano(FA) stral-re-nd mulanc P ri gas ismsate x. 50 μg/i.hiPolyglutxerts-FAsinmssod teaold olyzan anonwonoglutxerts-FAsp iat toabe dirasg ettrbe meFAsis rat lstiug. C phytnon edf -xcii the itthe a: e sut ini tt utake,amai-ina trpts bn gatioonal absorptdicfferm,pti afferennc P ri gass enraretp yg in theDeAa- epiugpmonnroduc (miniytot ,diphemid ni,e,iniobarb onl)2giveiesed produhFAsa trpts ,appnsumsocinlyeered b of dir ie fmusf gangliowonoglutx-toatni-FA. ion of exocrindiold o-FAsrsorshe oduh ametlye-monotrexat ctm 298)ladee, ley re-ofmusf gangliothehrnclveer pecaos,-tthe old o-FAe Stictomcety dc-xc ini the se ooegalososoflepanem aeaand whiosdlfdamapemembrc ua ctioCertoigmeeculatration. Its lowFAsatct mssla rtclygano(m 298)Mt cnsee ini the ismt phyu2 rinirs of acety diold o—FA— he acotinAration. Its lowFAseimimasknauli hic-c Bs 12cadc ini theD V hic-c Bs 12campersors P rid ssurposectiv d ise-up-moniutth-toraold o-FAss andhe old o-FA,rhe mesrse ifrntoolt ssurDNA Pnposslsg(B)e Iry ne in gangliothistn caf limduem- Bs 12cadc ini tsed yeachiinac ity vasbieathi afferenFAof utake stralanem aeistn c lyicorrl ebi; tcoits act are edion of act8prog y - ths8unche teetreasetsrf its ie mnicat oe odit int Am- diagn nitrinlex asg eteh re-uph ? ta inter n t pes. CNeira. crd fromt its ufuFA-ed witaretmt Aiv -xct c-c prz- ptaly08t iettrs tf is,itatelogynul.rd138eAa- inem ccsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- inem cc 139tiBmeV hic-c Bs 12 peganmsslomt ic stateem tA. Erytincpoice rgihiicre m rrowicAeropyn ew lsrgedissmoglobed-r me ahcytinc x- icAecew eses dissmoglobed-pooj ahcytinc x- icHec3- C-ioTaras-cledbaiompu IIhiHClymi.p.ioP ictulrmbra tSrrcausmys- tg i eus TSttrape Msuppled puic3 years V h. Bs 12casee ini theruFmlmul re ini theruion of exocrinDNAthetnposslsca cbraimt Ailoccmu C)ngion of exocrie homoglobedi Pnposslsngiron re ini theruV h. Bs 12caIutriic c ofacse ruFmlarsyganoH- 4d DNAthetnposslscaHec3- C- FmlarsyganoH- 4d Hec3- C- V h. Bs 12caFmlarsyganV h. Bs 12caV h. Bs 12callmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotiniron CsmpoundsinNot es otr bn of ect gassod teaequnat-edf trbpaug. cCOvil tt Feec3+in s onon takev upte synap- scutculaatlieumcaidtenteses oboitl,ehecauste-oi vil tt Feecd+in s msrktllae otest f trbyt suptaketsie pdepoesistectet ini tt ust of a psfie homh (,at thed thomo-hrosteyoglo-idnit)e W p ust ofwhiosdlfmbras ty posegus,catr bs txidlzhdrenegeibstanre oy teavea on roof (ses n mow)isuapUsadvaorse funcintaraswntoi kinase,rtarasn root,ensβecepton:l-cled kinase stralam e cf trbythdoea onon eonaeda, thenaedbietoabaioh re par- ths8duem- epi whicer hed deoe synakd ateostehiosdeentihe oerhject(so-cmalechi“whiosdlfs). N”)e in enpy oed am e e ismsate x. 1 mg/i;ed two enpyis ismsa-ure x. 2 mg/i ( ene Toa oessels par),cledn apothpupiconstars 10% (e.g. dic-xct ry utake straltarasn root-tr ctosisth xnuhdtagoeas, Iomyeo of hptakersmwitectcn- ecytincsosofsttpli fu(“lzydsu muehomoglobedi PnposslstinAtars 70% (e.g. totuieb dyr rsfie tr (~5 g)elsoed wit loe pnheecytincsed ytes. Winisposseose oteon bieathmaf-inooelogangty pospormonulo, Io whicerca wononuelyaurdbagc x- ) o abso,mirasng s oiaerrgythe synhomoglobed. Feec3+int isobab a radeasfsroof (=i kinasemsaofsroo in gn + Feec3+in)entirs urnbietoaerytincpoice rnesiteasmialtarasn rootficAecy Perurf its ufuiron re ini therulsoeob- rt essels par8duem- natiooc/iT-d omabsorptulconeisurpum 1 -Onofoiest ef2 ressurmog wit 5me mg ufuirone Dzspits aseeigntionithed produh thst trpts peca upt- 50%),hr trpts bitunpblem- keep upte pr parene adr, web dyr rsfimirasngfes te Cron re ini the toat Atut mifrRate thetnposslse-uph ?oglobediditianem ae2). T138).rug do a of gastricchoi re(ngest ngle p its ufubleehpupiheasopeancnundsaand eed fromtl) ctioCertoty pospoinistrati-nd n. Its ufuFeecd+intampoundsrr ametfneg eraemsat fceps(da lyif nit1me mg ufuirond e P vil tt - 3me mg ufuFeSO- 4d ,idivioan acn- mt Ailoitf nis)e Repres shpupicae tr rs2givetaketonvsculrwonthstinOculatration. Its ,n its actisitrvis-xct geaemsit , theyt bitefr hyperse- orop-tiloadr, web dyre prtr n ncreasas u-xct cttehiosde of its lowetsr ? nd- yg in of bier trpts (whiosdlfs). N)tinApther n of ACh stralcy Perurgan-ic aonal absorpteded ri-rto)epinatiooce pdot,ed in tea,l ofcnipvia a) imcy -rre-of utake ufuiron prz- ptaly08e prntiafton mea t,ealtpa behr trpts bit mncon e synap- eictyr me,heioIal aonf licDeAa-ygansse n ofubirond r trpts ghC mneroms releaasednbrtclygano(V hic-c C),h purdesnacxpupiFeecd+ine syntxidr the to Feec3+in, ie osoundrrers paonf nd.sssmpeestenaedbi.ioP enomaoistration. Its lowFeec3+insdltsgisse dby thefonssit cnsrdequneomeecularz-hihe gas ismestet hypersmembrcein s a iskpathoropdo jecre prtr re oy in gangit ,issucs8)h ?oimdyrohis) straidnithpupit uan (e (e.arasn root s oimi bd2 ganms e. Feec3+in s Pnxofmembrcef is,iFeec3+int ith x- rdisem,loyeav, theceptdo in A. Feec3+inearasyt-te fuarasn root oriobisobabdbagc x-osbieathmafooeloganrr nasinsoion erhe to inat trpoof ect gto fsroo in gn rsrnP hyperseapther n of ACh rdi,ide pri.p. injects : p oCergas pwitnatdingl najects sits haskluedssp.lpur the;ide pri.v. injects : flushpup,s rmowana. vesietana niumnf n etocgfic140eAa- inem ccsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- inem cc 14eptFe III tA. Cron:et hypers ncrts5 on pration. Its ganms epssk pospoigf ismptFe III-SdltsptFe II-SdltsptHl r-FeecFe III tFsroof ioP enomaoitetration.of acthii.v. i.p.ioUptaketsks gmafooeloganer pleen,foirop,iicre m rrowicOaoite utakeptFe III tA trpts d Duodeniptiupp jejuniptiUptaketsks ahcytincsosofinbore m rrowicLpar8tincrea tbleehpupicErytinc x- 2 ressuioTaraswntoisthicseigHomoglobedigHomoimdyredig= aggdonw bd2 fsroof ioFsroof ioTarasn rootptFe III Fe III tFs III-t ith x- ptFe III tllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPrd niumxine adrT dc uaeth Ttb-mbodusatUpontv- c ofr injury,atrsicoaguloms Ss abso is td simult:8tincmbo x- aeagafiap.npmbneesies2coaiescetsks ga “plugro p2, 148)smenttonal re-oien bes adrhdltsptbleehpupi)h ?oinesis) sUnimcy aayrdfmusf ganglioas utriv- c ofr clste– asetincmboslse– achiina ife- in f btaxa. Cfintp- mlstecn. setg anhrbstaomicaemicthi Peh thsio. obstanU pCx,e yo dry lte ufarf the bitefatninh; a8tincmbemsit acadcep leirusie achiinadsslodghu,r frCien acn- a ludira pCx,e pocaits c ith t capurpdepoaaires rupts hf pulmobsta2 ressurf ow (pulmobstasemtateem)tinDoduc mentted produhtrsicoagulobilsistoxaon ressu,ss ncreascoum rit adrhap-in ritg2A), rdisem,loyeavssurposerrd nisedlaxitoty pob-mboduse CNSed of li,ent-d omictsso fnsrl ebite b of dir ie ag ingdonw s hf ressureof bh t ,rhe meswceinpc etninhectcnvolvect ga utri-U pCi ltepob-mboion si08). A148). Fsurpose, wr sistyoty pob-mbodi ,rroduc se oubradmenticdsssolve t of iap.npmeshenrk→ iap.nssinpdgans02).A146)tinAahoropviewensetrsicoaguloms Sc- cads hasits5 on potentoforncsum r-nd d adrhapaoot s etowngit Amembrce wceintw waytee fceluidteetrsic- cads hi: 1)ic snv d ise-upfacse XII cconttsirnclveer a ps(XII tain, iutriic c s abso)te driv- sed fectssitssr nudbieri e Io whicum; 2) t snv d ise-upfacse VII cconVII tain(ext iia. vec s abso)tunterhap- na Neh re-uptg ilandzey-dpCOvbielipd kinases(tissuchpob-msinsoe mctit)e Bculatm of ism5e snv pe Mmialfacse Xtsks ga csmmorf iorptc acsinway.rug domlst dirfacse c se o kinaseat oneesies. “Aon of gan” ?oinlye-mapse kinaolysi08)csokeags hf pkinasesotag-ancmntsorene,oe prtrsieonap s hf iap.n, t snv d isesks gpkinase-old olyzpupicinhi- s ),rdtfferm)e Some td simult ofacse snnc P rirposerreteh re-upelossisthatepanss(PL)innes becd+inssurposiurdesnassinpdgantion. theghC ucesimbly,a becd+in uld tcaits ie adosslise-upfacse s ga elossisthatepanss rface,hrabre ic ect gaCioPlossisthatepanssmari-d wit lo-c pof bh tpfac in r 3s(PF3),rhe mesrs iof vasdte synag ingdonw eureof bh t ,rreaseo tissuchpob-msinsoe mctits)B)e cent Peruitation. oms Scar evsculrinhi- s rllow re-oaf is-ancmnts rennconf lices g“snowbrll”,r ul-toatnaAion edima -defd by gangli iap.n p2, 148)tinPrdg y gasensetrsicoaguloms ic- - at deeachiinat n ofupdeeasfsllows:ti1)scoum ritndpCOvipevss0ed produintp- ressurmogeeMoto gascety nae, wit fac in re II,nVII, IX,rreasX, rinirs of dir ieirthetnpossls; 2)etrsicoith xnctioCerpupicae hapaoot ditiantipob-mbpu III scutculiz- ths8poserrdtffertion. theton potevrgytheac in re; 3) becd+inatRlar re ppnvposiposanced hi-agantion. the + becd+in-izaethposieac in re; tl toed witnCOO-groups , thenithid becd+ingasce(Ci: iitrcep haEDTA (monisinpon y etnindhe acetarsygan)f a pshoiusinsosicoith xeaoe pr becd+in; oxalneo8d esed lpirre-ca becd+intsse soiusosicalceip8oxasedlas . CtRlargasense becd+inalorotiinas an assurposc use of of oduse of its becd+intatieMoto gasaoeoulddhavheto inalow- thrdvan- -eo vn ct tic apers e pr ife p2 rmoaalcem candhanysrncens octosistoundsd( tiip8sdlts)vo ettrs tf is,in bradonssi purt ndnlaretressurt tagusedlaaugmcp.imdyetoseb dyfic142eAa- pob-mbot ccsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- pob-mbot cc 143nglioion of exocrinmlst dirc- cads itnviv aXII XIIa aXI XIa aIX IXa aVIII + becd+in + Pl aVIIVIIa aXXa aPrdpob-mbpu II IIa Ttb-mbotptFiap.nsneana Fiap.n pBmeAon of gangliomlst ditiphi bh t E Io whicercaien be Thssuctepob-mbo- kinoduinV leylinrupcadisuClst dirfacse suCOOse-ecPbospiotepans th ametPFec3- Cbecd+in teloms SCitrcepicEDTA Oxalneoin . ion of exocrinmlst dirhin mova c + becd+inStnposslsesusnap serse- nd dn of exocbyscoum rit aRvpotentosusnap serse- nd dn of exocbyshapaoot- u a- pob-mbpu coith xptFiap.n aXIIa aVIIanVII tXII tPFec3- sid bec+se–se–se–se–se–se–seCOOse–seCOOse–seV + becd+in + Pl a becd+in + Plt(olospiotepans)sullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinCoum ritnDpCOvipevss02A)ruV hic-c Kcpc ervhs8posehepice γ-con-ndboxylo gastoi-noutxeat oasimducs8ogangle tey,urs acety facse snII,nVII, IX,rreasX, smadsorbeditn be loaubstanpkinasesrr amet aoorsnasesC, pkinasesSetntioan oaalccnghCarboxorsyl groups o fio P rid ssurCbecd+in m y t-d bieaithpupiconplospiotepanss rfaces02). T142)membrce wcer evsculrv hic-c Kcdc-xcCOvipevss0ty di input rnrigsos:tKad1 p2,nisinto enads r)te synchas d niulaemicthints;tKad2ine syngutVbpcs ia; tastKad3ca wenads r)t Pnposslzhdr tem wcerold opiobs renegnc P rirb lofonsistdsmssuras trpts ginOculata- coagulodth. S Tof ads ss o Rlars pconv hic-c K, 4-old oxycoumosisp.nsirncedit“false” v hic-c Kcn. Seprvgase rdion of act8atm he rd (e, wit) v hi-toatn Kce synv hic-c Kceptxideethoh r ot ofsytposslse-upv hic-c K-izaethposinelst dirfacse ctinCoum rits o fsorbed trbythafton eculatration. Its e Tosidnenre neethtetd sontv-Cie octioCiertblye Sttposslse-uinelst dirfacse clizaethailnfuncn drihz iscar x-arstatieMoto gas to gacrinmouorsmwrits conv hic-c Ke centt nitio P rid assuranhrdequneo8ta- coagulodtee suchinrh tiateedttrtheydse dbvmdusussissud bcahs. aieru ( r-sts.eeprdpob-mbpuin gmesrnSes Peruly,atrsi. aieru rh ttetv den t paretreet ry ctioump neethtethesdrmsgettaugse(-ltelneesisd nv hic-c Keo vn s),oivf psesotsynaaNaretad of liercaioduc lik pyttplaan bestt trpts hrseed -nd dIts lowatum rits (-ltelneesisd nmouorsmwriteo vn s),on. Sroti iskpirs of diicthi bh tpfal memb rinirg a diracetylsdl -xciylarsygan.rug dommmoiifrntoolt apther n os on thhysfbleehpupe W pwatum ritspy oed tachiinac e aonfbieathgevion v hic-c Kad1 pghC agulobiltoxaon ressu is urnss,o onoCmdaionssingest houneisurdayt,vt cnd t ofoiropoheaspnsumbiesytposslseenegncg eti radsut ini tt essels vn sgliomlst ditifacse ct CNSurgerurf erm, re ini ttrfacse cinrh tiaterepres shythdarasyt-t ametlyintaras vesigliowholsresselsor hf pki-tepob-mbedioouieMoto e)tinHapaoot hiruAomlst dirfacse is td simultiwinispostifacse tn be tey,edys2it ust ofmlst ditic- cads splirtotyuptgpkinasesotag gas oand enare duex oduse a nhi-agantcenoma.rug dohi ttan fnnagaihiinat td simultienic-nd a intercinlyecoith xarete prta- -tepob-mbediIII (AT III),ens esc of sretn:l-cled kinase sHapaoot acttee fcen ofubmlst in gnirhinacceneur ion ea sf gangliothed taoith xn oe othept1eme-fold sHapaootin s ,at the(tsnebstane prr r sthey)h ticngl vsscelys2-up-a timbras;nttsienic pH a - at s rolsrbitunelyaumembrc use ofercins an ahapaoot s ob wit loe syn-orcreepgutVsud bovreepludi sHapaoot mbneesies2wceinn tiipoth theom tgolse oalaret-COOse–seeneg-SO- 4d groups; tl toed witnsate x.ad10ee f20ensetrsiunetsr ic ect ga hi; meat mbneesiaaneeeser,f20,emeDeAa- ci-teagulodtee sinahe v-Cie ow prthwittiresgthe centrowanceton p prz- ptaly ctansoolddry zect ga utohbsf lieriunetsrthtetd s the (IU)eathbioassaynditionmla ig ett releaa atfneeh reprz- ptaly.rug donumbraemsnenipevss h ges2wceineigntionithed r evsculr vely, s:e(1)ntl tintat oiburhse funcnpoojsy of thchtse onthe ben (e—hapaoot s reee in libet cnd satlibieathitapoinisncrtsisurp pesercinat-ic funcnsklueeosteh tiateinjectuc;m(2) e -ic aonf he to oy to elyich gels ic n oasisistducs8 s revolvect gac ith xncn. neesiide prATIII;m(3)ntl t p mit nithpupica ahapaoot conttsira- Io e,hlid sthey p2,olyf ti- rtgpkinasesotop8sdlm Ssp m)tinIfhlid stheyectnihe g d thopaoot-inorshe biealeehpup,atrsi such rfrhapaoot se ifm y trang Rther d.ruFmrive in libepob-mborrd niumxin,tned owtt nitrfr5eme IU8 s rejectuc s.c.rtwoic fun e. tgmisrda lye W pw owtt nags hf ahapaoot,atrsi iskpathbleehpupilsesuff -xcii tyt-teses otplallow t of irmoiinjects ic fateihe g easestecteas2 hsp iat toas r-edgerye Hmnconrda lyri.v. doheaoo fio P rid as gpknvposigrow prniomlsts. Beimdysptbleehpup,aubstanpowanhls trpther n of AChint :emalerintnnconf lice amettincmbo x-ic pavia)innesw prthrolarsrration. I in gan,g Rthersersehaidn osseenegoan o-oroa. ves. T144eAa- pob-mbot ccsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- pob-mbot cc 145inHapaoot 3 xr5eme IU8s.c.ad30 eme IU8 .v. pBmeHapaoot:rnrigso, e Tof ade,hrostem of ism on potentnglioV hic-c K-ists.onCertoty pospcoum ritnt th har hic-c Kd Du Its ca totent/dayte Carboxylo gastoi-noutxe n oasitducscaV h. KndpCOvipevss- 4-Hld oxy-inCoum ritndpCOvipevss- Ad simult oclst dirfacse suI td s-in oms SI td s-in oms SPid sthey pMa timbracaV h. Kad1 pV h. Kad2 pV h. Kad3ngMmnads recPbyto enads recPbenpc coum SWarfaootinA Niocoum rolrdII,rVII, IX,rX ---- ---- + ++++ +++ + + + ---- I I ain, aIX a, aXa, aXIa,rXI Iain, aXrdII I ainAT III ++++inAT III ++++inllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLow-mbneesiaa-eeeserrhapaoot (ke-icerapesMW ~5eme)oheasarpossiblenre nee fir cts ganmnaedsttpli fihe g onsse fdcerda lyr amet y wopaoot,ad-ltepaoot,icinoxapaoot,a Rtipaoot,atinzapaoot)tinFy Perurf thoo mcatc agulobiltoxaia onon imcy aayte pr pw mbneesiaaadsoeserrhapaoot reaseoganeh re-upimdye o- on thes(bleehpup,ahopaoot-inhe biepob-msinso x-opavia)i s o ssecy Perurtheptricyclunfaonf hemultihopaoot.ptFiap.nspdgantT dc uae2A) s cn. lootop8fiap.nsnea ttrncreas, b-mbedi(facse tIIa)-f talyzan a kinaolytntnncmova c + tw oligopaptsicatotagmposc. CNeivmdusu fiap.npmbneesiesisctiymbr zetsks ga iap.npmeshv, thecepsobab plirt gto ftagmposc or edissolvedtlyinthicsse sPhicssendpCOvuse y kinaolysi0ine synas ue, wit tey,urs a,nplicsseo-edgee sPhicssesneanad simue clachiinat fug eteavssurposerof odu0ty dissolv dirclstsin(e ametd snyo dry lninfarf the)membb-msinsolysi08ismestelik pyttpli fsuccy furiun-ullrisothehrnclvmue clachiinaihe g ropynso-ed ggest ngncmbemscn. neesi surokinoduinine a ndsneaaemsphicssesneanad simue ed b wit loe synnt Au radhum n kidneycahen s.surokinoduhysfbotest neur gerthepininesrrcauskinodu. Bynttself,atrsihi ttanisinhnhi-agand.sssmue, wit;ionssingest binorshpupiconssphicssesneanmbneesiehdoea otrsicoith xnbecome ve in libeedioou-in optiretphicssesneans gphicsse sSrrca-ic kinoduhysfd by bieathsrrcauscocitainbpcs ia,rhe meslrobnelinacc e sissud tralcy Perurrpther nnconf lic sSrrcato- kinoduira- bon n 2given ,at theeasaat at Amhf pkimuestrcauscocitaninfenf lic pBithpupicons ncrea- bon n 2eoulddneu-ic ao發zyesrrcauskinodupmbneesies pW pw-ltephice,renubstan ndsnee onaemsphicssesneanad simue s(tissucinthicssesneanad simue ,atPA)rine v iltaug pW pwenic pH a lllatatieMoto gasaothed tad simue spatfneehhls linactailnfthicsse-ed neanbnundse f CNStatieMoto gasa ontedbiessurposc use of fiap.nspdsiaothed tpatfneeh re s ommoi adr, we iskpathbleeh-nd dirdoeasestedi inp releaaltephice oand srrcauskinodu. Altephice rs irbsta etorn-d oirod )t d simuexocbyscoith xarete pinthicssesneanad simue nirs of a, PAI)seeneghasttpli fsatlibieathin vesie Retz ischice,r its acted witaretonssingle teinaolytntne, wit te, tliothehrltephiceat oneesie, rllow oe osone“e thicseig vn sg pocanli fsatlibie gass psfirtwoicinjects smse fnnt s va c + 30 mitrinio d simuexocliothehfiap.nspdgan Ss abso canli fs,hitvhueath“plicssenered b of 1 ,”ss ncreasε- theocateiarsygan,dip- theo-moniubhnhoarsrgano(PAMBA), ttaraexamarsygan, ditiateinitar,rhe meseeve aonb of saubstanpkina sys.rdLart pupicaresselsfiap.nsnea ttatieMoto gasDeAacrod teaa ctionitugasinty pos8us amte syna Malaytianlpirttipma.ruIt hnhi-agand.ssscsokeeeaa ftagmposine synfiap.nsnea, toat Aion edit of a pv-in the on p teon f act8proby v, thecep- onon uhdtago ctiymbr zo gasDeRe of gasseihiisselsfiap.nsneaeo vn ced produsangle p.agulobiltoxaon tp- ressu sSian- iap.nssinnean(MW ~340 eme)led oibu pese func Mmisysimoxaon ressu,sanfcmd oprct“ Nidsistox”son tp- ressu2eoulddinatxpectuc pBcula of ACh rdi fe Am- bs ufubenefirt gd tral a of gastriccy wainot ttid as ef2 ressurf ow. T146eAa- pob-mbot ccsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- pob-mbot cc 147nglioAnclvmue clreaseon of acety fiap.nspdsia; tacrodptFiap.nsneaptFiap.n aTtb-mboteAacrodtiphicscntiphicsot-inn of ac th ametTaraexamarsygan urokinoduinHum n kidneyrmbraict Au r tSrrcauskinoduinStrcauscociiPhicssesneainAa- b dyre sydiphee nirfects icFts acinn in s, u adri td s-in oms Sllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIutri-U pCi l Ttb-mbemsFa sf gang2A)ruAon of ganglioeof bh t ,rh ametupontoou-int cttw prtollagn,son tp- hot ane fectrsmw oixingest injury e funcnv- c ofr wd.s, t snonituvhs8poseifm y trs oded islveer tept ga uluidt dir ie pc crisohf pkimsta2 h ?oinesisiei.e.,2cy a s hf reeehpupeinH its acticnthehrbteh re-upv- c ofr in-injury,aeof bh t canli fs, simultias a andze Amhf damapesconposancIo whicerimbracalitaretoaresselsv leylcDeAmodir ie mul-toAiloitfal membtoty pospe Io whicum,ingle teiby gangli NO˙8n. Sepdinecy lsoaeofyte anfcmdntoolt rolse Bculases (gan-smered b of ttral lthuthe lioeof bh t iconsdbrceinconposancIo whiceris rface (thi bh tpadsisosslvon ss)e CfrRat gastric, Io whicercafal memb,rh ametduem- throlars rmarwana. vesietcigrdi tt smskini,8ehrolarsbh vv-in the on thicse LDLs vn sglrtoaresseltin:hiose,ed produs8poserrdbobiltoxaonintat wctnletwesdreof bh t ienege Io wh-d oiume Tie adosslisepc crisorevolvete GPinIB/IX ,ensn:lyspkinases,at thed tngle thi bh tpcbraim of thch hariseWin h-d f thdt’srfacse ,e a nds whicerim o-d f th o kinase supoa nds whicerioou-int ct,atrsi.hi bh tpis td simultiweleaa atandze Aaet i t pesibsshath haaff ulue ,oinfiap.nsnea sPhi bh t ierofoinkbietoaeameseubstanmialfiap.nsneaeap.dges:ntl tinuhdtago aggdonw aly.ruPhi bh tpaggdonw alyed produs8lik e anf v ioh p- rof its, fdcertd simult,e thi bh t canltd simulaubstanphi bh t -Ondingl naju radncIo whicerimbra,nssphi bh ttepob-mbusgis cn. l,rhe mesobe Tof s2 ressurf ow. Ultsmutran,funcnv- c ofr iusinmet s octhe aieathitappob-mbusgasangle hi ttanisshoiidi ibieathalv- o snonrincludd r by bieath, we of vase-upiekinola ateostpob-mboxth oAad2ine syn ie aggdonw -d biephi bh t -Winisposseonvposssl a rt gd a lsrgerio. obstanU pCx,etrsiconssors Peh re s asnyo dry lninfarf the; in) ovolve gastricaccy ebculat pCx o a ss,o otiookcgrug dariseWin hf thdt’srfacse aeofytsaatkeyrrolsrbn pob-mboion si0. Lacketh thed tfacse ah hass pob-mbasactnnt,er c aco-xcH a lllt-tde afferenphi bh tpaggdonw aly. aRvlipevssre ini the ty pos8uiseWin h-d f thdt’srfacse canli fomicorar lyrorop-ticome ath, wev- op y gt reH aualeddsinmop y gt 2, 164),rhe mesrn produsangle of vase-upav iltaugmsacse e synabtrape Msitss.ruFmrmIts ,nAon of gan, ditiAggdonw alyinty Phi bh t i hiruPhi bh t ierigsor oeathbudhpupicafre sydimt Ainuelyatt tey,urs aimbras,etrsimh-d gakstao ytes. A re-ocses est cn. ld eee gastricressur(y ld1–4 μm),ore,yecepsobabtd simultibe v-Ciaemsalat oiioAnclvm-in the thii sg -ltelneesisd nshath h etecormohe on p iekaeaoatmheselinactevsscesg etislceh,sibthe pupiiekinola ,nphi bh tpaf-in tva dirfacse (PAF),hADP,reneg ib-msinsoxth oAad2in. CNS,urn, rll ty posse canltd s-in omlaubstanphi bh t ,rhe mestxplwit re-inhoplo -defnf adi8ty pos8pc crisgrug dapkimstatctioyqNeh rton potevr-in the teaa cticn. neesier n t peglioas uorsnagrses,at thed tnglnphi bh tpm o-d f th ,fnfmran,fGPIIB/IIIlioionttsirnclveercticn. neesi,fGPIIB/IIIl etowit mnc aos on ulue fermneap.nsnea; bcahs.hi bh tpcou-int it upt- 50,emepcopieh stral mnc thicorsmwstatieMoto gas ty fiap.nsneananeg ie u mnc dy vinyety nanagrsesed tnglnphi bh tinmeof thchts mit i uiencross-oinkpupica aeof bh t ienegfmusf ganglioanphi bh tinplug. T148eAa- pob-mbot ccsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- pob-mbot cc 149tiBmeAggdonw aly lioeof bh t iath, wenanagrsefGPIIB/IIIlngMmgakstao ytee G:lyspkinaserdIIB/IIIlngFiap.nsneaptnithpup:isct eveneseeme, evenesePhi bh tinAdosslisinAggdonw alyinPhi bh tpriseWin hf thdt’s ofacse ruFiap.nsneaAd simult ophi bh tinCat wctne pintollagn,inADP aTtb-mbot aTtb-mboxth oAad2inSekinola atA. Ttb-mboion si0ruAon of ganngFiap.nsneaptdys al membranncIo whicerimbracaAd simult ophi bh tinllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIon of acety Phi bh tpAggdonw aly 2A)ruPhi bh t canlbabtd simultibe em of iitainor edither n tem nd.salat oi,shoms hf ahe me,rh ametpob-mboxth oAad2inetpob-mbot,iciekinola ,nor ePAF,irncemialey,ep acetndingl phi bh tpm oo sucghcens oey,ep aclase ocouplbietoaGrs e teinait reatpm y tr tad simualy lioelospiotepvaseC adrhah r oa isbeediox-osmlars becd+intatieMoto gastinAmodirubstan apoterm, thistnisbeedi becd+innrigg as a cticn. neesier n t pega atGPIIB/IIIl,rhe mesrs enare du snv tid as gttsifap.nsnea-nithpupicn. e CNStat-ic aost,hADPbtd simulsoeof bh t iathinn of -nd dirady ylyr nychice,rthusrf ition edtop-tiier nAMPs vn sg- de affere Hmnc nAMPig vn sgeoulddsr a“l eatrsi.hi bh tpinnttsat ue, wit orre-.sFa sflan,funcntw mddsin tgerises (gan-s, becd+intastnAMP,ecepsobabctioCierbiesal membranists.onCert.ruPhi bh tpaggdonw alyeachiinat n ofu-d bieayracetylsdl iylarsygan 2ASA),rhe meses). Nstpob-mboxth osytpoice,rpurey atandc mnerothehire pu (erigsorlt-tlogvetu-d biee synleemessdl vstatgiohd),rhe mesesithai adri td svr ecitincmbed. A yes,canorroduc se oav iltaugmssurs). Naretag-ingdonw s inhe bieathsekinola rpurPAF.inADP-inhe bieaggdonw alyeachiinad esedvs oaiath,iclopidliknditiolopiddg yl;dinglce ogposc oralao rflaletcoey,ep a is-xct gonCert. ADP-inhe bieaggdonw alye se i n ofupdeotectcnnviv rers ao rd nv hroga atti radressu; oe os actfdcerinhe bi,nd dn of exoci08ir Rthersersr Aot hypers ex ischinmu Cgiss, thenculaogposc oln c y acn-erfneeiweleaeee gascety ADPbey,ep aineignula,arasby gangatetrsimhgakstao-xciyf n etapemembrnncsupupical membrandc-xc termeoulddactnli foarasyitrs pconnewlyrdfmuseureof bh t ,rhe meseoulddinaibt isc bugmcar Rtherson etgrug da utri-.hi bh tp vn sgliomAMPigachiinasr a“l ede y kiinecy lsoae niChintbra auace ametilo kiin)rpurey dipyridi-toaorsmembr cn. rbtd simulsoady yl x-icchiceemiala G-pkinase-couplbieey,ep a;d t ofoi ttaninb of saaoelospion n herodud t thenn cNstdowngmAMPgrug da utagrsef(GPIIB/IIIl)-ists.o-tiiCertopknvposicross-oinkpupicaephi bh t rug dirr cts isse dzaethposiliothehrg-ingdonw s -inhe pupiirs reusr Abciximsbin s a chimbr cdhum n-mnrareowonoclo-tiier aa- b dyrnsrl ebitegaihst GPIIb/IIIad t then). Nstpoe fiap.nsnea-nithpupisitsateostpoutopknvpossmsenech gastricf -xcap.nsnea sg dapaptsicndpCOvipevss,rhp s-infiaatsicneostpirofiaanen). NfGPIIB/IIIlngc ityt to ely, oe osely, wi pytnneghasedvsea etornbrn such theptdoeasabciximsbtinPres abso cdE such rfrAcetylsdl iylarsAgan hiruion of exocrinphi bh tpaggdonw alytlyinASAgimmduem- aosely, wi en). Nads ca aeof bh t nychooxyneaoduh B)e Sely, wi heinty pois td sas toat Atue synacetyle neethtepois inhi- enraret, wenaihls tpUsaags hf atrsi.hi bh tcitincreasspioh p rt esseledvsleylcDeAcetyle neethnposanchi- i08irsispRthersersr ASAs,at thed tnglns abso cxciisc of sonrdoeasesteeofyaa aolsrbn .hi b-ullr b of asDeSian- ASAsuhdtagoeas,x- Mwand it teys abso cdeed fromesietcyclo-tioxyneaodusmcp.imdyeeof bh t ,rh ametnheenorsho whicerimbras, tomwitslsrgecinsnaan be-d bi. W pr vg ofr intake,aeely, wi he is insisogan-iesarbstan of its thehrnuelyau aeof bh t iee ounpblem- eys nposslzhnnewicinhi- i adr, weed, thee y ore lsoth t snoecupevssroheaoo faddbietoaeameseubstae H its acticnthehncIo whicerimbras, udalaov rsytposslse-upposanchi- mar-inmirved. toto gas ty epdinecy lsoae by -in thetinApther nEare lsoth Aa- eof bh t Doducsuhts wa- eof bh t roduc d produh, we iskpatptbleehpup. Ee g etetrsi pw ASAsdodusatubradm fcen ofubthi bh tpfal memb (100ecmg/i),rulconsneas renegbrfdchotat-iconrince (aspaxcg eathma) ore lsogive0nsiscuumemiclopidlikncy Perusssc hass d ined rtearene,o oe oradily, leukopaviact asiscy -rre dircy a s hf a of gas. Clo isciddg ylireat tidlyif easestef its hsorsmwta inter rrdbee stinAsapaptsics, hire pu haabciximsbinnebietoabteinjectuc;mtrs tf isr ieir uduinined. tric ectm fcewand it-con oset dis.rd150eAa- pob-mbot ccsullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- pob-mbot cc 151 tA ciximsbinTirofiaan Eptsfiaatsic Hire pu tArgsexsaan lioion of acety phi bh tpaggdonw aly tArs,hido rtclygantiBmePres abso cdio d simuexoclioeof bh t nychooxyneaoduhayracetylsdl iylarsyganinSekinola rPAFatGPIIB/IIIl [welecp.clyfn ulue ferinfiap.nsnea] aTtb-mbot aATPecPbospioorshpn herodud DipyridiaorsinASA aTtb-mb-tioxth oAad2inAdy yli b-ulnychiceinio d sieoAnclveinADP aGPIIB/IIIl [Afn ulue ferinfiap.nsnea u mnc] aOseCOOH aO CCHec3- miclopidlik, Clociddg ylrdLartt nitrfclygetyl-insdl iylarsyganinPhi bh tPhi bh tpe pinacetyle edsaand by teeulnychooxyneaodusullmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPhicse Volu- Expahdtas pMajsurs).els par8 thii sgtrsidatgerirfcl ife- in f btaxas esc of e y fii ade,hi.e., u ypov lso cdetocgfsg daifm y trtepobat toat Atuestesonwhihte synap- parinty hcytinc x- iei.e.,2oxynear frCiers, smade synap- he the skivolu- liomesc -e hi aretressu rugodeed fromehitappob f othdetocg, atandpres shmposiliothehiisc of sonris ileys-xctita. W prmodeur gs par8on ressu,sad-inmiion. Its lowa thicse volu- ex iscahdta2given sut ini ttmeBessureofcseigctioCertobasesercinaf wr gactely, olytes, u adrthicse teinait e H its actareofcseigses (ituvhmnaedsestefd witneofcseigteinait e Tosse canln suionely atandpracltiweleamafoombneesies2(“? 2-xcH ids”)sment,8lik rthicse teinait ,e(1)ndo onon n c lyisokeeothehiisc of sonr haaceinpootectfilhe blsrbn poesion ctglombrreus; u adr(2) nith wr ga apossre prttsshoiu- icduem- tieir toll deosmo of rrd optiuse CNtepois olor actre,yeysl mwit witniisc of-ic rctfillaretp yssadi8ssuroloy houne -Ondingl ubstanhene,ovolu- ses (ituvalye se onssinarasi tyt-tntedbie adr, w tf is taoith vhmeed fromesi ty posse coll dmade synap- b dyrlsoelestectedd rtaug pCnmla ltiweleawholsresselsoristhicse,rthicse ses ( teachiinad by biem is trodipytnnegt lart cost,hhavhearpossibtheralfr ife,r haacems e. lioe aconeasss ncintsshepicef s BrpurCrpurAIDS mirusys.rdTn e. coll dmsmari- rr dtecteosisthoyeavas thicse volu- expahdtas—d tral wo ctiysacch sics, dhot ansaand old oxymoniuasr rme,ras sorbeditn e ctiysistaptsic, gvlipeetinDhot ans s a n:hiose ctiymbrrdfmuseurathbpcs iar haoinkbieathal1→6nd d t c iliothehtypeserl1→4iicrdghC msinmerccerisoiu- licefd witndhot anslowa meat mbneesiaaneeeserslow70 kDa (d,x- Mw ans70)rpur40 kDa (lart -mbneesiaa-adsoeserrdhot an, dhot ans40)e centthwittiresgthe-upimnglupmbneesies,r its acin oCie ow delye Sses er dhot ansmbnesiscuies2cchiinafilherbieetetrsiglombrreus u adrslarectexcormbie ganrare;atrsihirsibthon- rdisevposusussitakev upt oded-ingd bieathmbras ty poseormonulo, Io wh-d oieris absor Ate, te synd. totaretressu ovolu- , dhot anssoiu- licese oubradferinh ?o lu the skitrsimans.emgastridiressurf ow t ttid astinAsassuro iro esc of e y cmd oprsinmettpyis ismocitsembraecteophaslzhdrmenticlow-mbneesiaa-eeeserrdhot an, unlik e dhot ans70,2giveiarasyt-t he rothehrg-ingdonwbiltoxaon hcytinc x- eathalher dititieir s rface rrd optiuse W pwero-xcH ngelsits, lsrgerimbneesies2ysl accusinmulmul ruem- tieo oe orauienion ct,x- Mcormohe on re-ocses eriroysfhC u Peru-xcHn,funcnmbneesiaaneeeserslowdhot anscirsisc of sretihiisselsysl lthm- wardtsaat mncon meat mbneesiaaneeeserse prtrsiscasaags hf tgmi.rug dommmoiifrntoolt apther n osuchintoat Atue synthehrntineas toxaon d,x- Mw an ,rhe mesgiveo a m- antana niumn-xctitnnconf lieinHld oxymoniuasr rmei)h tasr rme)tsie p by biee synab rme. Bynmirtus lowetsd old oxymoniuagroupspyis ismic statezan a oe oslarectenegnc wit loeigntionithlyrdpossiblihiisselstheptroulddinatrsic- eide prin vednab rme. Hld oxymoniu etisrmeid. Umaugsedhot ansed tnd concae ttsienogy ? 200nter rrd optius oand enar use of satlif ti- stinGvlipee coll dmsctioCer liomrpar- toinkbiepaptsicnn tiipotb wit loe syintollagn,e ceny rdisem,loyeavssurressu orz-hihe gas,rers ao r muehomo lu the,nd ds esc of e y t tturbgan-s.rd152 Phicse Volu- Expahdtas pllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPhicse Volu- Expahdtas 153inGvlipee coll dmig= cross-oinkbiepaptsicnn tiip pMW 35, eme SCisc of son lioPhicse ses (ituvhtinPaptsicssMW ~ 15, eme SGvlipee MW ~ 100, eme SCollagn,sMW ~ 300, eme SPofcseigPofcse-igteinait icErytinc x- sinDhot an pMW 70, eme SMW 40, eme SHld oxymoniuasr rme SMW 450, eme SSucroseptFTof oseptBpcs iiptiLehionmmoocinmesenomaomdysptHld oxy-inmoniuf son Sr rme SPofcse-igses (ituvhide prcoll dmigB).els par888888datgerirfdetocg pllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLipd kinasesic stateem. Enomao-ed ytese of vased trbythtepanssedit of a pinty preslyce sic-r menn ylom irot e Bysistaletret, weoirop,iposseonnest nglomesc -e hi aon mwitectmialt weoyophr haacemnisind olyzan duexdrihzpice , Io whicercalipd kinasestepvassg- oiaerrgyms etyfonsistdse centremrothepdepoeugsemopr isesks d oiropombras adrsuppledposseow prthbnen-ic eoo mcatreet ry erigso.rug dohiropome tcitisihirsibepdep (60%) lowetsanc P ri gas fornchbnen eoo 2 rindalaov rsytposslsee synacetylconced hi-e-Ae Sttposslserrgymined.g of biertdingl tepto a deoe synold oxy-moniu-tin:ht rylAtlA (HMGAtlA)g- mevaposrtclygano(m 157A),rh prHMGAtlA he acointssposeoi b-oimi deonchi- .rug dohiroponc P risnchbnen eoo dferins nposslz deoVLDLspdepoeugseenegb lofonsistds. cCOslyce sic-r menVLDLspdepoeugseerle of vasct gto tp- ressu2ene,olik rtrsisn ylom irot ,rsuppledubstan,issucs8e pins etyfontds. Leftnlehi haacemLDLspdepoeugsd t theeibstanis urnt gto tp- hiropomuesua-urelduexdrihzpice ,issucs8e pnchbnen eed rol.rdLDLspdepoeugse frCymsaolipd kinasesBs 100, byrhe mesteny rdisbnundse fey,ep-in re reatpm y tr hptake lowLDLs gto tp-cahen s,sibthe pupitosehepicc x- e(ey,ep-in r m y tradncIoox-osisiem 27)tinHDLspdepoeugseerl pblem- uarasn risn bnen eoo df syntissuchmbras - LDLspde-xctitluse CNSpois way,nchbnen eoo diss,aras-clat tiddf syntissucese func hiropeinHl oplipd kinaseem as2cchiin tcaitsd ion gand.sss(pkimstath.) oriobisol a rt gotbevinyerostem statec t ttisindtas (seons stath)e Eh vvtiddLDL-cco-xcHen eoo d UsumatatieMoto gasaoerl psso-edcimultiweleaayed produde iskpathrbstao-igstlurosisievely,ls linwinisposre teaa ctiandc mioolt de lsosrbn HDLstatieMoto gas (d produh thLDL:HDLsquoaieru).ruga of gas. V-Ciaemsroduc se oav il-d r le reatphavhedi input rtm of ism5ethtetd sontenegeare lsotthLDL (chbnen eoo )seenegVLDLs(preslyce sics) 2A)e Tosidnusee se i dby thefedit oft dc uaeth pkimstathysistaplipd kinaseem ase CNSseons stathysistaplipd kinaseem as,8poseifm y trtinoer houlddinato lart lipd kinasestee-icelsrey diet ry d. tric esiet a of gastri atrsi.kimstatt teice,rpureubs.inDoduc B)e Cbnen yrxe n oditionnen-ic ipdl oralaonf trbpaugodis -exn t peintoait e Bynmirtus lownithpupib lofontds, atrsycpc ervh ctioump neethnchbnen eed rolvssurposesytposslse-upb lofontds; tp-ca154 li KTinLipid-Lart pupiAgposcrugaeslyce sicsoditiohbnen eoo drdiseleys-xctita ctionitugastoty pospoigf ismtinAmodirubstan pnhgs,8paeslyce sicsorz-atandz theeass psfiron ogyr rsditiohbnen-ic eoo mteaa basesrerildaretrescketh b pH a - at s m oo sucse Bculatepanssmariwr gand d oiusosienegnc P rirsate .kiomehiaras-clat t vehieugseicnthehrqueaemsm y irfcl yophr haressu sTo pois inu,ssses seem e sinse. uiense ocomultiweleaa layibthofnplospiotepansievmbytdhefedihe mesee faddof lier teinait —thehraolipd ki-rsnases 2A)e Accorhpupiconthehrm e cfand enascoitoy toneethnti radtepansieas sorbintssposet th athraolipd kinasectfdnadss-in gniu shys 4 taraswntoicn. s:inDoduc uasct g Hl oplipd kinaseem asinOcigso Dy vinyeMeanssojourntDiamdttr seihiissels(nm)isthicse (h)isC ylom irot Grs epi whicuma<1.006 0.2r5em VLDLspdepoeug hiropo0.95 –1.006 3 100–2em LDLspdepoeug (issel) 1.006–1.063r5e 25inHDLspdepoeug hiropo1.063–1.210e– 5–10 pllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc uasct g Hl oplipd kinaseem as2155inCbraim stateem lioLipd kinasesic stateem LDLd Diet ry s es LDLd C ylom irotd C bnen eoo 2 LiropombrainLipd kinasethetnposslsd C bnen eoo 2 gaeslyce sicsinStnposslsd C bnen eoo -ices gandgaeslyce sicsinB. Ctbnen eoo dic stateem sesteropombraoditiohbnen eoo -lart pupidoducsuB lofontdsoLipd kinasesptHMG-tlA-R he aco inn of ac tLiropombrainFetetissucinHedep Skbh t s mustluinOHinOHinOHinLDLHDLd HDLd VLDLd C ylom irotd remroth β-Sf n eoo 2 Grs:d C bnen eoo 2 a trpts d Grs::idnithpupiaand excormohe onidnilofontdso(BA)ru888888 Lirop:idBA etnposslsd 88888 C bnen eoo 2 ctioump ned C bnen eoo 2 ti r SColen yrxe n d C bnen eoo 2 F etyfontdsinLipd kinasethLepvasd C bnen eoo 2 Aaolipd-igteinait pllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinhiropome tciitsed produdeohbnen eoo ddsorsmwnn duenoganpupitoseexp y gasensptHMGAtlA he aconditiLDLsey,ep acla(nenipevssfeedba N)tinAt poseor P rid t nags,atrsi oait tcaits dither nnatioonal absorptt ttur-xcagan-s. CNSed of li,etrsyccn-erfneeiweled enastt trpts hf s es ganms e- oiusosiv -tepxe ns 2A, D, E, K)e ceny rve aad trbiaand ed produhtrsitt trpts hf s ncrroduc s icdigsPnxoi,ev hic-c Kcn.t gonCert,iaand eiuormonse Tosidngrietyftexdu rsditibulkrsmwketskg a tg anhunpf vaodteex op -teah r.rug dosrre dt,ilovasrre d (L),ssimvasrr-in gn (S),hliavasrre d (P),h luvasrre d (F), tcpCOvisrre d,r haa avisrre d,rinn of ptHMGAtlA he acoe Tie ad sieogroupensptL,sSetP,renegF (er tieir ic statetcs) atandz maugsen be loatrsi.nic pH a lllacesg etirrgym-upposanchi- 2A)e LrenegSierofoac in ngsen be ae orauieecte trbythbsingle enomaoisncrts,t to terbietoaexwand itinfirst-tale hot an the skitrsioirop,ioand enare old olyzsct gto ad sieoic st-tiotetcs. PrenegF rz-atsposiposae, wit fa pinene,oas acansiearsae, witssinarasat tiddlyina ely,lfs renalyeacrCier reatpmovuse ileclygansee synressurt - oiropo haave amh-d y tr re-ocely, wi ehzpice hptake lod enasmycoPnxoi,eamwnie d (A)e A avisrr-in gn htssposepossistnenre neeth onf lieinNa sflan vieweavas teys abso cdeed f-tiiememb,rht ini tt hzpice ,ot an theiciekvcese fctic n oposae, whe on re-ocrr-in gnese func hirope Dyspimehitapion of exocriptHMGAtlA he aco, hzpice c bnen eoo 2 ctirgas f easestefd.s,n of its hepicc-ed ytesec ityns trs atte .eediohbnen eed rolv vn sgathin prodpupitosesttposslse-uinLDLsey,ep agpkinases(apossre prtrsi o-rshe aco)e Bof its thehnewly cn. lo o-rshe aco isse n ofupd,etoo,itosehepicc x- inrh time tiitseohbnen eoo ddsmwnn dtiuptake lowLDLse synap- bssels(B)e Acandc rhpuplx,etrsiconieMoto gas ty esc of -nd dirLDLsed produs,rhe lsrbtsshepicecxcilestaan- syn-hicse rn produsmembrcein s ave aatde afferenlik pihselsoowLDLsbe-nd dirtxidizsct gto ttsierorbstaoslurocecxcteon f act8proby e centt mnero nee fir osrre diweleaayed -exn t pei oait acn-end fie re-oie produh thLDLv vn s.oAadro eters datgeraem,pimdye osuch rfrngle srre dtgimmdamapesconskbh t s must of-ic u re ceistnisk isse afferenbyscoibit latubr ty fiap.rsygan ogposc (se- rolar)tinNicinitarsygan oadritsr COvipevss- (pyridylacrb.nsp, xodth.nsp nicinit tr,clygapimox)ltd simulancIo whicerilipd ki-rsnasestepvase adr, w tbyslart paeslyceed rmdye vn s.oAt re-ocrr, tliothec ua,tnedepdinegiohdin m y tradv- odiuf son l a rc ( lushpupiaans rmo-end on)rmenticachiinad evs oaiath owtt ni5 on poetyl-insdl iylarsygan.suClsfiap trs odedCOvipevss02bezaf -xcap tr, etsfiap tr, gvmfiapozil)slart thicorsmwstepanssathanhunknowngtm of ism.rug dy2giveiamapescp- hiropo adrskbh t sinrh eug (myalgiactmyoe aca,trhabdi-rsmyopdsia)tinPrdbucolv art s HDLs oe othepinLDL;laonebstlrispyis appeolseve in libeedd rehe pupirbstaoion si0,ot hyperyrey atandhe pupiLDLvtxido gastinH9275ec3- -Popduns turrgytheaetyfontds (e - at nap thieno tr, dot nahexieno tr)see fabundithed rfish oi s.oDiet ry sua-ureli gasa sas toat Atusestart els vn sinty preslyce sics, dh afferensttposslse-uinVLDLsditiatolipd kinasesB,rreasem-igteiprctilestaan- car Rmrothepdepoeugs,clyllecpeas,otalnditiLDLsohbnen eoo drdi onon dh afferen a idisevpose afferetinHmnc diet ry intake2givec r Rlarsiweleaad rehe easeoganeh re-upo. obstanhedep t teice.rd156 Doduc uasct g Hl oplipd kinaseem asinllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc uasct g Hl oplipd kinaseem as2157rdLarts abso cdav iltailtox2 Fluvasrre dnglioAncum of sonr ha osuch rfrHMG-tlA he aconeon of acesesteropruion of exocriptHMG-tlA he acoinLDL- aRv,ep ainExp y gasinB. Reguloms ieathmbrasiaanohbnen eoo dconieMoto gas ty HMG-tlA he acoinditiLDL-ey,ep aclaLDLd ihiisselinOcultetrmiion. Its inExt an theicnse. uope lecxclacsen d Anclveinhptake lod enalyptHMG-tlAd rehe ticeinio produde y,ep asinmey traduptake lowLDLd C bnen eoo 2 C bnen eoo 2 Lovasrre dngMevapos tr3-Hld oxy-3--moniu-tin:ht ryl-tlAd HMG-tlAd Rehe ticeinA, wit fa pinExp y gasinBii-teaon of ganngO aOseCHec3- O aOseHOseHec3- CinNinOHinFseCOOH aHOseCHec3- CHec3- Hec3- CinHec3- Cinllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDiuormonse– An OropviewinDiuormonse(sdluormons)deedcirt g produde teiby gangli nrareo(eiuorsia)t CNSpoeiconrincocenss,atrsind cmteaaatlibietoidoducsuweleaa iarasynion ctonf liesg dapreho f-tiiee cfcts hf s ncrogposc i iconsugmposinnrareoexcormohe rinirs of dir ienncosg ettrpts hf NaClnditiwr ga.rug dommmoiifrntoolt i dby t liceferineiuormons idi:ngMoa“l o gas ty edsmws 2A): CNSedsorsmwsposre teassorbpupicaetissucesduem- ansiscum of sonrty f Nid,nchiefectcnntoseex. I inmbrasiaan(cn-eronitcer) elpoe -Winisa ia -e ormonectnihe g,se afferenion ct,xcormoheicnseNbec+seditiHad2inOsc hass a he the skisthicse volu- e prremoconieMoto-in thet A a toat A,rthicse teinaitdconieM- Mw a sas tiass apossre pronio of rrddsin u re Acitisihi ttand opa pese fi t an suwr gactf Nidsysl shpf te syncn-eronitcipti gto tp- capsl stanbge sg dof Nidsctirgasinty pissuceseoutofd.ssi adr, weedsmws atandcedse centte produh ththicse volu- u adri -eronitcer volu- meat a ia f-tiiu neethnposanot ane fectof Nidsvolu- u(EFV)e Dyaetharetonetrsicon of li,euduininemads ca:ntliazsics, ssep eiuormons, rlandh n eoon odit gonCert,iaaneosmo of ia -e ormonstinAa- rmarwanslibepoec ua.oDiuormonsisogvsepossnbgev useavas roduc ty fir tteohbici8ssurlart pupieh vvtiddbsselsrrddsin u ro(m 312)meEe g ete owtt nags,etrsyd ed produh op phsculr vei (gan- (welecp.cleigntionithly rehe pupiEFV)e adr, w tby onoCmdalzhnbsselsrrdd u rerug dc uaeth cossistwi ehze, teii ade pByrlart pupi op phsculr vei (gan-, ia -e ormons aiditosehee, tnheejectsretressue(ey-rshe the skingestload,npm 132, 306); con-ndy cmcp.puoi adrexerccts t neurdcertcein afferet Duem- tieoe afferen,xcor-in the on f Nid,nEFVh hareaaemsis urntdsors produh( he the skirrdload,np. 306).inStmp mse-upveaaemscossistwli,es ncintssanklweedsmw adrhapice , hirsisinmettpyses idse centtoduc preogaps ss ouseavae othiazsicso(m hyperyrcoibit late prK + -spalareteiuormons)e adrssep eiu-e ormonstinPrd niumxin car Rn cteii ade CNStesc -e hi e y fii adee(stocg),rh ametseons stats d maleti ehz oerhags,e Rn ctteiby ganinty nrareowivecroduh(annraa)e Bynmeat lod eiuormons ig etomics ismiads - maiu-int it nrar ry s ow. Ubr ty eibstanosmo of ec ssep eiuormons isse dby the. pMa eti eudu0ty diuormons thii sg isogzarlsoowrpther n of ACh 2A): (1)ntl d ed produhihiisselsvolu- achio a m- u ypo-end onoditionnlapse;m(2) isselsvss-inysimoxatiass duem- tieoe affertnheerytied ro-reneg ib-mso x-siconieMoto gas,xcap.ngpupiaaed produde iskpath utriv- c -e hirtc agulo the ot ngncmbosis. pWinisdeprets hf NaClnditiwr ga u(EFV he the) l a rc a a toat A0ty diu-e ormonethec ua,ttp- b dyrcaga uluidts tao e a-d.g of ory d. poterms(B),canfmran,f d simuexocliothehrbtax-t pai-rsnand x-tlh n eoon os abso (m 124)e Bo- tcaits liothehia fs shythisselsvolu- ,e orn ctressurf ow issjeopaodizsce ceisxcHea ss,oe of vasee synap- kidneytoty pos u oCmons,e Rnar,rhe me tcatalyzasit of a pe neeth o painand x ItinAapainand x Irlsoesnv tidm- anpainansin x IIiath, wefcts hf o painand x-oou-in optiretnchi- 2ACE)e Aapainand x IIiconimulmulse of vasehf olh n eoon e ceninmiisculocoepoe depc ervhse Rn ctncosg ettrpts hf NaClnditiwr ga eostpout tao e aactteehye osuch rfreiuormonse ACEnd dn of ace(m 124)nsugmposeehye osuc-in tvon ss0ty diuormons y kevs dir iis tao e a-d.g of ory d. poter.rd158oDiuormonsisllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDiuormonse159tiBmeP hypers ao e a-d.g of ory d. potermsenraretposs-nd cmdiuormonethec uanglioMm of ism on edsmw f Nidsmoa“l o gas ey diuormonsisEdsmwinHemoconieMoto ned Cnnlapse, udatgerirfclngncmbosisinSal cfand f Nidsormbn ned Moa“l o gas tyd bismw f Nid SPid e.npmbneesiesisColl d esmo of rrdd u rinDiuormonisEFV:ngNbec+se, Cl -in, aHad2inOinDiuormon DiuormonisAapainand xsnea uRela atAapainand x IatACEndAapainand x II Alh n eoon isllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinNaClnRett trpts cnntoseKidneyr2A)ruTe-ocses estical membranunet liothehkidsisneyrrs ena nephrolt CNSpoeiglombrreau acapsl stansseps,rulotofilhe uexoclioeofcseigf Nids gto Bowolo’srcapssieh(BC) yieldie p imstatnraret CNSpoeite ximsl tubsiesis(pT),enate x. 70% liothehulotofilhe uee se ormritvhueathisoosmo of rett trpts hfinNaClnditiwr ga. CNSpoei iickn-or neethtepol pscetharetlimb ty H, he’srssep (HL),caNaClnteaa trbythunacc mpf iiddlyinwr ga. ceistis8poserreor P sitsvssurposisogirpitdco e a- rr dttem of ism menticrllow erild-upenshalvpCx mnc NaClnctiandceMoto gas bn poesion ctm hel st CNSpoeict ttsl tubsies (dT),eNaClnditiwr ga e rinegaih jonally rea trbyt.oAt re-olthmthtepol nephrol, thistpc crisorevolvetg -landh n eoon -f thoo lren,xc t peglioNbec+sedgaihst K + surH + . CNSpoeionnlectsrettubsieis(C),ev- op y gt (ra- Iiuormon oCmons,inADH)ed produs8poseepi whic cttd ce-d r iltoxassurwr gacthe mesrs drawsesks d tosehrmarosmohirtmilteucliothehrbt sinr hel s eostpoutgnc wit lobn poesb dytinAsaa toat A,rwstatieMoto ythurareoe -erod tose Rn cttelvis. pNbec+setaraswntoitrncreas, ettubsiau acbras basesercina a rc d nsa fectofashiasseihirll segmgastoty pospnephrolt cenin utrimbrasiaanoonieMoto gas ty Nbec+seteasig-inntionithly rolar reatpskirrimstatnraretruTelsoesnieMoto gas on i tt is8posedriv-nd dirssuci8ssureMoty ty Nbec+setgto tp- cx-osmlinty pubsiau hen s.sAeacrCier em of ism a ovetgNbec+sedcross tp- m oo sucghEnar-in00 oiaerrgyd enraret, isse f Nx2cchiin tut“l edessurposecouplbiecp.wardhiaras-clat t hf o ubstanpdepoeug dgaihst a on i-teaht. F synap- mbraoi -erie ,eNbec+setea ovelate prex os ofadi8ty on ogyr(ATPmnisind olysia)eathNbec+se/K + -ATPfertnhconposanx- Mw ambrasiaanelpoe -Tosanchi- mbneesiesisse ocoic n dm- tieobasolmulrs tpUrlsoth tap- mbraom oo suc,rfacaret, wena-eronitc- Mum;hNbec+secai,etrs tf is,sesteescath ba Nsetgto tubsiau f Nid.ights eiuormons ien ofubNbec+serett trp-in thet Baseserci, eibstan, wenawardhsurposiscp.wardhiarasat t hf Nbec+secailbabtan be-d bi.inOsmo of Diuormonse(hiruAgposc: olorf l,shorof lDeSitrton poteon:d mainssinglite ximsl tubsiesioModitrfclygteon:eSian- NaClnditiHad2inOsae orcosg ettrb dm- gebstaniNSpoeite ximsl tubsies, pNbec+seesnieMoto gas edit oftubsiau f Nidndh easestef t pegdyspimehitapexwand itinrett trpts hfeNbec+seditiHad2inOe Bcdthmbrasxclackhiarasat t tm of ism5essurctiynisind cdalcoholsss ncreasolorf l (e Tof-ic u rilnft 171)e adrhorof lcthe mese rinpoutopknvposiddf synpon grre dircyllinmeof thcsmembrcef is,strsycnebietoabtin0he g rinirtriveaaemsin vesie ceny rve secaiestebe rea trbytee synap- tubsiau af Nidsngest glombrreau filhe uexoe Tossesedggastonith wr ga osmo ofs linanlo o-rst it it edit oftubsiau lu- n -WinisNbecgasaoerl takev uptnhconposatubsieimbra,inwr ga caiestefoll w edit ofusua seem e sg dofaraoi hurareoNbec+seesnieMoto-in the rehe esbNbec+serett trptwli,eskirdep of its thehrehe easesnieMoto gas on -ndy posee wardts, wena-erilrtoartubsieimbras meats a he yd eriv dirssuci8ssurNbec+setgf Nxe centreat A0ty osmo of ia vei nteaae hirgeivolu- lio lu etnraretruI dby t lic: rrd niumxin car Rn c u ypov lso cdfii ade,hmoa“l o gas tyd f tin edsmw,r haacu etglauc ma.rd160oDiuormonsisllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDiuormonse161nglioeKidney: NaClnrett trpts cnnnephrol eostpubsiau hen ndyTtiBC- CinpTisCortexngMehel sruTel Nse-or neinty HLislu- n CNtop-tionitciptiNa/K- aATPferNbec+seNbec+se&quoa;acrCier&quoa;inADH aHL pMaorf ltiBmeNaClnrett trpts cnnte ximsl tubsier ha osuch rfrmaorf lti[Nbec+se]nd d sic = [Nbec+se]ndcp.imdyti[Nbec+se]nd d sic < [Nbec+se]ndcp.imdytiNbec+seNbec+se, Cl -inNbec+se, Cl -in + Had2inOinHad2inOinAlh n eoon isK + Diuormonsisllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDiuormonsety pospSulfmbrmmdyeTrmaruTe-snttoduc fd witnre-oculfmbrmmdyingdoupe-SOad2inNHad2in. Teny rdissuioneleeferinoculatrmiion. Its . CNSed of lietoabt ditifilherbieetetrsiglombrreus,strsycrdissusg e terms anubsiau tecormohee TosidnconieM- Mw a sas i hurareoiit mncer reanhihiissel.rug dy2rnceonetrsilu-in s m oo sucoth tap- tubsieimbras. Lsep eiuormons hkeeotheat mncost ht inacy. ceiazsicsordismmmoifrsors Pehhly usge sg didnf isruor as,ingle acrboas renold aconeon of ac, oralaowintoatric ectm fely,ls i dby t lic.suCcrboas renold acon(CAH)ed n of-in re,ss ncreaspoetazolmmsicneostat Ahf-ina- , rncepreho fnithly iNSpoeite ximslic ubsiesioCAH catalyzasiCOad2inold a-in the/deold a the reygteons:inH + + HCOad3 –in? Had2inCOad3 ? Had2in0 + COad2in.rug donchi- i08uasct g tubsieimbras m fion e ueeHec+se, he mesrs tecormsct gto tap- tubsictof Nidsin exc t pegssurNbec+seerug dc , Hec+secap u rs HCOad3 –in,to a deoe f asinmo gas ty COad2inmialt weunsoneleeacrboas clyganioMmoo suc-td ceneleeCOad2inis8pakevinhptnhconposatubsieimbraneostubradm frsorsion e ueeHec+seditiHCOad3 –in -Winispos nced hi-e isse n ofupd,etens oeyacts sms rinslarpd,eso reatplris Nbec+se, HCOad3 –inditiwr-ic eosae orcos trbytee synap- fast-f ow dititubsiau f Nid. Lsss0ty HCOad3 –inHea ss,oeygaandh nise centIiuormon ve in libn ss0ty CAHnd dn of aceed produsaw pweroH ngel ouseioCAH s ave arevolved iNSpoeite by -in the0ty oesiaanrqueaemshumormePresgasini dby t licefer roduc d t, issflale iu-inthe a:aacu etglauc ma,aacu etm e wittisesknrispy ha pilepsa.oDorzolmmsicncepsobabtatlibietopofs linconposanynato lart in utrioesiaanp yssadi8d tglauc ma.rdLsep eiuormons ibthe itfarosemmdyin(frusymmdy),hlinc wnsic, ditibuic s-inntdse W pwoculatrmiion. Its ,r osroongd eiuorsisna a rc w pd t1 hters phersses fer onssiabcp. 4 h -Tosanosuch lserrpid,n uorsnanss,aenegbrief ( mnc-ceilareteiuorsia)tinTe-ocitrton poteonety posce ogposc i re-in iickn-or neeth pol pscetharetlimb tyinHe he’srssep, heeisr ieinirs of inNbec+se/K + /2Cl –incoiarasat tt A a toat A,dinglce ely, olytes,m- gebstanweleawr gacisse oexcormbie gahirsibeem e s. Excor-in the on becd+intastMgecd+intve are produsm Sly,ls Pnxocn of ACh ibthe i:h( thersers)inh araretpoispyenoganrensy vinwi he to t RnoPnxocnogposc. CNdby t lic: rulmo-tiie y ismw (addbietrvists.epath .v.n uorsje the skileftnvposriesiaanfii ade:eifm -d y tr diuf sone-upveaaemscapyga(gan-edvsleylc L50478irrdload he the); frac in raresese funiazsic eiuormons, h ametnheor-inn s ypov lso cdfii ade8e pnca ofitarexcilestaan- he the (<30 mL/mii); ki-rs niumxin caracu et Rn ct ypov lso cins i ade;ehrmarfs cem a. Ereacrytarsyganinis8flaleed iNSpoctnidoupeyllecpeasis ismnoPina eulfmbrmmdytruTelazsic eiuormons02benzouniay ed hares) ibthe itold ochas ouniazsic,xcaenzuniazsic, prechas -moniazsic, fand nychooniazsic.sAeposs-actsrettbra auae se chas realido cghcens oroduc s such the acn-erm y tr segmgas liothehiattsl tu-xcasies,rheeisr ieinirs of a Nbec+se/Cl –inco-setaraswntoghceus, tott trpts hf NaClinditiwrttanisse n ofupd. Ren ct,xcormoheicnse becd+ined produs,rn be loaMgecd+inre produsm CNdby t licaacemnimarwanslsietcdry cins i ade,aenegmoa“l o gas ty edsmwm Unwaosidd ore lsoth eulfmbrmmdy-set th eiuormons:h(a)t ypokalso a teaa ctiandoyqNeh rton ,xce eti eK + par8edit oftar-inmin ctsegmgastoty pospt ttsl tubsies ahesre t produdeem e sinseNbec+sed rinev iltaugmssurexc t pege prK + ;02b)thysistapslycemiar han:lyssnraa;02c)mnimar-innracemia—e affertnhe Usumauur gs ee-icelsrwivetey,ip-rreetgcp. skirrdt tpodude taaieruc. Sulfmbrmmdyeeiuormons0c msinpersiweleauur gsssurposetubsiau oigf icd enaly tecormory s absorrd162oDiuormonsisllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDiuormonse163 h ametfarosemmdyinLsep eiuormonsinNbec+seK + 2 Cl -inA.oDiuormons on re-oculfmbrmmdyetrmaruAntheiciecormorythetabso h ametpoetazolmmsicsuCcrboas renold aconinn of ac tNbec+seHec+seHCOad-ec3- Hec2 aOseCOad2inCAHndHCOad-ec3- Nbec+seHCOad-ec3- Hec+seCOad2 - Hec2 aOseh ametold ochas ouniazsicruTelazsicc tNbec+seCl -inSulfmbrmmdyineiuormonsinUrarsyganinGcp.clHypokalso ainNa sfle srreyinLsss hfinNaec+se, Kec+seHec2 aOsellmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPota etum-SpalaretDiuormonse(A)ruTe-ce ogposc oct edit oft ttsl -or neethtepol t ttsl tubsiei adr, wete ximsl rdep on re-oonnlectsrethe srheeisrNbec+seteare-d r trbytein exc t pegssurK + surH + . g didineiuormon ve in libn ss0tearelipevsssi f-tiiore CNStat aosttm feulfmbrmmdyeeiuormonsis(p 162),sposre tean are produein K + iecor-in the;eoi hop,iposre teaa iskpathnimarkals-inmiaghcens oroduc sdissuioneleeferwocultetrmiion. Its tina)tTraamherbn oditirmmas sic, ihird-d y f lietoaglombrreau filhe uexo,suhdtago etecormohe iNSpoeite ximsl tubsie. Tenyclygteonetrsilu-in s m oo sucothttubsieismbras. Bculairs of pos ncoty ty Nbec+se, u eh rtitsrexc t pegssurK + ditiHad+ . g dyisse ommmoly usgeeedio mnero neiweled eniazsic eiuormons, h ametold ochas ouniaed haic, of its thehoptoy retnare lsotthK + excormohe caan-l bcahso hop,ihe lsrthe anare lsotthtecormohe on NaClnctmeli gas troahso hoptinb)tAlh n eoon nists.onCert. ceninmiisculocoepoe detlh n eoon o ki-rservhsethe tott trpts hf Na + (Cl –infand Had2inOsfoll w)ein exc t pegssurK + e Ctssh asinmmbrannosuch rn teinaitdsttposslseHea s m fsugmposmuexocliothehrbtt trptsvcncesinpa toxaon tubsieimbras. Slinonolacsen , smadsorbedititsric statetc caa Rnon , s rsdi-xct gonCerteetetrsitlh n eoon oey,ep ain haa wanuomehitap osuch rfrngl oCmonstinTe-oeiuormon ve in oth elinonolacsen tdsorsvssopstfarcinanssie prco duaemsad-inmiion. Its ssursevscul dayt. cwo ctdsin pers exchinmu Cs idi: (1)ntl oesnv sin p hf slinonolacsen t gto a haaccum -e hi aon rfrngl oe oslarecteed fromen a c statetc caa Rnon ;m(2) anhihn of exoe fir lh n eoon -onimulmuld teinaitdstt-dinglcistroulddincoms no ofeneleeotectcyd bxintaretp inait haddincoms noncal -in thealnditintedbietoabterz-hiheueathdi onov rsytposslsr Aotdepoesiaanrpther n o-xc termtoat Atue syncn-erfneeh rte prgtiandad ct oCmonssieas evaneh rthbsingltdsorsvssopmgas liogynncomostiar(, hirsisinmett rfrmalsreprodt)e Cli iita hass iu-inthe aions of licenset produdeelh n eed ron osecormohe, h ametteropomirrhocistr pinascetcs.inAa- eiuormon HoCmonse(ADH)editiinDhCOvipevss02hiruADH,r oaonftaptsic, of vascte synap-se-os-erilrtp-ruiontatgiohdepc ervhse R-d r trpts hf wrttaninnap- kidneye ceisxcd. poter ismicy tradbsiv- op y gt atandcep acety ap- Vad2in totrma. ADHyenogan-ices8poserd ceneiltoxaon onnlectsrethe icepi whicumassurwr ga02brs ao r mueely,-setaolytes)t A a toat A,rwrttanissdrawsade synurareoihconposahrmarosmohirtiNtop-tionitcip rfrngl hel st Nicinitefsugsinmettce(m 110)editiereano dds produsruADH of vas.oAt tatieMoto gasaoebov-in iosseor P rid f a is- eiuorsi0,oADH aonimulmulsesmoculamust oftade,hibthe -nd dirn be loaisselsvsleylc (“v- op y sin x”)e centhi ttand. poter ismicy tradbsxcd.cep acety ap- Vad1in totrma. Bsselsrrddsin u rotiass;po. obstanv- octionric esisecailtey,ip-rreeto panaerdnce lsr Lyp y sin x (8-L-lysitefv- op y gt)ltd s lik e ADH. ObstanedCOvipevss0giveiaseofyatiandcinans liotheh wo acts stinDhsmop y gt i08uasctssurposethec sinpxaon diabetss iusepanuse(ADHned ini tandcy),sesc urnrannnuorsi0,ongncmbeaths-inmiae(m 148),oditiohroas r ypo-end onis(p 314);sis ism0he g rinirje the surviatepol nas s mut na (as “snuff”)e Fsssp y gt aaneornip y gt Usag smadadjal mevenv- octionric acesesinfilhe -in the localndiesposslae(m 206).in164oDiuormonsisllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDiuormonse165tiBmeAa- Iiuormon oCmonse(ADH)editi COvipevss- lioPota etum-spalareteiuormons tNbec+seCaa Rnon tNeuki-rs ypo.nic sseHec2 aOserd ceneiltoxe fironnlectsrershe V- octionric esiseDhsmop y gt Ornip y gt Fsssp y gtseK + Alh n eoon isists.onCertseK + ainHec+seNbec+sePeinaitdsttposslsndgarasat t capyga(anglmmas sicndgaeamherbn inAdiuormon = V- op y gt Ereano inNicinit inVad2inVad1inSlinonolacsen Alh n eoon isllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc ssurGaonricnditiDuoden ctUlcons CNetrsitproenshalgaonricner ruoden ctpep-in e hlcon,funcnmut na htssbgev senecteeuley disistwi ejuicpese fs ncrenpexwant smadtoaexpodu re-ocubjacposiconnin libetidsin ue layib (cubmut na). ceisteylf-disis-in the o a rc winispos n P liap.iptibetweeNSpoeionrrosivitold ochas arsyganina haacid-neuhe llz deomutu ,rhe merdfmus a p inan libecoropomnfuncnmut nalin u face,srs thpf geeedifavlrtoarold o-e chas arsygan. Mut naleiamapescchiin tpc ervhadbsiHeedcobpcs pyas ahbpcs ed rialt asicoposrzu re-ogaonricnmutu tinDoduc rdisem,loyeave prtrsif 2-xcH waret, wr use of sims: (1)ntoe ofitvhinpain;m(2) ,oeygmbr e ueehealare;nditi(3)adtoapknvpos hlconoey, rr doe -Tosr use-in e nate oahcsordispob ef 2d:h(a)tm frsorshe roaggdo eti essucis byrlart pupiHec+secp.puo;02b)tt are produep inan libessucisuley meat lonmut p inan ists;nditi(c) to ten ic ueeHeedcobpcs pyas am C. Doduc ssurLart pupiAgan isConieMoto ned Ia.iAgan neuhe llzIts . Hec+se-nithpupingdoupsss ncreasCOad3 2–in,tHCOad3 –insurOH a–in,tcc-edgebstanweleatosidnco e aed c, oralctiand wit lobn istsgan roduct Neuhe llzIts seretcts smo a r pupingest intake2lonseCaCOad3 ditiNaHCOad3 ,nd. pe, witss,ms rinshowseske(A) ete efte W pwaonf trb-d r le istsgans,etrsico e aed nissdidsin olved iNSpoeisgane gaonricnjuicp iNSpoe tpc c ss0ty neuhe llzIts . Upon mixdu rate prtrsitlkalsosrpanca ofic tecormohe iNtepol tuodenumpyis ismhirsilvetey,ip-rreedinegaih athbpsesrgroupspyh ametpasCaCOad3 ainAlPOad4 ,n adrexcormbie ga tecsmembrcef is,thetabsoe n trpts hf co e aed csorisbpsesrorsiducesismiiiore CNSpoeiteesgan-edcar Rn ctiusut ini tcy,r its ac tt trp-in theton ,e g cses eem e siwivecaucoindiare produein thicse vn sghf co e aecgasao(h ametmapn siuyncn-nxoco neiweled palalysianditiodry c t tturbgan-s)mePre-e cip-rreohe iNSpoeigrs lu- n0teare potsin pers ferwobstanimdye osuche,ss ncreasrsorshe rd n trpts hf obstanroduc duem- titieir ad trpf lietoare-ocurface lioere-e cip-rrebie atsgan e ,eplospi tr depre-in theton tp- b dyre prexce eti eintake2loinAl(OH)ad3 . pNbec+segasaorem it inssoiu- lisevpose atrsi.kesgan-0ty HCOad3 –in-r menpanca ofic etecormohesr haacem to terms att trptwli,inhike2HCOad3 –in -Bof its liothehuptake lowNbec+se, uits lioNaHCOad3 rh tibabtvomdyeeedio n-d y f lisanc P rpupid. tric esi on NaClniu-int ke,ss ncreasnimarwanslsietcdry cdfii -innre,aenegedsmwm Sian- fselsha a bu inp retnare l,isistscanssmaritakev betweeNSmealao(h amead1aeneg3 hingest mealaonnegt bedtgmi)tinNonf trbpaugoditscanssmari.keinprbi.inBof its Mg(OH)ad2e p by bsaa laxaclveinve in o(f its: osmo of ac esiett 170, atandf vasehf ohbnectabokitar athMgecd+in,sorisbobs)editiAl(OH)ad3 p by bsactionip -in the (f its: aonringee cfcts hf Alin3+in,sp.in178),etens o wo aitscanssmarifre Pehhly ouseavedio mnero nem Cbe CNn of acecarac depc he the.inA, wretonetrsirnd. pe, witsey,ep ac,ingle tarasmi ttanacetylciotens,atrsi oCmonsedgaonrin,aenegh ttse n o of vasct gte -inmut nallyr imulmulSpoeitoCietsl mbras ty atrsigaonricnmut na t are produecp.puoityinHCl. H ttse n ocomstue synenomao-ed gncmat in-hike2(ECL) mbras;wetsancf vaselsndonimulmuld bsingltvagus nesag (mialMad1iney,ep ac)editi oCmonallyrbsigaonrin.rug donore lsoth acetylciotensaenegh tts-inmiie canln stateehld bsioculssiaatlibiisists.onCertlt asirroahstoCietsl mbras viatepol issel.rug d cioteno,ep agists.onCer pf-ti Rnzepens,aunlik gt ropens,a.keinpseohb- toinocep acety ap- Mad1intrma, f easestserdn grreeoihconposaCNS, eostpoutg ki-rsby bsafert t ropens-hike2imdye osucheis(p 104)e centthooinocep acetnstoCietsl acbras kibnely rolaupiconthehMad3 totrma.inHe ce,slincnzepensiwiveygteathbesckpupinMad1iney,ep acetnsECL mbras tuesubmut nalinneuki stinH ttse n o ocep acetnstoCietsl acbras rolaupiconthehHec2 at th (m 114) fand rdisbesckhadbsiHec2 a-is- h ttse n se Bo- tcaits h ttse n oeofy a pivotalnrolese atrsi d simuexocliotoCietsl mbras,iHec2 a-is- -rs ttse n s ave aia fs shnd. potewi headtoaobstaninimulmntspyh ametgaonrinn(cntgao-in166 Doduc ssurtrsiga of gasrmacoaptsctUlcons llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc ssurtrsiga of gasrmacoaptsctUlcons 167ruion of exocrirac depc he theinN.tvagusinMad1inPidincnzepensinPoCietsl mbraatAChinH ttse n ECL- acbra aATPferseHec2 a-As- h ttse n s SCime- Iin Rwnie Iin Agan neuhe llzIts inAa-ontdsinao rf trbpaugd r trbpaugd CaCOad3 Mg(OH)ad2e Al(OH)ad3 NaHCOad3 A. Doduc uasctto lart gaonricnac deoonieMoto gas trepc he theinPanca otseK + Mec3- Hec2 aAChinHec+seHec2 aCOad3 Had2inOsCOad2inCbecd+inCbecd+inCOad3 2- Had2inO+COad2inHCOad3 -inHec+sePanca otseHCOad3 -inNbec+seHCOad3 -inNbec+seHec+seHec+seCaCOad3 CaCOad3 A trpts d OmeprazolesePeintnstump-nd dn of actiNbec+seNseNseSinOinHadNinHec3- CO aOCHec3- CHec3- Hec3- CinGaonrin- CHec2seSin(CHec2se)ad2inNHadC NHCHec3- N NCinNinHNseCHec3- OCHec2seCHec2seN- Hec3- CinSin(CHec2se)ad2inNHadC NHCHec3- CH NOad2inHec3- CinCaCOad3 llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinnrin-pc he aretpanca ofic tumorspyZ 2-xcHinger-Elteeotdsttdncmo)e Cime- Iin ,dingl fir tiHec2 a-is- h ttse n uasctthec sinpse oferci, otectro lvete by bsaimdye o-xc terao(CNS t tturbgan-sss ncreascoicusin p ;dncIoorareoeof ACh ibfuncnmale,es ncintssgynncomostia,tde afferenlibido,sem-igto-enco)e Unlik gcime- Iin ,wetsanert inenegmoari.otposiconion es, twnie Iin ,canlzItsIin ,wganms mo oIin ,wdo ao riNtop-tifneeiweleatrsi apice bioiaras a pe needcarobstanroduc.d Omeprazole (m 167) canlcaits max- Mimsl ion of exocri2HCl tecormohee Ghe ginocully iNSgaonricnjuicp- vei (gatrcapssies, pisirroah-sstoCietsl mbras via pol issel. CN atrsi dane milteucliothehmut na,g -c-in tvoric statetc is cn. loenegb ndmsctorsvalethly conthehATP-eriven teintnstumpin(Hec+se/K + ATPfer)rmenthiarasat ts Hec+sein ex-ed gt pegssurK + ihconposagaonricnjuicp. Ldi-xc op azole ohdepgatop azole te by binenra aaemseof AChesg daprintnstumpniu-inn of acemarifirst-tensadoduc ssurtrsi a ofsinmett rfrnatiooe ophags ctncf Nx2didsineice.rdIImePrinan libeDoducsuSucralfreeo(A) fd witsanumeraem avu-inmiiuynold oxmdyeorsiduce. H its ac f inismnoPg -atsgan of its i teii sato lart inthehovsculli daneoxaon gaonricnjuicp. Af aecoculaintake,es nralfreeombneesiessuhdta-edgo cross-oinkaretiNSgaonricnjuicp, cn. pupina paone reatpadbrcesato mut naleiesucheis adrexpodudeieept layibe. Hecem tnral-ins ewena-ercep siHad+ . Prinan scte syn dan,ina haave af synpopsiiet aypsiietenegb loclygans,funcnmut naleiesuch canlhealgmoaradrouieec. Sunralfreeois8pakev tg anhmicsy2 ti moahs(1 hteef is mealaonnegt bed-in tmo)e Is ismsorbet neur sc;r its ac atandf vasd Alin3+ segasaocanlcaits ctionip the.inMi op mmool02hi teaa semmsttpos of rrdinegiohdini COvipevste prga of aecsoneiltoxareanhn turrctteiinegiohdin,serd ci tpupin trpts ngest oculatrmii- Min. Its . Lik glocally ref vasd teiine-edgiohdinspyis pc ervhsemutu epc he thein adri n of s acan tecormohee Addof lierthetabsoe of ACh 2fre Pehh diarrhea; iskthofnpey,ip-rre dircat aocf licensengle gravan uestuc)eeigntionithly reonrincoitod tosr use of ut“lty.suCcrbenoxopose02hi teaa COvipevsthofnn:lyyrrhenitarsygan, he mesa a rc d dingl apense. s aryeoooPg( tntu eli P rp-in tao)e Ccrbenoxopose0onimulmulsemutu e teiby gan.oAt re-ocambetim ,wetsha ainmiisculocoepoe d-hike2fcts (duem- iu-inn of exocri211-β-old oxyn eooan renisind oionfer)rmenthpc ervhse Rn ctncosg ettrpts hf NaClnditiwr gae Is wiv,d enaref is,sexaconb ueehimarwanslsieseesnsistwi ehze, teii ade,rpuredsmwse Is istho tlete.rdIIImeEn ic uexocri2Heedcobpcs py-xcH ri C. ceistm irooigf ismoeofy ansem-igtotoolt rolese Spoeitothoion si0ityinohroas rgaonritianditipaptscthlconodidsineice. centt mnero ne hf o tibpcs ierthroduc saneomeprazole has teoven osuc-in tvoe CNStvasehf ihconeurdcers atmnxocirbpuis(p 270) orioloCingncmycinn(p 276),ric ed ronidazole (m 274) canln useavas aacesg etiituese Cbnl d ctrismu prcompnundsisse oave ave in lib;r its ac poeite augmthofnhzevy--mo ct,xpo u rocompncmidusrutrsirnposs-nd cmuer.rd168 Doduc ssurtrsiga of gasrmacoaptsctUlcons llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc ssurtrsiga of gasrmacoaptsctUlcons 169suC.2Heedcobpcs en ic uexoinMi op mmoolinB. Ctsoe cts Tofdu rsditip inan libe osuch rfrmi op mmoolinA. Ctsoe cts Tofdu rsditip inan libe osuch rfrs nralfree R =e– SOad3 [Alin2 a(OH)ad5se]ndS nralfree Csnv d onisbn idane tandvinon gas tpH < 4 Cross-oinkarein adr a pe needcarpaone Csre dirtyinmut naliniesucheisR =e– SOad3 [Alin2 a(OH)ad4se]nd+ – SOad3 -inHec+seRseRseRRseRseRseRseRseHeedcobpcs inpxH ri En ic uexoinh ametshoto-nd cmnriplbepoec uainGaonritisthPaptscthlconoAmnxocirbpuisCloCingncmycind Omeprazolese(2 x 1000 mg)se(2 x r5em mg)se(2 x r hie mg)se7 daytse7 daytse7 daytseInhe theinense.starsePeiinegiohdininey,ep aseK + Hec+seHClMutu eATPfersePoCietsl mbraatllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLaxaclvesinLaxaclvescpc ervh ganms c“lt ueeb itaatevacuo gas ey actsretlocally e fsnimulmul acn-eabsorpt op ttslsi0,on fsogesneb itaatctirgass,rpurbobs.rd1. Bulk laxaclves.oDismbn neensengle cn-eabsorptwulliathb itasctirgassfsnimu-e hi escpc puleti e ovemgastoty pospgp.clmust oftade (mop ttslsi0)e Ac simuexocliin utrimurrcttm of o ocep aceinby bsaainneukally icy tradpscetharetncf exlctiand an the ( hse SA)editi scetharetnc-e hixmuexoc(blur)rw w tbyst wena-kalu f-tiieliaoluesismioved iNSpoeisorptt re the.inHld ope lecronnloansspurbulk gn sin2hi compniduein oiusosiditinonf trb-d r le acrboold a ct to (gan-tlt asiex-edpsaneon8pakaretup wrttaninnap- b ita.inVegeoneleefiaerh ibfuncndiet oct edit istholorga. ceey ctioCer ty pospithpsistwaugd chintimbranwd.ssifd witareth ern:lyansrutrbe ae orvei (gatrtoidisistwi enchi- s, ph ametmbrasiodu (1L504784β-oinkehan:ut n e oandf esiessvs.o1L504784αan:ut nmdyeboadri ecsonrchett 153)tinBra ,r og tin mirbpupiwaone teiby ,ina habpusebie(fhixsebi) ae obobs r meni ecmbrasiodu. Obstanhld ope lecronnloanssd ed rivsee synap- sebiarmacolists.ofely,lesinpurkaray ogume CNg a tg oarold ope lecxcgn s ssurtrsirrd niumxin carctionip the ousually thii sg e owt iskpathimdye osuche.inH its ac e pr owtf Nids gtwketsk0c msinnero neiwele a pothoH a lllab itaatsmbnosi0,omutilagiaaemsviscaemsmas ierthcoulddcaits b itasa al vesi ( loua)tinOsmo ofs linan libelaxaclves (C)see f oiusosibrs aonf trbpaugopdepoeugsrutrbe nc wit wrttaninnap- b itadbsivirtue on re-ir osmo of ac esi. centesmo of rrdd u r (mdepoeug oonieMoto gas) tyd f itasctirgassfalwfy c r R pot ss,orutrbe ty pospnot ane fectoelpoe -Tosa uorsnaabsorptmut na i08unpaugo- maiu wit aat mncot oc lart osmo of rrdd u r nsengle lu-in s ctirgassmembrcef is,sa trpts d rfrmbneesiess(h ametn:ut n ,eNaCl) l a rc Minoosmo ofs li,we.emetsolueeombneesiesss rinfoll whadbsia c r R pot pupinm e tyd wr gae Csnv dtss,mwrttanrem ith ibfuncd f itaswinismbneesiesscaiestebe osg ettrb d. pWele Epssyn haGlauaer’srnalheis(MgSOad4 ditiNaec2seSOad4 ,nd. pe, witss),ingle SOad4 2–infad nissnonf trbpaugodilo o-rst itsscaf lice- maiu wit ely, onse-in e llty.aMgecd+inrlicaacemave abofitvh m- upc ervh of vasee synap- ruoden ctmu-e t na hf ohbnectabokitar/panca ohi-in,searctiytaptsic reatpave aonimulmulsemop t-rst lnise cens f o-fs lrensalsosrcafhdepoesiceldcirtamwrttathb itasdid ofrgei1–3 hing-ic eosarmiion. Its (mkeinpnely gt i0intn- Micssoiu- li)e ceny rre uasctto purgefuncd f itas(h ameteef is f itassurgery) ori- u aoneispos ned from tg oarskg a sd toig ettnse Glauaer’srnalh ( mncoNbec+seesnrgas)e se cat aoe dby the gt nimarwanslsietctn- Msistwi ehze, teii ade,renegedsmwm Epssyinsdltrlsoesn aoe dby the gt Rn cteii adeis( iskpathMgecd+inre-nxoco ne)tinOsmo ofelaxaclve of ACh acemave p by bd bsingltctiynid cdalcohols,tholorf l adrhorof lcthe mesunlik gglu-e t nescaiestebe narasat tiddtrncreas, ee cn-eabsorptmut na,g smsorbeas bsingltntn- Mold olyzpaugodidac ofrsic, lacssiodu. Fsrmposmuexocliolacssiodunbyscolas e-c-in ie toat Atusesidanefic uexocri2b itaatctirgassaenegm irofloraleiamape. Ldf-ic uioduni08uasct g apice fii ade8is trdt intoapknvpos bpcs ierepc he the hf omsinmoniar haf s to e Pehh a trpts d (f trbpaugoNHec3- L50478inonf trbpauginNHad4ec+se),eso asoe f aettsll hzpice c ma.rd2e Crri(gatrlaxaclves—purgaclvesincafhdepoes. Ldxaclves iNSpoctnidoupeexertindiarrri(gatrfcts hispos ncs icnmut nad (A)e Csnse Pehhly,plris f Nids eaa trbytrutrbnsrs tecormsc -Tosa u afferenfirbpupicatepol i itaspc ervhsemop ttslsi0;rexcit -in the athiansory nesag etharesdeedcirs tandulrs tnimarmo ollty.aAcc rhpup conthein ptrton rrri(g esieten tdintareueehl re-incses ei itasrrri(gatrcaonerwoilte synap-sehirgeii itasrrri(gatsaentrnaquinon nisdndh phsnolmereanededCOvipevss02fer ro-rst ilssseett 174).inMi its liolaxaclves.oIs ismamwsicly ohelddinlief reatpate eostton nb itaat ovemgasemop day ismsleyntcer ferinhealth; yetspob eii itasevacuo gassemopadsoek acemquitltnt sfle centtesireeferinfre Pehh i itaseicsyaretp ibnelyatsmbmsee synap- time-ho o od, rlbef in170 LaxaclvesinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLaxaclves 171suC.2Osmo ofs linan libelaxaclvesinB. Bulk laxaclvesinA. Snimulmuexocliotop ttslsi0sathanhna-kalu fieliaoluee Stormch ey,ep aclaCbrasiodu, dgar-dgaretera ,rbpusebiseHec2 aOseG = Glut n Csn an the RehixmuexoseHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseHec2 aOseNbec+se, Cl -inHec2 aOseInoosmo ofd r trpts seGinHec2 aOseHec2 aOseGseGinHec2 aOseHec2 aOseHec2 aOse2oNbec+ e SOad4 2- - Hec2 aOHec2 aOseMaorf ltiHec2 aOseGseHec2 aOseGseHec2 aOseGseHec2 aOseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinm ttsk g,sno ohispoat n trpts hf co-xcH nsctirgassfiit ogyfulghceus, purgareinhas possnbgev mdep athi(gadardhihec sinpse oftp an toe -Nowadaytpyis ismknownrutrbe cn-nxoco neie syncn-eabsorptcesg etigan-tlissemp hypers as possnacitisiheroprucal membstnt sflec. Non whirispypurga-in tvosrco dueetoabtesoidreasrsicy ess,oru“ilesndu re-oissel” ori- red tp- b dyrcate“i r uptshumors.”rug dc canln no obje the - tieoe - Msistwxocri2bulk to (gan-tlssurtrsirur-igtots liosupeli gassretlow-orsiducte“moderntdiets.” H its ac its liorrri(gatigturgaclves orioafhdepoes ismnoP welecp.clogzarls. Slecefic li,wtosre teaa iskpate hixmuevr depethe ce,se.emettieoe neiltoxarondh welecp.ttiem. Ctroas rintake2lonrrri-rst asemurgaclves din uptcitisiwr ga eosicely, olyte bplaan-0ty tp- b dyrditiodninpoutocaits stmp mse-upirbn ss0(h ameadcdry cdarrhythmiastseons stats r ypo-rskalso a).suCchass lioturgaclve depethe cein2hie centtef Aa the ref exlis8presgerbi ahestnre-ocigmo deoolol eostre umss rinfi lrer Aon turrcttef Aa the eicsil re-inhirgeii itasupeto a haibthe aret, wero-rsscetharetoolol -Tosa u gaveliaetweeNtiieturrctoneoasevacuo gassedepethcetndingl peeave prhe mestens ooolol segsinmettceae orvfi lrer Aohirgeii itasrrri(gatigturgaclve ilests cp.ttie ncsir ooolol.inA,c rhpupss,ms poss perilds eantedbi ucsilingltnexton turrcttef Aa the canlonsiscur. F araretctionip theettieohasriae-e t mstuempaaieruonnegtgaih orst ts to tap- hixmuevr,rhe mestennete by bsatl d eds rid osuch a a toat A0ty eicsyaresecp.othehupmop coposrctsegmgastmembrce-rdfmuu, d “i mpetsf ory pchas” foll waresece emuexocliolaxmuevr its mh tinoP gevsthcaits ssurooniernt(1). CNetrsicopos, semmf Nidsmas ier tandulr dirs synap- sses ei itasrsatlicksinenhadbsia trpts hf wrttan adrhalheis(e syn bcp. 1000 to 150 mL/d)e If, ducte- tieofcts hf o srrri(gatrturgaclve,ingle aolol eicsil prem tadess,msn ncs erthlsss0ty NaCl, KClnditiwr ga ysl beoe - M, rr c -T f aettsll deprets hf NaClinditiwrtta,ttp- b dyr R pot sswele anin afferee of vasehf olh n eoon (m in124),rhe trp-in thetinnap- kidneye ceeofcts hf olh n eed ron oi0,o its ac tssoc tradwele e - M,afferee on ct,xcormohe hf KCl -Tosancandulrs teostren ctK + par8addsupeto atK + ro-rsprets hf tp- b dy, evaneh rthbsiaofaraisbn UsumaKec+seesnieMoto gas ( ypokals-inmia). ceistons of li teaacc mpf iiddlyina he the skicn-eabsorpt op ttslsi0is(i itasf onia). ceabtan besct gdivanua seininpse“i ionip thee” tgaih mdepakes ty atrsiturgaclve,i adr, weviciaemscireug se clodude(2).suChoH aenof iaarrhea toat Atuhestinnelsi dans fii etoabter trbytein tieoels-inuma(h ametngest ils ctncse the) enegee aectrsicopos, heeisr ieincaits enoganre etecormohe ty ely, olytesnditiwr ga,inHea pup conthesdid ofrgeion f Nidtoneoas.in172 LaxaclvesinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLaxaclves 173inB. Cchass liolaxmuevr hneituIts inA. Snimulmuexocliotop ttslsi0sathmut nalerrri(g esithPap ttslsi0Irri(g esithlonmut nad Iu gavelinneedbietoineyfi licoposinNa sflnfirbpup r httef Aa the ref exinAgest na sfle evacuo gas fironnosinLaxaclveinLoss u gavelintedbi m frsfi lire um Ecs erthlsss0ty Kec+seNbec+se, Hec2 aOseRRn c ulsssthlonK + Alh n eoon isRRn ctncmbn ned lowNbec+se, Hec2 aOseRRf exinFirbpup A trpts r ht Secormohed lowf NidndB itasrnoptiaclHypokalso ain“C ionip the”ruLaxaclvein1ec2 aLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin2.a Sses eB itasCrri(gatrPurgaclve,iseRicinoleof AganinCaonerwoiltcomstue synRicinus0c mmu-e ni0s(caonerwchints; Fig: pres,epgaoeug,theebi);sis ismob wit loe synap- fir ti? 2d-inp y gtg hf tp- sebie(showsesken turrcin pzo)e Oculatrmiion. Its cri210–30 mLe firoaonerwoiltis cnll whadw pd t0.5ms a3 huley did ofrgeion amwrttathoneoa. Ricinole- Micsygan, brs ao rthehoiltiteylf, teaac tvoe Ctindtiass a a toat A0ty thehrbgsiaanp c ss-ices8revolved iNSfatidisistwon:eap- ruoden-d rptmut na of vassspos ncs o oCmonsedohbnectabokitar/panca ohi-inoihconposulessel. Trsi oCmonsdeedcirs cat aocf li on re-oges bladdban adrdid ofrgeion b loclygans via pol ielsiby ,g smsorbeas of vas on lip asee synap- panca osn(cn-eabsorpserd ttslsi0s s ave aonimulmuld) -Bof its on itsria eti enare l,roaonerwoiltis ofrdlyatsuioneleeferwtrsi a of gasrmac rhpuarythctionip the.oIs canln em,loyeavaf aecoculainsistwxocri2a Pnxon8is trdt ts r ao-inneisned from tg adr,o he y tt trp-in theton Pnxon8e synap- gut. Cconerwoiltisinao re dby the ngest tieoe sistwxocri2lipi-rs n lecrPnxons lik ly e fdepeth hisnelsi d- Midtlssurtrsir a trpts tin2.b LargeiB itasCrri(gatrPurgaclves is(p 177 ff)inAa-rnaquinon nedCOvipevss02p 176)ss rinofwchint trigiie ceny l a rein tieof vvesin(cnlia sennae) orifruiCh 2frofdus sennae) on re-osennawchint,ttp- barkpathRhamnuee frangsiagodiloRh.iturshiana,s(cortexngfrangsiag,roaocara saon a),ingleoooPs ty arhubarb (rhizoma rsi),hsurposof vfanx- Mw amt8e synAloefely,les02p 176). cenins Tofdu flnfea u rs hf o trnaquinon neded rivipevss0ae oirbusoto ythbsinglite cc-edt th s Tofdu rsdepic ectonft 177.inAmossnobstanito (itugass,rpoeisotrna-rs Pinon nnucloua fd witsaold oxylingdoups,nans liohe mesrs bnundeto atsugau a(n:ut n ,erhamn n ). Foll wareoe sis-in theton galet lllap ypalaf licenr nsengle o trnaquinon nn:lysssicc,rdid ofrgeion ettfttoneoasa a rc ngest a la-encxaon 6eto 8 h -Tosao trnaquinon nn:lysssiccttiem-rsselvss0ae oinan libebrs oralctivertradbsxccolas e-c ie - tieofctsvsee eroagly-e t ncs.inD phsnolmereanededCOvipevss02t 177)adso rsdevssopiddf synphsnolphrealein,seaesidcanehts lindid ovscrenlixmuevr,rits on he meshaddineisnotradm frsat A0inineae obrs sevscemavlergesroracts st Bidac-e dyl adrhodiuynpicoeulfreetoralctivert-icethbsigrs e-c ie ihconposaan libecoltn- Mirri(gatrtr iplbe Ghe ghbsinglincs erthdoutc, idac dyl ist to terms aold olysi0isth acetyleorsiduce,sa trpts etctnjuga-in thetinnteropotoaglucuroas racan ( agive atoineulfreeett 38),oditieiltstattecormohe iNto tap- tuodenume Oculatrmiion. Its cisinfoll whadngest aate x. 6eto 8 hteyodidsin ofrgeion ttfttcn. looneoa. Winisghe gineyosupesss ory, idac dyl te by bsaitod osuch w pd t1 hm CNdby t licassurooltn-rrri(gatrturga-in tvosrrdispoeapknvposthe athi aoe pupint2 ti ol foll waressurgery, myocdry lniu-infarc esiettues oke;sditip ivi p hf nc-e hief ih mdin asdid vassson re-oanuspyh ameinfid u r, iemorrhoidttinPurgaclves mh tinoP n 0he g sesisg eho fnilnctmelaiu sson unilest trigiie 3. Lubronitholaxaclves.oLi P depgrat inis(pgrat inuyn toli P dumi teaalmmmointn- Mf trbpaugodilomakes tecsfsogesa eosicmoari vailvetaleed.oIs in-erfneesiweled eneia trpts hf fre- oiusosivitse nsuley aopparet, wm sg dofewaa trbytrupgrat inopdepoeugsiwiveinby br a pe needcar aeign-b dyron nulomosein ecs icndcimppwaodss02tgrat inomos)t A pito ned ihconposabroachls P amt8canlrsat A0innte-igto depneumonia -Bof its liothece od-inther n osuche,siCh use ismnoP advi paug.in174 Ldxaclves diloPurgaclvesinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLdxaclves diloPurgaclves 175inA. Sses -i itasrrri(gatrlaxaclve: r minoleof yganinRicinuse t mmunisinGes -ulesaddbasePanca otsePop ttslsi0isCK/PZ =suChoHectabokitar/panca ohi-inisCK/PZinCaonerwoilinGlyce ol + 3 R minoleof ygansinB loclygansinDuodenumseRicinoleof acan – O – CHec2seRicinoleof acan – O – CHecRicinoleof acan – O – CHec2seLip asinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin176 Ldxaclves diloPurgaclvesinlioPhintsifd witareto trnaquinon nn:lysssicc SennawFrangsiaecRhubarb AloeinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLdxaclves diloPurgaclves 177ndS gau hf vvjecseRRhe theinAa-rnaquinon edgilysssicinB-c iein1,8-Diold oxy-e o trnon n-Aa-rnano inh amet1,8-Diold oxy-e o trnaquinon nn:lysssicinGlucuredcnsicinEn eo asinD phsnolinB. Large-i itasrrri(gatrlaxaclves: h phsnylmereanededCOvipevssinlioLarge-i itasrrri(gatrlaxaclves: o trnaquinon nedCOvipevssinGlucuroasdo ned D phsnolinB-c ieinGlucued ronmul aSulfree Bidac dyl aSodiuyigticoeulfreeineugau aLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- Iiarrheal AgposcsuCchass lioiaarrhea (ih ord): Manyhbpcs ed rial(h ametViap.o ohbnerae) tecormsrPnxonsrutrbe cns of pos neiltoxaon mut naleecs ed rocytesns att trb NaClnditiwr gandit,int2 te-ocambetim ,w imulmulSmut naleiecor-in ory an lilty.aB-c ie survirus-tlt asiiu-invadenap- guttwullif its inflampe need ofr-c izethbsi u afferenf Nidtoecor-in the ihconposalu- n -Tosancs icnmuscu-e hi ur oeyactsdwele e afferenrd ttslsi0.rug d sims hf o tiIiarrheal poec uainrdispoapknvpos: (1)ndeold a the eosicely, olyte deprets ;nditi(2)rexce eti -ndcin mncoti ol fre Pehcy. Diffneeh posr-ig use of sate oahcso(cntg ern)e. seedinerltvariaemlyr uitlctssurposssiturtotss.inAd trbyatrtowdeacemarinonf g ettrbpaugomas iersswele aohirgeicurfaceinerlaghcens ob ndoiather n to (gan-t, iu-inthe pup coxinspyrd ci tpupi, wmetoabtd ih d simu loenegeed fromenioMmdicinerthcofrcosl -oleesass aotdepoesiaalyrhirgein u face of its on re-opd. Usage mbraats Tofdu rhesg darncommethedave in libe o tiIiarrheal doduni08in tieort pegon e4–8 g. Obstanad trbyatcemarikaooin ( ysind mu loelu fiuyn lecmu )oditiohalktinOr ctncold a the soiu- lis(g/L tyd f ilrenwr ga: NaCln3.5etn:ut n hie, NaHCOad3 2.5etKCln1.5)e Oculatrmiion. I-in theton g:ut n -fd witaretsdltrsoiu- liod npaugs f Nidsetoabter trbytebof its Pnxons do ao rimmdiretrsiconarasat t hfinNaec+se han:ut n h( smsorbeas ri2Hec2 aO)adtrncreas, e mut naleepi whicume CNSpoistholorga,eyllecpeasfre Pehh did ofrgeion eti ol ismnoP pknvposod, deold a the lsndoucce efarcinc r Rc ectinOpioidtt Ac simuexocli opioid ey,ep-in or08in tieoncs icnnesag prexus toat Atisbn ion of exocri2pc puleti e o agic si- Mity enegeeoganr gasrmacsegmgase needan lilty.aceisto tiIiarrheal osuch wasrdfmuserlveinby bthbsiaatlicmuexocli opi-inumatpuctu r (mdeegs ar)ifd witaretm asinppd e -Bof its liothehCNS of ACh 2ereI-in the,nd. pito ory dep y gsiettnic caliniepethe ce),dedCOvipevss0w pwedCOph- ten l acts s haibebneisdevssopid. pWeeisas h phsnoxylatc caaw ill te by bxcilesthCNS of ACh, sopirrmmdyee easestses such b tin cal membstat na sfl dodape.inLopirrmmdyei0,ongrcef is,sthehopioide o tiIiarrheal car ir ti?hoioe -Tosa ki-rsposs difd wermsim ehf ihceabsorptctiand gassaenegmut na wiveyve armteove osg ettrpts hf f Nide W pwothedodape,d enare teaa ogzarle-upireus.oIs ismesn aoe sindby the gt infintsirolaw ogp 2 ytinAa- bpcs iereroduct Uts liotheceinegettce(h ametmonaimoxazoleett 272)e se otectrof lierswinise-c ie rdispoethcaits lioiaarrhea.aceistlserr lvetrsicice.rdIttshoulddin kepA0innmiadr, at na- bic-edtoes ave aiamapestosa u gabsorptflora aheichetin turietcdisghe otiasrtoidiarrhea.inAonringee sss ncreastaorff yganin(homs rsicyy: esackanda) ori-mo cthalheistey,ip-rreet u face p inait haacein iopearms aoelpcseal poe mut naleepi wh-e hiume Peinaitdden du fts mh tinoP iu-inthe aioe fectop inait ,tssurpoistrouldinmeanlcell deatht Allecpeasaonringee tisbnby brctionip the (cf. Alin3+inhalhe,ser 166),ra poec use of osuch itddiarrheainismdoubtfulgseDhmhlcontspyh ametpe, wn ( o rigrsicyy: g mu loepelis) ae oacrboolsind mu tlt asiexpsaneon8r trbpupiwatoptinceny rmteove trsicoioCerencxaon b itaatctirgass;dinyoadr, at teny rre devoide hf o yifavlrpaugo osuch.in178 Aa- IiarrhealsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- Iiarrheals 179inlioAa- Iiarrheals adr, wianimtrs hf o theinRrsidgas tm iroflorainOpioid-iney,ep acsePeinait-e t n witareinmutucsePeecip-rreohe on etu face p inait ,theeabpupicatemut nad Aonringee s:inh amettaorff yganinVirus-tsePathoionicndb-c ieinF Nidtoecor theinCl -inNaec+seTnxonsruGlut n Naec+seMut naleinjurythA tibpcs ierthroduc:inh ametco-naimoxazoleinAd trpuexoinh ametto tmmdicinerthcofrcoslseTnxonsruion of exocri p puleti serd ttslsi0inOpiumatpuctu rate prm appd ed D phsnoxylatcinLopirrmmdyinCNS Ecoganret op ttslsi0isDiarrheainO erthdeold a thein olu- li:inhalhe eosicglut n F NidndlsssthLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc ssurDis olvpupiGes ssen se(A)ruFoll wareoetsttecormohe f synteropoiNto tnels,mwrtta-in oiusosiohbnen eooltis oeldininssoiu- lisin tieofmus rfrmicellau h msinprexss0w pwnelsi dans ditiplospiooip- Midt. Winismoariohbnen eooltis tecormscrutrbnscanln emuletfiod, is pcy,ip-rreesin adr a psoges ssen se(ohbnel pdasi0)esePeecip-rre difhbnen eooltcanln raitc asinpor the gt- micell-t, p ividscttheeohb- toen eooltcsnieMoto gas iisnelsiisirolawinhadu fts ghceus, fhbnen eool-fd wit-nd dirssen secanln dis olv loolarece ceisxc osuch canln schitvh mbyrlass-nd cmocultetrmiion. Its hf oheaodsoxythooicclygan (CDCA) oriursodsoxythooic yganin(UDCA). Bculamari.nic oH a lllly l a red ring,w areoisombre bilsi dans (esss li on re-o7-old oxynidoupebe dirβ iisUCDAin adrα iisCDCA). Nt sflec, teny reere-e seruon sses ep por neethwtrsi otsl anm e ty bilsi dani.kesgat edit ofb dyin(cireug Iiag mmse SA);r its ac pois iu-intprodusicoioCdnpnely e prctroas rad-inmiion. Its of its on ncs o zpice ndcycling,wt 38)t Bilsi dans uhdtagoaalmmmoe t mprete tott trpts in tieoelsume Sses elolees via pol tecsfse omadenupuley drinov rsytposslsein tieofis ac keep-nd dirn si otsl nm e ty bilsi danstctiand (gatr(3–5 g)t Exoionaemssupely nc-e ovesingltnelctssurdrinov rsytposslsetyd filsi dans -Tosa depoesiaanrgan oaressupsinpriiddgait e affepupssrhirgeanihs rinofwn si otsl onerstinTe-oalhscrencompnsf exocri2nelsiiu-intprodusitrsicipa toxassurohbnen eooltupsinpakeghceus, ges ssen secanln dis olv lininstrsicourasehf o 1-ms a2 yi a of gas, p vidsctthatrohbnen eooltssen ses rinpu rsditiao rtooohirgei(<15 mm), ges ulesaddba cal memb ismno sfletteropodid vasinismtt gas, ohdepgaierusfse ohf na sfle b dyreeeser.sUCDAsismioreave in libe (dailved n ,e8–1e mg)oditiee ttanconeu-ig tiddtrbnsrs CDCA (15 mg/d;sfre Pehhindbarrhea, elyimuexocli teroponchi- s0ininthicse). Snon n a pe ne wiveey, ring-ic eosce emuexocliooucce efar poec ua.suC mpfrradwele surg llla a of gas, rodu poec uaoeofy a to rhpuate toug.inUCDAswiveyve an usefar inopaimstatbi -intstatmirrhocis.suChoHeormonseacem tppodudee fsnimu-e hi eepc he the adrhecormohe ty dilueed filsif Nide ceisttr iplb has l tlbepoec sinpse ofteigntionitce.suChoHekd emonse imulmulSpoeiges -ulesaddbaee fcat aocf enegeicsypyh ametegeinyolk,sthehosmo ofelaxaclve MgSOad4 ,ingle ahoHectabokitar- lre diferuretsdri(gsi- Mev mdencs erly)e ChoHekd emonserdisemsinproyeavs and tiges bladdbancal memb ferinIiagnmmooftpurtotss.inPanca ofic nchi- s02hi f synd lapearscrenanimsls rre uasctto ofitvhin,xcormory iusut ini tcy on re-opanca otse(L50478idin uptudeiisistwxocri2fass;dn eo ored rhea, in-ereyvia). Nt sflec, hecormohe tyedpsaca ofic nchi- s0teaac tv tradbsxcohbnectabokitar/panca ohi-in, tieonc-ic eoo oCmonslt asiis of vase gt- esselade synap- tuodenrptmut na upodio n-d werme prcti- e W pwoculatrmiion. I-in theton psaca ofic nchi- s,eyllara ceinrh tibabmadenssurtrsir depoaleinac tv -in thetbsigaonri racan (tieofip ast, pdepoes-e hirly)e Tgrcef is,sthey rre trmiion.erbi asesidan- vei (gatrdodaper a pstinAa- fhi ulettce(car from vis) Usag m favlevimulSmetee lsma(hxce eti eaces-e mulmuexocliogasein tieonatioocn-eabsorpse aocf)t Ao rad2pc pulettg oarsk-eabsorpsectirgassfiitimpedbiehestnre-ohi ttans rinmixradwele gasebubaugs. Def a pupinagontspys ncreasdime-hicon (dime-hylsinpolysiloxan )oditisime-hicon ,tsk0c msinnero neiwele cofrcosl, oral0he g ocullyintoapk ervh sypalaf licliogaseaem ane etemi ol deoonrgassm 180 ObstanGatioocn-eabsorpeDoducsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinObstanGatioocn-eabsorpeDoduc 181suCA : ChoHic yganinDCA : Desoxy-CAinUDCA : Ursodssoxy-CAinCDCA : Cheaodssoxy-CAinUDCAinGes -ssen cn. lobsxcohbnen eool Ilsum Excor thein ga tecse St moahinDuodenumseCK/PZinFofsint n witareincti-ucseAddof liinofinIime-hicon in“Def a pup”ruCe Ccr from vi e osuch rfinIime-hicon inSytposslsety b loclygans - maiu wit eti rinDAAinCDCAsuCAinUDCAinDCAinCDCA CAinUDCAin“Panca ofin” oioolapearscnanimsls:sePeinaan ,eAmylan ,seLip asinPanca ofic enchi- inB. Rof vasehf psaca ofic nchi- s0ane etrsirnd.eofnr gasinlioGes ssen dis olu theinCireulmuexosuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc Ae in lresMo agFal membinTe-osses d tis Tofdu flnunisrmacskof tsl amust oftade isitrsionri tradmustleefiaer.rdIttcat aocfs gt R poteers atnsempuleeion eitsrio agnesage CNSexy, taretm ttrepc -e grams,rpoeib tin sethceempulees conthein psorptctrdghcens octivergeionrα-m cc-edneuki s iNSpoeisos itre oCeethwtrsispf-tiieli lullwm Effneeh axasaocouras, br sindlhe gt io agnesag0,on fskof tsldmus-inthgs. Simpretncf exlcti aocf licen fsei-xc oryr imuli,octiveyeavvia pol dorserthdoots conthe io neuki s, l a rewele-secp.opdepoeip the hf tp- b tint NeucultecireuiCh menthpc pagreetoffneeh empule-ices8retoare-ocpsorptctrdifd wit ion of -secry ius neuki st cens f esag poapkn-inthruon p hypers ovscrxcit the hf m cc-edneuki s ( aghxce eti emustleecti aoc-in thes) duem- trsicoio(gatrbarrageion etansory imuli.rdNeucomust ofr tarasmisvesi (B) tyd io agnesageempulees contheionri tra amustleefiaer pakes eofnr at ten io a encdplre -Tosanesageempuleenlibeur ssin cetylciotensa(ACh)8e synap- axas top-ti fnilt AChgb ndmsconniconitarsthooinocep-in or08at ten io a ncdplre -Ac simuexocliinposssi ocep acecchass depolarlzIts ty atrsincdplre ,8e synhe mesahpc pagreededan lonftotposoale(APi teaeedcirytein tie etu rnundaretsdrcolemmaghcen AP8pres-e geaceme of vasehf Cbecd+ine syncssfsnorageioa-edgan ll-t, te-ocarcothicsesrorpoesiumse(SR), w pd tpoe mustleefiaer; tieoridueininCbecd+incsnieMoto gas iiby bsaa cti aoc-in the hf tp- myofilamettce(hly, omesin oft lllacoupling)ioMmanhe ls,mAChgisxcold olyzbthbsiacetylciotensn eo asin(p 100);rexcit the hf tp- ncdplre tcesg etsicce If no AP8foll wt, Cbecd+inis8pakev upulegaih athtp- SRi adr, wemyofilamettcthdelax.suClin lllly emp toolt roduc (weled eneihxcepts hf dolttougn )odllriNtop-tifneeiweleaneukal cti aol hf tp- mustleecmbrae(A, Bett 183ff.)laCba-kally actsretmustleedelaxattcth(A) lart mustleesen bsiaug gassre atrsi d sitoxaon na-kacpsorpt dn of aye cn-e neuki st ceny rre uasctd tpoe a ofsinmett rfrmdin asmustleesp amspyh ametit etpsorptdistrdt se BonzoIiazepenss tandhrdcersheave in libn ss0ty tosa un of aye tarasmi ttanGABA (m 226)sstnGABAighthdesin ep ac.aB-clofensonimulmulseGABAigBthdesin ep ac.aαec2 a-Adeeho,ep agi.onCertls ncintsscposrdensaenegtlzIsrdensa kibnely d inp y ynap ofs lin- ius of of vasehf ex-ed it ory aiiioracan tarasmi tta0.rug d ctivulegatrtoxinspyt tsnus0tox-nd d (f its liohnundet tsnus)oditistrych-e nin di fs shnsheave ofscxaon na-e neued ronml ynap of ion of exocicy tradbsxctrsi iiioracan n:lyensa(A)t A aa ctise-rs Pgan-0ty tnsunreonrwit losp yad ty anesageempulees d tpoe cpsorptctrd, io a ectivuleiassedevssop -Tosa uvolve gasinhf nc pito ory mustleegdoups ncdt peacselifotinBo ulfiuynPnxon8e synCloonridiuyigbo ulfiuynisitrsimmmoi.otposipoisot eknown -Tosalereal dodunig anhadultrlsoapsinpe x. 3 L1154 10 –6inmg -TosaPnxon8bescks nxo-ed ytoslsety AChgit io ag(a haave apalag etympaaos of) nesag ethares. Deathgisxcf itsthbsipalalysi0 hf nc pito ory mus-inthgs. Inj besct gtrimusesiaalyrstn fius-intuug Iodape, bo ulfiuynPnxon8t th Agisxcuasctto a of8beeplogosp am,hi aobidsinmus, aohalasia0ty tosalart e ophags c etphpuctga,eyitispaonof sahonia igh pothoH a lllariduein UsumaMgecd+inlevsss ave acchass ion of exocri2AChgatandf vas, iean-0ion of exocri2neucomust -e hir tarasmisvesitinDolttougn in-erfneesiwele ely, osinme oft lllacoupling d tpoe mustleembraatbsi un of eng Cbecd+in of vasee synap- SRe Ctinic uasctto a of8mdin asmustleesp amsig ttetharettpsorptdisrodusiyitiskof tsl amustugodidtrdt sa uvolvarethxce eti in of vasehf Cbecd+in(sesigngatrnimarwhop-ti fa).su182eDoduc A, wretoneMo agStabsocsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc A, wretoneMo agStabsoc 183seDhpolaed rizIts inAttetureededion of exoruion of aye cn-e neuki rug tsnusseTnxonruion of exoinhf ncf vas G:lyense Stoychnin Ry,ep aseists.onCer CsnvulegatsMyo nolytoesicI affereedion of exoruion of aye neuki ruBonzoIiazepenssinh ametIiazepamnGABAigh.onCer B-clofenin(GABA = γ- iiiobutyri racan)inB. Ion of exocri2neucomust ofr tarasmisvesi enegeey, ome oft lllacouplinginlioMe oft smc ssurinflPganarettkof tsldmustleesen inAa- epelaptscsoAa- palkin onian roduc Myo nolytoes Dolttougn seMustleedelaxattcthMgecd+inBo ulfiuynPnxonedion of aACh-ncf vas Mustleedelaxattcthius of ion ee needcaro theintotposoale Sarcothicsesin opoesiumseAn lonftotposoal Mo a eneuki ruMo a encdplre aACh ey,ep ase(niconitar) MyofilamettcthCat aocf li Cbecd+inMemera eftotposoal Mustleesen inmc 10 hie aAChint-TubuleecDolttougn sei n of s Cbecd+in ncf vas Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinMustleeRelaxattcthMustleedelaxattcif its a flidcanipalalyg etssrmacskof tsl must oftade athbin pup cod io agncdplre tthooinoceptorspypoutulessckaretneucomust ofr tarasmisvesi (m in182).aAcc rhpup conwhebstaney,ep alonsiscupsacyof vdmscona8besckaden aginrexci-d w the hf tp- ncdplre eten tdintareueehl inaondepolarlz dirs syndepolarlz di amustugodelaxattci(p 186)t A aadjal ms to tion eelndieonos of0,omustleedelaxattcthoelpcconNicurslt asisurg lllap c du rhinerltao rt tturbsthbsimustleecti aoc-in thes on re-opaaieruo(m 216).suNondepolarlz dirmustleedelaxattcthCueae oisitrsind cmferwchint-edCOvrenared rowipoisots on Sou prAmbre anhn tlves. pWeenis Tofkdbsia cueae -- pprenarrow,seaesinimsl sut t sapalalysi0 hf skof tsl amust oftade w pd tatshotomsim eaf aecre-opoeeotdsp yadsitrncreas, e b dy;inieathgfoll wt of its nc pito ory mus-inthgs fii e(nc pito ory palalysi0)t Ki lreedgam canln of n welecp.t iskpbof its a trpts hf re-opoeeotde synap- gao-innoocn-eabsorpe aocf isivirtus linnil -Tosacued rae oingrcy ett rfrna of moimmdicinerthemp toolc oisid-tubocueaed e -ceisxccompnund fd witsaa qureeruarynni osinionsf om (N)ndit,intsthehoppnsf - ncd ty atrsimbneesie,ra poptiarynNlt asiis te cc-ednmu loeti.nic oH a lll pHt cens ftwoigtoti witss ofrgednNla mseoralctmmtndin favlnobstanmustleedelaxattc sg dofixraigtoti wit ofrgeion trsiqureeruarynNi d- Mc e tlssurtrsiro agnculrs te trbpai -intty.sud-Tubocueaed eiis ghe ghbsii.v.iiu-inje the (avscuge dodunaate x. 1e mg)e Ctinb ndmscontp- ncdplre tniconitarsthooinosin ep ac welecp.texcitpupi, wm, actsretotseancomps o wit ists.onCerscowarls2AChtinByapknvpostdirn sibin pup hf ncf vasd aACh, is bescks neucomust ofr tarasmisg ets ghMust ofr palalysi0 devssopsewele-sesesiscp.t4n fi. d-Tubocueaed eie easestsepon oto y8retoare-oCNS -Tosa daieru rouldypoutiexpbreean-0m ttrepalalysi0in adri neiltoxaro ba ofhr,rhe leedemwit-nd dirfarcinc nsciaemsbrs pucappaugohf ex-edp y gtg any pd g. Fourpoistaffe etcs rinmh tibabpakev conNed fromenc nsciaem-ednes0satharmiion. Its hf aesiate pri-rsomenrodu (ion eelndieonossia)teef is em-edgtg anmustleedelaxatt -Tosanosuch rfratse - Msle dodunPhausfsscp.t30 miie Tp- turw the hf tp- nosuch rfrd-tubosiscueaed eicanln shotoenhadbsiarmiion-ndulr diraesidetylciotensn eo asa un of a,ndouccreasnemmoogmin (m 1e2).aion of exoinhf AChgbaffkdowsecchass trsicoiceiand a exocri2AChgatf vase atntp- ncdplre m frisse Cbmps o wit “t teofnr gas”dbsxcAChgrfrd-tubocueaed eie synap- ey,ep-in oreyllars tarasmisvesi toabtereono od.inUnwsos d of ACh p by bd bsid-tusinnocueaed eirsat A0e syn inonimmunc-e cy trad of vasehf hi (gmd eie sytholstimbrah, sea pup conbroachosp am,h red ofsria,eyiti ypowanslsighMoralctm-e onss,ms fdllriN essel rrdd u r canln stand ibrssctto ganglioas rbesckadenbsid-tusinnocueaed e.inPancuroasuynisiarsytposce c msinpouitiaowsfre Pehhcinuseavaitiao selik ly e ff its hi (gmd ei of vasehr gan- Mslioas rbesckade.oIs ismaate x. 5-folsicmoari.otpositrbnsd-tubocueaed e,iweled arsomew asiposs turw the hf a the.inI affereehze, tto y8ditiessel rrdd u risse oat ibrssctto besckaden iroary cdMec2 a-xcohbninoceptorspyan nosuch ao rihs radbsxcnert pancuroasuynesnsint saouccreainthcuroasuynohdepiphcuroasuytinObstanaondepolarlz dirmustleede-e hixmassfibthe e:dalcuroasuy,dedCOvelade synap- alkaloannPnxoflr d; rocuroas-inum, ges gmd e,omivacursuy,da haa. I-incursuy -Tosali ttanuhdtagocsfspd wnc-e aemscf vvjecn adrd easestfdepeth hithoepice ore on ct,ed from tg in184eDoduc A, wretoneMo agStabsocsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc A, wretoneMo agStabsoc 185 aAChinA. Non-depolarlz dirmustleedelaxattcthArrowipoisotaon naiisinaemsSou prAmbre ansinBesckaden irACh ey,ep assuNo depolarlzIts ty ancdplre Rehixmuexormacskof tsl mustugsru(Rc pito ory palalysi0)thArttionoal vpostlmuexosunece emaye (pluesion eelin aeonossia!)inAa- Iotp:xcohbninsn eo asin un of asinh ametnemmoogmin se(nognculrs te trpts )sud-Tubocueaed eiPancuroasuysuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDepolarlz dirMustleeRelaxattcthCNSpoisnrodu cPhas,nanlyr uccinylciotensse( uccinyldiciotenspys xame-hoasuy,dA)ruin carclin lll emp toolc . SnTofdu flli,weoe tanln desc ibradpsiardoubleeACh mole- Mesie.oLikeeACh,r uccinylciotens ocfs otsea.onCersasiecdplre tniconitarsthooinosin ep ac, yetsis pc by bsamustleedelaxa-in the sunlik gACh, is ismnoP old olyzbthbsin cetylciotensn eo as. H its ac is ismandoubsoto yohf nanslecefic thicsesthooin-ices eo asa( Usumaciotensn eo asett 100).suSuccinylciotens i0 deon radmoariolar-ndcintrbnsrs ACh adr, wcef isnrem ith ib2 te-ocynap of tlefttcn. sevscsl minrsss,xcf it diraesecdplre tdepolarlzIts ty ac r R pot pupidu fts ghceis depolaed rizIts ibisoalcintresgerssahpc pagreededan lonftotposoale(APi t tpoe cu rnundare amustugombraememera e, sea pup conctiand an the hf tp- mustleefiaer. Agest uje the,efin- mustleetwelahcso(fascicu-e hi thes) tanln ob Usage sAtnew AP8odninbeaeedcirytenesthtp- ncdplre tanlyrisengle memera e has bneisall whadto opi-rslarlzstinTe-oAP8is duem- opetpup hf volts.e-edgaryteNa- oftntaspc nait ,tall wareseNaec+se licen fflaw trncreas, e sdrcolem-e a adr,o f its depolarlzIts . Agest atifnw mirbpseons t, te-oNesthftntasscpots aut mo ofs lin(“ih d simuihe”),ingle memera eftotposoalrorpuricen freabsoginlevsss,i adr, weAP8is nd cfromenioAs possintsstp- memera eftotposoalrorm ith ib-e t mpretely ncpolarlzod, onewhadopet-edgtg ofoNesthftntas, iean-0atnew AP,gisxcemp hyperse CNSposicice hf ncf vasdgACh,d rapan affkdowsebsiACh es eo asaa -inlars repolarlzIts tyhtp- ncdplre tane eiean-0atorpuri ofoNesthftntarexcit ai -intty iNSpoeisdjaieMotsdrcolemmaghWeled uccinylciotens,r its ac poare teaa pop-tioCerenttdepolarlzIts tyntp- ncdplre a haadjoitaretmemera efregi st Be- Me its te-oNesthftntassorm iteinac tv t-icetpyan AP8odnestebe naesgerbi iNSpoeisd-injaieMotmemera etinBof its mmmoitkof tsldmustleefiaerhinerltiorgav tradanlyrbsia epups- ncdplre eedan limuexoclioouchefiaerhc e pr engthsxcupccon30 cy,d thii sgpc pagres tyntp-ighP trncreas, e ncsir oobrae If , weAP8fii s, atrsimustleefiaer rem ith ibfaedelaxre etrre tinTe-onosuch rfrats(gadardhdots liosud- Mcinylciotens Phausfanlyr bcp. 10n fi. Ctinic ogesisghe g atntp- s(gep ath aeonossia m ffaciltoo y8retubIts tyntp- daieruioAsin,xp besc, ciotensn eo asa un of ases rinunpaugo- c e eaocf tp- nosuch rfr ucci-ednylciotense CNSposifnw pgaierusfwele a tion of de ini tcy inopseudociotensn eed raasa(= nanslecefic ciotensn eo as),ingle uccinylciotens osuch isteigntionittlyinpc poss d.suSian-0popoCerenttdepolarlzIts ty ancdplre s0teaassoc tradwele an noslux ty aKec+se lic,rnimarkalso a8canlrsat A0( iskpate cdry cdarrhythmias). inOnly gt aifnw mustleetimas0(h ameadex aot ofr mustle) ae omustleefiaerhinsupeliradwele mt Aiplb ncdplre s. Herle uccinylciotens cchass depolarlzIts inIis ibrssctovers, e ncsir ofiaer,rhe mein o pot sswele aocti aocfu re CN aot ofredp y ur oeiast, he mesmh tibabpakev iNto tacc e du arethyessurgery. CNetkof tsldmustleefiaerh heots mm-in orenesag has bneissevsced,rACh ey,ep-in or08sp yad gt aifnw dayttovers, e ncsir ecmbraememera et CNSpoisicice,r uccinyl-xcohbninetrould evokeaa popoCerenttdepo-rslarlzo neiwele cti aocfu reyiti ypop-tikalso at cens f of ACh acemlik ly e fl a rsesespoly aoumo ozbthpgaierusfuhdtagosoginfoll w-upcsurgery. 186eDoduc A, wretoneMo agStabsocsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc A, wretoneMo agStabsoc 187inlioAn the hf tp- depolarlz dirmustleedelaxattr uccinylciotensseDepolarlzIts DepolarlzIts inAcetylciotenssuSkof tsl amustugecmbra Rapan ACh cf vvjecnbsin cetylciotens es eo ascsePeipagres tyedan lonftotposoale(APi aAChin1 RepolarlzIts tyneth plre 2 aAChin3rdNew AP8ditions aocf li canln edcirytsuSuccinylciotens estfdeon raatbsi cetylciotens es eo ascseSuccinylciotenssePopoCerenttdepolarlzIts tyneth plre rdNew AP8ditions aocf li canestebe edcirytsuCsn an the Cat aocf li Memera eftotposoal Naec+se- oftntasuCloasd a(opetpup noP p hypers) RepolarlzIts suCloasd a(opetpup p hypers) Opei Memera eftotposoal PopoCerenttdepolarlzIts suNo repolarlzIts ,d ronewhadopetpupicateNaec+se- oftntasuemp hypers Memera eftotposoal SuccinylciotensseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- palkin onian DoducsuPalkin on’stdisrodue(shakaretpalsy)tane ecssfsyndromer fermseoralc itsthbsianeded ion ee neohf nigroonri tal dopamin seneuki st cenlrsat A dirssri tal dopa-ti fne de ini tcy f vdmsconover d sitoxaonxcohbninergesrcn-e neuki s a haimbplaan-inhf ssrioparbpdal cutpp.opdthwaytpyoloi-tifns ythbsipoveroxaon movemgase(akare-e sia),imustleestiffn ss0(rigi ofy),inremorrsomfreab, p hdu flniio(geiltox,i adrgaitodidsinturbitce.suology ? toec use of mrodu rs s rinaimse atnreono pupidopamin rgesrcal -in the hrm tpp y gtg ohbninergesr ypop-tian lilty.seL-Dopa. Dopamin titeylf8odnestsepon oto y8n sibssel-b tin barrier; har-ndts ac isson turrctpey, rsoac L-diold oxy-e phsnylplaain (levodopa), teave in lib0inineepres sh dirssri tal dopamin tlevsss,inbef its itlis8prrasat tse acrsss0tosulessel-b tin barriervvia aesiiiioracane cdrrierva haist tose Pehhcindeacrboxy-e lo ythbsiDOPA-deacrboxyl asettkesgatininsssri tal tid ue. Deacrboxyl the lsoinpakes eofnr sespdCOphscsl orgras heeis ehopamin tismnoP ntedbi,mlik ly f it diinuneds rpaugo osuchs0(tachycdry ,nared rhythmiastrsat A dire syn c simuexocliinβin1 -adeeho,ep as [t 114],i ypowanslsi, a havomitpup)t Ex aoceisbrrctpe by -in the hf hopamin tcanln pknvposodnbsin un of asehf DOPA-deacrboxyl ase(carsinnehopa,ln icorazide) t asido ao rpon and a y8n sibssel-b tin barrier, seav diin gtriceisbrrctdeacrboxyl the unposuch-icett Exce eti eelyimuexocli b tin dopa-ti fne levsss wivef vdsconuneds rpaugode-e ocf licpys ncreas uvol e arynmovemgassru(dyskaresias)aenegmehts rt tturbgan-ttinDopamin tey,ep ali.onCert. Defi- Mcienttdopamin rgesrtarasmisvesi in tie etsri tumacanln i mpetsf ythbsitagohinddCOvipevss02bk ercCOptin t[t 114],ilisued rideetcsbtagotens,rohdeptagotede)tane enon agoh compnunds0(ropiniroleettrrmm-e pexole)t cens fi.onCertls imulmulSdopa-ti fne ocep ace(Dec2 a, Din3rd,rohdeDin1 cesg etimas), haibelart clin lll ve ofscxatrbninlevohopa,lyitisherltitsriagt adther n o-tifncssm Iun of asehf monoamin toxm-e d as-B (MAOigBth). ceistisonchi- affks ehown hopamin tinstrsicorpemsssri tum a hacanln seey, witss un of ythbsistandf gitense CNan limuexoclionorepensphed e,icepensphed e,lyiti5-HTvvia MAOigAinic un- Mfan besc -Tosao t palkin onian osuchs0on etaf gitens wiveeyat A0e synde affereedhopamin tinan limuexoc(enoganre levo-rshopa R potee) orifrsynneukipc nan libe me oft smc (de afferetoxyn lll foa-edpe ne oribesckythbioan limuexocliobninunknownnneukiPnxon)m Iun of asehf y thohbn-O-me-hylsintarasfeo asa(COMT). L-Dopan adrd pa-ti fne bncom tinan limusthbsime-hyla-in the scenlrsapotepers nchi- canln ulessckythbsit weapon ,tall waren mnc aeclevsss hf L-dopan adrd pa fne toabtd schitvh msk0c rpemsssri tum. inAa- ohbninergessioAa-i.onCertlnt2 mustaed arsthooinocep ac, ouccreainn izItropiny8ditieipdCOden (m 1e6),insupe y sssri tal ohbninergesrover d si- Mity enegpoareby ofitvh rigi ofy0ane etremor;r its ac akaresiatismnoP kn-inthreretor teave g exiceibomenioAtropiny-selik spdCOphscsl tsicf of ACh a haimmdirsinmett rfrcogno wit cal memb ed ftwn si olsinerpaugododape.inAmistsdense Eaalyrori-ilnipalkii-xc onian oloifns t licawivebabpempo-rseaedly ofitvhthbsiamistsdense Theinunedalyaretme oft sm hf a theawivin gvolve, in-ereyvia, besckaden irligrad-edgarytetheathftntasshf tp- glutamas /teNMDAt totima, t A mas ly sea pup conainIimfs shree of vasehf ocetylciotens.inAdmiion. Its hf levohopa pluee cdrnehopa ( agn icorazide) rem ith ngle mmmoive in lib0 a of gas,sbrs e easestsep vidsgn iefitdinyoadr3–5 yva haistfo -inlarethbsign ua elole rfr ymp om ctiand ol,nan-off f NctuIts s,i adrdevssopsinmett rfrorobuccofacis teosted b dyska-ednesiast cens flass-nd cmdrawbacks on elevohopa toec uaowivebabdelayodnbsineaalyrmonotoec uaowele dopamin teysin ep ali.onCert. Ta of gasrmacadtganre edisroduere Pirss trsicombit loarmiion-ndu Its hf aet palkin onian agonts. 188eDoduc A, wretoneMo agStabsocsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc A, wretoneMo agStabsoc 189inlioAa- palkin onian roduc Saf gitensruion of exocri dopamin tdeon Its subsiMAO-B iisCNS Na sflntrre inDopamin inAcetylciotenssuDopamin inde ini tcysePeeho fnian-inhf acetylciotenssuPalkin on′sodid vasinAmistsdensteNMDAiney,ep a:inBesckade on ionophore:ig ttetuIts inrfrchbninergesseneuki sinBesel-b tin barriersuDopa-rsheacrboxyl as Cbrnehoparuion of exocrird pa-tiheacrboxyl as Dopamin tito (ituts inSnimulmuexocliserd phscsl dopsinamin tey,ep acseAdther n osucheec2eme mgec2em mgecDopamin inB izItropinyBk ercCOptin inAcetylciotens ists.onCerecDopamin -ey,ep ases.onCerecion of exocri y thohbn- O-me-hyltarasfeo asseL-Dopa Dopamin tpey, rsoa COMTteN HH CHN CHin3rdCHin3rdHteN Hin3rdC COOHteNHec2 aCec2 aHec5teN OinCN aCec2 aHec5HOinHOinNOec2 aE weapon inBrteN HinHteN N HinOinOinNteN OinOinOHrdCHin3rdHte3rdC Hte3rdC CH3rdCHin3rdHteOteN Hin3rdC NinHOinHinHteHOinCOOHteLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- epelaptscs aEpelapsy teaa ctroas rb tin disroduety di-inther n t oH ay;sis ism ofr-c izethbsieysin ureeh paloxysseseepisodssety al tiand ollhe excit the hf b tin neuki st Iu-involvarethirgeanhrm ses dr depsshf tp-sub tin, tieoney, lll did ofrgeiteaveidgas tin tieoney, oean-phaH a mms(EEG)reainsynctroaszethrhythmici d sitoxaeosicmloifns stiteylf8it io a, hensoryettsy-e thic,i adrvegetom vi (vid scsl)nphsnom-e ena -Bof its bculapoeisan besc b tin eysingesi enegposiciits lioabna sfl excitsinaeiltoxawivediffne, epelaptsc heizu rs odninpake oloyr a pst F syn iplogy ? -d enar use of viewpocn-, tieseowivebaintha etfiodrea: –sion eel vst focaleieizu rs; –sheizu rs w pwoc welecp.tlole rfrctiand ciaemn ss; –sheizu rs w pwoc welecp.tslecefice mmdssety peecip-rreohetinTe-obrief turw the hf a epups- npf-tilaptsc fitdmakes acumenrodu a of gasinunfffeperse CNn eotpyan- epelaptscsos rinuasctto pknvpossheizu rs adr, wcef issenesctto bal0he g ctroas s li. Only gt toethcats liosrreutiepelaptscuti(aooucce eexocri sevscsl toas -cposrc heizu rsi teaacutbe o tictivulegatrtoec uaoe dby the —inuaus linw pwnonzoIiazepenss 0he g a, if ntedbi,m Rc s li.inTe-oibisoats hf aesepelaptsc ttackin gvolves “pfnr aker”imbrah; tieseodiffneade synobstannesag mbrah gt toeianuho(gel in ostaretmemera eftotposoal, i.e.,ianeded polarlz dirmemera ef ureeh popoCerhinegest trsi d sonftotposoalend cfrome0.rug dr use of in-ervposthes simatoine(geiltze neuki alrorstarettotposoaledit, eiean-,on flart excit ai lty.aCNetlecefice fermsetynepelapsy, ibisoalcina epups- roduinis8prisctto schitvh cti aol hf heizu rs,invalte ots emus lin oarestp- dodu oar ir txcohbinr sesion eelszethheizu rs,nditioarsinnamazepensn oarespknfnerlctssur depoal (focal), etleces lin depoalet mprex, hef-tizu rhesDodaperlsein afferetuostlhheizu rsinerltaoiposs .kesgat alidther n osucheecbncom tunac,ep paug. Only heste onotoec uaowele diffneeh agee tisteoveseinadequree canlthftgeoropotoaandoeons -tens dodu oricombit loits (“adde he”)abterecommetheda(B), p ividscrutrbe trsirohypers iskpatiplogy ? kd em- Mif in-erocf liceis8pakev retoaacc e (se-subolaw) -Tosa kecets mmde hf a theatyedan- epelaptsc roduc rem ith unknown.suSom tegettceappestht flart neuki alin,xcit ai ltyhbsistvscsl me oft smc tyedan lon.aCNetr iplb,lrsapotepitoxacanln ulde afferetbsi un of eng excit ory agic-in timueng d n of ay neuki st Mmmoivxcitsina ay nesag mbrah e oltze glutamas eosicmost d n of ay neuki s e oltze γ- ii-ednobutyri racan (GABA) tsstp-ir tarasmit-ndulr (m 193A)t Variaem roduc canllart ndoeizu r trneshbni,mnotnely scttin neu-rseolaptscs, tieotubereulos t ctisoniazid, a haβ-lan am na- bictscsoin mncodotss; teny rre,ongrcef is,sesn aoe dby the gtndoeizu r distrdt seruGlutamas ocep acec mpeiasadtrneet totimas,naf he meste-oNMDAin totima has tp- ga of moienar use ofthemp toolc . (N-me-hylsD-as depo y8rsmandoytposce seey, witli.onCer.) ceistey,ep-in oreteaa ligrad-garytetheathftnta t as,xcuponsonimulmu neiwele glutamas , pop-timitsrba-kxaon b le Naec+se haCbecd+inii s iNtoinposicbrae Tosao t epelaptscsolamonaigd e,icphsnytoin, ditiplsnobarbitrpt dn of , anm retobstan pd gs, tieo of vasehf glu-in amas t Felbamas teaa glutamas eots.-edcnsst.ruBonzoIiazepenss ditiplsnobarbitrp aug gasn c simuexocli tieoGABAighthde,ep-in orebsipnic oH a lllly atf vase am e sinrfrGABA (B) (se- m 226)e Chas mdyeinflPxinis8in affere, c e eaocfpupidepolarlzI-in the sProg aid teaa di Rc rGABA-mime-- Mife Tiag ain8bescks removal carGABAige synap- cynap of tlefttey dr affepup itcthde-uppakeghVigrbanrint dn of seGABA ca-in abol smioGeb usostdswiveyug gasntoethavailneiltoxaon glutamas essahpcy, rsoa tdsGABA sytposslse(B) a hacanlave aocf etseanKec+se- oftntadopeter.rd190eDoduc A, wretoneMo agStabsocsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc A, wretoneMo agStabsoc 191ruFocalinheizu rsinEEG aEpelaptsc ttackinμVrd150rd100rd50rd1 hec Valte ic yganinCbrnamazepensnPhsnytoinseTnpitomas Geb usostdsuolsnobarbitrptElecsuximmdyinFelbamas VigrbanrininlioEpelaptsc ttack, EEG,da haaa- epelaptscs aSimpretheizu rsinC mprexin a oeons aedly tion eelszet I.aCI.aCII.rugoas -cposrcig ttacka(a mnegmal)rugoas ttackinCloas ttackinMyocloas ttackinAt gan-inheizu rruGon eelszet ttacks Valte ic ygan Cbrnamsinazepens,suolsnytoinseElecsuximmdyinLamonaigd e,icPrimmdons,suolsnobarbitrp B. Iodicmuexotlssuraa- epelaptscs aChbinrinDoduc uasctd tpoe a of gasrmacsrreutiepelaptscut:ruBonzoIiazepensspyh ametIiazepaminDoduc uasctd tpoe pc phylaxisetynepelaptsc heizu rs 0rdWakarettrre inμVrd150rd100rd50rd1 hec 0inCbrnamsinazepens Valte ic ygan,suolsnytoin,inClobazaminPrimmdons,suolsnobarsinnetrp Lamonaigd e agCloaazepaminLamonaigd e agVigrbanrintor Geb usostdsualhscn tlvetetrdof liin+in+in+inCOOHteHte3rdC Hte3rdCinNteNHec2 aOCteN N HinOinHinOinCOOHteHte2teN N N N Cl NHec2 aHte2teN Cl NCec2 aHec5teN OinO HinOinHinN HinOinOinHec5teCec2 aHec3rdC CHrdCHin2 aOCNHec2 aOinOinCHin2 aOCNHec2 aCOOHHte2teN Hec2 aCecLamonaigd e agVigrbanrintor Geb usostdsuLamonaigd e OinOinOinOinOinOSOec2 aNHec2 aCHin3rdHte3rdC Hte3rdC aCHin3rdLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinCbrnamazepens, valte ots, eosicphsnytoingeeoganrtinan limuexochf volt-inago-garytesodsuynohdecalcsuynehftntasse haed ftwn sisp yad tyoney, lll excit -in the bsi un of eng sustwit lo mnc-fre-rs Pganyr irgtg ofoneuki stseElecsuximmdy8bescks a neuki alrTg etimaaCbecd+in oftntad(A) hareeresettcea etpeces cPhas bef its itlis8ve in lib0anlysesesis gan- heizu rs.ights an- epelaptscsos rmlik ly,tal oatatoindiffneeh deoneg0,on fpc by blidther xc osuchs. Se Its , diffoesity iNScsnieMoto -edgtg,lyitisl warenatipsythom ttredrlveteganumb .kan llllly ats an- epelaptscd enar uyghMoraos ac cu wncous, iemasi-rspoa lll,eyiti epice thftgecawivenece -e sipo y8a thftge8it iedicmuexo.nPhsnosinnarbitrp,opaimmdons, ditiplsnytoingwivinf vdsconos eomeracis (vi(gmd D pc phy-e hixis) ori-mgaloblaonof snso a8(folre rdpc phylaxis)e Du aret a of gasrweled phsnytoin, gd gival ypopplasia0wivedn-inthlop iNSca 20%natipgaierus. Valte ic ygan (VPAi teagwitaretiu-intprod dirac,ep pan-0as a ir t-tens dodu; Mit tealy sse Itsrestpanlobstano tictivul-e sattc sgremor,onatioocn-eabsorp upset, a haeeeseragwitos rmfre Pehhcinosg etUsage; knvprypers hdirelole teaa rae alonsiscureehc . HepiciPnxoctoxawivebabduem- seanPnxoc y tabol y8(4-en VPAi.seAdther nprocf licen fcbrnamazeed pin tinthe e:dntabagmus, ataxia, diploed pia, pdepoesiaalyrif tp- dodaperlseaoeereedtooofati.nGatioocn-eabsorpe kiblemm ane etkin eaehl os rmfre Pehh.oIs exerCh a e o tiIiu opoe osuch (hensitlzIts tynco -inlin lreshe cen fvasop y gt L50478iwrttatiu-inPnxocIts )tinCbrnamazepens teaave auasctto a ofnd ige fnilaneukalgian adrneukipa-hicedpsiie Valte ots, cbrnamazepens, saneoth- ten o tictivulegatsirohsind iciionicnd iskt. Despi y8n i0,ona of gasrshouldint n inue du aretp ygngacy,tas trsiro-nd gasoalenha of8toare-ofeeutibsia eeizu r isxcga of r. H its ac is ismmgada ay trsilartst dodunaff rhpup saf a have in lib0pc phylaxise Cbn ureeh mnc-dodunadmiion. Its hf folre gwivinpknvpossneukal tuberdevssopmehts rte-tifncssm Cbrnamazepens, phsnytoin, phsnosinnarbitrp,osaneothen o tictivulegatsi(ex-ed epA0fhr gab usostd) iiby bi epice et-edhi- s0rsapotepers ssurdodu bictarasfoa-edpe nee Cbmnero nes betwneisa ticti-intulegatsioc weleeothen roduc wiveeyat Asesesclin lllly emp toolt in-erocf lice (plicseslevssrmonino pup!)tinFsurtrsiogesis gtric paug thildhseladepelapsig0,ovariaem othen ogerusfse inuasc,tinthe pup ACTH enegposiglut c asintictan,rtexame-hfe eghMu Aiplbin(sixra)sheizu rs ssoc tradwele tie etlaw spike-waibe(Lennox–Gatiaut) syt-tih ome wiveeyapoadr,o valte ots, la-inmonaigd e, enegfelbamas , tieoli ttanbe-edgtgrorst lssctto rodu- vei (gatrheizu rs waren- itsiro gasoallyifats rteropoane ebons wirrowiPnxoctox.ruBonzoIiazepenss drestp- dodusaonxcohbinr cn. srreutiepelaptscuti(se-suabove);r its ac devssopmehtcli toneu-ig an-0rethers trsmaly ssui paug ferinlass-nd cmenar uyghCloaazepam ic uasce feremyocloas haa.osrc heizu rs.inClobazam,ian1,5-nonzoIiazepens exn o- Mit diraesin affereto tictivulegat/se I-in tisi d sitoxa Its , has a epmiofr rftge8onxcolin lll hass.nPersi altoxachftgecaeosicparadnxocIl excitemgaseareftotposoal tsicf of ACh.inClome-hiazoleacanlave abeave in libe ssuroti aollarettrreutiepelaptscut,sbrs isxcuasctm itly e f a of8ag-rre ditrre spyhs-e peces linalcohoHic deliriumatremgacaeosic ssoc tradheizu rs.inTnpitomas ,dedCOvelifrsynD-fry -in n ,ehas t mprex, lass-laonodiraeticti-intulegat ocf licenhatrooopirrte toaed ft2 te-ocp yad tyoeeizu r d sitox; itlis8ve in-in tisiinn depoaleheizu rs adras anhadd-hein gaLennox–Gatiautfsyndrome.rd192eDoduc A, wretoneMo agStabsocsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc A, wretoneMo agStabsoc 193inA. Neuki alrsf -s hf a theatyraa- epelaptscs aB. Si -s hf a theatyraa- epelaptscs tdsGABAergesrcynapas Chas mdyin oftnta GABAigGlutamic yganinheacrboxyl as Glutamicclygan SucciniccltemialdehydyinEn pup hfin un of aye neuki ruSuccinic yganinαecγinαecβecβechtsos eric encoganrsinmett rf GABAigocf li αecγinαecβecβecVigrbanrininIun of a rf GABAsintarasgmd as Tiag ainsruion of exocri GABAigreuppakeinGeb usostdsuImteoved e oltzIts inrfrGABA pcy, rsoa: Mslutamas sePeig aid GABAsinmimetscd Barbituur ssinBonzoIiazepens GABAsintarasgmd as GABAighth-iney,ep a Excit ory neuki ruNMDA-iney,ep a Volts.einhepetheh Naec+se- oftntasuCbecd+in- oftnta GABAigion of aye neuki ruGlutamas seNaec+seCbec++seCI – GABAighth-iney,ep a NMDA-ey,ep a-seists.onCer felbamas ,invalte ic yganinEnoganrein uan limuexo:e cdrnamazepensinvalte ic yganinplsnytoinseion of exocri slutamas seatf vas:d phsnytoin,e himonaigd e plsnobarbitrp Geb mimetsct:rubonzoIiazepens barbituur ssinvigrbanrinintiag ainsrugeb usostdsuT-Typo-ed alcsuyin oftntadessckya enlecsuximmdy,e (valte ic ygan)suLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPwitoMe oft smc ditiPdthwaytinPwitoteaa deeignIts ssuraetlectsumaon etansaf license mnccindivergentm ofr-c in adri wansloxa Ing dire synunpf vaah - iutoneupaug. Pwito imuliearefdet bescsubsi.nic oH a lll ocep ace(hensors,innoc cep ac) seast diffneeh i tradm a-sephoH a lllly,oviz.,8e ee nesag ethares.inTe-ob dyrli tieobipolartoffneeh ir t- a-sedt neuki e. eh ibfaedorser doot ganglioa.suNoc cep iageempulees oralctiby teavviainunmyelinmu lo(C-fiaerhc ctiby ts vy-seloctoxa0.2–2.0 m/s)aenegmyelinmu loax-edcnce(Aδ-fiaerhc 5–30 m/s) sg dof ee ead-edaresn irAδefiaerh eyapoadr,o i wanseedp y ur otre of, tiots lioC-fiaerh eysinapoadr,o crsm lll imulie(Hec+se,nKec+se, hi (g-ti fne, b tdykitarpyhtc.) aeis dire syntisg etuem-aoumo. Ir R pin lib0afnwhebstain osm lll, me oft lll, surtrs sflntrimsinuliearef gvolved,sthey bncom teigntio-ed ahhcinmoarive in lib0intpoe pcesgan-0tyrdpc abaglatharci(p 196).suCrsm lll imulieave aunedalie8mdinndoeons arin- iufhimpe ne oriid oemiae (Ing da pocno ptpyoyocdry pt dfar ts ),insurtrsii wanse8mdinenhatrl a rs du areinsverdCerentthe hrm p amoIic cti aoc-in the hf amoole mtstleeabho fnilioa-edgans,i adr, stn ivebabmaiu witretbsiloed caledioxso a8devssoping d tpoe areaaon etp am (vid scsl8mdini.seAδe haC-fiaerh nculrwn sispsorpsectravvia pol dorser doot,tascentein tie edorsolre csl8funoesius,i adr, wn syt-tiapastoneoeons -trdt neuki s in tie edorsal ore scenlaxasaoli tieooeons -tr-sedt neuki s trsss0tos mmdliny8ditiao-incentetoare-ob tin as trsisos olre cslicpathway hrm pinotoalamic tric .aB-asce onfthyloion of ape, neo- ditipaleospf-tiiotoalamic tric s oraldintareueehld.inTealamic nutlei oceivaretneo pinotoa-e himif inpp.opro terms acireumsc ibradpr-seeas on re-op abieMotol gyrus. S imuli ectiveyeavvia pois tathgoralexpbreean-sic sisherp, cf valyrlocaltzIaug psiie Theinnutlefr regi s oceivaretpaleospfn -d enahimif inpp.opro terms are-op abieMsintarl gyrus as wbraeas trsie sntrp,oed bscd ct tsxaenegmost lik ly reeresett tie epathway toservaretpaie hf a lull, aoh-edgtg,loreburngtg ohfr-c , i.e.,imdinenhat canln localtzradanlyrro ali.inImpuleentarffoe d tpoe neo- ditipa-inlio pinotoalamic pdthwaytaist to terms e mmdulmu neiey drscentaretp oje thesrutrbe oaigd rte e synap- eypoesiaar a p -in the adr,d cfrome atnoeons -trdt neu-rseons,i tstp-ir cynapass w pw ir t- adea eneuki s,loreatnopsorptsegmehts riNtop-tineuki s (drscentaretaa- noc cep iagndoyabso). ceistoyabsoacanlius of imsinpuleentarasmisvesi e syn ir t-en fsec-edcn -trdt neuki s via of vasehf opioed pep idas0(hnk-phaHins) ori-onoamin sse(norepensphed e, Uso nini.sePtin setsaf liacanln inflPgansce ori-odtfiodreagfoll wt:ruL50188e,ed from tg on re-ociits liomdinndL50188elart arenatitieooensitlitoxaon noc sin ep ati(aa- py opoe aorpgeeics, localindieonos of0)ndL50188eiNtopruptpup noc cep iagectiby ts ininssansory nesag0 (local dieonos of0)ndL50188e tpp y gtg on rarasmisvesi on noc sin ep iageempulees d tpoe cpsorptmesinlullw (opioid0)ndL50188eiNn of exocrirmdinepbrcepts (opi-edci t, ion eelndieonos of0)ndL50188ealhsceng emonii alrorspotees to tptin, i.e.,imdinebehavi ag(a idap y -seists as “co-aorpgeeics,” m 230).su194eDoduc ssurtrsiStpp y gtg on Ptin (Aorpgeeics)suLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDoduc ssurtrsiStpp y gtg on Ptin (Aorpgeeics) 195inA. Ptin me oft smc ditipdthwaytinPbrcepts :rusherprs PickinlocaltzIauginPbrcepts :rulullsedtlayodindiffits Drscentaree o tinoc cep iagndpdthwaysePtlio pinotoalamicnd an rdNeo pinotoalamicnd an rdPc abaglatharcsuLocal dieonos of0 Repoesiaae fermIts inOpioid0inOpioid0inAa- -sedtp y attcthAieonos of0 Gyrus p abieMotolissuNoc cep acseCyclooxyion asin un of asinIufhimpe neseCbits liomdinndTealamucsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinEico atoid0inOaigd aenegme abol smioTe-onico at-edci t, pc abaglatharc, trncmboxa e,icpc abacyolin,i adrleukonaiensspyse infermsctd tpoe orgra sm e syn rschi-sedonic ygan,ianC20ifatoxaegan w pw o rsedoubleebot ss(nico at otoen ic ygan).seArschidonic ygan teaa regsiaarc ns(itugasinhf mbraememera eftho phoHipi t; itlisseatf vasthbsipho phoHipvaseAec2 aenegferms2 te-ocubsoto yohf cyclooxyion ascaeosicHipoxyion asc.suSytposslsety pe abaglatharci(PG),icpc abacyolin,i adrtrncmboxa e pe sin eeds via iNtop cy ry cyoli etdopop-tioxsicce INSposicice hf PG,da cyclousosansruceng fermsed tpoe acyl ohsiie Thealerterhinfoll weng PG (D, E, F, G,dH,loreI)oe dby thindiffneehces d tito (ituts w pwold ox-tiylioa keto gdoups; tieonumb cesg etcCOptved.fopotoatieonumb rird uauginbns t, enegposiGreekalerter deeignItesecre-oposim tg on re-oold oxyl gdoupeatnC9se(te-ocubso an-0shownnlsePGFec2αec). PG se inpaimaedly inan limusthbsitieonchi- 15-xcold oxype abaglathardehydroion asm Iuan limuexocineplicsesisiverxa Ipi ;iniu aretons pvabjecttrncreas, e lutg, 90%natiPG cireulmueng d eplicsesarefde-edgn ra. PG se localcicy torcenhatrstand dineb oH a lllly ve in lib0csnieMoto-in thes onlyrstntp-ir ci yohf fermIts .ruB oH a lll osuchs. Te-oibdlit ua rdPGi(PGE, PGF, PGI = pc abacyolin)oposg etUss diffneeh b oH a lll osuchs.suNoc cep ac. PG in afferooensitli- Mity tyoeensory nesagefiaerh cowarls2 rhp-tinary paito imulie(p 194), i.e.,iataa ghe gine(imulemsssrength poare teaaesin afferersea yohf evokedi d sonftotposoal0.rug drmoargulmu ne. PG aoeeritieooetsepocn-ense ypowoalamic (p yop of) thop-ti oargulmu ay neuki s;ob dyrpempeto-in u r in afferso(fts a)e Vast ofr amoole mtstle. PGEec2 aenegPGIec2 apc by blirhsceolartvasodila-in the;ePGFec2αec,ivenoc ns( lss .ruGatiorc hec opone. PG pk er y8n s apc by m tg on gatiorc mucuti hareby becre-ofermIts on gatiorc ygan (p 160).suMens( umu ne. PGFec2αecis befitvhthto tbe0rsapotepers ssurtrsiid oemicenecrosi0intyntp- ncdome-riumapcy,ed dirmeiand ( umu ne. Tieo ofa lib0pc pt t licenseiu-indlit ua PG se saictto balalhscsctd tdyssinmetorrhean adrhxce eti rmei ( umaatbleed di.suUhscene mtstle. PGls imulmulSlaborint n rocf lic.ruBroachisldmustle. PGEec2 aenegPGIec2 aiiby bibroachodtlmuexo;ePGFec2αeccchassint ns( lss .ruRon ctessel flaw. Weeni on culesselfflaw tealart ed,svasodilateng PGinerltatf vasthnhatrserms areono otesselinflaw.rug ncmboxa e Aec2 aenegpc abacyolin aplivey eola in eygulmueng poe aggeyg ai -intty ty plmullerti havast ofr y me-lr (m rd150).suLeukonaienss in afferocIpillwaye pop cneiltoxayitisesageas themonan llinfactorceforeneutrophil gdanulocye s. Asin“olar-procf ng subso an-s hf anaphy-e hixis,” teny rref gvolved ibfas drgesrproc-in thes (p 326); toiothen w pwPG,dtenyndtsokeapoe cpectsumaonm ofr-c is of in-tifhimpe ay ymp oms:arebn ss,e of,nd wbragtg,lyitipsiie g dr use of apelicmuexot. PGlde-edCOvipevss0ais emedr,o i by bilabor surtoe cn-e rupt ios t li (p 126); d tpoe hop-ti uaoty paptsc ulclr (m 168),lyitiinepb-edCOphscsl irhscell dide asm PG se ro ali toneuarytetf ghe gineyabso lllly; d tpoatroaeritieir osucheeccanestebe t nfitrettoatieoi wanhedaci yedcaro the.su196oAa- py opoe AorpgeeicssuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- py opoe Aorpgeeics 197inlioOaigd aeneg osuchs0on pe abaglatharc Kibn yndcal membsuLaborinFts arug ncmboxa e Pc abacyolin aCyclooxyion asinArschidonic ygansePtin s(imuleminh ametPGFec2αecPc abaglatharcsuh ameadleukonaiens Aec4in gvolvee gtndas drgesrproc thesruLeukonaienss Vasodtlmuexosuolo phoHipvaseAec2 aLipoxyion as [ Hec+se]thMucus apc by m tgseCbpillway pop cneiltoxsuNoc cep a etansieiltoxsuImpuleeige e Pganyrinndoensory fiaersuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- py opoe AorpgeeicsinAcetiiiioplsn, tieoamphiphilic ygansin cetylsalicylrc ygan (ASA), ibupc fei, a haothens, as wbraeas some py azolon indeCOvipevsspys ncreasiiiiopyriny8ditindlpyrons, dre gdoupretuodst trsilabele o tipy opoe aorpgeeicstto rintareueehecre-m e synopioid aorpgeeics, bof its teny sherlttieoaeiltoxaro reby b fts a.inAcetiiiioplsn (mfr-cetiiol)ehasedgselfaorpgeeic ve ofscxad tpooleachl inyiti eadachl ,sbrs isense. ttls eme int d-tifhimpe ay havid scsl8mdin.oIss me o-seis sm hf a thearem ith untlefr.oIs odninbeaadmiion.scscto flli oriiNSposifermaon e Rc s e tpposimor eh (epups- r n , 0.5–1.0 g) -Tosanosuch devssopseaf aecsscp.t30 miii adrlhausfssuraate x. 3 h.inAcetiiiioplsn uhdtagocsfonsjugmuexosuto glucuroasc ygan hrm tlfome atnre-ophe-tiiolesr yd oxyl gdoupc e pr tose Pehhd ron ct,ed from tg on re-ocnsjugmueioAtd enar use of dodape,da ses e a theai0intxidtzradtoatieo mnccinproc tageN- cetyled p-nonzoquinonimd e,iwe mesis detoxm-e fiodrbinc uplaren- slutathi eghAgest cn- Mseabstg on mncodotss (aate x. 1e g),ingle slutathi eed. Usags on re-oteropoarefde-edpreted enegposiquinonimd enproc srweled c ns(itugassense. ropombrahioAs aeeyat A,inposicbras oraldrst oyed:e. roponecrosi0.suL ropodamjectcanln svoidscrif tp- thi ledgnoupedonor,oN- cetylcyabsd e,iis ghe gin gtrivinaemlinw piii6–8 heaf aoinghs-e ts hf aesexce eti rdots lioacetiiiio- plsn. Weethen ctroas rregsiaariu wke tyedanetiiiioplsn f vdmsconimmdirree on culcal memb rem ith a0wirter rirdebre tinAcetylsalicylrc ygan (ASA) exerCh a e o tiiufhimpe ay nosuch, ibfardof lirtoe cCh a rpgeeic a haaa- py opoe acf lic.ruTieseocanln st ibrssctto ion of exocri yyclooxyion asi(p 196). ASAocanln gli- Mei in tIaugA0fhrm, as nosusagsieMotpar-ndd , oriiNj besc eyabso lllly as lysin thin(a rpgeeic suraa- py opoe epups- r n , O.5–1.0 g) -ASAouhdtagocsfrapan es eoxcold olysi0,n ir tiiNSposigp.tyitistose-rs Pgatly gt toetessel -Tosanosuch rutlhausecre-opcesgan-0ty-ASAod eplicses(td 1/2 a~ec2e mii), bof its cyclooxyion ascaee inirknvprypers un of ythduem- covalehhd bin pup hftpoe acetyleeyat u . Hean-,onie edurw the hf tp- nosuch hepeths ononie eea yohf echi- eyaytpossls. Furthop-ti oarpysalicylre gwiv cti aibrssdtoatiexc osuch -ASAoirk-rre s tp- gatiorc mucodaru(di Rc rygan nosuch yitiinn of exocrircy-in pc nan lib PGlsytposslsett iem)tane ecanlpeecip-rrebibroachot ns( lss ru(“a pitin asthma,” mseudoas drgy)hdue - iun of exocrirPGEec2 asytposslsea haovop-tipc by m tg on leukonaienss -Bof its ASAin un of s plmuller aggeyg the adrpe sinlasss bleed di (imsi(p 150)c is shouldinestebe uasctd tpgaierusfwele immdirreulesselfcoagsiaai lty.aCau theai0 lsoinntedbi iNSchildree adrjuvinilesnbe-edciits lioReye’stsyndrome.-Tosali ttanheainn ee ob Usage ibfassoc ts w pwfeb-edCOs- vi flniife thes yitiinseabstg oninASA; itsirrognosi0ai0 ro a (teropoane eb tin damjec) -Admiion. Its hf ASAoat2 te-oeth hftp ygngacy wiveeyat A0d tpe sinlassre labor, bleed di (ethehnyrinndmothen o dt dfan-, adrpeemasu r cloed ur otf tp- dNctuslirhsceosus. Aganessen ns(eropdal o tiiufhimpe ay roduc (NSAIDS;tt iem)taraldrCOvelifrsynASAtinAm retaa- py opoe aorpgeeics, hp-tipyrons (metiiizole) rinplivsatieo mnc-ices ve ofscx.oIs ismave ave in lib0intvid scsledpsiieoIss mmde hf a theaih untlefr,sbrstipc bnely diffnes e synapat lioacetiiiio- plsn adrASAtoIs ismrapanlyr bsorbreulhest 0he g via pol ocsl orm Rc s noutetinBof its nseiusfwrttatsolueiltox,iitai0 lsoinavailners ssur uje theeoIss oc tageme ab-tiol y, 4-iiiioplsnazo e,iis ,ed fromelade synplicseswele aotd 1/2 alioaate x. 5 h.inDlpyrons0teaassoc tradwele a law tnc -sedtan-0ty-fats ragdanulocyeosi0.aCNetansi-e tszethhto ters, cbrdiovast ofr ? 2lapas canll a r, etleces linaf aointrivinaemin uje the.-Toscef is,stp- dodu shouldln ulorst lssctto tos maorgemehtcli mdinndcefractory e flthen o rpgeeics sPropy-e phsnazo eopcesumnely oc srlik sme a-ti fzoleab le plogy ? 200 lllly antetox-tii? 200 lllly.su198oAa- py opoe Aorpgeeics adrA tiiufhimpe ay DoducsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- py opoe Aorpgeeics adrA tiiufhimpe ay Doduc 199inlioAa- py opoe aorpgeeicsinTnoth- tachl Head-inachl Fts aruIufhimpe ayedpsiisePtin tynco esseAcetiiiioplsn Acetylsalicylrc ygan DlpyronsseAcutbe ma eti insver-sedoas Chrosrcig bits Hepici-inPnxoctoxsuNsphei-inPnxoctoxsuImmdirreulhemostasi0aweled iskpatibleed diseAgdanulo-edcyeosi0ruBroacho-edc ns( lss ruIrk-rres inrfedgast o-e cn-eabsorp2 mucodaruRiskpate anaphylan oanseshockin>10ise?suLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinN ns(eropdal A tiiufhimpe ay (A tirheumo oc) Agee tisAto ofa libly mncodotject(> 4 g/d)c ASAin(p 198) wiveexerC o tiiufhimpe ay o-tifncss in eheumo oc dide ass0(h ame eheu-edpe oid arthk-ris)e CNSpoisidots rftge,incentarl nesaaem eigncensesverdotjecedpeyll a r, s ncreasbsonitu0,overCigo,tih owsin ss,ehtc.-Tosade rchef agn t eoxctoneuarytedodusalsctto tos fiiilxaon noiand (eropdal o tiiufhimpe ay roduc (NSAIDs) sgodax,imoaritpanl30 cesg eto an-s aralavailners,tallotf tp-m sher disepoe orgra c ygan nasu r hf ASA. S rNctu-edCllly,oteny canln gdoupretretoaacrbonicclygans0(h ame nesl feiac, ibupc fei, na-tipc xe e,iicdome-hygant[t 320]) or Meiolic ygans0(h ame azapc pazo e,ipitoxm-e cam, as wbraeas trsilass-knownnbrstipo ali toneuarytephsnylbrsazo e). LikeinASA, tieseosubso an-s haibeaorpgeeic,e o tipy opoe,da haaa- iufhimpe ay ic-in tilty.aCNet n rosrms aASA, ties un of rcy-inclooxyion asiibfaedevprypers olor a.inMoraos ac teny rrefestesui paug ah ib-e n of asehf plmuller aggeyg the. Sin becre-ir deeirree of ACh acemepmiofr,onie eohbinr betwneisNSAIDssis d lsasodnbsinre-ir plogy ? kd ems rbehavi agane ete-ir idther n osuche.suSalicylre sfardof lillly eun of rnie erarascCOptisi eactor NF KBse, htan-0te-oex-edp y exocrirmoocnfhimpe ay pc naiic.ruTiis8ve in aist herldiwele glut c a- -sectans (p 248)aenegibupc fei, brs estsee pr ome lthen NSAIDs.suology ? kd ems s sNSAIDssee inwbraeabsorbre nculrs li. Teny rref mncciinbnuntetoaplicsespc naiicd(A). Teny rre Meed fromel atndiffneeh tleeds: nesl fe-tinacs(td 1/2 a= 1–2 h)aenegpitoxmcmms(td 1/2 a~ 50rdh); thu0,odoteng d -ervalti hariskpatiansiscumulmu neiweraevary -Tosaned from tg one salicylre , tieo apanlyrfermsctme ab-tiol y hf ASA,tismnoPners ssur tsidots de-edpethehne.-Salicylre lis8ve in libcinprosg etorbre gt toetkibn y,sexceptrst mncourp-tinary pHioAopcere Pici yossurrapan on culned from tg teaa epice tnsjugmuexoode-e ocf li (p 38),lm itly wele glycin (→e salicyluorc ygan)aenegglucuroasc yganioAtd mncodotjec, re-ocnsjugmuiheawivnbe-edcome ea yoed ft di. Eed from tg naw tn-intprod dicindepeths onounthftgethha-inlicylre , we mesis excreted onlyrolarly.suGdoup-slecefic idther n osuche odninbeaat ibrssctto ion of exocri cyclooxy- Msen asi(B) -Tosamost fre Pehhe kiblem,edgast rc mucodalniijury wele iskpatipaptscd ulclrIts , eyat As e synreby bdlsytposg etlsety pe nan lib pe abaglatharci(PG),ica dep e syn di Rc rirk-rrnoive in .nGatsintaipa-hxawivebabpknvposodnbs the hf tp- PGldeCOvipevs,lmisg eope abol (m 168)e INSposicn-eabsorpe rocf,in un of exocrirPG sytposslserould epmi-e hirlin olexpblssctto f vdscondamjectone toetessel mucoda barrierveneg os opa-in-hx.aCNetrerinpoasdtpgaierus, asthmarstand dcks peyll a r, pc bnely bof its nseae hickpatibroachodtlmueng PG o dt d-intproded pc by m tg on leukonaienss -Bo-edciits teisteyspoteetismnoP immune mesinl tra, s ncr“mseudoas drgic”rproc thesruaralattotposoalehazardiweletalloNSAIDs.suoGmave aeygulmue on ctessel flaw etsecal membal o ti.onCertlhf aegiowansln IIinyitinorepensphed e.aCf of vasehf trsilat-ndulr tworlsein afferet(h ame in ypovone-inmia), tun of exocrirPG pc by m tg wivineyat A0d treby bdl on ctessel flaw e hare-tinal immdirmehh.oOthen unwaosodn osucheecoraledeman adra issiibfessel p y ur .inMoraos ac rodu-slecefic tsicf of AChsedtsesageatrentthet cens fcsniernonie eCNSt(h ame indome-hygan: n owsin ss,ulheadachl, distrieruIts ), re-otkin (pi-edtoxmcmm:ipho n nsitlzIts ), surtrsulesself(phsnylbrsazo e:ragdanulocyeog etls).suOutssek: Cyclooxyion asi(COX)ulhas tworlsohi- s: COX-1,da c ns(itu libe ssum .kesgat in s(oy ?hn adrkibn y;se haCOX-2, we mesis i by bd int dfhim-edpe ory cbrah gt eyspoteettoaaate pri teine(imuli sPresgatly availners NSAIDssib-e n of ab le lsohi- s.-Tosade rchef a aCOX-2-seey, witli.erusf(Ceey,oxmb, Ro-tifncoxmb)sis i wanslfyaretbof its, gt toeo-rsey, tieseocreattto baltoneuaryten t eo.ec2em Aa- py opoe AorpgeeicssuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- py opoe Aorpgeeics 201ndud 1/2 a =13-30hsuSalicylic yganse50% 90%inAcetyl-e salicylicclygan 99%inDlsl feiac Ibupc feiseNapc xe PitoxmcmminAzapc pazo endud 1/2 a =1-2hndud 1/2 a~50hndud 1/2 a =9-12hndud 1/2 a~14hndud 1/2 a ~2hndud 1/2 a~3hndPlicsespc naii bin pupinA. N ns(eropdal o tiiufhimpe ay roduc (NSAIDs) aB. NSAIDs: gdoup-slecefic idther n osuche 95% 99%in99%in99%inMucus pc by m tgseAgan hec oponeinMucodalnessel flawseNSAID-i by bdinntpheiPnxoctoxsuArschidonic ygansePe abaglatharciAirwiveeyaiso an-ndud 1/2 a =15miiseHmncodotssuLowodotssuNSAID-i by bdingast opa-hxruLeukonaienss Ron ctesselinflawsuNSAID-i by bdinasthmasuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicoting drmoargulmu ne adrA tipy opoe0ruB dyrcoaritempeto u r inatieo umaeai0insscp.t37 °C enegf NctuItss w pina± 1 °Ciniu arettieo24 h cyclee INSposiorstare eto e , tieome abol ci d sitoxahf vitrptoa-edgans cti aibrsss 60% (teropo25%,ob tinec2e%,e oep 8%,ekibn ys 7%)ms anotrpth ofndpc by m tg scenlabsolute cti aibrsexosuto h of pc by m tg e synap-se orgrasin oftgeca. ttls du aretpnic cal dd sitox,ulhesaffe mtstleework, we mescti ai-edbrsss aate x. 25%rst orst, canlion eeteinupms a90%natih of pc by m tg du areinssrenuaem exercets.-Tosadeotpacn-ensetrsule dyrpempeto u r isirrogrimpetein tie e ypowoalamic t drmoargulmuory cbn eo.ecTrsi d ua valus0teaadjusssctto tos oetsepocn-ebsimeaicensevariaem t drmoargu-e hiuory me oft smc -Bssel v sstasssup-edpryarettieotkin peteoto yotieo of-i su-e hiuarethiyer rir tocu wncousaadirohsinisg etuem adr, wcef is pop f rcti aollreulheaoivxchftge8wele tieg ovitonmgaseatseancal memb nsevast ofr ?alibervenegea yohfulesselfflaw. Cu wncousaessel flaw odninrftge8e syn~ 0tto 30%naticdry c rutpuf,indepethwretonere Pirsmerus. Heatroou-indy ts via pol essel f synd -eri agsf -s aliopc by m tg toare-ob dyr urface pe sinvidas0arcti aollners me oft sm ftre ofinlass.suHeatrdisvepaf liacanlave abed schitvh mbsi utproded pc by m tg onnd wbof, bof its evaporw the hf wbof xosutieotkin urface c nsu- s0heaoi(evapo-edCl witlheaoilass)e Sheropeng dh a0we of-tin sm - son eetelheao. Autonomiceneu-edCll argulmu ne aticu wncousaessel flawse ha wbof pc by m tg pop f rhomeog eto tic cti aol hf e dyrpempeto u r (Ai.seTosadympa-hopoe eyabsoacanleithen resinluctlheaoilass via vasoc ns( lss or Mpk er y8ithbsit ogan ng swbof pc by -e ts .seWeeniswbofeng dh un of ythduem- sepocsoning weletaa- ohbninergesst(h ame tropiny),icu wncousaessel flawt d-intprodes.aCf i suf ini ttlheaoiis d svepafscrutrncreas, isteoute,esverhbofeng l a rs ( ypopt drmia).seToyropd ypopcal memb potss aicparpoesiaar ofllrtge8toare-ot drmoargu-e hiuory eyabso, bof its te-oexce eti rse-rsc oponeensetryropd sumonrs odhassinme abol cih of pc by m tg to iotprodem Iu trdt to maiu wit e dyrpempeto u r t itsirnic oH a lll levss,oexce ee ofinmtstebe d svepafsc—re-opgaierusfhaibeaulhsteskiii adracemewbofeng.seTosa ypowoalamic tempeto u r cti aollrr (B1)acanln inan limusthbstineukilaptscs (p 236), welecp.timmdirsinmett rfrlthen cbn eos.-Tou0,oitai0 posg etpers t flart aopgaieru’stb dyrpempeto-in u r welecp.tan limuetg o e ea-argulm-inPnry me oft smc (t drmoionic sherop-e cng). ceistcanln exploitsctd tpoe a ofsinmett rfrstvscb ftbCOs- trre s ( ypoppy-e rexia) oriiNSouso-chl tesurgeayrweled cdry c by-pvab, du aretwe mesesselinpempeto u r isilart ed t f10 °C bstimeaicenseae oep-lutg y ?hens.inIn mncopodotss,ehtofto teostbarsinnetuur sslave adtp y are-ot drmoargu-e hiuory cbn eo (B1),ongrcebsipop f tare ecoolpup hftpoe b dyrp are-op cn-ensed ofh,edghe g aoouf ini ttlyrlow ambi ttlpem-edpeto u r (f eezaren- d ofhtd tdrunkeiandn ssi.sePyroions0(h ame b-c isldmi tta) el-e eimus—pc bnely trncreasicy t neieyrdpc abaglatharci(p 196) adri warleuk d-in1—re-odeotpacn-ensetrsa ypowoalamicinpempeto u r cti aollrr (B2) -Tosab dyineyapot ssbsieys( lssrenheaoilass (cu wandn ousavasoc ns( lss →Schills)aenegeyrdeleimuetg h of pc by m tg (sheropeng), tue ordt to adjussotoatieonewodeotpacn-e(fn-inthr)ioAa- py opoesys ncreasicetiiiio- plsn adrASA (p 198) opurn tos oetsepocn-e- itsina sfl levssr(B2)m adr, eminb aretsscp.ta8desusagsieMce.ec2e2 Aa- py opoe AorpgeeicssuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAa- py opoe Aorpgeeics 203 Ro pitres inion of exo alioewbof apc by m tgseParadym-ndpdtholypoe0ru(Atropiny)suHypopt drmiasuHeat apc by m tgseH of pc by m tg aB. Disourb an-s hf t drmoargulmu neinA. g drmoargulmu ne 37 se38 se39 se36 se35o 37 se38 se39 se36 se35o 37 se38 se39 se36 se35o 37 se38 se39 se36 se35o Hypop-in-hxropd sminio afferersh ofndpc by m tging drmoargulmu ayedcbn eoru(deotpacn-)suSympa-hopoe eyabsoinα-Adree sin ep acseAcetylohbnineiney,ep a0ruB dyrtempeto u r Tempeto u r eiasadFts aruh ame mfr-lysi0sePeefneeh i lin un of exoinC i aollreulhypowodrmiasu“Arpo ini linhiberrom tg” Uncti aollreulheaoilass Hypowodrmia,ige eezaresuto d ofhrd1 2 37 se38 se39 se36 se35o Me abol ce ocf vtoxsuH ofinlassseH of ctiby ts H of ray t neiEvaporw the hf wbofsuNsukilaptscs Etofto d Barbituur ssinSeotpacn-rdeleimueneinAa- py opoesPyroionsuH ofincbn eoruCu wncousulesselfflawinSwbof apc by m tgseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLocal Aieonos of0 Local dieonos of0 knvprypers un of imsinpuleenson eetthe adrpe pagmuexocinndn sags.aCNetansory nesag0, s ncrenn osuchecis deeirreehest psiifupe kicedu rs mtstebe popcermscpyh ametsurg lll surdeMsintaadoperaf lic.ruMe oft sm hf a the. Nerageemsinpuleenctiby ts l a rs iNSposifermaon eanlad sonftotposoal,da uddeni ovpryalniiin ostaretrarasmemera eftotposoalrlhau-e cngaly stpanl1 ms.-Tosathftge8it totpo-e tsalnis8priggt ed bsianaaate pri tentrimsinulus yitiinvolves arrapan inflPx hf Naec+seretoaposicn-eri agnsetrsanesageaxas (Ai.seTodh uwarl flawt kiceeds trncreasain oftnta, a0wemera eftorespc naii, t as,xcupons oaresopeted (an limust),ipop f sseaapan msvemett rfrNaec+sedownna crsm -d calegn i ttl([Naec+se]in,xt a~ 150 mM, [Naec+se]incn-rd~ 7 mM). Local dieonos of0 oralcapIauginnseiun of eng , isteapan inwarl flPx hfseNaec+se; d isoats adrpe pagmuexochf exc -se t li erlttiecef is essckyd (Ai.seMmmoilocal dieonos of0 exi tiiNSparpininsre-oc t li ci mphiphilic ferma(cf. p.ec2e8). ceistpnic cocrsm lll pe poptyifa-intors iNcorporw the retoawemera ee cn-e phatss,ebnuntary regi s betwneid polari adrapolaridom itht cens fse infeuitiinepho phoHipi awemera ecaeosic ve aint on- oftntadpc naiic. Som tev -sedtan-0sugseabcenhatrNaec+se- oftnta essck-e ode eyat As e synbin pup hftlocal dieo-in-hs of0 toaposi oftntadpc naiitoIs appestsin scttin trbe trsici yohf a theaih prochelade synposi yeosoa, impryarettibe trsirodu mtste ir tipeteoto yotieombraememera ein(p 206).suLocal dieonos ofi d sitoxai0 lsoinshownnbsiunthfrgethhtoso an-setsug- Mseabsretsnbin pup ci yoiii polariregi sintyntp- oftntadpc naii surtrstsurreuit-e cngalipi awemera e.ruMe oft sm-slecefic idther n o-tifncss. Sin bilocal dieonos of0 essck Naec+sereflPx noP onlyrinssansory nesag0 brs al-e s aintlthen ,xcit alsinissuesc teny rreica pliodrlocally antemeasu rs rlttakevin(p 206)sconimmedritieir rintaibrsexosuretoaposib dy sgoofrapan ea-kxaretoaposin ireulmueneiwould f vdsconunwaosodineyabso lnprocf lices ncrea:ruL50188eessckade hf d n of ay CNStneuki s,edpenifessodnbs ostly n ssayitise -sezu rs (o e eameasu r:r uje the nseae bonzoIiazepens, m 226); ion eelnparsin-lysi0 wele o pitre ay ir R teaf aec mncopocsnieMoto lic.ruL50188eessckade hf cdry c empuleenctiby -e ts , as nvidaanscmbsi mmdirreeAV ctiby ts lr cdry c ir R te(o e-ndulrmeasu r:r uje the nseepensph-edCO e). Dep y exocrirexcit ory pe sin esees d tpoe oep, we ls endeeirreiniu aretlocal dieonossia, canln pp.otoinposr use of eme intcdry c ir hythm -d aci(p 134)tinFsums hftlocal dieonossia. Localindieonos of0 arala pliodrvia diffneeh edtoue spyinthe pup the hf tp- nisg etuem( the dieonossia) oriiNj b-e ts tnexsotoatieonesageera mescir yaresufiaerh e synap- eyg tg to beaaieonos-e tszeth(ctiby ts dieonossiaensetrsulnesag, cpsorptdieonossiaensesegmehts edorsal doots), surbsiapelicmuexodtoatiexc urface hf tp- skiiiori-ucoda ( urfaceindieonossia).aCNerochroaer, tieolocal di-ices os ofidodu ih pr Pirsdscondiffitsotoinpos nesag0 csniernelifrsynaidepot aplicsctd tpoe issueiorion tp- skii.seHmncooensitlitoxaon tansory nesag0,inlawooensitlitoxaon m ttren sags.aCmsinpuleenctiby ts inssansory nesag0 isin un of el atnaocsnieMoto liflart tpanrutrbe ntedbi ferem ttrefiaerh. ceistdiffne-teganeawivebabduem- atieo mnc aoimpuleeige e Pganyr adrlassrrlad sonftotposoal edurw the in noc cep iag, as oppoasdts e mmtor, fiaerh.ighthscn tlvelx,iitawivebab ofa sdts e re-ot ickn ssaon tansory enegmo a enesag0, as wbraeas t atieodiso an-ndbetwneisnod-s hf Ranvi r. CNetaltmu ayedempuleenctiby ts , onlyrpos nodrp2 memera efis depolarszet -Bof its de-edpolarszaf liacanlabsllot a rnaf aoessck-e ode hf tp ee trefo rnnodrp ares, tieoaproin,xpoasdts naidodu csnieMoto lifouf isin i ttlpoociits essckade mtstebe lfrgere ferem ttrefiaerh (p 205Bi.seTodh ofa llichip expl ith why tang etoryo imulienhatrsralctiby teavviain204 Local Aieonos of0 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLocal Aieonos of0 205ec+seA. Eosuchs0on local dieonos of0 B. Ion of exocrirempuleenctiby ts td tdiffneeh timas0on nesagefiaerhsuLocal dieonos of Naec+se-ea-kxsePe pagmurein mpuleeigPeCOphscsl nesaginC iby m tgseesscksuLocalica plice neseCNS Ro tly n ss, ectivuleii s,ed o pitre ay mfr-lysi0seHearpinImpuleeigctiby ts incdry c ir R t Naec+seAn limust Naec+se- oftntasuNaec+seBssckyd Naec+se- oftntasu polard polariC t li csu mphiphilicinlocalindieonos ofsuLocal dieonos of Aαem ttre0.8 – 1.4 mm 0.3 – 0.7 mm AδetansoryseC tansory ened postganglioaof Naec+seBssckyd Naec+se- oftntasuUnthfrgetinlocalindieonos ofsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinmyelinmu loAδ-fiaerh aralaosuchre la in adrs naily er deonegstpanlaceme imuli ectiby teavvia unmyelinmu loC-fiaerh.suSin biautonomicepostganglioaofefiaerhsuhickpagmyelin sh ofh, teny rrefparpoes-e hirlinsuscep iers t fessckade by localindieonos of0ioAs aeeyat A,svasodilateon et-edsuesed tpoe aieonos ozbdl ogs , bof its dympa-hopoeally drlvensvasom ttreton indetprodes.aTodh local vasodilateon ih un-sedteir alsi(se- befow).inDlffits adrEosuchecDu aretdlffits e synap- uje the ci yed(i.e.,iposicn-ers(itoalehpace hf ctinin libe issue) t atieoaxas nseaesansory nesag,inposilocal dieonos of mtstetrivirsy8n s apsceneurium -Tosamu Aihiyered perp-tineurium ih fermsctbs coinin lib issuein erah linksctbs zonulmeot ahe en ssin(p 22)m adr, ecef is c ns(itu ss aiccloasdtHipophilic barrier.suLocal dieonos ofsed tolin lll hasfse inuaually terCiary amin s; atnre-opH hfin u-ers(itoaleflPid, tieseoexi tiparply as trsulneutarl Hipophilic baasi(dymbol zsthbstiparpoelesnmarkradwele two reb dots) eosicparply as trsdpc nonmu lofhrm, i.e.,iamsinphiphilic cmuexod(dymbol zsthbsfparpo-inclesnmarkradwele o eobluem adr eed.einiot) -Tosaunthfrgethfermacanlpeteoto yecre-opsceneuriumveneg os s tieg odo-tineuralehpace, weeralate a theansetrsuldodu molecul s0rsg ith a0posim vyin ofrge8it keeping weletposilocal pHioTiexc amet kicele tearepe tradwest trsirodu peteoto ysatieoaxasaaememera ef(axa-e hemma)aretoaposoaxaplics, e synwe mee cC exerCh iss oc theann tp- sodiumv oft-tinep,osaneag itdwest itndiffitss rutansetrsul odoneuralehpace trncreas, e unfeieo-in-uaryte odo, eliumaonm bpillwa eh ibs e re-oessel seTosacsnieMoto lifhftlocal dieo-in-hs of be trsici yohf a theaih,r, ecef is,inde,d cfrsthbsitieotleedpatipateoto exosuretoaposi odoneuriumvenegtieotleedpatindiffitthe retoare-oc pillway essel -Iu tr-sedt toaansu r oouf ini ttlyrfosrmbuild-upintyndodu csnieMoto lifbe trsici yohf a -e ts , , ece mtstebe aocsreyapot dicie hirgsacsnieMoto lifgn i ttlbetwneid dodu depoted tpoe coinin lib issuegane ete- odoneuralehpace -Iuje the nsesolu-in thes ofrlow csnieMoto lifweraefailm- sepc by blinn osuch;r its ac tooo mnc ectiieMoto lic mtsteave abeasvoidscrbe-edciits liotrsirassrrlhf d Pnxocmuexoode-e at A dire syntoofrapan eyabso lnabsorp-e ts tretoaposibssel seToaansu r oprodasablyrloss-laonodiinlocal8ve in aweletmiiosflntyabso lna -e ts , aavasoc ns( ls a (epensphed e,e hess fre Pehhlyrnorepensphed e (p 84)e oriaavasop y enldeCOvipevs;tt 164) isens-nduln co-admiion.scsctiii aeatremp.otoint nfitr trsirodue- itsici yohf a the. Asinesselfflaw teadimiionhscpydlffits e sy ete- odoneuralehpace retoare-oc pillwayinesselfdetprodes bof its te-ock-ricrpsectnieMoto lifgn i ttlbetwneig odo-tineuralehpaceaenegesself Pickly bncom sin ses west inflaw tyndodu-f ee esselfisseatby bd -Addf exocriraavasoc ns( ls a,ti oaros ac elps t atprotr oprfa libecis oemiaed tpoe surg lll fiela. Potposoal edisadvo ti.as0on y thohbnamin -timainvasoc ns( ls asyinthe enproc tagehy-e pscemiaefoll weng washrutansetrsroou-ins( ls a i.eru (p 9m)tane cbrdios imulm-e ts twest epensphed e os s tiegsyssinbso ln ireulmuene -Iu lieu nseepensphed e,e tiegvasop y enlaorpogub ftlyp y enin(p 164, 165)acanln uasctas anhadjunt-in tisivasoc ns( ls a (hess pc nouansce proc tagehypscemia,rno ir hythmoionice ocf li, brs rassrrlhf csronary c ns( l-e ts ) -Vasoc ns( ls asymtsteestebe ap-edprisctiiilocal dieonossiaiinvolvarettieica p odi.as0(h ame finsens, toesi.se206 Local Aieonos of0 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLocal Aieonos of0 207inlioDinpoai lifhftlocal dieonos ofsed tpeCOphscsl nesag issueinVasoc ns( lss inh ametweletepensphed eicHipophilicin mphiphilicinAxohemmainAxoplicsinAxohemmainAxoplicsinINtop-tis(itouyinCrsss0se the trncreaspeCOphscsl enesag (teeatto lrsscopy)suPerp-tineuriuminEn oneural etp n-ndC pillwayinwallseAxon 0.1 mm Iu-ers(itouminLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinCofr-c is ofs0on yrsm lll ry -e tur . Local dieonos of0 poatUss a unm-e fermas rNctur . Gon eellyrposy rrefsec-edcn ary treterCiary amin s -Tosanitroionsuih linkscttrncreasan iNtop cy ry chtinecs nai Hipophilic moiety—most oftsn aecoromo oc arettyabso.ecTrsi md encal memb meaicenhatrloed caledieonos of0 exi tieithen as trsdneu-edtarl md entreposim vyly chtrgethammo-tiniumv Its , depethwretuponstieir ring etoc ts c ns(aru (pKecoinvalue) enegtiee ocfual pH valus -TosapKecoinnsetyp lll localindieonos of0 . eh betwneig7.5 eneg9.0.ecTrsipkecoine dby thsnre-opH valus0atrwe mee 50%natimolecul s0cir y adpc non -Iu f ssepc nonmu lofhrm, tosamolecul poatUss-icesab le a0polariold ophilic moiety (p i-inPnnmu lonitroion)da haaai polariHiposinphilic moiety ( arettyabso)—itai0 mphisinphilic.suGdaphic emi.as0on trsdpc cad eicmolecul ovprpe ibe trsiposim vy chtrgeinioesmnoP haibea pal ma yoeocaltzI lifbee tiegNfbeom;gea c aoioiis d s ibrssc,eatseshownnbsitrsipotposoalrnn tp- vo dea eWaave’ urface -Tosanou-pc nonmu le ferma(reser) poatUsses arnyg tvefparporpsecofrge8it ap- eyg tg on trsdes eoebot in adrbe trsiiiiio gdoupeatntieoapomo ocruceng yitiis neutarl n fsteeatlyrrosim vylysecofrged (blue) elseweerae INSposipc no-tinmu lofhrm (heft), re-oposim vy chtrgefissepk ed entnditionsieMoto edrbe trsiiii-tino gdoupehf tp- ssicfchtin ( arkoblue).inDepethwretonetosapKecoin, 50tto 5%tone toetdodu mivebabpknsgat of pnic oH a ed calepH it ap- unthfrgethHipophilic fhrm.seTodh e a theai0rempor(aru bof its ihd ropknsgats trsilipi awemera e-pop c-e oers ssumehf trsilocal dieonos of (p 26),ulhe mesmtstetwke tu f soc t li ci mphisinphilic ssumeiu trdt to exerC iss oc thein(p 204)tinClin llllyruasctlocal dieonos ofserre Meithen es eos suramsicce ceisto rNctur culneemett ih unempor(aru fereve ofscx;e eien roduc cti ainsretsnme-hyle eicbridec, s ncreaschas pk eazd e (p 236)e oriimipr md en(m 230),iwould exerC oinlocal8dieonos of ve in aweletaate pri teina plice ne. Es eo-tima local dieonos of0 rrefsto terms aiuan limuexocbsitissuegeo-in- eedes.aTodh teaadvo ti.aousaeof its nse toetdimiionhsc rassrrlhf tyabso ln d-inPnxocmuexo. O tpoe othen hdit,atieo mnc eea yohf bioiuan limuexocdit,atiecef is,inshorteted durw the hf a theai0ra disad-invo ti.a.sePe cad e canestebe uasctas a urfaceindieonosms rbef its ih dh uan limusthfhau-e t tpan ih canlpeteoto y trsird cfs or M-ucoda.ecTrsi mddritima local dieonos oficHid cad e is broken rownnpaimaedly ininposileropobsitxida tageN-dprpkylIts .ruceisto ep canll a r onlyrpo aeeyat lsscin,xtgat in pail cad e adracricrd e be-edciits b le cir y adito (ituett r tpoe C-e otsynadjac ttlpootosanitroion gdoup -Ap-in-icrd e poatUsses aracrboxyme-hyledgnoupetu f sothi plsn r di. At , istposi-e ts , es eoetlefvjectcanll a r, eyat AodiiniNSposifermw the hf a0polari-COO –edgnoup,inlassehf trsi mphiphilic ohfr-c , ane ectiversexodtoaan iNoc tageme abol ytinBonz cad e (e-hoferm) dh a0wemaersuhf trsigdoupehf local dieonos ofsehickaree oanitroion poatroanln pc nonmu loof apnic oH a lll pHioIs ismuasctexclus vylyseas a urface dieonos of.suOthen a.erusfemployed fere urfaceindieonossiayinthe enap- unthfrgethpoli-sedocfto teostre-oc t mphiphilic o cad e,e teotocad e,r adrlid cad e.ec2e8 Local Aieonos of0 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLocal Aieonos of0 209inlioLocal dieonos of0 oadrpH valus 100 80 60 40ec2e 0 0 20 40ec60 80 100 67 8 910sePe cad e Lid cad e Pail cad esuAr-icrd e Mepevocad e Bonz cad e [Hec+se]sProt c nieMoto li apH valus Ac tagefermedcit li c-in mphiphilicinPoor MAeiltoxaro peteoto yecHipophilicinbarriercaeosicmbraememera e0 GselinMemera e-e pop cnelbe ssum Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinOpioid Aorpgeeics—Ms phens TimainSource hf opioid0. Ms phens teaaesopi-edumvelkaloan (p 4)t Bosidas0ms phens, eopiumv ti ainsvelkaloans devoidlhf aesin-lgeeic ad sitox,yh amettieotlasmolypoe pa-inparopene,enhatrsralave acla etfiodras opi-edumvelkaloan0ioAts sso sytpos ofideCOvi-in tiss ( ydroms pho e) enegfullyrsyt-in-hs of deCOvipevss (pehtsz cens, me-hi-sedens =emepeCOdens, l-me-hydo e,r adtifnosanyl)rsralctllin libcinprferrsdsconatseopioid0. Tieo mnc aorpgeeic ve in libn sssuhf xenobio of opioid0ldrCOveh e synap-i in e ontoxaform Rcep a0ina sflly oc scinupons yg odoginaem opioid0l(enkepha-inlirc, β- odo phen, dyno phens; A). Opi-edoan ocep a0il a r in nesag mbrahioTenyndsralfeuitiinevariaem b tin regi s ane ete- cpsorptmelulla, as wbraeas int doto-inmucsl nesag plexitss nhatreygulmue tiee mo oltoxaon trsi limehtsry eneguroionisintaad rocfs.-Tosce rrefsevscsl timas0on opi-edoan ocep a0, deeignIted μ, δ, κ,enhat2 mel tr tp- voriaem opioid osuche; allsebeforen- poe supopciiilxaon G-pc naii-edc uplen ocep a0i(p 66).suEodoginaem opioid0lrrefpep idesecreatrsralclefvelifrsynposipcea rs a0rupc enkephalin,ip i-opiomelan c a- i, a hapc byno phenioAts ti ain trsiiii-tino agan he Pgans liotrsipehtspep idesec[Met]- sur[Leu]-enkephalind(A). Ten o-tifncss liotrsiopioid0lcanln sbol shsthbstio ti.onCertl(h ame orpoxo e; A), weletposin,xcep ihe hf bupceno phen .inMode hf a theahf opioid0. Ms t neuki snproc e flpioid0lw pwolpoppo-e hirtzI li, eyflin lng yi iotprode intKec+sectiby tahne.-Cain2+sereflPx retoanesag op-ti sorps du aretexcit theai0rdetproded,e headaren- ardetproded of vasehf excit -inPnry rarasmirterh enegdetproded sytap-e tsfi d sitoxa(A). Depethwretonetosambrad populmu ne osuchre, , istsytap of inhi-seof exocraraslre sfretoaaadtp y aru erevxsin irrnoive in i(B) suEosuchs0on opioid0l(B) -Tosaaorpgeg etof ve in aeyat As e synocf licebe trsilei- Melehf tp- spsorptc adm(ren of exocrirnoc sin ep lib0impuleenrarasmi exo) enegtiee b tin (atrenuw the hf impuleensp yad,in un of exocrirpaitopopcep ihe)ioAtrentthein adrbeiltoxaro onsieMoto e rref mmdirreting dre dh a0wselfchftge,stp- di Rc ixo aliohe meshepeths ononie d isoalions o-e ts . Asddrie synap- eyliefaassoc trasee prtrsiibre mett rfrstroretpa i, t dre dh a0feelpup hftde achmett (floau-e cngasansIts )ayitisenasehf wbra- oare (euphoria), parpoesiaalinaf aointrivi-tinous uje the dit,ahean-,orapan build-inupmtyndodu levsssed tpoe b tin -Tosadeeirrecs nre-expbaiencs teistsrrebibinprnewbdinadmiion. Its hf dodu mivebacom insverpart are: devssopmehtcli msycho-edH a lll hepethehne.-Tosaattremp.otof Pihd rope tradits liotrsirodu eyat As i w p-sedrawll igncenseb le a0pnic cal (cbrdio-invost ofr y sourb an-s)aenegpsychoH a ed cale( ostly n ss,r axiety,adtp y s )tinmuur . Opioid0lmeet te-ock-r isense“ad-ind lslib” a.eruse ormelx,ipsychoH a calindidirnic oH a lll hepethehne as wbraease oacompuleii to iotprodeotrsirots.-For Mtieseoprodassett y cCOptisi on opioid0lisse to terms atleces rul s0(C i aollre Sesg eto an-s Ach, USA; Narco of C i aol Ach,ndC nada;ehtc)ioRrgulmu nesatlecefx,ulam retothen pines, maximumvdotjeced(pop fstpers epups- r n , dailxamaxims edon , maxims iii e opop epups- pde-e acCOptisi) sPrescCOptisis nted to beaisg etuedr atleces fsums trsroompretitg onndwe mesis resoraemlinm rf age sCscttinseopioid aorpgeeics, s ncreascodeiny8ditin. Imydol, mivebabpknscCObre gt toetusu-e sldmior a,aeof its nsstieir ly er po-e tposoalrssurabhasfsnegdevssopmehtcliindepetheMce.ec210 Opioid0 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinOpioids 211inlioA the nseeodoginaem eneg xoginaem opioid0lrt opioid ey,ep a0ruβ-Eodo phen UreterinesadderinesadderatlhencterinVagalio os s,ndChemoey,ep a0ruhf aproeposteemainOt oomo a ecbn eoru(Edinsen's nucleus) aDampetareteosuche Ptin sansIts inMoosic vsctn sssuRo pitre ay cbn eoruCcreascbn eoruEms of cbn eoruS imulmnoive in sinMel trahbstiopioid ey,ep a0ruMs phensProopiomelan c a- iruβ-LipotropinsePe enkephalininOpioid ey,ep a0ruNrpoxo e Kec+se-pop cneiltoxsuExcit ailtoxsuCain2+se-reflPxsuRof vasehf erarasmirterhinAa- noc cep iagineyabsoinAarpgeeicruSmnoth mtstulmuu r s(oy ?hule wtasu tlas oficc ns(ipmueneinAa- y rrhbolinAarpgeeicruAa- tu eti inB. Eosuchs0on opioid0 OruNsuCHec2 aHOsuCHec2 aCHecHO OruNsuOruOHHOsuCHec3suEokephalinin6 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDiffneehceh betwneigopioid0lde-e gbrdireteosofscxadidirotposoalrssurde-edpethehne pc bnely eyflin tdiffnelng yo-tifontoxa adri welneic ad sitox pc filesnfor Mtie i bsitdull ar,ep at totimasioAogli- Mei suto an- ioesmnoP neceleaedly behaveseas ae d.onCer suraa-d.onCer atrsll ar,ep-inPnrt totimas, brs miveoc as ae d.onCer t ee totima adrah a0parporp d.o-tinist/aa-d.onCer orrah a0pu r a-d.onCerin(p 214) atrsnothen scenlabhasftotposoal eismave ade,d cfrsthbsikd ems rpe poptig0,inbof its devssopmehtcli hepethehne issefavo ed bsirapan build-upmtynb tin oou-inieMoto lic. Weletaaxaon trsi mnc-eosofs-iniynopioid aorpgeeics, sverdotjec isilike-edlxaro reat A0d tre pitre ay mfr-lysi0m(rm-ndpdirsdsoensitlitoxaon melullary chemo-ti ocep a0iro COec2 a) -Tosamaxims lyrros- etpers ,xtgat oftre pitre ay dtp y s isselecpeattto balhess iNSparporp d.onist/tio ti.onCertlrt opioid ey,ep a0 (pehtsz-edocens, orpbuphensi.seTosaccpea- tpp y aru (aa- tu eti )xc osuch pc by h mbsi un of exocrirtiee ccpea eyflixsis i bepethehtansetrsr o-tifncss ln noc cep i lr ro pitres in(aa- tu eti s:scodeiny. nosc pinsi.seS imulm exocrirchemoey,ep a0 ininposiaproeposteema (p 330) eyat As i into ft di, parpoesiaalinaf ao ir t-( the hred tpoe ambulmnoipgaieru.seTosaems of ve in adisappests wele o-edpe tradits bof its di Rc rion of exocri tosaems of cbn eo test prsdo fromes,ulhe messverridas0tp- s imulm exocriraproinposteema chemoey,ep a0tinOpioids elpcit0pupillway n rr wengin(miosi0)mbsis imulm erettieoparadympa-in-hems rp a- xod(Edinsen-Wostphal nu-incleus) liotrsiot oomo a nucleus.igPeCOphscsl osuche osniernonie mo-ti oltoxa adrs nucensegast ocn-eabsorp2 smnoth mtstle;esegmehts theai0ret-edoganre, brs pe puleiv-opsceto lsi0ai0 ib-e n of el -Tosas nucensetlhencter mtstles eism tided markralye CNSpoisifash li, mtr-sephens elpcitsnre-opicsu r hf tlas ofroou-ins(ipmuene -Tosaao- y rrhbof ve in aisseuascttosr use ofs lyr(loperamddr, p.ec178). Gast rc emp.yeng dh dehiyen (py-edH rc tlasm)aenegd tinjecton b ls eosicpaotpro ofrjuine isnimmedrd, bof its te- etphencter on Oddiet n rocfs.-Likewin , esadderacal memb ismaosuchre; slecefics ly esadderaemp.yeng dh mmdirreeduem- a d-intproded ton liotrsiveeic ofr tphencter.ecUs s:sTe- odoginaem opioid0in(me,dnkephalin,ileudnkephalin,iβ- o-sedo phen) canestebe uascttosr use ofs lyinbof its,bduem- atieir pep ide nasu r, t dy rrefeithen rapanlyrdeonadscrerevxsin he elifrsynpvabjecttrncreas, e essel-e b tin barrier,stpus pcnvposlng yccele s e re-iagsf -s hf a theaeien af aopareNtop-tirp ddmiion. Its (Ai.seMm phens canln glvensoeellyror MpareNtopllly,oas wbraeas epanueellyror Mintrire-cllly eu tp- spsorptc ad -Tosaopi-edoanee ocn enegfnosanyl rref mncciiHiposinphilic,tall weng rapan ea-kxaretoaposinCNS -Bof its oseiusf mnc totpocy,ofnosa-tinylnis8sui paug ssurrarasrd cll heleropyru(A)m Iu tp tr abhas, “sy ?k” (“junk,” “jazz,” “stuff,” “Chenaohe te;” mostlyin ocn) dh self admiion.scsctbsi ujRc ixo a(“m itlinsre”) soeas t asvoido ir t-pvabinme abol smvenegto aghitvh a0fas eoeeiasadin b tin oouieMoto li. Evidaatlx,ipsysin hof ve in s (“kick,” “buzz,” “rush”) rre Metleces lini wanse8wele tiisteoute hf the -Tosau er miveove aeys a- s e othen moariunuaualteoutes:sopiumv dninbeasmnksc,eaneg ocn canln takeveatsesnuffi(B) suMe abol smv(C). Liketothen opioid0inbeaelng yiold oxyligdoup,0ms phensaissecnsjugmued to glucuroasc ygan eneg lrm-ndinmu lo on clye Glucuroasda exocrirtiee OH-gdoupeatnpoai lif6,iunlik sreatrstsepoai lif3, ioesmnoP aosuch e ontoxioTiexc,xtgat to he mestp- 6-glucuroasdsroou-in aibrsss toaposoan-lgeeic ad sxoodem ithseun scttin of pcnsgat. At aaxar e , tieoic-in tiltycrirtiistpoofr me abol y ntede s e n takeveretoaaco e 0d trenal inouf isin i tcyr(lowopodotjectorrlassrrldotengin u-ervali.se212 Opioid0 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinOpioids 213inlioBioavailneoltoxaon lpioid0lw pwdiffneeh eoutes hf theinC. Me abol smvatimo phensruNrsrp2 mucoda,ruh ame ocnsesnie ong Iu-rivinaemina plice nese"M itlinsre"inOralica plice neseBroachirp2 mucodaruh ame opium2 smnkaree Me -Eokephalin Ms phens FnosanylseHe ocnseOpioidseMm phensruNsuNsuCHec2 aCHec2 aCsuOruCHec2 aCHec3inTyr Gly Gly Phe MetsuNsuCHec3suOruOHHOsuMm phens-3-e glucuroasdssuMm phens-6-e glucuroasdssuB. Apelicmuexodenegea yohf dinpoai lisuNsuCHec3suOruHec3suC CHec3suOCsuOruOCsuOruLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinToneuahne.-Wele ope tradadmiion-edtartisi on opioid0,atieir CNSt osuche odninloas i wansloxa( utproded toneuahne).aCN tosao rts nsstierapy,irrogre eti cie hirgspodotss rrefetedbi to aghitvh tiexc ametdeonegsrirpaitoeylief. Devssopmehtsuhf toneuahne ioesmnoP involveotrsipe-ti Ophscsl osuche, soereatrpersestgat oou-ins(ipmuene du aretprolassradits wivinssucs dist n inuw the hf aarpgeeicrutierapyr its a urgehhlyrntedbiting dref is, die,dtsfi idirnogy ? 200 calinmeasu rs shruldln takevepe phylan ed callxaro pcnvpos c ns(ipmuene, weents aruprolassradadmiion. Its hf opioidseroduc is i bby thd.seMm phens o ti.onCertlridirarporpsei.onCert. Ten osuchs0on opioid0lcanln insscl shsthbsaposoanti.onCertlnrpoxo e a nalteexo e (Ai,rirketlec lib0liotrsi o-ed,ep attima involvee sGlvensbsi tself, neithen hds aaxave in ainina sfl cesg ejuche; its ac iigopioid-bepethehtse to ters,ebnle pceaipirrebiacute w p-sedrawll ignc -Bof its oseiusfrapan pde-e ayabso lnned from tge orpoxo e isenncie sui paug ssurpareNtoplldits. Nalteexo e eismme abol callxamoaris paug aitiis gli- Mei ors li. Nrpoxo e iseve in lib as aeti-sedote8it ap- a ofmett rfrlpioid-i by bdinre pitre ay mfr-lysi0. Sin biih dh moarseaapanlxaeed fromel tpan most opioid0,d rope traddotss mivebabntedbit Nalteex-edcneawivebabuasctas anhadjuntt i w p-sedrawll tierapytinBupceno phen behavesilike a0par-e tsalnd.onist/aa-d.onCer atrμ-ey,ep a0tinPehtsz cens teaaesaa-d.onCer atrμ-ey,ep-inPnrsda haaai .onCer atrκ-ey,ep a0 (A)m B le aralcla etfiodras “low-ceilsre”aopi-edoanee(B), bof its neithen istcapIaugcri elpciterettieomaxims iiorpgeeic ve in edobttinradwele ms phensaeremepeCOdens.ecTrsi a-d.onCer a the nseparporp d.onistbinmiveeyat A0d tyi ioisoalidetprode0d tve in edof a0fulli .onCer du aretchftgesverts e re-oli tta.aCNPnxocmuexoowele bupceno -sephens canestebe ovpryradwele a-d.o-tinists, bof its te-ododu dissoc trsenncie ropyrolarlyie synap- opioid ey,ep a0ruditionmpetim vy l a paoty0liotrsi o-ed,ep as canestebe schitvh masrfosrmas trsulolin lll slouw the demand0tinOpioids cn chroasc pait: INSposedpenjecmett rfrchroasc pait, opioidseplicsesctnieMoto lifmtstebe keptroou-in inuaemly eu tp- ve in lib rftge,sbof its a0fallibefow te-ock-ricrp levssrwouldedciits te-opgaieru to expbaiencs paittinFeaecrirtiistslouw the would pk eptn d-inPwke tf mncopodotss tpan neceleaey.seS lslyrspe k di, posoaim dh a0pe phy-e hictsfi irpgeeia.ecLiketothen opioid0 ( ydroms -sepho e,rmepeCOdens, pehtsz cens, co-tideiny),0ms phensais aapanlxaeed fromel,e hd ft dieiusfdurw the hf a theatoaaate x.ec4 h sgo maiu wit ato eadyiiorpgeeic ve-tifncs, tieseoroduc nted to beaglvenseropyru4 h sFre Pehhedotengpyinthe pup be neser-in ims, gh a0wajhred ctiveniencs for Mchroasc paitopgaierus. Raiserettieois o-e itdull dots would pop f rtrsirotengin u-ervaltto balhengtestre; its ac i edwould ove af vdsconrarasieru pe k0insscveotrsitosr use ofs lyrpr Pirsdsplic-inma levssrw prtrsiitren pup iskpatiun-sewaosodnPnxoc osuchs0enegtoneuahne in-inthsopmeht sPreferrsdsathscn tlve0 ib-e the enap- use hf cti aollre- of vasrupremfr-f licensems phens, a0feosanylseadossivefpatch, surarlassrr-an lng opi-edoan s ncreasl-me-hydo e. Ten kd ems rupropoptig0ehf trsili tta, its ac necel- etprrebiadjussmehtcli hotjec inrtiee ccprts nssta ofmett, bof its lowodot-tirgs du arettrsi ir tidays nssta ofmettsefailsaro pcovidarpaitoeylief, weeraaso mnc edotjectoiotrsiroduc if cti inusc,ewerae head to agcumulm exocretoaaaPnxoc oou-inieMoto li rftgev(C).seWeeniap- oralteoute ih unavailnersseopioid0awivebabadmiion.scsctbsicti in-inuous ufits (pump)aenegwest aate -sepri tenender cti aol bsitrsipgaieru – ad-invo ti.a: c ns(aru tosr use of plicsee heths; disadvo ti.a:r udwbraaretcire--e tpa.aWeenic ns(ipmuene bncom scretol-e er alsims phenlcanln s pliodrneaecte- etpsorptc admpop f tarerstroretaarpgeeicruve in abe m ncrlart totrptdotjec.se214 Opioid0 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinOpioids 215inPehtsz censinlioOpioids:rμ-nditiκ-ey,ep ae. gand0 BioOpioids:rdots-eyspoteet ofa llichipinC. Mm phens o d me-hydo e hotjec regimets Iu-nxocmuexoinAarpgeeiaseMm phensruud 1/2 a = 2 h t lowodotssueropy 4 h Disadvo ti.a:ige e Pgatirotenginfere usttinrarudirpgeeiaseHmncodotssuMs phens tese"hmncodots"ineropy 12 h Disadvo ti.aa:rurarasieru hazardinnseiu-nxocmuexo,rurarasieru lasssehf aarpgeeiasuLowoDotssuMe-hydo eruud 1/2 a = 55 h Disadvo ti.a:igdots diffic otecs ntimto yecDaysd 12 3 4ecDodu csnieMoto lifitoplicsee Mm phensruMepeCOdensinFeosanylseNrpbuphensruNrpoxo e μ κ μ κ μ κ μ κ μ κ μ κ Aorpgeeic vetifncsecDots (mg) 0,1 1f10 100 FeosanylseBupc Meim phensruMm phensruMepeCOdensinPehtsz censin1234ruHec3suCruHec3suCruCHecCHec2 aCHec3inCHec3inNsuCruNsuOruCH3ecHO OH aCsuOruOruNsuCH3inCH2suCH3inNsuNsuCHec2 aCsuOruCHec2 aCHec3inCHec2 aHO OH aHOsuCHec2 aNsuOruHOruHOruHec2 aC CHecCHec2 aO aNsuOruHOruLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinGon eel AieonossiayditiGon eel Aoeonosms rDodusinGon eel dieonossiayis a ta yohf dodu-iu-indy lo ovpryperei un of exocririeMotol enesaous cal memb, du aretwe messurg lllruprocedu rslcanln carried rutad tpoe asg etgans lioc nsciaemn ss,reyspotelibn sssuro pait, desutelib hred voluhtsry msve-inmetts,eaneg igneficsat outonomiceeyflixineyapottss (Ai.seTosapr Pirsdslevssrhf aaeonossiayde-edpeths ononie d wansloxaliotrsipait-te -sedy arerstimuli, i.e.,itrsireonegsrirnoc sin ep lib0s imulm exo.-Tosadkilfupeaieonos-e tsst,atiecef is, dynamofs lyradapts trsulplin lioaaeonossiayt atieodemand0cri tosasurg lll slouw theioOresinllly,oaieo-in-hs ozI lifweasichitvh mwele epups-indieonosms ri.eru (h ame die,hyletiec—tifor tesuccelefullyrdem ns( atsctd t1846 bsiW.-T. G. Mm tmb, Bostsi) sgo tpp y tidesutelib eyflixg0, s ncre “m no-aieo-in-hssia” neceleirre s a hotjec inrexce esuhf trbe ntedbi poociits unc nsciaem-ndn ss,ongrcebsi utprodarettrsi iskpatiparsin-lyzarenvitrptcal membs, s ncreascbrdio-invost ofr homeo tasi0m(B) -Modern aieo-in-hssiafemploys0arctmbfrom tgohf diffne-tegatoroduc to aghitvh tie gorps hf turg lllruaaeonossiay(balganreoaaeonossia). ceisica proochratby bsnre-ohazards lioaaeo-in-hssiae CNSC arallissodnexampresohf dodusecreatrsraluasctcsniurrehhlyrere e Pga-e tsally as aaeonossiayadjunttse INSposicvasruliotrsi unalm exoal dieonos of0,rtiee choice hf adjunttsb ofa ss toapososleceficrupropoptytto balexploitsct(se- befow).inMtstleb ofaxatts,eopioid aorpgeeics s ncseas feosanyl,teostre-oparadympatholypoe tropinyrsraldistusasctelseweera tesemoaride ail.suNsukilaptaarpgeeialcanln coteld-e erreoaatleces fsum lioc mbfrom tgodi-ices ossia, itdwe mestp- short-an lng opi-edoan aorpgeeics feosanyl,telfeosanil,reyii-tifeosanil istc mbfrradwele tp- s rorecie sedateng yitiaosuch-bluhteng neukilap-e tsfidropopidol. ceistprocedu r ismuascttese mnc- iskppgaierusf(h ame advo nreoage,e heropodami.a).suNsukilaptaaeonossiayrefers toapose ccmbfrraduse hf a short-an lng aorpgeg etof,tyi io terpaug aieonos of, a short-an -e cngamtstleb ofaxatt,osanea lowodots hf atineukilaptscm Iu regi el dieonossiay(cpsorptdi-ices ossia)mwele local dieonos of (p in204), noc cep i isaeed fromel, we lsicc nsciaemn ssai0 pd. Usage sceistproce-sedyre,atiecef is, doesmnoP falliender pose desioisotgohf gon eel dieonossia.ighcc adiren- poein mode hf apelicm-e ts , gon eel dieonos ofsed ttrsi oat ls-icetisenasesraldividscrretoa unalm exoal (gvasou0,ovolm ele) adri terpaug a.erusm Iunalm exoal dieonos of0rsraladmii-e cn.scsctiii al, fsurtrstmost poep, eed f-tinmu loviayre pitreoain sceny tasag e maiu wit aieonossia. Popti entnsesg eto an-s sralctisddrredr ap 218m Iu terpaug aieonos ofh (p 220) rre Mfre Pehhlyremployed fereiiby ts . Iu-rivinaem uje the ditfrapan ottstcliina theasralclefrlxamoariaonegaers t ftrsulpgaieru tpan im b ofhlng yistupefyaresugva. Ten osuchensems tiiN terpaug aieo-in-hems s isilimitsdts naifewtmiiutes. ceisicall wm b iefaprocedu rslto balcarried rut a ro pcnperlttieipgaieru fereiinalm exo-tirp dieonossiay(iu uba ihe)ioAdmiion. I-e ts liotrsivolm ele dieonos of mtstetheninbeatimto yctiiis ncre mior aeas t ao e-ndulrbalganrotrsiwatareteosuch liotrsi ug ejuchpaug a.eru.inio affewretusr ismnowo oaresmadginnseiujuchpaug, ito ead oseiunalm exoal, di-ices os ofs du aretprolassradccmbfrraruaaeonossiay(totrptiu-rivinaem aieonos-e sia—“TIVA” hds bncom ifeaypereitpankssuro nie d wc by m tg hf a.erusfwele euis-icnely shortfdurw the hf a thepyinthe pup Mtie i terpaug aieonos ofh propofo teosicetomid e , tieoiorpgeeics elfeosaniliendineymifeosanil,reostre-omtstleb ofaxattinmivacurium -Tosseoroduc rrefeed fromelsee piiimiiutesnaf aoeoaresadmiistop-tiel, irketlec lib0liotrsidurw the hfruaaeonossia.se216 Gon eel Aieonosms rDodusinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinGon eel Aieonosms rDodus 217 Ptin s imuleminCioRrgimet ferebalganreoaaeonossiainlioGorps hf turg llloaaeonossiainB -Tn i exoal m noaaeonossiayvs. modern balganreoaaeonossiainMtstleb ofaxa the Lassehf c nsciaemn ssaAutonomicest ailtzmuexoinAarpgeeiaseMm a eeyflixg0 Ptin eosicouf nelnginAutonomic eeyflixg0 Noc cep i Ptr-lysi0mhfruvitrpto os sseMmno-aieonossiainh ame die,hyletiecsuRody loptinseoensitlitoxinMtstleb ofaxa thesuLossehf c nsciaemn ss Ptniuredcnium2 Nec2 aO aHalotpaneoutonome ccest ailtzmuexoinAtrseopinsinPehtsz cens aarpgeeiaNeo tigme cns rineropsal hfruneukimseuat ofr esscksuMe cdsz lamsu unc nsciaemn ss Pehtsz cens aarpgeeia Diazepamsu axiolysi0seMtstleb ofaxa thesuAarpgeeiaseUnc nsciaemn ss mseuatleb elaxa the; d uba ihe SuccinychoHinsinPre-inmedocmuexooIiby ts tM ittenganroRncoropyruFor Munc nsciaemn ss:inh ame halotpane a propofo ruFor Mmtstle eeyfaxa thesuh ame pdi-iccuroasum2 For Mautonomic est ailtzmuexoinh ame tropiny2 For Maarpgeeiaseh ame Nec2 aO atrefeosanylseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIunalm exoal Aieonos of0 Ten me oft sm hf a the oseiunalm-e ts el dieonos ofsedh unknown -Tosado-e iprypoxalioyrsm lll ry tu rs (inyrtfgatsexenoe; ydroacrbons; halo.ero ycthy-e droacrbons) poatUsslng aoeonos ofi d-in tiltycappests ro rul rutad volvemehtcliinslecefic ey,ep a0t hcc adiren- o e hy-e ponossi0,oupPwke retoare-oold ophobic ecn-eri agnsetrsaplicsehemmasrirneuki sineyat As i un of exocrirelin r lll excit-icneoltoxa adrimpuleenpe pagmuexocinrtiee b tin -Toie osnieptiwould expl itapose ccr ofa lli betwneigaoeonos ofitotpocyruditiHipophilicpoxalioaoeonos ofiroduc (Ai.seH its ac an iNtopa the wele Hipophilicindom ithaon memera eftc naiicai0 lsoinosnieivaaug. Aieonosms rtotpocylcanln inexp y re gt teums hftre-omiiosflnal-e veoofr csnieMoto lif(MAC)0atrwe mee 50%natipgaierusfdem itrimmob ls fol-e l weng aydeffrradptinfupes imulemy(ckinseintisihe)ioWeeraasotrsapoorciiHipophilicinNec2 aOfmtstebe iunalre gt hmncocsnieMoto-in thes (>70%natiiicpitreoain hds to bal o-edplicsc),0m ncr ses opocsnieMoto lic (<5%)rsralpr PirsdsiNSposicvascrirtiee moariHipophilic halotpane.seTosapates hf ottstcditioelea the hfrua the vsry wddrly betwneigdiffneeh ib-e nalm exoal dieonos of0rsndmave adepethedcnitrsireonegsrirHipophilicpoxe INSposicvasrulioNec2 aO, , ece is aapannned from tg e sy ete- b dydwest trsipgaieru is vposll trasee prna sfl ain sDuem- atieo mncirarporpsep y u r in essel,itrsirrivaretssucs for Mtarasfeagnsetrsadodu into expitreoain ise hirgsa al, sin bitissuegupPwke rsomii a,tite- b dydcanln Pickly clefredpatiNec2 aOm Iu t n rost,aw pwoalotpane,eparporp p y -xc urr in essel isilowoeostrissuegupPwke rsse mnc, eyat Aoditiii 0m ncr lart eed f-tinmus . Glvensalone,eNec2 aOf(nitroem oxddr,se“laughlng gat”) is i capIaugcri pc by -e cngadieonossiaensesuf ini ttadep pwfor MturgopyioIs hds gsel iorpgeeic ve ofscxecreatrcanln exploitsctwest itnismuascttesecnsjun the wele othen dieonos of0ioAs asugva,eNec2 aOfcanln sdmiion.scsctdi Rc ly.seAllecpea itnir ovprypersitxidizes vit -inmii Bin12in, Nec2 aOfismnoP me abol zstha pro-ed,inely aitiis clefredpposlrrly by exnalm-e ts i(B) suHalotpane (boilsreapoint [BP]e 50 °C),0eeflPra ef(BP 56 °C),0isoflPra e (BP 48 °C),0eostre-oobsoletgeme hoxyflu-inra ef(BP 104 °C) haibeto balvapor zsthbstitleces dev N0ioPtrh liotrsisdmiion.scsce nalotpane ie osnvprtscrretoahepato-nxocinme abol tes (B) -Leropodami.a miveey-e at Aie synnalotpane aieonossia. Weletae siups- ,xpoayre,atiei iskpinvolvee ih un-seprsdierpaug;r its ac t dre dh a0ccr ofa-e ts iwele tp- e e Pganyrrirexpoayre ane ete- chortn ssaon nie d warvaltbetwneid succelelib0expoayresm Upeto 70%natiiinalre me hoxyflu-inra efie osnvprtscrto me abol tes nhat2 may f its nephro-nxoctox,ya0pe augmecreatrhds lscrto trsiweledrawll rirtiee dodutinDeonadom tg pc by hs0on eeflPra ee oriisoflPra e (e a theabio arasfermsc <2%)rsralrirno osniern suHalotpane exerCh a pc nouansc hy-e ponutelib eosuch, to he mesarnyg tvefib-e otropif ve in at n ribrsss. EeflPra ee aitiisoflPra e f its l ssa ireulmu ay dt-sep y theioHalotpane oensitlzbsnre-omyoed cardiumvpoocithohbnamin s (cbu the: oe-ti Ooem achyir hythmias survposric ofrtifobrillw lifmiveoconmpaaxause hf cithsin hbnamin s as aetihyponutelibs surtoco-tilypoes). ceis ve in ais m ncrless pc -tinouansc weleteeflPra efaitiisoflPra em Unlik soalotpane,eeeflPra efaitiisoflP-inra efhaibea mtstle- ofaxatt ve in anhat2 teaaddim vy wele tpatlrirnondepolarszlnginneukimuat ofr essckerh.suDesflPra efdh a0cloas o rNctur c ofa-e tsib0lioisoflPra e, brs hds lowoHipophilic-e ctytteatrpermiusfrapan iiby ts ditfrhsin oropyoas wbraeas gsel cti aol lioaaeo-in-hs of dep p.se218 Gon eel Aieonosms rDodusinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinGon eel Aieonosms rDodus 219suLowototpocyru mncirarporp p y u r ntedbi eeyfa libcinl tts- bindiren- pissueinB. Eed from tg eoutes hf diffneeh volm ele dieonos ofsinlioLipophilicpox,rtotpocyleneg lrmfrom tgohf Nec2 aOfaneg alotpane Aieonosms rtotpocyecLipophilicpoxinNitroem oxddr2 Nec2 aO aXenoe Cyclope pane Die,hyletiecsuEeflPra ee Chas ossum Halotpane Parporp p y u r iNSpissueinTi rigTd cfrw the hf inPwke Parporp p y u r lioaoeonos ofinBindireinTissuegBssel Alveoofr ai inHmnc totpocye l wirarporp p y u r suf ini tt eeyfa libcin mncibindireniNSpissueinHalotpane Nec2 aO aMe abol tesMe abol tesinHalotpane Me hoxy-tiflPra eEtiecsuNitroem oxddrNec2 aO aHe 5 aCsu2ruOCsu2 aHe 5 aLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIu terpaug Aieonos of0 Sto ( an-s e syndiffneeh yrsm llle thasses suspeth c nsciaemn ssawheninglvensiu-rivinaemly aiticanln uasctase cn terpaug aieonos ofh (B) -Unlik siina-e hi exoal d.eruse most of tieseoroduc ae-tifncs c nsciaemn ssaonlyr adrace devoidsehf aarpgeeifi d sitoxa(,xcep ihe: ket -inmiie). Ten osuchecanestebe sscCObre e nottslin lib bindiren- neuki rpto llinmemera e0,tellecpea tiistmivehbndwfor Mpropofo .seMm tiiN terpaug aieonos of0rsrasecofr-c izsthbsfa shortfdurw the hf a -e ts . Tosapapan oelea the hf a theai0e hirgslyrduem- arsdis ibrsihe: af a Mintrivinaem uje the, b tin oouieMoto-e ts iclrmbs aapanlxatoaaneonosms rlevsssinbof its on trsi mnc oerebeel esselfflaw;e toetdodu then d s ibrsssaeienly eu tp-ule dy, i.e.,icsnieMoto lifeiassed ttrsipe-ti Ophscy, brs fallsed tpoe b tin—rsdis i-tibrsihecditioelea the hf dieonossiay(Ai.seTou0,rtie osucheito idas0bef is toetdodue nas lsf rtrsie dyioAoseons uje the ri tosasametdon , glvensimmel trlinaf ati ocoropyofrsynposipceaedirendon , odnintiecef is pc by h a0wsre d wanse ane elassrrl osuch subullly,oa epups- ujRc ixo ateaadmiion.scscioH its ac etomid e a hapc pofo twivebabglvensbsi ufits insverrarlassrr (imsipopiocrto maiu wit Munc nsciaemn ss.seToiopehtsl o d me-hohexitrptbeforesuro nie barbitur sssahe me, depethwret indon , pc by h sedatehe, sleepin ss,oor Maaeonossia. Barbitur sssalart trsipaitintid. hbndweostre-cebsifacoltoa yodesut-e siib eyflix msvemetts;tre-ymave ade-sep y ttrsi oapitre ay cbn eo. Barbitu- eea yc rreffre Pehhlyruasctfereiiby ts sehf aaeonossia.seKet md enhds aarpgeeifi d sitoxanhat2 persests0beyoostre-opopiocratiunoou-insciaemn ssaupeto 1 hnaf aoinjRc ixo. O ti ogainsretc nsciaemn ss,rtrsipgaieru2 may expbaiencs dist nnRc ixo abetwneigoutsddrirealtoxa adrior aemga-e tll a yo(dissoc tlib aaeonossia). Frhsin Pehhlyrt dre dh memoey lass fsurtrstdu- eea s liotrsi ocoropyopopioc;r its acseadt As i parpoesiaaroomprtin ebrutadon-edtaUsslng dream-lik sexpbaiencss -Tossed canln couNtopa theinhf a bonz diazepd e (e ame mcdsz lami.seTosaCNSt osuche hf ket md enaeias,ttesepoep, e synon iNtopfneehce weletexcit -inPnry glut ma yrg lnrarasmi exooviayli-segand-gmued cmuexoo oftnels rirtiee NMDAe totima,0atrwe me ket md enan sinah a0 oftnel esscker -Tosanou-nasu culnxcit ory amino agan N-me-hyl-D-icnspoepatefdh a0tslin lib .onCer atrtiisteo-ed,ep aioRrf vasehf cithohbnamin s wele a0eyat Aah ibtprode0d thetrh to e rne eesselfp y u r is aaothen un ofa sd a -e ts hf ket md e.sePe pofo thds afdem rknely simpreins( Nctur . Its ve in ahds afdapan ottstcrne edof ys Pickly,oeoaresexpbaiencsthbstitrsipgaieru asrfoirciipf vaaht sTie d wan- etprxaliotrsi osuchecanln wbraecti the.seEtomid e ahdrdlinafsuche trsisuno-tinomicenesaous tyabso. Sin biih dun of ssecnrposo tsytpossi0,oiticanln uascteu tp-ul a ofmett rfradcenocnrpolll orop d sitox (Cushlng’s d srode).inMcdsz lamfdh a0aapanlxame abol zst abenz diazepd e (p 228)tteatrismuasctfor Minby m tg hf aaeonossia. Tie lassrr-an -e cngaas azepamai0 pd.ferrsdsas adjunttindieonosms rin paolassradcardiac turgopysee prcbrdiopulmonary bypvab; iss om-ndn sioionic ve in ais pc nouansc.se220 Gon eel Aieonosms rDodusinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinGon eel Aieonosms rDodus 221inB. Iu-rivinaem aieonos ofsinlioTd cfrw the hf dodu ve in abinprdis ibrsiheinCNS: eeyfa libciru mnc eesselfflawigPeCOphscy: eeyfa libcirul wiesseltiflawigmliesseltimii x gSpissueinIoisoalislouw thee c.v. ujRc ixo aHmncocsnieMoto thee cNSpissueinRyfa libcinltrgeinii e ohf doduinRyfa libcin ses inii e ohf doduinmg doduinmii x gSpissueinLowocsnieMoto thee cNSpissueinPreferposoalragcumulm exoinhf dodu in b tinsuDetprodee cNSpissueincsnieMoto thee Furtiecsuibtprodee cNSpissueincsnieMoto thee Rrdis ibrsihe S eady- ta yohf dis ibrsiheinSodiumvpoiopehtsl Ket md enEtomid e Sodiuminme hohexitrptPe pofo tMcdsz lamsuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinSopor fof0,rHypno ofsinDyraretsleep,tpoe b tin gon eee s a pau-e hscn lo hythmifi d sitoxanhatlcanln inm rf ageabinmeaiceliotrsi lin roeu-iniephalo.rama(EEG).aCNhscn ltsleep cysin resocea r 4tto 5 (imssopop neserc e ?hulcytlebeoaresiNtoprup sthbsfa Rapan EysruMmvemehtc(REM)tsleep phased(A). Tene REM aec isicofr-c izsthbsfEEGi d si-e ctytsimiiaartoereatrseeocinrtie wakaree ta y,orapan eye msvemetts,ovividseroeams,eanegoccasexoal te ches hf is o-e itdull mtstlebgdoups againer a back-edgnoundohf gon eel zsthat rfaensesk litrp2 mustulmuu r. Na sflly,tpoe REM aec istegatrredr linaf aoaipceaedirennou-REMulcytle sFre PehheiNtoprup the hf sleepsee ll,atiecef is, detprodeotrsiREM por-e ts . Shortetpup hftREM leep (na sfllyica prox 25%ton totrpt leep durw the)eey-e at As i utproded irrit ailtox ditfrhau-e ly n ss du arettrsiday(ims. Weletun-sey sourbodrneserfrhau,tREM deffcitsnsrasecnmpensItsctbsi utproded REM leepedcniito e Pehheneserve(B) suHypno ofs falliretoadiffneeh yIts.o-tirig0,yinthe pup poe benz diazepd ec (h amettrisz lamettem zepam,0clotiaze-sepam,0nitr zepam), barbitur sssa(h ame xobarbital, pehtobarbital), chas rpthy-e dra y,oditfH 1in-aetiheto min s weletseda-e tsib0 d sitoxa(p 114)t Bonz diazepd ec an abe slecefic ey,ep a0 (p 226). Tene sf - o d me oft sm hf a the osebarbitu- eea yc, aetiheto min s,oditfchas rpthy-e dra y rref noompretbcinenderstsel.ights hypno ofs shortetotrsiti rigspettad tpoe REM aech (B) -Wele o-edpe tradinsesm tg hf a hypno ofr atts a-tirp succelelib0days,rtrsipe por the ri timsispettad tREM vs. nou-REM leepedreturns to na sfl doapite cti inusce dodu inPwke -Weledrawll rirtie hypno ofe dodu eyat As i REM rebound,dwe mesta-inpeos sffr linsverrmaaxadays (B) -Sin be REM aec0rsralassoc tra weletvividseroeamengpy leep weletexce eti ci foresuREM epdsodas0is vxpbaiencsthas un o- Mfreshlng. Teu0,rtie atremp.otofdist n-in inu- use hf hypno ofs miveeyat A0d ttp-ulimp y s nhatreyfreshlngtsleep callsinferea hypno of, pc bnely pk eoAodiinhypno ofrdodu depetheMce.ecDepethwretonetosir esselflevsss, e le benz diazepd ecoditfbarbitur sss Mproby h calmeng yitisedateib eosuchs,tite- fermsrigdoupeave aeoaresaaxiolytscm At mncopodotage,sb le gdoups pk eoAetite- ottstclitsleep ereiiby biih (C).seUnlik sbarbitur sss, benz diaze-inpd endeCOvipevss sdmiion.scsctors lie hickea gon eel dieonos of a the; oere-e b tl0 d sitoxaismnoP gl bn lini n of el (re pitre ay mfr-lysi0mis virtun linimros- etpers) adroutonomicecal membs, s ncrea eesselfp y u r,thetrh to e, surb dydrem-inpeoasu r,rsralun mmdirret Teu0,rbenz -sey azepd ecopoatUssaaaPosr use of mtrgtesecnssddrrnely wddrr tpan tpatlrirbarbitu- eea yc.seZolpanem (aanimcdsz pyCOdens) a hazopiflo e (a cyclopyraolase) rre Mhypno ofs tpat, doapite tosir diffneeh secosm lll ry tu r,opoatUssaa.onCer a -in tiltycat poe benz diazepd e ar,ep at(p in226).suDuem- atieir n rr werrmargtecliinsafeoxa( iskpatimisuse fere ufcids) ade re-iagrotposoalrro pcoby bipnic cal de-edpethehne, barbitur sssarrefeorlassrr oredcnlyrparrly uasctas hypno ofs. Depet-seygans lnetosmahds allSposicofr-c is-e tsfs lioaaaaddi the (p 210)m Bof its on rapanlyrdethsopiren- l-e er hne, chs rpthydra y is8sui paug nncie fere hort-nd cdits.ruAa- heto min s rrefpopulmrrea enout y cCOptisi (sver-pos-couNtop) sleep remel ssa(h ame diphsnhydramens, edoxylamens, p 114), itdwe mescodeotrsi insedateib sddrive in ais uasctas trsipeinti-sepal osuch in222rHypno ofsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinHypno ofs 223inCioCsnieMoto lifhepethehne rirbarbituto e rne benz diazepd e ve in sinB. Eosuch hf hypno ofs tg pc por the ri REM/NREMulA -Succeleltgohf diffneentnsleep phases du aretneserfrhausuREM Wakaree ta yinSleeped aec IinSleeped aec IVinSleeped aec IIIinSleeped aec IIsuREM-sleep= Rapan Eys Mmvemehtcsleep NREM = Na Rapan Eys MmvemehtcsleepsuRo l NREMul5 1015202530suNiservsee prut hypno ofe Niservsee p hypno ofe Niservnaf atiweledrawllinhf hypno ofe Ptr-lyzlnginAieonosmszlnginHypnoionicinHypna.ogicinCalmeng,saaxiolytsc Trisz lam PehtobarbitalsuEosuchruCcnieMoto lifitoesseltiPehtobarbitalsuTrisz lam Barbitur sss: Bonz -sey azepd ec:suREM Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinSleep–Wwke CytlebditfHypno ofsinTie rnic oH a lll me oft smsreygulmu-e cngatosasleep-wwke hythmarrefeos c m-inpretbcinknown -Tos r is evidaaceanhat2 heto min rg l, chslin rg l, glut ma yr-edgof,tyidradcenyrg lnneuki snrrefmoarsean lib du aretwakare tpan du arettrs NREMcsleep aec. Viaatieir ascen pup Mtialamopitrp pc jRc ixos, tieseoneu- eei snnxciteanhalamocnrpolll pathwaysd adrion of GABA-yrg lnneuki s sDuelnginsleep,tinputofrsynposib tin abso de-edtprodes, glvpup iseotofdimiionhel tpa-e himocnrpolll d sitoxaenegdisern of exoruliotrsiGABAnneuki sn(A). Ten shlftttesebalganrobetwneignxcit ory (red) ade ern of ory (onegn)nneuki gdoups Mundrrli s a ireay antchftgetiiisleepsuproponslox, f it dieium- arsm itrl wiininposimoan di, po iotprodeotowards efrlxd f anosi (mcdday sdeona), then t ade-seoline again,tyidrfinlllym- arsochritsnpe k abef is mcdneserf(B1i.seTa ofmett rfr leep d sourb an-s.sePlogy ? Posr use of measu rs rref n-sey y thdr linwest f itll tierapyahdssefailge sC itss hf issomrfaeinthe saemo-e ts el pe augms (onief, axiety,a“st y ”),sephic cal oomprtinrve(ccpea,ipait),oor Mnie d sesm tg hf s imulmnoisto ( an-s (cafsuens-cti ainsretbts aaec0, sympa-in-homims of0,rtie phyllens, s ocscttinseao- ytp y arus). A0millus( atsctfereemo-e ts el st y f(B2), tieseof d as cahasfsnulimbalganroitrfavo rrirexcit ory reflP-e encss -As afdeat A, nie d warvaltbetwneid goiren- bedweostfallaresa leep bncom s elassrr, totrpt leep durw the detprodes,tiyitisleep wivebabiNtoprup sthbsftts aalsuwakare popiocs.ecDepethwretonetosttima hf issomrfa, abenz diazepd e0 (p 226) weletshortfor Mintop cl trfdurw the hf a thearref n-sey y thd, h amettrisz lam rne bro oz lam (ud 1/2 a~ 4–6 h);aas me azepamasurtem ze-sepam (ud 1/2 a~ 10–15 h) -Tosseoroduc hort- Mei trsili ganyrrirfallaresa leep,lhengtestinPntrpt leep durw the, ditfrhby bitp- e esin Pehnyrrirno tu oal dwwkensres -Tosy an absfaugmehtaresiNn of ory d sitox.seEvenswele tp- lassrr-an lng benz diaz- Mepin s,otrsipgaieru awwkesnaf aoebrut 6–8 h rfr leep, bof its inonie moan diulnxcit ory ad sitoxaexceede sosasumcliinrnic oH a lll idirnogy ? 200 calsiNn -e bits i(B3). Ten dodu ve in awiv, its-e er, bncom iunmasksthatiday(imsawheninothen sedateng sto ( an-sa(h ame e-hynol) are d sesmedweostre-ipgaieru howsfsnulunuaually pk nouansc eyspoteetduem- a0synyrg sms rintopa the ( mmdirree ail-e ctyttoocsnieMoto e lr roa i.seAsnre-omargtecbetwneignxcit oryd adrion of ory ad sitoxadetprodes wele agec t dre dh a utprodiren-ethehnytto-suwards shortetsctday(imsasleep popiocsd adrwsre fre PehheiNtoprup the hf no -e tucn ltsleep (C).seUse hf a hypno ofrdodu shruldlno inbea,xtgadscrbeyoost4 wk, bof its t l-e er hne wivedethsop. Tosapiskpatia o-edboundidetprode0d tsleep proponslox ae-ti aododu weledrawll wivebabavoidsthbstitapnelng sffrtrsirotensverr2ttoo3 wk.seWeletaaxahypno of, tosapiskpatisuisin idll orophotjec canestebe ign age inSianrobenz diazepd e iu-nxocmuexo wivinbncom ilife-tid.atetpup h linwestinothen ieMotolenesaous ytp y arusa(htpa-e nol)arreftakevesimultaaeaemly aitican,e moarover, bnsta ofra weletslecefic bet-sez diazepd e anti.onCert, poe benz -sey azepd ecoshruldln glvenspreferponroinah sleep remel ssasvertsie allibutoobso-e lyt sbarbitur sss in224rHypno ofsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinHypno ofs 225inB. Wwke-sleep pi ttae, st y ,eaneg ypno ofrdodu ac ixo aWakare a yoNREM-sleepsuNsukins wele rarasmirterh: aHmto min ighcetylchoHinsinGlut ma y Norepd ephrinsinGABAinlioTarasmirterh:twakare a yoyitisleepinCioChftgeceliotrsiaroem c oa theaiu tp- vldrrlyinHypno ofinHypno ofin1su2 a3in1su2 aEeoAo el st y inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinBonz diazepd ec Bonz diazepd ec modifinafsuchiib ey- etpottss s aoensopyopopcep ihes; slecefi-d callx,tre-ymrender at to termis offneeh setowards aaxioionic stimuli, i.e.,iaaxio-tilypoe ac ixo. Furtiecm is, benz diaze-inpd es exerC sedateng, aetiosnvul aru,tiyitimtstle- ofaxatt (myotonolypoe, p.ec182) ve in s -AllSposse ac ixosfdeat A Mfrsynougmehtarestrsiad sitoxaatiiin of-inPnry neuki snradrace cl trthbsftpo-ed,ific betz diazepd e ar,ep as nhat2 fsum on iNtogrll parh liotrsiGABAinledre-ed,ep a-chas sdsrooftnel oomprex. Tene ion of ory rarasmirteriGABAnache t e opei trsimemera efchas sdsrooftnels.inio affeedfchas sdsroonby mahne rirtrs neuki rptmemera efve in libly short-ed,ircuirved. pottss s adepolarszlngf n-seputst Bonz diazepd e ar,ep atd.onistbiniotprodeotrsiae ontox rirGABAnpo itsteo-ed,ep aioAt a glvenscsnieMoto lifliinGABA, bindiren- phe ar,ep as e ll,intiecef is,ebabiN affeed, eyat Aoditiii nseaugmehtsc eyspotee. Excit eoltoxaon trs neuki 0mis dimiionhel.seTosr use of i bby tixosfferebenz -sey azepd ecointhe sa axiety a yslasso-ed,iofra weletneukipoe, phobic,eanegdt-sep y tvaldisorders, s omyocardialf n-sefar the (detprode0d tcardiac t imulm-e ts duem- a axiety); issomrfa;spredi-ices os of (paropeoasti ) medocmuexo; Mepilaptsc seizu rs;eaneg ypert rfaens etk litrp mustulmuu ry(cpas oflox, resid-e cty) inSianroGABA-yrg lnsynaptss rreft n-inffrrad- neukll tissue0, slecefic iin of-inPixocririeMotol nesaous cal memb0lcanln inschitvh ;tfereii ( an-c t dre dh l tts-secoftgetiiiesselfp y u r,thetrh to e,tiyitib dydrempeoasu r -Tosasosr use of Minbex rirbonz diazepd ec, f ltulmurasee prreferponro- phe Pnxoc rotenpc by -e cngare pitre ay ytp y the, is ga ofrr Mnianl1me eostreusaexceede soatlrirbar-e bitur sssarndohthen sedateve-hypno ofsinbxamoaritpan tenfoldt Bonz diazepd e Mintnxocmuexo canln ta ofra weletaftpo-ed,ific ao- yote8(se- befow).inSianrobenz diazepd es ytp y ey- etpottsitoxanoa,xtgcn ltstimuli, outomo-e tsvsirrivaretdkillsarndohthen task ey- e Piraretpreceseaoensopimm aft adira-e ts iwellibe mmdirret suTrisz lam (ud 1/2 arirelrmfrom tg ~1.5–5.5 h) is etleces linlik lym- a mmdirinmemory (aosorogra sa mnssia)menegtoedciits rebounda axiety ereii omrfaerne eday(imsat nfits . Ten sts atoxaon trss a haothen ddvpryr oa thesa(h ame rage,e v oHeru ho tillox, hs ly ar tixos),0eose re-iag utproded e e Pganyriu tp- vldrrly,e nas lsi poocucttilscreresuspethraduse hfin aisz lamfdvesom couNtr ssa(UK).seAllecpea benz diazepd ecodr wbrainPnl eee l,itrsipoatieoltoxaon peosi rptox chftgece(noachalganr,eparadnxocmlevxsin itemeht)weostre-i iskpatipnic cal de-edpethehne weletchroasc its wtsteestebeinsverssekge sCsnieivaauy, benz diaze-inpd endepethehne eyat As frsyno kd d hfinhablouw the,itrsical membal oouNtopparhesuhf we mesbncom ioloifeer du aretabsti-senencs ved. tly n ss anda axiety;aeieninseizu rs wivel a r -Tosseosymptomsineyinssucs chroasc d sesm tg hf benz -sey azepd ectinBonz diazepd e anti.onCert, s ncseas flum zenil,rpoatUssaae ontox fereben-sez diazepd e ar,ep as, brs re-ymhickeiu-in aineifi d sitox. Flum zenil dh a ve in-e tsib0 o- yote8it ap- a ofmett rfrben-sez diazepd e orophotjec aftanln uascsepoatopeoasti lxatoaaroemeipgaierusfoe-tidofra weletafbenz diazepd e.seWeeraasobenz diazepd ecopoatUss-e cngad.onCer a titoxaindi Rc lynougmeht chas sdsrperme eoltox,tinvpryr d.onistbinexerC aigoppoai e ac ixo. Tosseosesg eto an-s giib eiseotofpk nouansc eysu-e ly n ss,nnxcitemett, axiety,aditions-e iul eib seizu rs -Tos r is, veyet, norutierapse of i bby tixo fsurtrsiagits.ru226 Psychornogy ? 200 cal inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPsychornogy ? 200 cal 227inlioAcm tg hf benz diazepd ec Aaxiolysi0seplus aetiosnvul aru eosuch,insedatehe,imtstleb ofaxa thesuDiazepamsuRin1su = ClsuRin2 a = CHec3inRec3in = Rec4in = HinBonz sey az Mepin inRec4inNsuNsuRin1suRec3suOruRin2 aIun of exocriulnxcit ixo aHyper-inpolars-sez ixo aGABAinGABA-gmued Clsu-se-ooftnel Clsu-seBonz diazepd ec Unoppoaodnexcit ixo aNa sflinGABA-yrg lnern of exoruEnhganreinGABA-yrg lnern of exoruGABA-yredgof neukedcnseBonz diazepd eti ocep aruGABA- ocep aruChas sdse c nophorsinGABA= γ-amino-tibrsryc aganinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPlogy ? kd ems censeBonz diazepd ec Allibenz diazepd ecoexerC tieir ac lic be slecefic ey,ep a0 (p 226). Ten choice abetwneigdiffneentna.erusfis dict trthbse re-iagsleel, i wanslox,eanegdurw the hfruac ixo. Tosse, itdtucn, eyfliermpnic co-ed,osm lll idirnogy ? kd ems propor-e tsese INdividualibenz diazepd ecorsm ite cNSpe- b dydfsurvpay yiffneentnhengtes ri timsiradrace chitflxaeed fromel tprcpeae bio arasfermw theioIna tiw lifmivega-e tlil a epups- ,osm lll oa theaere es aalsustepsa(h ame di zepam)0bef is on iNan libinme abol te sui paug ssureenmleved fro-e ts iis fermsd. Sin binie d war cl ryd pc by hs0wiv, i parp,ebabrnogy ? 200 -d callx an lib al, i parp,ebabexcreurasemoarislarlyitpan tperpareNt sto ( an-,inme abol tes welliagcumulm e weletc n-in inu-dreygulmrirotengnditions ibrss etpgneficsatlxatoatrsicsorpt osuch inBio arasfermw theebagiicaeithen atse tosm tuerusfcnitrsiriazepd e aengn(diaz- Mepam: N-dealkylw lifatrpoai lif1;inmidsz lam:oold oxylw lifhftre-ome-hyledgnoup ononie dmidsz le aeng) suratrtiee diazepd e aengn tself. Hld oxylw re mid-e sz lamfdh Pickly eed fromel foll wengedgly uroasdom tg (ud 1/2 a~ 2 h) -N-de-inme hyldi zepam (na d zepam)0im bio-til00 callx an lib alnendergoesmold oxy-e hi exofatrpoai lif3fcnitrsiriazepd etiring. Teeoold oxylw ed pc by h (ox ze-sepam) againais pnogy ? 200 callx an lib inBy virtue rirtrsiaglass hs f-herose di ze-sepam (ud 1/2 a~ 32 h)a al, stellimoariso,oitsinme abol te, no d zepam (ud 1/2 a50–90 h), are eed fromel slarlyiradragcumulm esedyraretrope tradinPwke -Oxazepamsuendergoesmcnsjugmuexoctoagly uroasfi d-iniloviayitstold oxyligdoupe(ud 1/2 a= 8 h)a alti onll excreu tg (Ai.seTosapftgetrirelrmfrom tg hs f-herose fereyiffneentnbenz diazepd ecosurtrsiasean lib me abol tes isteopd. Untrthbsftiee shahradaraaso(B) -Sto ( an-saweletae shortfhs f-hefeanhatarrefeos c nvprtscrtosean lib me abol tes canln uasctfereii-sedy theaerem ittenganrorfr leep (leser eesuy rreaein B) -Sto ( an-saweleta foresuhs f-hefearrefpreferpaug ssurfore-nd c a xiolytsc a ofmett (leser onegn rrea)inbof its re-ympop f rm ittenganrorfsusteadyiplicseslevsss weletspups- dlilyindoning. Mcdsz lamfenjoys0its bsitrsic.v. eeiute8it predieonos of medocmuexoo altidieonos of c mbfrom tgoregimetstinBonz diazepd e DepethehnesePe lassradeygulmriits on benz diaze-inpd es canlhead to pnic cal depetheMce.ecWele tp- lass-an lng sto ( an-samar-e ketradinitsally,rtiistpe augmfweasless osg eviaem u oompaeiahe wele othen depet-seygans-pc by lng drduc bof its on trsseyglaystha pearganrorfrweledrawllinsymptoms. Ten sts atoxaon trstabsti-senencs syndrome is i vpryrlyrprlw ed torutierelrmfrom tg ud 1/2 a,apftgaretsrsynmildedto modera yo(d. tly n ss, irrit ailtox,seoensitlitox s aoounda atiHiserc issomrfa, aeostrrsmulaemn ss) s adr ma of (dt-sep y thee pdiic,eyglirium, onyitim ltses-sezu rs) -Some of tieseosymptomsrpoaee diagnosms rdiffic otiss, beoditiid soii-seguishaaug srsynposio ecosuesinllly a of- MedioAdmiion. Im tg hf a bonz diazepd etianti.onCeriwould abrup ly pk voke asg etti encs spgns -Tos r are d bby tixosecreatrsto ( an-saweletintop cl trfelrm-e cnom tg hs f-herosnrrefmostffre Pehhlyicneuasct(v oHet rreaein B) ru228 Psychornogy ? 200 cal inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPsychornogy ? 200 cal 229inB. Ra yohf lrmfrom tgohf benz diazepd ec A. Bio arasfermw theehf benz diazepd ec Mcdsz lamfDiazepamsuas gly uroasd ighc lib me abol tes aIuan libinOxazepamsuNo d zepamsuTrisz lam Bro oz lam OxazepamsuLs me azepam Bromazepam Flunitr zepamsuLs zepamsuCamazepam Nitr zepamsuClas zepamsuDiazepamsuTemazepam Pr zepamsuA pliodrdodu hc lib me abol tePlicseselrmfrom tg hs f-hefeinHypna.ogicineosuchruAeuase he ailtox Aaxiolytic ve in 0203040506010 >60 h Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTierapyanseMdiic-Dep y tvalIlln ss Mdiic-dep y tvalilln ssionseoses asupsychoms rdisorder hf ae in anhatel a rs Mepisod callx e pruta,xtgcn ltf itsioIn Meidoionous ytp y tg (melganhoHia),e moel isipersestehhlyrlar.eMdiiayreferssuro nie oppoai e ons of li (p 234)t Po-e tserusfwivelscillw robetwneigtieseotwoulnxrrsm-saweletintophe ss hf no sflinmoel. Depethwretonetosttima hf disor-seygre moel swengsfwivealtgcn te abetwneigtosttwotdi Rc thesa(bipolar dt-sep y thee cyclo hymia)mo rr a rein nncie o e hi Rc the (unipolar dtp y the) ruI. Eedoionous Dtp y the Iu toie osn of li,otrsipgaieru vxpbaienc-ices pk foundamispay (beyoostre-e ob Usagr’s empathy)weostfeelengsfrfr t-sevs r guilt bof its on imasinlry mist n-indy . Ten doiibeto an aeremove is i n of - MedioInaaddim li,otrsryrsraldisourb an-sinmoshlyref a soma of nmuu ry(issomrfa, alossehf a pet te, cnsstipatehe,ipalpit -inPixos, lossehf l ofdo,oimtotpoce,eetc.). Al-in-hopea tisipgaieru mivehaibe ufcidflin-hopeart, psychomm afreuardom tg pct-sevsrusfoufcidflrimpulees frsynbeoditcar-e ried rutioInaA,eeedoionous ytp y tg i0seillus( atsctbsitrsilaysrsfrfr mbopocsl-inors; psychomm afdoiib, symbol zsthbse a epueelscillw the, is s rorecifrhby bl.seTosr use of a.erusffalliretoatwoulgdoups: L50188 Teymilaptscs, poatUsslng a pc -tinouansc eoltoxa- ars-eleva yode-sep y re moel h amettp- aicyclic ao- -seygp y arus; L50188 Teymers of0,rhailng a pcedomfroht a tiw reteosuch ln psychomm aseroiib, r gme m noamd enoxddode0d n o-e ctorh.suIriwould n wroreeto admiion.scseroiib-enhganlng drduc, s ncreasampos -e smin s,os naipgaieru weleteedoionousseygp y theioBof its reis tierapyafaile t e eleva yomoel brs rsmorosnpsychomm-inPnrnern of exo (Ai,itrsirassrr ofe ufcidsiniotprodes.seTaicyclic ao- ytp y arusa(TCA;d pc totima: dmipramens) haibehastre-e lassrstcditimostf,xtga tvalsosr use of Mits;r its ac d ttrsipaer dof d-c t diru aibebeeocintprodirely supersedrthbse re- tasotonii-tslin lib reupPwke ren of-inPnrsa(SSRI; pc totima: fluoxetiie).seTosaieMotol sts n-memescsctelnginon trstTCAsnimros s a 120°cdips-inbetwneigtosttwotflgakare aroma oftiring0,yin t n rod soiicuexoctoatrsiclatseraretsyabso pd. Unt8it pheaothiazd etitima neukilaptsc0 (p 237). Ten sidsinchainanitrogenai0 pd.domfrohtly pk no-tina sd at rnic oH a lll pH.seTosaTCAsnhaibeae ontox ferebole o-ed,ep a0 eostrrraspor srsfrfrm noamd e rarasmirterh rne behaibeas anti.onCerte cNSbole otlec s. Teu0,rtie neuki rpt o-edupPwke hf no epd ephrins (p 82) yitise-e rotoniia(p 116) is i n of el, weleta ey-e at Aah ibtprode0d t d sitox. Mtstarinoe cetylchoHins ar,ep as, α-adcenocap-e t as, ditioecttin 5-HTeaneg mto -inmiie(H 1in) ey,ep a0 sralesscked.aCNhsc-infneehce welettrsiropamd ensyabso is eeyfa libcinmii a.seH i iNtopfneehce welettieseotaras-inmirter/modulmu arsto ( an-satarasl sss Mretoaaaaao- ytp y aruive in ais stellihy-e ponospolll. Ten clinoerpt osuch emergss M linaf aopaolassradinPwke, i.e.,i2–3 wk,suas evidaacethbsfan eleva theehf mseltianegdoiibioH its ac sie alteto lifitinm roamd enme abol sm h a rseas sohe as tierapyais startsc sCsnieivaauy, adap-e tsib0processes (s ncreasdowneygulmuexoruliocnrpolll tasotoniieanegβ-adcenocap-e t as)arref otim trlineyspoteiaug. In Mheelleyt to ter0,rtie TCAsndofeos rm-e pk vyomoel (no euphoria).suA trh srsynposiao- ytp y aruive-tifncs, acute8 osuche h a renhatarrefevidaat ave ad thetlleytiNdividuals -Tosse vsrye cNSreonegsamoditiid vidualisto ( an-s eostreusapk vsdsra0aamembalg ssuryiffne-tegatiofra clinoerptits (p 233), baascseupcnitrsirivergsnt pi ttaes hf istopfne-e encs weletamd enrarasmirterh/modulm-e t as. AmirCOptyHins exerCh aaxiolytic,insedateib idirsychomm afdampen diulne in s -Tosse rref sefupecNSrep y tvaulpgaierusaheorsralaaxious anda gtoa yd. Iu t n rost,a ssipramens pcoby bssupsychomm afa tiw li. Imipramens 230 Psychornogy ? 200 cal inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPsychornogy ? 200 cal 231 A. Eosuch hf ao- ytp y arus Ampos amens Immel tr Wulnek 9 Wulnek 7 Wulnek 5 Wulnek 3ruEndoionous ytp ices the Imipramens 5HTe aseNA aIun of exocriuley-upPwkeecDe ini ttadrtvaulNa sfl mseltiNa sfl drtvaulM,fH 1in, α 1inBsscka sariuley,ep a0ighchseNA aEosuche hnnsynapt lnrarasmi exoinbxa un of exocriramens ey-upPwkeecrne by ar,ep atdnti.onCeminLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinh a pi s antintop cl trfpoai li. Ite should n eosed tpat, d ttrsiorgft sm,e bio arasfermw the on imipramens headssuro ssipramens (N-desme hylimipra-inmiie). Likewias,ttrsiresme hylndeCOvi-e tsib0riramerCOptyHins (na rCOptyHins)ai0e h ss dampen di. Iu nondep y tvalpgaierusaheosasecnmprtinrvesralrirpd.domfrohtly psysin hoionic suesin, tieoioxiolytic-sedateibulne in wivebab sefupecNSne orts to belnginebrutaadremporlry “psychosoma of un-secoupleng.” Iu toie osnne the, clinoerp Mitsreas“co-airpgeeics” (p 194) wivebatinotbl.seTos sddrive in celiotaicyclic ao- yt-sep y anrvesralhirgslyri t ibrsaaug toatrsicneoltoxaof tieseocnmpounds to binegtoedrne bssck ey,ep a0 fereeedoionousserarasmirteristo ( an-s -Tosse ve in sindethsop acutelyioAnti.onCem at mtsta-e rinic choHino,ep a0 headsos natropiny-e hik see in ces ncreas achycardia, iin of-inPixocrirexocrins glgads, cnsstipatehe,ulimpdirreemi tu i the, ditfblurrsdsvf-in theiruChftgeceiieadcenyrg lncal membnsrasecnmprex. Iun of exocri neuki rptoithsin hbnamin reupPwke gerosneiseotofsuper-ulimpoascteuhi Rc sympa-homims of ettimulm exot Poaierusaa r supersensitliesuro cithohbnamin s (h ame epd ephrins itinsscel dieonos of ujRc ixosfmtstebeedrvoidst). O ttrsiothen h al, bsscka srulioα 1in-ey,ep a0 wivehead to ortho ta oftihyponutelheiruDuem- atieir y tixoic ampoiphilicinnasu r,rtie TCAoexerC memera e-st ai-e hiz reteosuche soatlcanlhead to disour-tib an-sahf cirdiac impuleenoonby mexoinweletar hythmias as wbraeas detprodes itinmyocardialft n roctillox -AllSTCAolart e re- taizu r tid. hbnd. Weeser otin wivineyat A0frsyno s imulmnoieosuch ln a pe-inPitotinMapk nilens, adre rocyclic c m-inpound,dhirgslyrd. Umbl-sataicyclic agenAs i teums hftitsnpnogy ? 200 caledrne clinoerptac lic. Mcraserins lsoinpoatUss s a re rocyclic ry tu r,obut yiffnes issofmrreaiih dutprodes it rosyn-seapt lncsnieMoto lic hf no epd ephrinsinbxabssckaretpresynapt lnα 2in-ey,ep a0, eea hrr tpan reupPwke. Moarover, itahdsseless pc nouansc tropiny-hik s d sitox.seFluoxetiie,salong weletserotolens, efluvoxamens, idiraroxetiie,sbefores torutiermoariey,ehtly dethsopsc gnoup oiulSSRI. Ten clinoerpt osofscx hf SSRIfie osn-in tdscsctoompaeaaug toatratlrireonab-e hinhel ao- ytp y arusioAdhradadvaa-e tlgecointhe s:tabsehne rircbrdio-nxoctox,tifnwerroutonomicenesaous tddrive in c, aeosteyfa lib safeoxawele orophotjec.seFluoxetiietf itss lossehf a pet teo altiweeserfrhby mexo. Its m itrddvpryr ve-tifncscointhe s:torop roem cc issomrfa, arrsmoac akatoieia, axiety,aditidisour-tib an-sahf sexualical membtinMoclobemddridh a0newteopd. Unti-e tsib0rirtiergnoup oi MAOrion of orse IN-2 heof exocri it roneuki rptdeonadom tg rfsusasotoniieanegno epd ephrins f itss snulibtprode0d tnxrrao llulmrremens hevsssioAsupsychomm afs imulmnoiteymers of a -e ts is trsipe.domfroht femuu ryoi MAOe ion of orsioAg rldrr memesc0rirtii0e gnoup,nraraylcypk eiie,sf itss ir o-sevs eiauga un of exocrirtosttwotisozym s eMAOe A aeostMAOe B -Tos rf is,epresysrem-inic vlrmfrom tg d ttrsileropohf bioionicinsmin s,os ncreas yramens, he mesaref n-sesesmedwitrfoel (h ame asradcheese ane eChiao- ),iwellibe mmdirret Tobavoid trsseyassrr ofeag ypertga tvalcrisi0,otierapyinweletraraylcypk eiiemo rr hrr notts-e lyn lib MAOrion of ors calls fere ain-sesettadieuaryrdul-s -Wele moclobemddr,intiisnhazbrdais m ncrrhby bl bof its ite cno tiw esaonlyrMAOe A aeostdoesme ad taineyvs eiaugaolorea.se232 Psychornogy ? 200 cal inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPsychornogy ? 200 cal 233ruSasotoniiruDopamd e Aaxiolysi0oα 1in-Bsscka sruPtr-sympa-ho- lypoe ac iitox I bby tixo AmerCOptyHins Poaieru:ecDep y tva, a xiouc, aegtoa yd a50-iem mg/dedtd 1/2 a = 9-ieh Imipramens Dep y tva, no sflindrtvaul75-iem mg/dedtd 1/2 a = 15-6eh Dssipramens Dep y tva, hickerfsudrtvaulane eenyrgyin20-4m mg/dedtd 1/2 a = 48-96hseFluoxetiie 3em mg/dedtd 1/2 a = 1-2hinMoclobemddrinlioAo- ytp y arus: ac iitox pk fil s e5-HT-Rocep aruM-ChoHino,ep a α-Adcenocap a D-Rocep aruNorepd ephrinsinhcetylchoHinsin50-15m mg/dedtd 1/2 a= 30-4mhruPtaieru:ecPtaieru:ecPtaieru:ecPtaieru:ecDoiib, rnyredgy Dep y tva, hickerfsudrtvaulane eenyrgyinDep y tva, hickerfsudrtvaulane eenyrgyinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinII.eMdiiaseTos oloic phasedisicofr-c izsthbsfvxsinagg eee l elw the, fleser ri idrod,tyidraulpgah 200 callx utproded psychomm aseroiib. ceis is symbol callx llus( atsctiiruAhbsfa disjointrth ry tu r anda ggres- etpvalclas oto ec. Ten poaierusaa r os a-tit nfidaat, cti inuaemly an lib, howe pk g y tvalincohneehce rirtoopear ane elaoastpup hftassoc tixos, radragt ir o-sespoteiauy (csorncsally,rsexually etc.).ecLitiium lic. Litiium m ctsa(h ame ceto e, cbrbona s)arrefve in libyin t n-in aollarestos oloic phase. Ten osuchebhsin omes evidaat a prox 10 dnaf aotiee starh liotrsrapy. Ten smallSposr use of Minbex necelel a yslfre Pehhem rf alnginon Li +susasum hevsssioTosr use of levsssinshould n kep obetwneig0.8–1.m mMtiirufas oresmoan diiesselfsampresioAt mnc-e er valubsnre-re dh aapiskpatiadvpryr ve in s inCNSosymptomsrinthe safd enrasmoac beaxfaenr seizu rs -Iun of exocrirtost onllruac ixocensevasop y tia(p 164) headsos inpolyurfaernertiirs . Teyroid cal membni0seimpdirree(p 244), weletc mpensItoryd dethsopmett rfr(se eyroid) goitea.seTos oe oft sm hf a the oseLi ixosecrsm its to bsically ely adofraioChemd-d callx,tlitiium sttrsileearest of tiesalkoleinme als, he mesinthe sas ncrbi 200 callxulimporAah elemettseas sodiumv idirm-inPassiumioA trh srsyniNtopfneehce weleserarasmemera efc tixo flux s (viayixo oftnels idirumps),0etlitiium eosuch lf2 majnr spgneficsacs pears to bsimem-inera efytple the osephospha- yyHinoai ole bisphospha- s,otrsipeintipal lipan sesg etora youasctbsfvarious ey,ep a0 ininparasmemera efspgnallares(p 66).suBsscka sari toie imporAah spgnalotaras-indy theapathway headsos n mmdirree ail-e ctytri neuki sa- arsspotdeto an tiw liinon memera efey,ep a0 fererarasmirterhinorrr hrr cosm lll pgnalsioAghthen sitsrulioa the oselitiium wivebabGTP-bindireinpk neinsneyspoteiaug fere pgnalotaras-indy theainitsatsctbsifermw the on tiesag-inonCer-ey,ep a oomprex.suRopan oti aol hf ao acute8attickerfsumdiiaymiveey Pirbinie use hf a neuki-e lypt ln(se- befow).inAltgcn te a ofmettc. Msel-to -ineoltzmuexoo al oti aol hf oloic a hy-e pooloic epdsodas0ivesom totimas ri bipolar illn ssiwiveale aeo schitvh inweletrosiao- osnvul arus valpk o e rne ecbrbamazepens, s wbraeas e prcblciumin oftnel essckers (h ame rop pamdl,0nifed-e cpens, nimodipiie). Eosuche ace delayst aeost pareNtcinenprlw ed totre-omecpa-e n smsreyspoteiaug fereao- osnvul aruedrne cbrdiovasesiaarac ixos, otlec iib-tilytinIII.ePe phylaxfsecWele cti inusc a ofmett fere6eto 12inm rths,tlitiium m ctsapeyvsntrtost o-d currshce rireithen oloic a rep y tvaul a ys,fve in libly st ailtzoresmood at a no sfl levss.se234 Psychornogy ? 200 cal inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPsychornogy ? 200 cal 235 A. Eosuch hf litiium m ctsain wiiiaseDive8seDive6seDive4seDive2tiNa sfl ta yinDtp y theeMdiiaseHtiNaseKsuRbinCc BoruMgsuCaruSr BaecLi +suNa sfl ta yinMdiiaseLitiiumseDive10inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTierapyanseSchizornrshiaseSchizornrshia dh a vndoionous psysin hosi0orirepisod cicofr-c . Its chitfinsymptoms eyfliermartoopear disorder (i.e.,idis a st,lincohneeht, dl200 caledtiiakare; impos atnhel iNtollierualedcti eht; bssckagetriridrouexo; abrup inereakare hf a t tin rirtoopear: claims ri belng sto terms aoutsddriagencies nhat2 oti aol tisipgaieru’s -hopeart),tyidrauldisourb an- hf ae in a(moel ina proprs-se te otre-oslouw the) yitiosepsychomm aseroiib. Inaaddim li,opoaierusaexn of delu-in thell paranoia (persecu lifminia)mo suhs ly ar tixos (cearcaln ssihetrare hf voices) -C n rostarestosse “poai ve”insymptoms,otrsiso-callel “nega ve”insymptoms,oviz., povprty rirtoopear, so-ed,iolrweledrawll,tyidranhel rfa, ssu rigadhradimporAahnroitrdetd cfrarettrs sts atoxaon trstd srode. Ten disrup thed adriocohneehce riridrouexo is symbol -d callxteopd. Untrthat poe top left (Ai0eose re- na sfl psychic a y is8 llus( atsctas M p 237 (bottom left).inNeukilaptsc0ighf aoedmiion. Im tg hf a neukilaptsc,intiece dh at firs aonlyrrsychomm afdamp-e ening. Ts mehtaresparanoid idrod0eose hs ly ar tixos lodeotrsi sto terlibyim-inporAahnro(A,idimmare hf fPhahylclas s);e h its ac sie psychoms rprocesses stellinpeosistioInasie course hf wnekt, psychof Mprocesses onadually na sflized(A);ttrs psychoms repdsoda wan s,odllecpeasecnmprete na sflizIm tg hftst f nestebeinschitvh bof its on trsipersestehnrorfsunega ve symptoms. Nonetrsl ss, trss chftgecea r spgneficsat bof its re- po-e tseru vxpbaiencss eylitf srsynpositor-semett rfrpsychoms rpeosi rptoxtchftges; csralrirtisipgaieru is ma sarodi aoealti otucnos naifamdliaa oommuntox envir n-inmeru is accel eee l.seTosai nvpnmembal ( a olassical)oneu- eeilaptsc0 cnmpeiseotwo olass-sahf c m-inpounds e prd soiicuev- ,osm lll ry -e tuces: 1.rtisipheaothiazd esndeCOvst asrsynposiao- heto min pk ehtpazd eti(pc totima: chas promaziie),yinthe pupe re-iagairpogu s (h ame poioxattheaes);e adr2.rtisibutye pheao e0 (pc totima:e hs oporidol). Acc adiren- phe ,osm lll etory tu r rirtisissdsroofin, pheaothia-sezd ecoditfpoioxattheaes canln sto o-e itdel iNt nalipha of (chas promaziie, arriflupromaziie, p 239 idiripeoazd eticassrners (rriflupeoazd e, flupheaaziie, aflupeo- xol, p 239).seTosaao- psychoms ree in ais pc bnelyindyem- a a anti.onCeroe ac ixohatidop-e smin fey,ep a0 -Assdsrsrsynposirem itseao- psychoms ra the, neukilaptsc0 dis-e pliveaddim lirptac lic wengm- atieirtianti.onCem atse– mtstarinic cetylchoHins ar,ep as L50478se tropiny-hik sve in s;se– α-adcenocap a0 fereno epd ephrinsinL50478ldisourb an-sohf bsselfp y u rti ogulmuexo;se– ropamd eney,ep a0 inrtie nigro aio-e tll yabso L50478lnxrrapyramedfl ms aserisourb an-s; inrtie rreaepoatrsm L50478se o- ems of a thes(p 330),tyidrd ttp-ulplouiuaryrglgad L50478l utproded secreu tgruliopaolan lne(p 242);se– heto min ey,ep a0 inrtie oerebraledctrtex L50478lpoatiels f itsahf sedom tg.seTosse ancillwryreosuche ace ale aylicf el d thetlleyt to ter0tyidrvsry in i wansloxinii ditiid vidualisto ( an-s.seOthen d bby tixos. Acutelyc t dre dhinsedatehe weletaaxiolysi0oaf aoneukilap-e tszom tg hssebeeocstartsc sceis ee in acsnulbab nilezsctfer: “psychosoma of un-secoupleng”oitrdisorders weleta pk eiieruedpsychoionic cnmponeht; neukilapta-e nrpgeeia (p 216)abinmeaiceliotrsibuty- eeipheao e droporidol u oombfrom tg weletaa opioid;otaraquilizIm tg hf os a-tinxcited,a gtoa ydopoaierus; a ofmett rfseygliriumnrasmens wele hs oporidol;tas Mwbraeas sie coi aol hf oloian(se- p 234)tsuIrishould n pointrthou anhateneuki-e lypt lsndofeos exerC aigao- osnvul aruedr the, on sie coi asry,tre-ymwivehart e taizu r tiershbnd.se236 Psychornogy ? 200 cal inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPsychornogy ? 200 cal 237 Wulnek 9 Wulnek 7 Wulnek 5 Wulnek 3ruaf aostarh liotrsrapyruChas promaziie Butye pheao e tima:e Hs oporidolruSad tixo Autonomicerisourb an-indyem- a tropiny-hik edr theinMovemehtcdisordersindyem- adopamd e dnti.onCeminAo- ems of eosuchruA. Eosuche ri neukilypt lsniveschizornrshiasePheaothiazd e tima:e Neukilaptsc0igLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinBof its re-ymion of tosasosrmoarg-inulmu ayaieMo ac neukilypt lsncanln em-inploysctferecoi aollel hyponosrmiase(p 202).inAdvpryr Ee in s -ClinoerpcinmoausuimporAah eostre-rapy-lrmftare arefvxsinrrapyramedfl risourb an-s; tosse deat A Mfrsynropamd eney,ep a bsscka s.inAcute8dyab rfae h a reimmel trlx ae-ti aoneukilypt zmuexoo al rrefmloifeerel bxamoPnrnemmdirmettc,epartiesiaalx ue re- hetdc neck,tyidrshoulderoregixo. Ae-ti ao es aaladays to morths,taipgrkisso-e n an syndrome (pseuroparkissonCem)inorrakatoieiaa(mo afre tly n ss) wivindethsop. AllSposse disourb an-socanln inta ofra bsfadmiion. Im tg hf ao- parkis-in drduc on tiesao- ohslin rg l tima,ins ncreasbiporidee ( .e.,iio acute8dyab -innia) -As afdule,Sposse disourb an-sodisap-e pearoaf aoweledrawll ri neukilypt linmebby tixo scbrdive8dyakd esiaymivebhsin ome evidaat af aochroasc neukilap-e tszom tg fere es aal years,epartiesiaalx Mwheigtostdodu is discti inusc. It is duesuro yperoensitlitox on trstdopamd eney-ed,ep a yabso aiticanebabex cerb rel bxaadmiion. Im tg hf ao- ohslin rg ls inChroasc its ri neukilypt lsncan, tgrulcca thee giib eiseotofhepa of damjectas- eto,iofra weletohsleonasi0 -Arvpay parr,tibrsadr ma of,iadvpryr ve in sttrsima-e hpgnant neukilypt l syndrome (tk litrpinmtstleb esidlox, hypertosrmia, stupor)ecreatrca vndifatallx u trstabsehce ririn-in ga tvalcouNtopmeasu rs (inthe pupe ra ofmett e prdai aolens, p 182).inNeukilaptsc ac iitox pk fil s. Tene markodrdiffneenceceiiea thestlec raens etisipheaothiazd es,nposiredeCOvipevss aeost irpogu s, he mesmivepartiallxteo- etUmbl-rtoots on butye pheao e0,nsraseimporAah itrdetd cfrarettrsr use of Mitse ri neukilypt ls. Relevant pir me-ti acointhe s:tao- psychoms ree ofscxse(symbol zsthbsrtie rrrow);ttrsf,xtgatruliosedatehe;weostre-i eoltoxa- ainby bivxsinrrapyramedfl advpryr ve in s Ten li ttaseygpends tgorefa lib diffneenceceiieaa-e tlgonCem towards dopamd enradrage-ti ylchoHins, otlec iibuy (p 188). Teu0, etisibutye pheao e0 tarry a utprodel piskpatiadvpryr mo afreac lic bof its etisymhickeao- ohslin rg l d sitoxaene,e npoce,errefpro e to upse tosabalganrinbetwneig aiotll ohslin rg l ostdop-e smin rg l d sitox.ecDeCOvipevss botrare airipeoazd etimoiety (h amettriflupeoazd e, flupheaa-sezd e) haibega ofrrtao- psychoms rponut-ed,yitpan do drduc cti ainsretaigalipha ofin tdsroofin (h ametchas promaziie,ttriflu-e pk maziie)ioH its ac sieirtao- psysin ho of eosuche ace qurptoa libciniid soii-seguishaaug.seAsntory tu el dirpogu s on trssepheaothiazd es,npoioxattheaes (h ame chas propoixe e, flupeo- xol)rpoatUssaaed,eMotol nutleem u he mestosaNa too is eeyphicra bsfa cbrbone. nkeloviaya doubs-inbotdeto tisissdsroofin sunhik stisiphe-tinothiazd es,nposy yispliveanaadded tpysinmilaptsc ac iitox.suClazapd e is trsipe totima on trsseso-callel atim lll neukilypt ls,taignoupecreatrcombfres afdefa lib hickerflnxrrapy- eeamedfl advpryr ve in s weletsupopiorulne ofscx iiealleviw retnega ve symp-e t ms. Nnwerrmemescsari toie olassrin-inthe sapisporidons, slgazapd e,tyidrsor-e tsndole. Tword soiiguisharetsemuu rsens etisse atim lll agenAs ace a mncrrtae on-e ctytfere5-HT 2in(ere5-HT 6in) ey,ep a0 tpane fereyopamd enD 2iney,ep a0 sosteyfa lib etUlyn lictytferemesslimbic,eas oppoaodsuro nigro aiotll,tyopamd enneuki s suClazapd e ale ayxn of s mnceae ontox ferindopamd eney,ep a0 on trstDec4in totima, d taddim lieto H 1inheto min yitimtsta-e rinic cetylchoHins ar,ep as -Clazapd ee may f itsarote–depetheMt seizu rs aeost onyiusscytosi0,onecelel a oditclosasehema oH a lll m rf alng. It is s roreciinsedatedi. Wheigeererifira weletaffatoxaecie,e bole flupheaaziieeaneg s oporidolacsnulbaba pliodrit romustulmalx as depo inpeypato lic.se238 Psychornogy ? 200 cal inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPsychornogy ? 200 cal 239ec40%ec40%ec20%ecl ss sedatedi etororeciinDopamd e- ≈ ACh eosuchruTriflupromaziie 3e – 15m mg/ded1in10in50suClazapd eseFlupeo- xolTrifluopeoazd etiR=H Flupheaaziieec2.5 – 1m mg/dedHs oporidolru2 – 6 mg/dedR=HsuLsss-an lnginor “depo ”inneukilypt lsni.m. 50–15m mgaeiery 2 wnektni.m. 50–15m mgaeiery 4 wnektedR a=suOruC C 9seHti19edR a=suOruC C 9seHti19ed25 – iem mg/ded15 – ie mg/ded-dof n o e -dof n o einDopamd e- < ACh eosuchru nxrrapyramedfl disourb an-sDopamd e A. Nnukilypt ls:oAo- psychoms rponutcy,rsedateib,tyidrnxrrapyramedfl ms a ve in sinRinRinAChru2 – 1m mg/dedRefa lib ponutcyinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPsychotomims of0 a(Psycheyglils,tHs ly aroions)inPsychotomims of0 ace aaug toaylicf psysin h cicoftgecehik stiots mloifeerel ue re- course hf arpsychosi0,os ncreas llu-in thelay yistnrpohe osepopcep ihe0eose hs ly ar tixos sceis expbaiencs wivebatihf da omhik scofr-c ;titsneeoAo el or Mintollierualtrrraspoai lif pears ar d-e equrte otre-ooutsddra.seArpsychomomims ofree in ais pic al-e sllxteoc adedrd ttp-rsori s on porAraitsindrawnhbsfan artistnenderttp-rinfluehnesense.ys rg l didadieuhylamddri(LSD) -Ase re- intnxocmurth m e waxecoditfwan se hik swarose ost oports seearestos fanrorfsutrsiporAraysct to termsucnoiNt naignl-e y ?e,ephosphod. nrobluish-purple,0eose flueruate8it sizedeas fovinwel tprcpeaaaedmoilng zoom leos, tprotarestrsi llus tgrulioabstritsachftgeceiiepropnrpohe eose gk nesqur mo theste Pganec. Ten dio-e bol c cbrocmuuce dh popceOvsteas sia of- Men di. Illus tgs ale aae in anheaoensrsens ehetrare yidrsmoll;aoounds (ro e0)nsrase“expbaiencsd” as flootaresbotmd0eose viaualnemm y theseas odnrsa(“synyonos-in ta”).aCNhnxocmurthiNdividuals seeanhem- etUlvss remporlrilxtsrsynposioutsddriaose passrjudgemehtcon siemtUlvss eose re-iagons of li. Ten boundlay betwnei etUlfweostre-ienvir nmentnbe omes eesurrret An elw tng sensr on bewretoneinweletrosiothen dostre-icosmos setsain.seTos sensr on timsiis suspethra; t dre dhinneithen pd. Unt8ns opaer. Oo ter0tyrb etUeigtoatidofeos exist,tyidrnxpbaiencsstifnl anhaterrrasceidrnxplgaw the, hehnesetosasd c “psycheyglil” (Grnek yglosi0o=ineyvslw the) emmly retexpatelheahf c s-in ciaemn ss.seTosai nterusfcfos ncrillus tgs aose hs ly ar tixos ca lcca thesllxtbe omeulnxrrsm-lyitpd.atetpup (“bad” s o“bumserCOp”);ttp-rind vidualiwivefeel pk vokedsuro sucnov oHeru s oto oommite ufcidse IN-2 tnxocmuexo is fell wra bsfa phasedririn-in ga s fatigu ,tfeelengsfrfr hamb,tyidrhu-inmiliw retemptiiess.seTosaoe oft sm hf sie psychomo-sesetofree in arsm its untlear -Some hs -e hy aroionsos ncreasLSD, psisscin, psisscy-ineon (srsynfung ),ibufotetpu (rosaiutaae-inousrglgad secreu tg hf a toad),imescaHinsin(srsynposiMexocmt f erusrseLophophodainwelliwmsiityidrL. diffusa;speyo s)abearoa etory tu rpt otUmblaonro- 5-HTe(p 116), aeost,osm lllly sytthes zsthampos a-inmiie-deCOvst hs ly aroionso(4-me hyl-in2,5-dims hoxyampos amens; 3,4- o-e ms hoxyampos amens; 2,5-dims hoxy-e 4-e hylnampos amens)arreftoopear s iniNtopagt weletrosia.onCerieoc gnf exoruai e hf sie 5-HT 2Ainey,ep a -C nvpryrly,inmosh hf sie psychomomims ofree in 0tyrb elorullel by neukilypt lsnhailng 5-HT 2Ainanti.onCeri d sitoxa(h amtclozapd e,tris-e poridons). Ten sory tu rsfrfrothen agenAs s ncreas e roold of neaeonolru(srsynposiosmpipliht, C neaeos sa lia—e naseish,amarihugaw),imtstimola(srsysetosaflxaagbroc, Amloita mtstariw),ior Mpheacyclidins (fermsalx uasctas antin-e teraaug srnerel dieonos of)idofeos o-sevsal a epmilaa oonne the.tHs ly ar -inPixosiwiveale ah a reas advpryr ve in sruaf aoinPwkefrfrothenisto ( an-s, h ame scopbnamin a haothen ,eMotolly an libe par-sympa-holypoes.seTosapopsiaarpsychos imulmno,ime-inPhylrnedioxy-ehtpampos amens (MD- eMA,o“econasy”) acutely dutprodes neuki-e rptdopamd enradrno epd ephrins rs-e lyase ane f itss s yglaysthaad selyn libseygsrnereu tg hf f isbrtin 5-HTenesaeti amfrols.inAllecpea dethsopmett rfrpsycho-til00 calndepethehne idir amansnt psysin h cidamjectf nestebe cnsstdscsctes- eraautnhel te Pglae rirchroasc its ri psysin ho omims of0,stos oloufa tu r andin ommsa,iolrdis ibrsthe on tiesstdodus are pk n of el (Scheyuug I,-C n rollelecDodus) ru240 Psychornogy ? 200 cal inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPsychornogy ? 200 cal 241 A. Psychomomims ofree in aoseLSD iiea porArait artistinLys rg l didserieuhylamddr 0.eme1 g/70 kg HNsuNsuCHec3inC 2inHec5inC OsuNsuC 2inHec5inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinHyponoalamdl ostHypornicsal seH rmon se Te-iendocrins syabso isecoi aollel bse re- brtin. Nnrvalcells hf sie hyponoala-inmts sytthes zs sosteyfyase messessrrse tosm an-sathate ogulmus shehohy-e pornicsal (AH) h rmon teyfyase orraresetosmtUlvss secreuel iNt nre- b dydas Mh rmon s Ten li tta cnmpeiseotrsiso-d callel neukihypornicsal (NH) h rsinmi ectinTosaaxhell processes hf hyponoa-tilamsc neukins pc terms anie neukihy-e pornicis, heers re-ymstnreotrsinor -inpypt das0vasop y tia(= ao- yiurs of h rsinmi e, ADH) yitioxytscin sosteyfyasesetosmcon dsm nl iNt nre- bloel. Trsr -inpyut lllly (ADH, p 64,ioxytscin, p 126), atiesstpypt da h rmon 0 ace giibn po-e reMo allly surviaotrsinasaliwucosatinTosahyponoalamdl eyfyaslng h rsinmi ecerrefpypt das. Trsyfreachatieirtitirgstlcells d ttp-rAH lobe by way hf ainporAal vasesiaareiute8cnsststareshf swoulsorillly oonne radcapdllwryrbeds. Tene firs aon tiesstlies d ttp-rhypornicsalul alk,otrsiseons ocnrrsspotds toatrsiccapdllwryrbed hf sie AH lobe.tHe r,rtietihyponoalamdl h rmon 0 diffussrsrsye re- bsself- atieir tirgstlcells,aheosa a -e tsitox srsyfcoi aolioH rmon 0 eyfyaset asrsynposiAH cells eMo anre- bloel, ue he mestosyrsraldiso ibrssd to poriph aalsuorgftso(1).inNomentlmuu ryoi eyfyaslng h rsinmi ec: RH–eyfyaslng h rmi e; RIH—rs-e lyase un of eng h rmi e.inGnRH: .onadotropin-RH = .ona-indoeylinfs imulmtbsnre-teyfyase of FSHru(sollatle-ttimulm eng h rmi e) yitiLHru(luneintzoresh rmi e)tinTRH: eyrotropin-RH (pc tieylin) ettimulm bsnre-teyfyase of TSH (royroid ettimulm eresh rmi e = eyrotropin)tinCRH: cnrpolotropin-RH ttimulm bse re- eyfyase of ACTH (adcenocnrpolotrop-inic h rmi e = cnrpolotropin)tinGRH: .rowle h rmi e-RH (soma-2 tncrinin)fs imulmtbsnre-teyfyase of GHru(.rowle h rmi e = STH, soma otropic Mh rmon ). GRIH soma o ta on un of s eeyfyase of STH (aost le ahthen pypt da Mh rmon syinthe pup issulin, gly i.on, aeostga ain)tinPRH: paolan ln-RH rsm its to bs chfr-c izsth a vsraautnhel. Bole TRH aeostvasoan libyinrestsorptpypt da (VIP) are emmlocmurttinPRIH un of snre-teyfyase of paolan-e tsnnditionuld n idaat calne prdop-e smin tinHyponoalamdl eyfyaslng h rmi es are moshlyradmiion.scree(pareMo allly)e fereyiagnosms rprodi sa- arest AH cal -inPixo.seTosr use of coi aol hf AH cells.inGnRH iseuascteuahyponoalamdl infertiltox u homenotofs imulmtb FSH yitiLHise-e creu tg atdeto inby biovulm exot Fsurtri0sepurpoao, itaisonecelewryrto mimdl trssephic oH a ltintop irtent “pulem ele” rs-e lyase (a prox eiery 90nmii)abinmeaicrulioa pk g ammel infus tgirump.inGonadoeylinfsupeoa.onCertrareseGnRH dirpogu s thatebinege prieryinheeaaavidloxrto GnRH ey,ep a0 on AHed,ellsioAs afdeat A0hf sie norphic oH a lsuenintoprup radey,ep a timulm exo, on-e ctiolraugmetteu tg hf FSH yitiLHiiutput is fell wra bsfa paolassraddetprode. Bu-in eeylin, leuproeylin, go eeylin, eostrrip-e t aylinfrref secteuapgaierusah prpro ta -inic car aromaa- arsby bipc by h tg rfsureston.scons, he mespromoses tumor M.rowle. Teston.sconsslevsss fallias m nc as af aoextiepw the on tiesrestes (2).seTosayopamd enD 2ina.onCertrbromm-incCOptd enradrcabergoHins (pp 114,i188)e ion of paolan ln-eyfyaslng AH cells (ii-sedby tixos:fsupp y theense.actatehe,ipki-e lan ln-pc by lng tumors) -Excy tva, brsaestena sfl, .rowle h rmi e rs-e lyase caigale aeo i n of el (iidby tixo:edr romegaly) (3).seOctreotddridh a0soma o ta on ana-inpogu ; itaiso secteuatiesra ofmett rfsesoma o ta on-secreu resplouiuaryrtu-inmorh.su242 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy243inPRHinPRIH A. Hyponoalamdl osthypornicsal h rmi es GnRH TRH CRH GRHinGRIH ADH Oxytscin STH(GH) Paolan lnACTH ADHTSH OxytscinFSH,iLHruOvum witu ruexo;seEs rod ol,sePe sesmeroneinSr amatoiones s;seTeston.sconsseToyroxinsinCnrposolruGrowleinSoma omebbicruLactatehe Milk ejRc ixoruLabor MH 2inOinHyponoalamdl eeyfyaslng h rmi es Sytthes soealti ofyase of AH h rmi es AH-cells Sytthes soSytthes sedRefyase us inbloeledRefyase us inbloeledNnukrulhypornic sedAhehohypornic s (AH)suA pliy tixo pareMo alle rslle 1 90nmiiedRefyasethamouNt Pulem ele rulne lyaseedRhythmic timulm exo AH-ed,ell FSH LHruPersestehh timulm exo D 2in-Rocep as GnRHruLeuproeylininDopamd eia.onCer BromocCOptd ese23tinCelew the on h rmi e secreu tg,se",osm lll can. Im tg" aIun of exocriul paolan ln Bu eeylininHyponoalamus secreu tg hfru STHe Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTeyroid H rmon oTosr uyinTeyroid h rmon 0 accel eee nme ab-inol sm. Tenirteyfyase (Ai0isteogulmusl bse re- hypornicsal glycopk nein TSH,e heos-teyfyase, d tture, is coi aollel bse re- hyponoalamdl rripypt da TRH. Secre-inPixocrirTSH detlfres asnre- bloelslevssorfsutryroid h rmon 0 eises;abinmeaiceliintiisnnega ve feedbickeoe oft sm, h rsinmi eipc by h tg ias“outoma ofllly” ad-e jusssd to dsm nl.seTosatryroid eyfyase0 pd.domfrohtlysutryroxins (Tec4in)ioH its ac sie an libyfermseappears to bsirriiodotryronins (Tec3in); Tec4in sedi nvprtecteuapgrrms aTec3in, ar,ep atde ontox u tirgstlorgftsobewret10-feld mncrrtferinTec3in. Ten osucherirTec3indethsopsrmoarieopan-inpyeaneg sh a0shor sr du ruexoitpan doesecreatrrirTec4in. Plicseselrmfrom tg td 1/2 afereTec4in s ebruta7 a; t at fereTec3in, its ac ds nncie 1.5 d -C nvpryixocrirTec4ins aTec3ineyfyase0 io-sedbd ; 15m μgrTec4incti ainst10m μgrririo-sedbn tinFsurtrsr use of purpoaos,eTec4in s cho-tisen,odllecpeaaTec3inis trsian libyfermoealtibe tta absorbed srsynposigutioH its acinweletTec4inadmiion. Im tg,rmoaricnsstaruedbloelslevsssncanln schitvh bof itsseygsnadom tg rfeTec4in s e aslar.eSihne sg etorpm tg rfeTec4in s maxisfl frsynontemptiinstomach,eTec4in s Pwken ebrutae 1 / 2inh bof isinereakfas .suRyphicrmsntrtosrapyansehyponoy- eeiidlsm. Whethen pdisfry,t .e.,if itsl bxatryroid d srode,enr seons fry,t .e.,iey-e at AaretsrsynTSH de ini tcx, hyponoy- eeiidlsm is ta ofra bsforel ddmiion. I-inPixocrirTec4in. Sihne tooieopan an tiw lieliinme abol sm etteile te- hazbrdaoftcar-e diac os aload (aosinl lec oris, myocar-e dial ufar the),otierapyaiso sually starh- Meege prlararoteonditionadually in-intprodel. Ten fsorptm ittehaonrodos-tey-in Pirbda- arsstnreoesee eyroidh m e yt-sepends tgoind vidualineeds (a prox ed15m μg/d)tinTeyroid supp y theetosrapyans Mee eyroidhgoitea (B). Ten f itsahf goi-ti ao(soryma)aiso sually aadieuaryrde i-inti tcxrririodbn t Dyem- a a utprodel TSH r the, tosatryroid is ac tiw eegtoedraiseo nilezw the on tieslittuga odbn aavail-e aaug toaaslevssoat he meshyponoyeiidlsmin s evprtec -Tos rf is,etosatryroid in-intprodes8it size. Inaaddim li,oit roroyroid eytple the ose odbn as imulmtbsn.rowle.inBof its hf sie nega ve feedbickti ogulmuexo hf siyroid cal memb, royroid ean tiw liecanln i n of el bxaadmiionsinrraPixocrirTec4inroteony PivaHeru t nre- ut-eddoionous yailxtiutput (a prox ed15m μg/d)t Dtp Ovst rfr timulm exo, trssecno tisatryroid eyg y es8it size. aIfoesee eyroidhgoitea sh estepersest- Meegfererooilass, intprodiree odbn asuppcie (ponassiume odbda raaugts) caigale aeoulne in libyin eyvs eireshvergrowle on trsseglgad. Iu rldrr pgaierusah prgoitea dyem- secodbn ade ini tcx t dre dh aapiskpatipki-e vokare hypertoyeiidlsm by intprodiresecodbn ainPwkef(p 247): Dyrare chroasce y xisfl timulm exo, tryroid collatlesedianln ome inbepetheMt rirTSH timu-e la thes(“outonomicepossue”).aCf sie codbn e atppci is i tprodel, tryroid h rmon e pk dy theaintprodes8he ug TSH ecre-inPixocdetprodes dyem- afeedbickeiin of-inPixo. Ten d sitoxalioautonomicepossue,e h its ac persesth at a mncslevss; noy- eeixd e is eyfyaset0d tnxc ss, deat Apup issecodbn -inby bd hypertoyeiidlsm. Iodbzsthm cteprophylaxfs. Goitea sedethemdl inoregixos heers soile ace de i-inti t itriodbn t Usedririodbzsthraaug m cte sllowse odbn aey Pirbmettse(150– 3em μg/d) to bsime eostve in libly pct-sevsrusfgoitea.se244 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy245inB. Ethemdl goitea nl its ra ofmett e prtoyroxinsinA. Teyroid h rmon 0 -teyfyase, ve in c,tdeonadom tginTeyroid aEosucherecell:iney,ep atde ontox L-Toyroxins, Levotoyroxins,e 3,5,3′,5′-Te roiodotryronins,eTec4inLiotryroninse 3,5,3′-Triiodotryronins,aTec3inTec3inTec4in10in 1 a=su~ 90nμg/Dive~ 9nμg/Divsu~ 25nμg/DivsuI -suI -suI -suI -suHyponoalamus TRH aTSHruDetprode0d tisenssitoxins aTRH aHypornic sed"eyvs eeaTec3in" a3,3′,5′-Triiodotryronins Urins FecsstiDe odbnaseedToyroxins TriiodotryroninstiDe odbnam tgincouplengruDurom tginTec3inTec4inDivsu2. 9 ed10 Divs30 4020 aTSHruHypornic sedNo sflin ta yinI -suTec4in,ru inTec3inTec4in,ru inTec3inTSHruTec4inTosr u.inadmiio- etora tginIun of exoe Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinHypertoyeiidlsm ditiAo- tryroid Dodus Teyroid orop d sitoxaitrGraros’ d srodee (A) deat Astsrsynfermw the on IgG ao- -e bodi s thatebineg- a an an tiw g TSH o-ed,ep a0 -C nte Pgatlyc t dre dh oroppki-e by h tg rf h rmi e weletoelew the on TSH secreu tg.rGraros’ d srode caigaba yinspottaaeaemly af ao1–2 y -Tos rf is,secnctiolrtosrapyacnsststsyoi eyvs eiauge atpp y theensetryroid d sitoxabse meaicelioao- tryroid dodus. Inaothen ferms hf hypertoyeiidlsm,os ncreash rsinmi e-pc by lng (moaph 200 callx bhsinnign)etryroid hehoma,otrsipeeferrreintiec use of ms hod is eymovll ri possue,e eithen byt trgery oaoedmiion. Im tg hfed131 codbn aint tf ini ttadotjec. Rod oio-sedbn s Pwken up iNt nreyroid cells ealtidetoroys tossue weleiiea sp dre lioa fewinmillims scsabsfv irtlng β-(elyn ron) partatles du pup irvedod oo tisadof x.suCsniean diicodbn -inby bd hyper-sutryroidlsm,ose- p 244 (B).inAo- tryroid dodusmion of toyroid acal membt Ryfyase of tryroid h rmon e (C)ais pcecsdra bsfa chtin riryvsntsioAsumemera efrrraspor sr an libly accu-inmulmtbsn odbda euatiyroid cells; toie sedfell wra bsfoxidom tg to iodbn , iodbnI-inPixocrirtye sbn aeysidues d ttpye globu-e lin, cnsjugmuexo hf sword iodotye sbn e gnoups, radrfermw the on Tec4inaadrTec3inmoieti-s -Tosse reac lic ace cotllyzsl bxatryroid peroxidoss, he mesis locs -e bzsth u trstam lll border hf sie collatsiaaed,ell memera e. Tec4in-cti ainsrettryro-seslobulinfis s orsth usddritosatryroid col-e litles u trstfermoof tryrocell ie supxoe endocytoms rupPwke, cnll ienendergoeseclysosomal utzyma of old olicis, eaa-seblsrettryroid h rmon to bsieyfyaset0as eey Pirbd -Ar“tryro ta of” ee in acsniey-e at A srsyniNn of exocrirsytthes so afre-e lyase. Whenrsytthes sodh arrsstel, tre dnt tryroid ee in adethsopsraf aos yglay, as s orsthcnll iencti inuss to bsiuti-e hizrttinAo- tryroid dodusmferelass-nd cintiec uy (C) sceioureaedeCOvipevss a(teioureylrnes,npoioamddrs) iNn of e poroxidossaene, npoce,eh rmi e syn-sethes s. Inaorder - arsstnreoesee eyroidin ta y, swortrsr use of peintipl-socanln ina pliodritrGraros’ d srode: a) m rothen-e apy weletafpoioamddrah prgnadualodos- eeyby h tg asnre- d srode aba ys;ab) ad-e miion. Im tg hf mncsroteonhf a thio-seamddrah prcsniurrshtoedmiion. Im tgruliotryroxins s aoffse dimiionhel h rsinmi eisytthes sioAdvpryr ve in s ri toi-inoamddrs ace parr; h its ac sie poatieil-e ctytri onyiusscytosi0 sh to bsikep oitinmiad. Perchas a y, giibn otolly asotrsiso-d dium m ct, iin of snre-t odbda rump.oAd-sevs ee reac lic inthe saaplaeroe anv ia.suCsmpaeeege prpoioamddrs, f snre-r -inpyut ldimporAahnroisrlarabrsaitaiso sec as anaadjal mnivesciNtionyph ldimagare hf bi eibinmeaiceliotechne m e whei eaccumulm exoteuatiesreyroidhglaneg shins abe esscked. Shor -nd csreyroidhatpp y thee (C). Iodbn aint mncsrotject(>60em μg/d)ulnxerts afrrrasient “tryro ta of” ee in aitinhypertoyeiid,obuto sually ested tne eyr-inoil, udividuals. Sihne eyfyase is lsoinessckedc sie ee in adethsopsrmoarieopan-inpyetpan does reatrrirpoioamddrs suClinoerpta pliy tixocointhe s:tp yop-e ereu vefsupp y theensereyroidhaecreu tgruacc adiren- Plummsage prLugol’s solu-in thes(5%e odbn a+ 10% ponassiume odbda,in50–1em mge odbn /egferea maxisum hfed10 d)ioInasiyrotnxoclcrisi0,oLugol’s solu-in thesis giibn toiothen e prpoioamddrsinaadrβ-essckersioAdvpryr ve in s:ealler-ingiys;acoi asd bby tixos:icodbn -inby bdsutryrotnxocosi0.ecLitiium licmion of toyroxins rs-e lyase. Litiium m ctsacanln secteusteadrulio odbn afereeopan reyroidhatpp y thee itriodbn -inby bd tryrotnxocosi0. Ry-ingaadirenadmiion. Im tg hf litiium nsumdiic-rep y tva illn ss,ose- p 234.se246 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy247suC. Ao- tryroid dodusmdostre-iremodas0oioa theinA. Graros’ d srode B. Iodbn ahypertoyeiidosi0 i vndemdl goiteasuI -suHypornic sedTec4in,ru inTec3inTSHruI -suTSH-e hik dnt -e bodi s Tec4in,ru inTec3inAutonomous tossueedTec4in,ru inTec3inLysosomeinStnrjece itrcnll ieinI -suTec4in-suClOec4in-suPerchas a y Iodbns itinhmncsroteseLitiiumseixosecI -suesuTec4in-suTye sbn e Tye sbn e Ie Ie Ie TG Sytthes ssuTec4in-suTec4inPoroxidoss TeioamddrsinPe pylteiouracilsuCsnvpryixoe byalnginabsorp thed Carbimazols Teiamazols Mothimazols RyfyaseseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinGlucocnrpoloid Tosr uyinI. Ryphicrmsntrtosrapy. Ten d onllructrtex (AC)apc by bsnre-tglucocnrpoloidructrtosol (old oftrtoso e) yititos oiae-intolocnrpoloid aldon.scons. Bole n.scoidruh rmon 0 ace vitallx mporAah itradap-e tatehe eyspotess to atrsssoslouw thes,ins ncreasd srode,e. Iuma,onr strgery -C r-e tssol secreu tg is s imulmtba bsfhypo-sephicsal ACTH, aldon.scons secreu tg bse aosio ga tn IIteuapgrratsiaae(p 124)ioIninAC failu ry(pdisfry AC issuffi tcx:edAhdison’s d srode),ibo prcsrtosol aost l-eddon.scons must bsieyphicra; whei ACTHe pk dy theaisade ini ttn(seons fry AC is-e atf ini tcx),rcsrtosol alo enneeds to bsiey-e plicraioCsrtosol is ee in tva whei giibnsuorllly (3m mg/d, 2/3 a.m., 1/3 p.m.)ioIninatrsssoslouw thes,nre- dose is raisea bsf e5-eto 10-feld. Aldon.scons is pooalx ulne in libyviaotrsiorel eiute;teustead, e re- min rolocnrpoloid fhe oftrtoso e a(0.1 mg/d)sis giibn.inII.eology ? dynamdl trsrapyinweletglucocnrpoloids (A)ioInaurphic o-til00 callx hmncscsnieMoto thes,ncsrtosol erinhthen glucocnrpoloids atpp y eall phas-sues (hxudatehe,ipkilife Im tg,rstarrfermw-in the) hf sie inflammmu ayareac li,t .e.,e re- orgftism’s defga tvalmeasu rsina.ainst fereign ot esxiouc wit . Tri0seee in ais mel tra bsfmt Appls fnmposinnettc,eall hf he mesinvolve alte Im tg0 ininioneerrrascCOptdhes(p 64)ioGlucocnrpo-ed,oids ion of tosaexp y theenseiones ut-edcodirenferepkiinflammmu ayapk neinse (phospholipode-A2,ncyclooxyionode 2,e IL-2-ey,ep a). Ten exp y theensetrss iones is s imulmtba bsftiesrarascCOptdherufachereNF ΚBin. Bindire t nre- glucocnrpo-ed,oid ey,ep a oomprexapeyvsntssraraslo-d cah tg afeNF ΚBins anie nutleem -C nvpryr-inpy, glucocnrpoloids augmett tosaexp y -in thecrirsome dnt -inflammmu ayapk -ti ins, h ame lipocnrpon, he mesinmsucnoiN-inhmof snphospholipode A2 -C nte Pgatlyc eeyfyase of fr-chidon l didais dimon-e cnhel,eas is trsifermw the on inflammm-e t ay mel t a0 on trstpro taglaneie eose leekotaien-rsori s (p 196)ioAt iery hmnceddonjec, norionomofree in 0twiveale 2 oti aibrss.ecDesirbdave in s As ant -allerg ls,secmmunoatpp y attc,eereao- -inflammm-e t ay dodus, glucocnrpoloids yisplivevxsin,elleru ve ofscx a.ainst “endesirbd”oit-e flammmu ayareac li0.ecUnwantrthve in s Wele shor -nd c Mits, glucocnrpoloids are pkac callx fresrulioadvpryr ve in s,ryvsnhat poe mncrer dotjec. Lass-nd c its icehik lxrto f itssechftgecemimdlkarestrsispgnceliinCushare’s syndrome (vndoionousrulroppkiby h tg rf csrtosol). Se Pglae rie re- dnt -inflammmu ayaac li:ehart el pes staonro- infec li,tyglaysthwound ehetlsre,n mmdirreehetlsrepatipaptsc ulsin,ersioSe Pglae ribex gg eee l glucocnr-in tcoid d sli:ea)aiutproded gluconeoion-suesi0 sosteyfyase of glucose;teusulin-yt-sependeru c nvpryixocrirglucose t nrreslysin,erddrs (adipoai ytm itly est Naaug ue re- f ?e,eneck,tyidrtrunk); “n.scoid-dio-e betos”s foeusulin eyfyase is issuffini tt;e b)aiutproded pk nein cotlbol sm welese trophytri tk litrp mustulmuu ry(teinulnxrrsmiti-s),ion.sopnrosi0,ogrowle re-inPaadm exoteua ufattc,eakd trophyioSe-in Pglae ribsie in ains callx weak,obuttinow mloifeer, min rolocnrpoloid a theinrf csrtosol:hm cteradrfluid eytpnmemb, hy-e pprten thee edsm ; KCl lods e prdaisrrsensehypokalv ia.suMeasu rs fs of tenum eress oPeyvsntengruDodu-Inby bd Cushare’s Syndromese ) Usedrircsrtosol deCOvipevssge prl ss (h ametpd.dnosolo e) ot eegligiels min r-sealocnrpoloid a titoxa(h am,ttriam arolo e,tidexaehtpason ). Glucocnrpoloid a ti-e ctytri tiesstcassrners isrmoaripk -tinouncraioGlucorpoloid,eao- -inflammm-e t ay radrfeedbickeiin oft ay (p 250) a -e tslicen ttp-rhypornicic ace cnrrslmurttinA tnxclus ibly ant -inflammmu ayac s-insrner does eos exist. Ten “glucocnrpo-ed,oid” rslmtba Cushareoidhaymptomsedianestebe avotdel. Ten raaug ltstsyrslm-e tsvn d sitoxa(ponutcy)ge preefereonro- ructrtosol,aheosa min rolo-nditiolucocnr-in tcoid d sviti-s ace asspgnet0a value rie 1.0. AllSltst l glucocnrpoloids are ve in-e tsvn orllly.se248 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy249ecUnwantrt Wantrt A. Glucocnrpoloids: peintipal aost dvpryr ve in sruInflammmutheind.dn ss,in wbraare heat, paio;sestarinGlucocnrpoloidedr theinMin rolocnrpoloidedr theinHyperten theruDiabetossumeraatusruCnrposolruurphic oH a llllyinhmncscsnieMoto theinMtstle Mwbakn ss ssuGrowleniNn of exo Skitseatrophy Tossue atrophy Triam arolo eightdon.sconssePd.dnosolo eecDexaehtpason inGlucos inGluconeoiones ssuAmino didsinPe nein cotlbol smseKsu+tiNase+ MH 2inOinh am,tallergse autocmmun- d srode, arrrasplmnoed.jRc ixoruHetlsrepat tossueniNjuryindyem- ab-c ia,e viritsc,efung ,e. Iumae 1 4 7,5 3e 0,3e 1 0,8 0 0 3emeruCnrposolruPd.dnosolo eecTriam arolo eigDexaehtpason inPonutcyinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinb)aLoerpta pliy tixo. Tim lll advpryrseee in s, its ac ale ah a relocs py, h ame skd trophy ot wucosallclasnezw theinweletcaneidfl fung . Ts minimdzge ayabso l bsorp the af aoinoalau tg,sedeCOvipevssgshould n sectreatrhaibeainhmncseee natipkeayabso l elrmfrom tg,ins ncreasbecloehtpason d prop tga y,e flunosolbda,obudrssnede,enr flu cason e pk p tga y (p 14)tsub)aLowest rotjectpoatielst Fsurlass-ti am mebby tixo,taijusst tf ini ttadotge ahould n giibn.oH its ac d tremp -inire t nhart nre- dose s anie minimal ue-ti in libylevss, itaisonecelewryrto Pwkef us inacc un anhateadmiion. Im tg hf exoio-tinous glucocnrpoloids well atpp y epki-e by h tg rf vndoionous csrtosol dyem- sean tiw lielia a un oft ay feedbicktioe oft smioInasi s mann ac a iery harinroteionuld n “buffneed,” soanhateun-sephic oH a lllly hmncsglucocnrpoloid a -e tsitox eostre-i nt -inflammmu ayaeosuchruare bo prpeyvsntrttinEosucherirglucocnrpoloid admiionsinrraPixocrn adcenocnrpolallclrtosol pki-e by h tg (A)ioRyfyase of csrtosol depends M timulm exo bsfhypophicsal ACTH,e he mesinmsucnois coi aollel bs hyponoa-tilamsc cnrpolotropin-eyfyaslng h rmi ee (CRH)ioInabo prtp-rhypornicic aosthy-inponoalamus t dre ace cnrtosol rocep as tprcpeaahe mescnrtosol ca vxerC a feed-e bickeiin oft lieliaACTH surCRH eylyase. Binmeaiceliotrsse cnrtosol “nNic as,” tre ogulmu ayaieMo asacanlm rf a whethen trsian ualobloelslevssorfrtp-rh rmi ee cnrrsspotds toatrs “nNt-point.” In trssebloelslevssonxc eds trsiset-point, ACTHe iutput isadetproded ene, teu0, ale atrsicclrtosol pkiby h tgioInasi s way cnrposolrulevsso s maii aineege peuatiesey Pirbdintonec. Tieseygulmu ayaieMo asarsspotdins asytthetsc glucocnrpoloids as trsy doins acnrposolioAdmiion. Im tg hf exoionousrucsrtosol er eny hthen glucocnrpoloid re-inby bsnre-tamouNt rf vndoionous csrto-in olineedbda- amaii ainrh meoonasi0 -Rs-e lyase rf CRH yitiACTH detlfres ("iin -e bft lielia mncrrtieMo asabsfvxoionousruglucocnrpoloid”) ane, teu0, csrtosol se-e creu tg (“odcenocnrpolallatpp y the”).ighf aownektnhf expoau r toaurphic o-til00 callx hmncsglucocnrpoloid doaos,etrsicclrtosol-pc by lng pnrpohec on tiesad-e onll ctrtex shrink (“odcenocnrpolalseatrophy”).ahtdon.scons-sytthes zare c -inp diox, h its ac rsm its unae in rttinWhenrglucocnrpoloid mebby tixoiis sud-e detly e pheldc sie atrophsc cnrpex ssuunaaug toapc by bt tf ini ttacsrtosol aossea ponuttiallxtlife-tpd.atetpup cnrposolrude ini tcx wivedethsop. Tos rf is,eglu-incocnrpoloid tiec uy ahould always n intapscreeoffabsfgnadualoeyby h tg on trssedotjec. Rygimens ferepkyvsntetg hfedodcenocnrpolall trophyioCsrtosol secre-inPixocis mnceeuatiesemalx mornsretaise loweeuatieslmtb yvsnlng (circadisnulrhythm) sceis fach emmloes reatrtieseygu-e la ayaieMo asacti inus - arslyase CRH as ofCTH u trstfanrorf mncemornsreedbloelslevsssnof csrtosol; acc adirelyc eoensitlitox - afeedbickeiin ofPixocmustulbabloweeuatiesmornsre, heersasotrsiop-e poai -rh lds trueeeuatieslmtb ) Circadisneadmiion. Im tg: Tene yailxtdose of glucocnrpoloid is giibn ue re- mornsre. Ethoionous csrtosol pki-e by h tg well haibealrsadx bhguo, trsseeygulmu ayaieMo asabewreteyfa libly in-inoensitliro- inn ofPixoioInasiesemalxinmornlng h ua0 on trstnextaday AtRF/-inACTH eylyase aost dcenocnrpolallatimu-e la theswell deatmotinb)aAlte ga y-day tiec uy: Twice trssedailxtdose is giibn rn alte ga y morn-inire0 -Onatrs “off” day Avndoionous csrto-in olipk dy theaisaall wra t ah a r.seTosayisadvanti.e ribeithen rygimenin s e rocrudrscehce rird srode aymptomseddu pup re-tglucocnrpoloid-frestintopval.se250 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy251suHypo-sephic sedAh onllructrtexruCnrposolru3m mg/divsuCnrposolrupk dy theaendertino sflinons of licinExoionousruedmiion. Im tgruAh ono-d cnrpolalseatrophyruDetprode0d ticlrtosol pkiby h tginweletcsrtosol dotge < dailxtpkiby h tginCsrtosol de ini tcxruaf aoabrup in,elew the on edmiion. Im tgruCnrposolrucsnieMoto theinno sfl circadisn tims-courseinMornlng dose Iun of exocriulvndoionousrucnrposolrupk dy theinElrmfrom tg riulvxoionousruglucocnrpoloideddu pup divtimsinStarh lioemalxinmornlngrucnrposolrupk dy theinAioCsrtosol eylyase aostf snmodifby tixoibsfglucocnrpoloidsinCRHinACTHsuHyponoalamus Celew the on clrtosol pkiby h tginweletcsrtosol dotge > dailxtpkiby h tginh04 8121620244 8inGlucocnrpoloid-inby bdsuiin oft lieliaclrtosol pkiby h tginGlucocnrpoloidedcsnieMoto theinh04 8121620244 8inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAndrogeos, Anabol c S.scoids, e Ao- androgeosinAndrogeos rrefmlstulintzores tosm an-sues. Ten endoionous sfle .onadal h rsinmi eiis trsin.scoid reston.sconsrsrsye re- intopatitiolrLeydiglcells hf sie restsctinTeston.sconsrsecreu tg is s imulmtba bstihypophicsal luneintzoresh rmi e (LH),e heos-teyfyaseois coi aollel bs hyponoa-tilamsc GnRH (gonadoeylin, p 242) -Rs-e lyase rf bo prh rmon syist to terms ti iedbickeiin ofPixocbs circulm erestes- eron.scons. Ryby h tg on teston.sconsrs tidiold oteston.sconsrh a r0 i mosh tar-e gstlorgfts;atieslmt aopoatUssesa mncrrruaf ontox fer androgeo ar,ep as -RopaniniNtrahepa of dgsnadom tg (plicsestd 1/2 a~ed15 mii)ayields andron.sconsramonginothen me abol tes (17-keton.scoids)ecreatrare vlrmfromsctas cnsjugmues u trssuurbn t Bof its hf eopan hepa of me ab-inol sm, teston.sconsriso nsuiuaaug fer oalle use. Allecpea itaisowbra absorbed, itsuundergoes virtullly oomprete pct-seayabso l elrmfrom tgtinTeston.sconsr(T.) deCOvipevssgferinclinoerptuse. T.geerers ferei.m. depo niNje -e tslirare T.gpk p tga y aadrT. hept n o ein(ereehaoreats). Tense ace giibn in riciinsoluPixocbs deep it romustulmaniNje -e tsli supxo diffus tg on trsgeererrsrsye re- depo ,geererodes quickly smloteoffatre dcylaeysidue,ms ayield fresrT. Wele in-intprodereslipophslicf y,geerers well tenegtoedrsm iteeuatiesdepo ,geostre-idu ruexoion e h tg ths rf is leogthsn0 -ArT.geerergferinorel its icere-iundef n o e -Owire t nre-rufatoxaecie nmuu ryoi undef n l did,npoi0seestea s absorbed iNt nre- lymph, eaa-seblsretirms abypassrre- liiba nl eMo a,yviasetosashodacof dy hc sie srnerel circulm-e tsli s17-a Meuhylteston.sconsrisone in lib bxatrsiorel eiute dyem- aits i tprodelinme abol c t eoltox,obutobof its hf sie ehepa otnxocctytri C17-alkylmtba andro-insrns (choHeonasi0, tumors)aits its ahouldulbabavotdel. Otolly an lib mes.scolonsrised1α-me hyl-diold oteston.scons. Trras-e de sfl ygliiery ayabsos fereT.gace ale 2 availaaug.seI bby tixost Fsurh rmi e rsplicrsinmeh itrde ini tcx rf vndoionous T.rupk dy thea idiralliw vesra ofmett rfseereas acsnc a,yT.geerers feredepo niNje -e tslirare optimally suitec -Seons fry sexruchfr-c is of0 aidil ofdo rrefmlin-in ainee; h its ac fertiltoxaisonotspromos-sued -Onatrs coi asry,tsr amatoiones se may befsupp y h bof its rf feedbicktiiin oft lieliahyponoalamihypornicsalinsonadotropin secreu tg.inStimulm exo ri tr amatoiones se in sonadotropin (FSH,iLH) de ini tcxrucanln schitvh byniNje exo ri HMGinaadrHCG. HMG er humanlmonop italinsonadotropin so b aineegsrsynposiurbn sensepoatmonop ital homenoaostf0 einc in FSH r titox.rHCG, humanlchorioasce sonadotropin,gsrsynposiurbn natipkes-tihaor homen, r cehik sLHtinAnabol cs rrefteston.sconsrdeCOvi-e tsvns (h ametclon.sbol,ams srolo e, nmt-eddrolo e, sm aozolol) reatrare secteuayt-seeoltomtba pgaierus,geostmisusea bsfath-e lytos,ebof its hf sieir pk nein anabol cseee in . Trsyfach viaostimulm exo ri andro-insrn ey,ep a0 sos, teu0, ale ayisplivean-eddrosetofrac lic (h ametvirilezw the in frsinmfle0,os pp y theensetr amatoione-in ts).seTosaao- androgeo cypk neconsser cesh a0oompetitliroanti.onCerion TioIninaddim li,oit sh pe sesmin a titoxe hes rbynit iin of snsonadotropin secre-in thes(p 254)ioInbby tixos:icnlmon, iin -e bft lieliasex drlibyin hypersexulltox;rupk ta ofacsnc aioInahomen:sra ofmettsensevirilezw the,ah prponuttialo nilezw theruliotre sr tagetofrcoi ascep ivr ve in .seFlutamddr, anaandrogeo ar,ep ainanti.onCeripoatUsssreta differshtochem- eolallatry tu r,e.ackh pe sesmin a titox.seFbnasterddr iin of sn5α-eyby hode, aren enzyme c nvpr eresTioiNt ndiold o-sureston.scons (DHT). Teus,nre- androgeo- eolostimulus is eyby bd euatiose sossue0 ininhe mesDHT icere-ian lib tr cins (h amerupk ta s). T.-bepetheMt sossue0 nr fal -inPixos rrefnotser hardly af in rt (h amerutk litrp mustle,enega ve feedbickeiin -e bft lieliasonadotropin secreu tg, aidil -e bfdo). Fbnasterddr canln secteuln nignrupk ta s hyperpliciaa- ashrink re-tglaosseaos, poatiely,ms aemm oib mi tu iu tg.in252 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy253inTirgstlcellruDiold o-sureston.sconsinA. Teston.scons ditideCOvipevss aTestesinIun of exoe Esteasutleavjece RinTeston.sconsresteasuin rici soluPixo Sk litrp mustlesui. mt Dtpot injRc ixoruEstea tleavjece OtolainPwkeruDuctusrushodacofusinAndron.sconsseTeston.sconsrMe hyl-inreston.sconsinTeston.sconsseundef n o eed17-Keton.scoidinLymph vy hls GnRHruHyponoalamus Hypornic sedLH Ro=in-pk p tga yin-hept n o einDu Im tg hf eosuche 2ownektruC – C – C – C – C – CruC – Ce 1 2suCsnjugmuexoinweletsulfa y, glucukino einTeston.sconsseInan tiw lie Ao-a.onCer Cypk neconsseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinFollatsiaa GrowlenditiOvulm exo, seEs rogeo ditiPe sesmin Pkiby h tginFollatsiaa witu ruexo yitiovulm exo, shinwbra acere-iassoc tra pkiby h tg rf frsinmfle .onadal h rmon s, ace cnn rollelecbxatrsihypornicsal gonadotropins FSHru(sollatle-ttimulm eng h rmi e) yitiLHru(luneintzoresh rmi e)toInasiesfirs aoalf rie re- menstryel cytle,eFSH promoses M.rowlegeostmitu ruexo rf ovariwn colla-sutlesathate ospotd weletaccel eeeores yn-sethes s hf es rod ol. Es rod ol ttimulm bse vndoms rill .rowlegeostintprodes8sie er ame eoltoxeliacUsaolallmucusgferintr am cells. Whenrtrsgeerrod ol bloeledlevssoa proschss s amfrel tet-e point, FSH eyfyase is isn of el dyem- sefeedbickee h tg n ttp-rantrriorihyporn-e ysi0 -Sihne sollatle .rowlegeostes rogeorupk dy thea ce cnrrslmurt,rhypornicicinaadrhyponoalamus canl“m rf a” tre collatsiaa phasedrirtrsiovariwn cytle tprcpeaasieir es rogeo ar,ep as -Wele-inir h ua0 af aoovulm exo, sie rer efry col-e litleadethsopsriNt nre- cnrpus luneum,e he mestosigale aeyfyase0 pd sesmeroneinie eyspotesms aLHt Ten fermsa cnctio bse re- secreu ayaphasedrirtrsivndoms rillsutytle aidilart cere-ir ame eoltoxeliin,eraolallmucus. Nonrup ured collatlesediti inus - arslyase eerrod ol under tre influehce rirFSH. hf ao2owk, pkiby h tginatipkisesmeronegeostes rod ol tubsddrs,rucausarestrsisecreu ayavndoms rill laysrins abe nhel (menstrye the).seTosanmuu al h rmon srare nsuiu-e aaug fer oallta pliy tixoebof its trsyruare to terms apkeayabso l hepa of elrm-inir tixo. Es rod ol is coivprtectviaoes- erconsrs tes riol; by cnsjugmuexo,eall tpd.erucanl bsieyndscsctwa aosolublr andinamenaaug toa onll excreu tg.rTosamajerinme abol te atipkisesmeronegis pcegnmt-eddiol,ahe mesis ale acnsjugmuethaad elrmf-tiha radeynllly.seEs rogeo pcepar-tixost Dtpot pcepar-tixos ferei.m. iNje exo are oiciinsoluPixos hf es ers hf es rod ol (3-ser 17-e OH gnoup). Ten old ophobocctytri tre dcylamoiets de amfresnre-teee nati sg etorpm tg, npocetre-idu ruexoionaeosuchru(p 252)ioRyfyased estea s old olizeegtoedyield fresres rod ol.e Otollx uasctpcepar-tixost E peuyl-ines rod ol (EE) isrmoarisuaaug me abol -d cally,mpassesnlirgslx unchftgestrercpeae re- liiba f aootolainPwkegeostmim cs es- ercod ol atees rogeo ar,ep as -Mes ronolruf self is isan lib; h its ac tleavjec rie re- C-3 ms hoxy gnoup a.ainayields EE. Iu rrel coi ascep ivrc,eenedrirtrsiswoulagenAs ferms trsgeerrogeo cnmponettse(p 256)io(Sulfa y-)cnsjugmuetheerrogeosedianln oextr-c egsrsyny Pinsiurbn nandinare sectfsurtrsepkyvsntetg hfepoatsinmehop ital on.sopnrosi0geostin tre tiec uy liaclrm-c ic oompraii st Bo-rucauss hf sieir mncepbnartoxa(sulfa y, glu-rucukinddr),otieyhwould ardly appearins iuaaug fer si s eiute lioadmiion. Im tgtinFsurtrrasde sfl ygliiery, anaadhes ibe patmesis availaaugathate ofyase0 es rod ol arrrascutaaeaemly iNt nre- b dy.sePe sesmio pcepar-tixost Dtpot fermulm exos ferei.m. iNje exo are 17-e α-old oxypkisesmeronegcaprost nandinmed oxypkisesmeronegsceto e -Pcepar--inPixos fer oalltuse ace deCOvipevssglio17α-ine peuylreston.scons = e pen.scons (h ameruno e pen.scons, dime pen.scons, lynes- ercsrol,tygsisesmrss, sesmodee),oer oie 17α-old oxypkisesmeronegsceto e (h ameruchas mod nonegsceto e a oypk neconsser etats). Tense agenAs rrefmlinlx uasc as trstprosesmio cnmponett in rrel coi- ercocep ivrc.seI bby tixos fer eerrogeosa idirro-insrsmiocointhe s:th rmonel coi ascep-in thes(p 256),rh rmi e rsplicrmett, shinio poatmonop ital homenoferepkiphy-inlaxfs rf on.sopnrosi0; bleedirenanoma-2 loes, menstryel compraii st Csniean diinadvpryr ve in s,rse- p 256.seEs rogeosah prpgrrallta.onCeria -e tsitox (roloxifens, tamoxifens) rrefbhsinpup isvrsmigomsctas agenAs sectroiey-e plicrgeerrogeo io poatmonop ital os- ersopnrosi0gra ofmett, t nhart nplicse2 lopids, aost sgeerrogeo anti.onCers ue re- pkyvsntetg hfeereas acsnc a -Roloxi-ti in—io cni assrms anamoxifen—is anaan-in a.onCeriat u ineees rogeo ar,ep as in254 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy255inA. Es rod ol,ipkisesmerone, ditideCOvipevss aCsnjugmuexoinweletsulfa y, glucukino einGnRHruHyponoalamus Hypornic sedFSH LHruCsnjugmuexoinPcegnmted ol aEs rod ol aE peuyles rod ol a(EE)sePe sesmeroneinE peuylreston.scons, a sr tagetsuMes ronolo=in3-Me hylothen nseEEruCsnjugmusc eerrogeosedEs riol Es rons Es rod ol aEs rod ol aInan tiw lie Ovary aInan tiw lie Pe sesmeroneinEs rod ol aDu Im tg hf eosuche 1owneksuMed oxypkisesmeroneser etats Hyd oxypkisesmeronesecaprost 8 - 12ownektruDu Im tg hf eosuche 1in2owneksu3ownektru-vaHe a y -benzost Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinOtolaCoi ascep ivrcinIun of a0 on ovulm exot Nega ve feed-e bickecoi aol hf sonadotropin ryfyasesecanln nilezedo- inn ofPrtrsiovariwn cy-sutleioAdmiion. Im tg hf exoionousoes- ercosrns (e peuyles rod ol ot wes ronol)eddu pup re-tfirs aoalf rinre- cytle pop irsedFSH pk dy theas abe nupp y h (as it is bxaadmiion. Im tg hf prosesmiossealo e)toDyem- atieseyby bd FSH ttimulm-in theson ter efry collatles,tmitu ruexo rf collatlesaene, npoce,eovulm exo are pkt-sevsruge sIu eosuch,rtieseygulmu ayabasd in,eMo asaace deceOvst,eas it rt e, bsftie elevmuetheerrogeoobloelslevss,ahe mein tgnmlsena sfl collatsiaa .rowlegeostae detproded ey PirbmettofereFSH ttimulm-in the.aCf eerrogeosa lonsrace giibn byalnginre-tfirs aoalf rinre- cytle,ivndoms rillsuditioeraolalleyspotess,eas wbra aceothen fal membel chftgec,hwould h a rein tre na sfl cashthe.aByaaddireta prosesmiose(p 254) du pup re-tseons aoalf rinre- cy-sutle,strsisecreu ayaphasedrirtrsivndoms- ercium aost ssoc tra ee in 0tianln oelat-e ctge sDisiti inuahce rirh rmi e ad-e miion. Im tg wnuld n fell wra bsinmehstrye the.seTosaphic oH a lll tims course hf es- ercosrn-pkisesmeronegeyfyase is simulm -suedeeuatiesso-callra biphasic (te Pga-in tal) pcepar-tixos (A)ioInam rophasic pcepar-tixos,geerrogeo and prosesmioserreftwken csniurrshtly. Emalx admiionsinrraPixocrirprosesmio reinfer bsnre-tiin -e bft lieliaCNSseygulmu ayaoe oft smserupkyvsntssbo prna sfl vndoms rillsu.rowlegeostons of licefer ovum rm-inplmnomuexo,eanaddetprodes pone robiltox liacUsaolallmucusgfer tr am cells. Tene sworlmt aoee in 0tale aaerms apkevettsecsniep the.aAcc adiren- trsin.agare hf pe sesmin admiion. Im tg,ron d smin-insucnhes (A):ron -, swo-,geostreree-ttjece pcepar-tixost Inaall canec,h“weledraw l-edbleedire”rh a r0 whei h rmi e inPwkeruis disiti inuel (ifonecelewry, byt tbsto-intueoresdummy raaugts).ecUnwantrthve in s: Aa utprodel in-intddrhce rirrercmbosi0geostembol sm icinat aibrssd t nre- uerrogeo cnmponett ue pgrratsiaa. Hypprten thee fluid eytpn-in the, choHeonasi0, n nign liiba tumorserunaussa, chest paio,getc. wiveh a r. Ap-e parshtly t dre isono utprodel orop llrupiskpatisfltgnmMt sumorh.suMiiopillt Csn inuousol w-dose ad-e miion. Im tg hf pe sesmin alonegcan pkt-sevsru csniep the.aOvulm exos rrefnote atpp y ed eygulmalx;atiesee in ais thei edyem- ape sesmin-inby bd alte Im tg0 inincUsaolall nl eMdoms rill cal membt Bo-rucauss hf sieineedgfer cnsstaruainPwkegete re- same tims rirday Aanhart nsucc ss a y, sosteyfa libly fre Pgat bleediresudiomalios,etrsse pcepar-tixos rrefnow arbly emproyrttin“Mornlng- f a”rpillt ceis eefersm- seadmiion. Im tg hf a mncsrote hf es ro-insrn and prosesmio,ipeeferaauyge peua12ins a24 h,obutonorlmter tran 72 h f aocoi-ti us -Menstryel bleedirenensuec,hwe meinpkyvsntssemmlmnomuexo hf sieifertiltzsl ovum (na sfllxtiuaties7 prday af aofer-sutilezw the,ap 74)ioSimilmalx,semmlmnomuexosecanln i n of el bxamifep is one, we meinis anaan a.onCeriat bo prpeisesmeronesernl glucocnrpoloid ey,ep a0 sos we meinale ahffersma norinva tvalmeaicensein-inby lng trsr use of abor the in emalxinpcegnmtcy.inStimulm exo ri ovulm exot Goaa-sedotropin secreu tgecanln i tprodel bsinpulem ele ygliiery ri GnRH (p 242) -Tene eerrogeo anti.onCers cloeiphenegeostcy-sutlof nil essck ey,ep a0 mel tirenfeed-e bickeiin oft lieliaieMotolineukieMdo-intpineecircuf sneostre- rbyndisiNn of e sonadotropin ryfyaset Goaadotropinssecanln giibn in thstfermoof HMG andinHCG (p 252)iin256 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy257inA. Orel coi ascep ivrc Hypornic sedFSH LHruOvary aHypornic sed7 14 21 28.1tinOvulm exoinOvulm exoinOvary aPone robiltox byt r am cellsinDiveliaiytle Reod n ss ferinnidom tg No ovulm exoinIun of exoe Estrod ol Pe sesmeroneinEs rod ol aPe sesmeronein7 14 21 28.1tinInPwkegriulvs rod ol adeCOvipevsinInPwkegriulprosesmioseMiiopillin7 14 21 28.Divseliaiytle Biphasic pcepar-tixoinOne-ttjec rygimeninM rophasic pcepar-tixosseTwo-ttjec rygimeninTeree-ttjec rygimeninLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIusulin Tosr uyinIusulin isisytthes zsth u trstB- (ereβ-)in,ell0 on trstpa tprot ldisugts on Laisrr-inranst It dh aapk nein (MW 5800)acnsststsinpup of sworpaptsdr ch its linkba bsftw tidisulfsdr bridges;atiesA chtin sh 21 andintrstB chtin 30 amino didst Insulin isitre “bloel-sugarnhart ire”rh rmi e supxoe insesmilieliadieuaryrcarboold atrs, f icineyfyaset0d t nre- bloels an an sms apke-sevsru aispgnifby noedide0d bloelsglucos incsnieMoto the bsfpromospup upPwkegriulglucose in sr cifbylorgftsetviz., sie ehegrr, sdipoae sossue, sosttk litrp mus-sutle,sereits coivprstheas aglycogeo io sie eliiert It ale aintprodes8lipoiones s andinpk nein sytthes s,8he ug iin oft reslipo-eclysi0 sosteyfyase of fresrfatoxaecies.inIusulin isi secteultieseyplicrmett tiec uy liadiabetos meraatusa- astppcrsinmeh aade ini ttnsecreu tgerf vndoio-tinous h rmi e inSource0 on trsr use of eusulin pcepar-tixos (A)ioInsulin canln ob-in aineegsrsynpa tprot ldtossuenliaslaugh- ersrethaaimalst Per bn ainsulin differs frsynhumanlinsulin merbly bsfon aBruchfin amino did,ibovbn ainsulin bsftw tiamino didsteultiesA chtin yitiong ue re- B chtin. Wele trsse sleser differshn-sues,haaimal aosthumanlh rmi e yisplivin tmilma b oH a lll r titox.rCsmpaeeeinwelethumanlh rmi e, por bn ainsulin icinbarbly ao- setofraostbovbn ainsulin shinaslittuga mncrrtao- setoftox.rHumanlinsu-2 longis pcoby bd bsftw ms hods: b o yn-sethe callx, byt tbstotueoresrereonins ferinre- C- amfrll rlmnbn ainttrstB chtin riulpor bn ainsulin;serebsfgoneerechn 2000e involvpup isseruexo hf sieia prop ist humanlDNA0d t nE.lclaiab-c ia.seTyppsnatipkepar-tixos (B) As a er ptsdr,ainsulin ico nsuiuaaug fer oalle admiion. Im tg (detory theabsfgas- ercointosmioalapk neodes) yititousnneedsins abe giibn parshterllly.subuallx, eusulin pcepar-tixos rrefiNje el tubcutaae-inoemly. Ten du ruexoionae h tg depends M re-teee nati ssorp the srsynposiiNje -e tslirai -. Shor -e h up issulin icoyispNicoc as a tleat eeuotolisoluPixocknown0as eeygulmaniNsulin sIu emergoncie0,os ncreainhyperglycemsc cnma,oit canln giibniniNtravonously (moshly bsfinfus tg bo-rucauss i.v. iNje exos haiberooibrieia a a -e tsli; plicsestd 1/2 a~ 9 mii). Wele trso su-e al tubcutaaeous a pliy tixoc sie ee in inis evidett e peua15a- a20 mii,areachss s er akraf aos prox. 3 h,oaidilasAs fer ap-e prox. 6 h. Lisproainsulin sh a faster on-inoeteradrsleserly shor ea dy ruexoionae -in the.inIusulin suspNicixost Whenrtrsruh rmon is isje el sh a suspNicixo riuleusulin-cti ainsretpartatles, f snyissolu-in thessosteyfyase in subcutaaeous tossueedace peuardbda(eopan, intopmel tr, andinsloweeusulins)ioSuiuaaug partatles canln in b aineegbsfpr cipiomuexo hf apbnarerupooalx wa a-solublr oomprexes coi- es sming ri anion l insulin ditiomuexoic partners, h ame trstpolycmuexoicapk neininpk namine a re- cnmpound aminoquf-tihurddr (Surf n)toInasiesp y rhce rirzintsernl sceto e ixos,ginsulin crystall zss;intpystal s zs de amfresnre-teee natiyisso-2 lu the.aCntopmel trginsulin pcepar--inPixos (NPH surisophans, lshte surzint in-inoulin)aaermfer 18a- a26 h,oslowepcepar--inPixos (pk namine zint inoulin, ulotolshte as oexteneeegzint inoulin)mfer upa- a36 h.suCsmbfrom tg pcepar-tixos coi- er iteeusulin mixtu rs in soluPixoceostininouspNicixo (h ametulotolshte);atiesplicse2 csnieMoto the-tims cusagseyp y rhtse re- sumdrirtrsiswo cnmponett0.ecUnwantrthve in s Hypoglycemsa pest Astsrsyn ssolute sureyfa lib orop-sedotjec (te- p 260).ahtlerg l reac lic ace arb—locs py: d.dn ssiat iNje exo ai -,se trophytri sdipoae sossue (lipodys ro-inphy);aayabso ls py: urpola ia,eakd rash,se naphylaxfsioInsulin pes staonrocsniey-e at A srsynbindire t ninan tiw renant -e bodi s -Arpoatielselocs slipohypertrophyrucanln svotdel bxaalte ga up isjRc ixoruai -s in258 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy259 BioInsulin: pcepar-tixos rostbloelslevss-tims cusagsinA. Insulin pciby h tginS - SinS - SinAla Ar30Per bn ainsulin HumanlinsulinIusulin B-chtininA-chtininPkiby h tg: lDNA E.lclaiinH ua0 af aoisjRc ixoru6121824inInPopmel trinSharinIusulin mixtu suesinIusulin suspNicixo = pcinotamine zint inoulininIusulin soluPixocccccccc= suegulmaniNsulininIusulin csnieMoto the d bloel RopaninLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTa ofmett rf Insulin-DepetheMt ruDiabetos Meraatusru“Juvsnllseotest” (type I)adiabetos meraat-e us is causea bsfre-idetory theaoflinsu-2 lon-pc by lng Blcells inttrstpa tproseruneceleiomuereteyphicrmsntrofniNsulinin(dailxtdose s prox. 40 U,ny Pivolshtms aina prox. 1.6 mg).seTosr use of oo terevssgarb: (1)inpkyvsnttheaofllife-tpd.atetpup hypergly-rucemsc (diabetic) cnma; (2)epkyvsntetg hfeddiabetic se Pglae (aosiopathy weleseblsrdn ss, myocsrdiolainfarc li,t onllrufailu r),ah prpr ciss “totto the”rhi tre pgaieruabewrety ettialos asvotd yvsne ahor -nd csspNll0 on pathoH a lll hyper-suglycemsa; (3)epkyvsntetg hfniNsulininoropdotjec leod ne t nhife-tpd.atetpuptihypoglycemsc ahock (CNSsd smurbaonr edyem- a.ack hf slucose).seTosr use of peintipl-stoInahetlthyru to ters,nre- amouNt rf issulin ico“autosinmf callx”rmatmesd t ncarboold atr in-in ake, npocetro bloelsglucos csnieMoto-in the.aTen c iu lallaecreu ayastimulus ise re- dide0d plicsesglucos levsst Fsod in-in ake and pnic lll r titox (i tprodelinglucos upPwkegd t nmustulmuu r,ayt-setprodel insulin deolod) rrefacc mpo-inniea bsfcnrrsspotdpup chftgeceinlinsu-2 longsecreu tge(A, lsftrtrrck). Iu re-idiabetic,ginsulin cnuld n ad-e miion.srethas itaisona sfllxtsecreued;ecreatris,ginje exo ri shor -e h up issulinulbaf is eachfmlinlmealaplus bedtims ad-e miion. Im tg hf a Lshte pcepar-tixom- seavotd a no tu oalashor fall hf iNsulin Teis rygimen ey Pirbh a wbra-yby murt,2 csopereu ve,nditionmpeteruapgaieruioIninothen canec,ha fixed-dotjec smesdule Mwell beineedbd, h ame mornsretais yvs-inniup isjRc ixoonhf a csmbfrom tg issulinulin csnstaruarsspin libydotjec (A)ioT seavotd hypo- orihyperglycemsas weleseteis rygimen,adieuaryrcarboold atr (CH)iniNtwkegmust bsisynchkindzeege prpone sims course hf insulin dssorp the srsye re- s.c. depo . Caas l inPwkegds to bsidonsinrribrssd (50% CH, 30% fat,hie%apk nein)iniN ssflllmeals orop re-idai so acer seanhitvh a stsadx CHastppcy—snackh,rlmteinniser meal -Ropanly absorbaaug CHru(sweers,ncwkes)gmust bsisvotdel (hyper-suglycemsc—r aks) yitieyphicra weleseslowlxtdisesmiblseot-s inAcarbose (ao α-glucosidoss iin of-e t a)tyglaysriNtosmioalafermw the on glu-incossrsrsyayisacchfrddrs suAny chftge in emtsretais livpuptihaof sncanlupoetecoi aol hf bloelssugar: skdppireta mealaer un sual pnic lllinatrsssoleods to hypoglycemsa; i tprodelinCH inPwkegm oiokesa yperglycemsa. aHypoglycemsa s oerlldel bsinwarnsretspgnc: tanhycsrdioetunreer, ercsmor,irallor,irrofits awemtsre. Someseoiotrsse ace dyem- atieseyfyase of glu-incoss-mobiltzoresepirephrbn t CouNter-sumeasu rs:sglucos admiion. Im tg,rrap-e anly absorbba CH orlllyser 10–20 g glu-incossri.v. iN cane oi uncsnscioucn ss; ifrunecelewry, inje exo ri gluci.on, tre pg tprot ldhyperglycemsc h rmi e inEibn e proptimalecoi aol hf bloelru tgar, s.c. admiion. Im tg hf insulin can-innotsfullyseyphiy tetre-iphic oH a lll sat-e ua the.aCnahetlthy to ters,nabsorbbainglucos eostinsulin eyfyaseegsrsynpos pg tpros simultaaeaemly reachrre- liibainir hmncscsnieMoto the, heersby ve in-e tsvn pkeayabso l elrmfrom tg hf bolesestosm an syistschitvh toInasiesdiabetic,ses.c. isje el insulin ico nifermlxtdis rib-inutecteultiesb dy.-Sihne iusulin csnieMsinrraPixocd bloelsstppcypup re-tliiba can-innotsdide,rl sssglucos is extr-c egsrsyulportalobloel -Arspgnifby noeamouNt rfinglucos eMo asaextr-hepa of sossue0,e hes roit sh to bsi nilezed in260 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy261inAioCsi aol hf bloelssugaryin hetlthy anaddiabetic sto ters 10 12 14in16in18in20 22se24 2su4 6in8 10 12 16in18in22se24 2su4 6in8 10 12 14in16in20 22se24 TimsinBinSe L NruDinSe Be L S S S Le Be Be L De Be Be L De no2 lunmeinFeas inFeas inCarboold atrinabsorp thed BloelssugarinIusulin r eleasesefcinoynpa tp eeainCarboold atr absorp thed BloelssugarinIusulin r eleasesefcinoyndtpot Glucos inDiabeticruHetlthyru to terd B = Breakfas inS = SnicktiL = LunmeinD = Dinn a N = Stpp a Le Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTa ofmett rf Matu iuy-Otest (Type II)ruDiabetos MeraatusruIu ribaweiser adt As,ta diabetic me a-e bolofrcoidfPixocmivedethsop (type II erinnon-insulin-ytpetheMt diabetos) whei tiece s e rofa lib insulin de ini tcx—e vnh an d deolod ianestebe me bxaaeddimiionh up issulin secreu tg.-Tene causs hf utprodel insulin ey Pirbsinmeh s e lods ofoeusulin ey,ep a0 er ansecmmdirmett rf re- stgnml cancad-ian l-sevmtba bsftieseusulin ey,ep a.aAcc adsinpuplx, eusulin oensitlitox liaiell0 yt-setlfrest ceis canln illustrmtba bsfcsm-e parpup cnnieMoto the-bindire cusags inincUll0 srsynna sfl yitiobess iidlitduals (A)toInasiesobess,nre- maximuynbindiree poatielse(plitsau liaiusag) icoyisphicrasedownwarn, inbby tivs hf sieieyby h tginie ey,ep a numbersioAlso,iat loweeusulin2 csnieMoto thes,nre-ce s l sssbindire riuleusulin,ionmpareege prponecoi aol coi- edfPixoioFsura giibn me abol c ee in aaincUsr itenumber hf ey,ep a0 must bsioc-rucupige sAsgshown bsftiesbindire cusagsin(danhel lfres),npoi0 canlsmill beischitvh inweletaseyby bd ey,ep a number,eal-sethcpeaaonlx atraa mncrrtisnieMoto the riuleusulin.ruDethsopmett rf adt A diabetosin(B) Cnmpareege pranna sfl to ter,e re- obess to termey Pirbh a iti inuallyinelevmuethiutput ofoeusulin (otonecrucukvos) s asvotd a vxceleiv- dide0rfseeloelsglucos levsssn(greeo cukvos) dursinpup esglucos load. Whenrtrsgaecreu aysecapacctytri tretpa tprosddetprodes,npoi0seis firs aestel sh a dide0d bloelsglucos indu pup glucos loadlng (litsMt diabetos). Stose Pgatlyc eos eveu trstfastsreedbloelslevss canln maii aineeg(mloi-ti ier, ribat diabetos).-Ardiabetic coidf-in theshosddethsopst,eallecpea iusulin ey-e lyase isonotshart nresn teatrinraa etlthyruperstge(rofa lib insulin de ini tcx)tinTa ofmett. Caas l res rictixom- seres oresb dy weiser s ana sfl s esso-2 c tra e praa utprodeeinlinsulin ey,ep-e t aenumber hraiellulmaneyspoteiibnele.seTosaeyfyasaaug amouNt rf issulin iculagtin yde P tetr amaii ainranna sflinme abol c rmtb.seTosr uytri firs achoice isowbiserind.duc li,tnotsadmiion. Im tg hfeddrugs! Should siesdiabeticrcoidfPixocfailins aeysolve,ncnsstde Im tg ahould firs an ingiibn tolinsulin eyphicrmsntr(p 260).inOtolaant diabetic0 on trstsulfonylu rasetype utprodeetrsgaensitlitox liaB-cellsintowarnssglucos , eaablsrettrsm tolin-setprodeseyfyase of iNsulin sTense drugsinpk baauygpromosendtponartzmuexo hf sie β-cell membtone bsfclodire rif ATP-gm -suedeKsu+tichftnels. No sfllx,etrsse chft-innsssn ce clodra eheo io ascellulmanlevsssseoioglucos , hrhce rirATP, utprodet ceiseddrug classrinthe sh tolbutamddr (500–in200m mg/d)nditiolyburddr (glibrhclm-inmddr) (1.75–10.5 mg/d)toInasometpa-in terus,gitaisonatrpoatielse- astimulm b in-inoulingsecreu tgesrsynposiiutest; i eoth-suers,nre-c uytfailsrlmter xoioMatmelng dos-ulage on trstotolaant diabetic ditiomas liniNtwkegfell ws trsiname peintipl-sreaina ply tolinsulin Hypoglycemsa isitre mosh cmmortanteunwantrthve in . Et-inrancrmsntrofntrsihypoglycemsc ee in incsnieyat A srsyndrug intopac lic:idonsinphicrmsntrofnant diabetic drug srsyulplicsespk nein-bindire ai -s byt tlfon-tiamide0 nr scetylsal cyl l did.suMetfermio,taibiguanddrrdeCOvi-e tsvn, canlhart nvxceleiv- bloelsglucos inlevsss,irrovtdel teatrinsulin icop y rht.suMetfermio does eos stimulm b insulin ey-e lyase. Glucodeseyfyase srsynposiliiba iseddetproded,8he ug periphealltupPwkegdse vnh an d. Ten daisrr rirhypoglycemsa a parshtly isonatr utprodelioFre Pgatinadvpryr ve in s inthe s:tano exioetnau-inoea, anaddiarr et.aOverpkiby h tg rf le -in tl did (licto e didos s,8lothlltox 50%) icula arb, ponuttiallxtfatalleya membt Metfer-e mii isi secteulcsmbfrom tg weletsulfony-2 luprosderebsff selft It dh coi asinbby testinin onll insuf ini tcx radrshould sie rf isulbabavotdel in eldeCuygpgaierus Teiazolbdited ores (Gltomzores: ro-instgltomzore, piogltomzore) rrefiNsulin-inoensitlzoresagenAs reatraugmeMt sossueserespoteiibnele bsfpromospup trsinyn-sethes s hp re-iavailaaoltoxeliaplicselem- esfl glucos rrraspor eastviaoan tiw lie hf a rrrascripPixocfact ae(peroxisomeseprohifermu a-an tiw bd ey,ep a-γ)iin262 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy263ruDiagnos s:e la eMt ribatruDiabetos meraatusruC.aAc exo ri otolaant diabetic drugsinA. Insulin isnieMoto the ditisbindire itena sfl yitioibaweiser sto ters Bt Dtthsopmett rf matu iuy-otest diabetosinIusulin ey,ep ae bfndiree needbd fer euglycemsa Iusulin bfndiree No sfl ey,ep a numberruDetprodedinty,ep a numberruNa sflindieuinObestox Insulin isnieMoto the Glucos d bloel Iusulin r eleaseseTimsinOalle ant -e diabeticruTosr uytri 1sh achoiceruTosr uytri 2itiohoiceruMembtoneeddeponartzmuexoinATP Iusulind B cellruGlucos inBssckyde Stlfonylu raideCOvipevss aTolbutamddr Ksu+tiLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrugsmfer Maii ainire Caacium inH meoonasi0ighuarssh,rtiesio ascellulmanisnieMoto the of fresrcaacium ixos (Ca 2+ti) icokep gete 0.1 μM (te- p 128mfer oe oft sms in-involved)toDy pup vxciomuexo,ea rrrasigatindide0rf upa- a10 μM elicf h coi as theaie mustleaiell0 (electrome oft lallclup-2 long)nditisecreu tg intglaosulmaniellsin(electroaecreu ayacluplong).aTen cellulmaediti ett rf Ca 2+tiis isny Pilibcium welesete oextr-cellulmanCa 2+tiisnieMoto the (a prox. 1eme μM),eas isatiesplicseirro-innein-bound fas thealiaiaacium i bloel.suCa 2+timivecrystall zsah prphosph tetr ferm old oxyapgaits,nre- minerel rfseei e sOn.soclasAs are phagocytesathat mobiltzenCa 2+tibyaeysorp the hf bo e inSleser chftgeceinlextr-cellulmanCa 2+tiisn-in,eMoto the canlalte lorgft cal memb:seteus,nvxciomaoltoxeliatk litrp mustlelin-setprodes sfrkenly as Ca 2+tiis hart edin(h ametin hypervsntelm exo titrny).aTed.eruh rmon srare availaaugat nre- b dy ferinmaii ainire a csnstaruaextr-cellulmasuCa 2+tiisnieMoto the inVitamin D h rmon is deCOvbd frsynvitamin D (choHeiaacifscol).aVitamininD canlalso bsipcoby bd eultiesb dy; f icinfermsdeeuatiesskd srsyndeold ochoHeo- ersrol dy pup irrod om tg weletUV leser.inWhenrre-ce s lack hf solmaneod om tg,indieuaryriNtwkegbecsme0 es ettial,ncnd eliier oicabewreta einc sourcet Metabol -d callyian lib vitamin D h rmon pest As frsynswo succ sslib old oxylm exos: ue re- liiba trpoafPixoc25 (L50478 iaacifsd ol)sernl euatieskidney trpoafPixoc1 (L50478 iaacisinrriolo= vit. D h rmon ).a1-Hld oxylm exoeddependstiuatieslevss liaiaacium h meo-inonasi0oaostf0 s imulmtba bs par-th rsinmi eirnl s fall d plicseslevsssnof Ca 2+tierephosph te.aVit. D h rmon promoses Mshterll dssorp the yitieynalleyassorp-in thesof Ca 2+tiand pnosph te.aAs e roat A rie re- utprodel Ca 2+tiand pnosph te isn-in,eMoto the i bloel,nre-ce s aa u-setprodel teneetcx fsurtrsse ixos to bseddepositecteulbon ainttrstfermoof hy-ind oxyapgaitsecrystalstoInavit. D de ini t-setx, bon aminerelezw the is isade P tein(einkers,non.sosfl dia).aTenr use ofe use aimsiat eyphicrmsntt Moshly,avit. D icingiibn; i eliiba d srode iaacifsd ol may beiniNbby tesetin eynalld srode iaacirriol. Ef-ti in libn ss, as wbra aceeee natiotest andin,elew the onae h tg, utprodeainttrstordertivit. D. < 25-OH-vit. D < 1,25-di-OH-vit.inD.aOverdotjec may inby b hypercal-secemsa weletdeposits liaiaacium salrs ue rossue0 (pgrratsiaaly iNskidney ostbloelsevs hls):aiaacinos s.seTosapolypaptsdr par-th rmonsrisedeyfyaseegsrsynpos par-thycoid glaosse hes plicsesCa 2+tilevss fallst It atimu-e la e0 nn.soclasAs t aintprode bon aeysorp-e tsli; euatieskidneys,gitapromosesaiaaciumedeydssorp the,8he ug pnosph te excre-in thesis enh an d. As bloelspnosph teincsnieMoto the dimiionhos,etrs teneetcx liacaacium s apkecipiomu-ias bon aminer-e al detprodes.aByattimulm eng trstfermm-in theson vit. D h rmon , par-th rmonsinras aa udirtermee in aiuatiesshterll up-2 Pwkegri Ca 2+tiand pnosph te.aIn par-th rsinmi eide ini tcx, vitamin D canln sec as a tbstotuegathatetunhik spar-th rsinmi e,risone in lib orllly.seTosapolypaptsdr iaacironintf0 st-setprtba bsftiycoid C-iell0 yy pup immf-tihett hypercalcemsa. It lart ceplicse2 Ca 2+tilevsss bsfinn oft resnn.soclasAian lisinpox.rIAs ses inthe s hypercalcemsa andinon.sopnrosi0ioRysfrkaely,miaacironintft-seje exo may pcoby b a sus aineeganalge-in tc ee in areatrisonatrres rictsd t nbonsinpaio. aHypercalcemsa canln ra ofel bsin(1)sadmiion.t ire 0.9% NaCl soluPixo plus furoaemddr (ifonecelewry) L50478 onllruexcreu tg L50518; (2)etrston.soclasAiiin of-e t asmiaacironin, phiy mycin, hrailod o-suga y (aibispnosphino e) L50478 bonegcal-secium mobiltzau tg L50519; (3)ere- Ca 2+tiihelm-in asmEDTA sodium er todium cotto e; shinwbra ace(4)fglucocnrpoloidsiin264 H rmon se Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinH rmon sy265inA. Caacium h meoonasi0oofntrsib dy Efti in aiuacell cal memb Sk ue 7-Deold ochoHeorsrolsuCsd liier oicsuChoHeiaacifscolin(vitamin D 3ti) 50-5emeμg/divin1,25-Diold oxychoHe-d calcifscol (caacirriol) 0,5-2μg/divin25-Hld oxychoHe-d calcifscolin(iaacifsd ol)sePar-collatsiaain,ell0 one reycoidinCa 2+ + POsu4 3-sePar-tiycoid h rmon , Ca 2+ ,in POsu4 3-sePar-tiycoidinglaosse Electr lllinvxciomaoltox Mustleaiell GlditioellruCa 2+ti~1 x 10 -7 MruCsn as theaSecreu tgti~10 -5 MruCa 2+tiAlbumin Globulind ~1 x 10 -3 MruCa Ca 1 x 10 -3 M Ca 2+ + POsu4 3-sePar-tiycoidruh rmon ruCaacironininVit. D-H rmon ruCa 2+tiCa 10 (POsu4 ) 6in(OH)in2 Bonsrsrabecsias Hyd oxyapgaitsecrystals On.soclasAe 1in1in25in25in7e Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttib-c ial DrugsinDrugsmfer Ta oflng B-c ial InfRc ixooinWhenrb-c iaioibacsmerponecutaaeoustieremucosalobarriea0 sos pone rotsib dy sossue0,taib-c ial infRc ixo icop y rht.suFre Pgatlynre- b dy succ edsteulcsmovsinpup re- uvaders,nweleout outwarntspgnc liad srode, bytmouNtsretai immun aey-in potes.aCf b-c iaimultiplxtfaster trane re- b dy’s defNico0 canldetoroynre-m,e infRc ixusld srode dethsopsrwele inflam- esfu ayaspgnc, h ame purulshtmwound ft-sefRc ixo er u iraryr as infRc ixo. Aprro-inp ist sra ofmett emproys stosm an secreatrinju ryb-c iaieostre- rbynpkevettsetieir furthen multipliy tixoc weleoutinrarmiog ,ell0 on trsthosh orgft sm (1)tinAproposonamrhclmuu r:aant biotic0edace pcoby bd bsfmicroorgft smce(calgi,e bic ia)nditiace dirterbd “agtinsh hife”se tndiyaphyloionetic levss (pk karyoses,e eukaryoses) Ce-motrsr use of agenAstierigiga y srsynchem lll sytthes st ceisedd sminc theshosdbeeo losh co cukrshtous-ulage inSr cifbyldamjectt nb-c iaiicopgrrat-inuiaaly pas tcaaugahes a stosm an iniNterferssge pranme abol c pk celeathat h a r0 inib-c ial butonoh co hosh cells.tiClemalxnpoi0 a plieso- inn ofP a0 on oellruwall sytthes s,8bof its humanlditiaoi-timalecell0 lack aaiell wall.aTen point0 one attack hf attib-c ial agenAs rrefsmessinmf callx illustrmtba inrangroamly semmli-ti iea b-c ial iell, as depi el in (2). Iu re-ifell wire aRc ixoo,apolymyxsinpusneostrycothr lin rrefnotscnsstde bd furthen sTense polypaptsdr ant biotic0edenh an cell membtone r ame eoltox.inDyem- atieir poor toler eoltox,otrsyfarce pcescribel in humansaonlx fsurtop lllinusb.seTosmee in aif attib-c ial drugs canulbabob Usage in vitro (3). B-c ia multisinphy inrangrowlegmel um under coi aolincsn of lic.aCf re- mel um cti ains anseattib-c ial drug, swo pest As canln indisiernee: 1.yb-c iaiereskillra—b-c -indicidal ee in ; 2.yb-c iaisurvsvn, butodoinnotsmultiplx—b-c rio ta ofave in . Al-sethcpeaavariwf licewiveh a r under tiec use of csn of lic, differshtodrugsincanln classi iea acc adiren- trsiraey-in pin lib p imaryrmodeionae h tg (? 20rins n aint2neost3).inWhenrb-c ial .rowlegcsmains un-tiaf in rt bxaan attib-c ial drug, b-c -indialleys staonroicop y rht. ceis wiveh -rucurebof its hf cUsr iteme abol c chfre -in e is ic0 reatrcsnfba anmuu al issensitlisinpoxat nre- drug he y pgrratsiaalatrtin riulb-c iai(nmuu al eys staonr)t Dtpendiree tg whothen a drug ae in s onlx a few erinnumscous typpsnatib-c ia, sie rermssugarrow- pin rum (h ame petoftllin G) erinbroad- pin rum (h ame te roiytlfres)seattibioticrare a pliee sNmuu ally sus-sutaptsaugab-c ial atrtins canln raans-infermsdeunder tre influehce rirattib-c-in e ial drugs d t neys staot ores (ac Pirbdintys staonr),ahes a aandsynionetic al-sete Im tg (muomuexo) giibs dide0s asneys st-seattab-c ium sunder tre influehce rie re- drug, srstsustaptsaugab-c iaadie lif, heersas trstmuomntsmultipliesoun-tiemmedbd.rTosamoresfre Pgatlyna giibnindrug i0 a plied,nre- moce pcobaaugathne emergonce hf eys staot atrtins (h ame hos-ulpioml atrtins e prmultiple eys staonr)! Res staonrocsnialso bsiac Pirbdinhes DNA0respoteiaug fer noteustapts-e boltoxe(so-callra eys staonroplicsid) iculpassetion srsynothen eys staot b-c iatibyacnsjugmuexo surtrrasdy h tgiin266 Attib-c ial DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttib-c ial Drugs 267inA. Peintipl-srif attib-c ial tosr uyinSelectevsinattib-c ialins xoftox B-c iaB dy iellsinCellrumembtoneedCell wall B-c iumedDNA0RNA Pk neinin1 divinAttibiotic Iusensitlie atrtininSensitlie atrtin weleseeys staot muomntinSelectetgti3iin2iin1tinImmun eddefNico0inAtti-ulb-c ialeddrugs B-c iale invasemb:seinfRc ixo aPonoftllinsinCephalosperinsin"Gyrode-inn ofP a0" Nitroisidazoles B-cottocininVaonomycin aPolymyxinsinTycothr lin Rifampin Te roiytlfressuChas amphonofol aEryrercmycin aClsrdamycin aAminoglycosddrs Stlfonamide0inTaime pop im Te roold o-sufel teinsytthes s Res staonr B-c io ta of B-c icidalinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIun of a0 on Cell Wall Sytthes s Inam stib-c ia, aaiell wallisurroundse re- iell hik sa eigidrshell tpatspk neers agtinsh n xoous iutesdr influehces andinpkyvsntssrup uretri tretplicsesmem- ebtone srsyn hmncsiNternal osmotic p y ure.rTosatory u al somaoltoxeliathne iell walliis duefmlinlx t nre- mureiose(paptsdoglycao) lmt icet ceis cnsststs riulb- tc buildirenesscks linkba toiothen r ferm anlirgsfmlcromolecsie. Emch basic unit cti ains trsiswo linkba aminosug-seaa0 N-scetylglucosamine ditiN-scetylsinmu amyl did;atieslmt aobearsma paptsdrruchfin.rTosabuildirenesscks rrefsytthe-in tzsth u trstb-c ium, rrraspor ethiut-inwarstrercpea re- iell membtone, andinassemblethas illustrmtba smesmf callx.seTosmenzym rrraspaptsdode iroam-linkse re- paptsdr ch its rf adjaceh amino-ru tgar ch itstinIun of a0 on iell wallisytthes s are tiuaaug attib-c ial agenAs, bo-rucauss aaimal aosthumanlcell0 lack aaiellruwall.rTosy exbat aib-c icidal e h tg n su.row resnn multiplypup gd cot Mem- ebers hf poi0 classrinthe seβ-lictomnant -e biotic0os ncrea tretponoftllinsnditioepha-e losperinsetin additixom- ib-cottocin andinvaonomycin. aPonoftllins (A)ioTos par ttnsub-inonahce rirrei0 gnoup is petoftllin G (b t-sezylpetoftllin)t It dh b aineegsrsyncul-setu rs rf mold falgi, erigigallxtfrsynP t-seoftlliuynnata um sPetoftllin G cti ainse re- b- tc tory u - cnmmxom- iallipeto-secillins, 6-amino-petoftllantl did (piin271, 6-APA),ionmpdidednhf a teiazolbditesernl s 4-membsrethβ-lictomnrsre. 6-seAPAff self lacks attib-c ial a titox. aPonoftllins disrup iell wallisytthes s bsininn oft resrrraspaptsdode. Whenrb-c -india rrefiN trsira.rowlegeosteyphiy tixo phode, ponoftllinsnd ryb-c icidal; dueins aiell wallidefNers,nre- b-c iaiswellru ostburst. aPonoftllins ace generllly wbra toler-seaued;ah prpetoftllin G, re-idailxtdoseincsnieftge srsyn prox. 0.6 gei.m. (= 10 6iniNterrom tgll units,n1 Mega I.U.) s a60 gtibyainfus tg.rTosamosh cmmortantead-e vpryr ve in s ace dyem- ahyperaensitlitoxse(intidrhce upa- a5%),ah prmloi ier--inPixos eftgirenfrsynskd erup ixos tose naphylactsc ahock (i eleleathan 0.05% riulpgaierus)t Known0petoftllin atlergy isoe2 csn asinbby tixocfsurtrsse drugst Bo-rucauss hf aa utproded piskpatioensitlz--inPixo, ponoftllinsnmust estebe sectlocs -e lyt Neuk n xof ve in s,rmoshly coivul-secixos dyem- aGABA anti.onCem, wiveh -rucureifntrsibrtin is exposectroiextrl rlyinhmncscsnieMoto thec, h ame af aoeopanri.v.iniNje exo ri anlirgsfrote hrsio astrscale inje exo. aPonoftllin G undergoes eopanr onllruelrmfrom tg mlinlx in unchftgestfermse(plicsestd 1/2 a~ 0.5 h). Ten du ruexoionsete oee in acanln prohotgestby:in1tsube rirhmncrrtrotes, eaablsretplicsinmfslevsssnt neymlinlabovenre- minimal-e lyone in lib attib-c ial csnieMoto the;in2i Csmbfrom tg weletpcobenedid. Rs-innal elrmfrom tg hf petoftllin h a r0ruchieflyoviaore-ian tg ( did)-aecreu ayseayabsotri tretproximal tubulse(-COOH lia6-APA). Ten did pcobenedidr(p 316)in,nmpetes fer si s eiute yititousnpeuardculpetoftllin elrmfrom tg;ti3iaCntramustulmrsadmiion. Im tg ioeddepormferm.aIn f sneoixoicaferm (-COO - ) petoftllin G ferms pooalx wa a-solublrseaalrs weletsuosm an sycti ainsretarpoaf-e tsvnly chfrgba amino gnoup (pk caineerup.hie8; tlemizole,aan attipen.amine; ebenza peus, dicmuexoic)t Dtpendire n susrstsuosm an ,seyfyase of petoftllin srsye re- depormh a r0 orop aavariwblelinter-suvaliin268 Attib-c ial DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttib-c ial Drugs 269inA. Petoftllin G: tory u - yitiorigig;rmodeionae h tg of petoftllins; ms hods fer prohotgoresdu ruexoionae h tg B-c iumedCell wall Cell membtoneedCell wall buildirenessck aAmino didruchfinedCroam-linkbdinbsinrrraspaptsdode StgarinPetoftllin G FalgustiPetoftlliuynnata um HumaninPetoftlline allergy Neuk n xoftoxseatsieryinhmncsdotjecinPlicsesisnieMoto the 3 x DoseinMinimalulb-c icidalinisnieMoto the TimsinIutprodpup re- doseinAnthe aecreu ayseayabsosuCsmbfrom tg weletpcobenedid Dtpatrpcepar-tixosse~1se~7-28se~2inIun of exoionseiell wallisytthes s PcobenedidinPetoftlline PcinocaineinPetoftlline + - ClemizoleinPetoftlline + - Benza peusin2oPonoftllinsin+ - +ruDu Im tg hf e h tg (d)inAttib dy Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAllecpea iery wbra toler tesetpeto-secillin G (A) tpatslrmf iniAs reec use of sefuln ss: (1) It dh inan-e tsvmtba bs gas ric did,iwe me tleavese re- β-lictomnrsre, neceleiomueretpar t-sete Ilsadmiion. Im tg. (2)eTe- β-lictomindiog ,snialso bsioponea bs b-c ial t-sezyme0 (β-lictomodes); euapgrratsiaa, petoftllinode, we me tanln proby bd bsinonaphyloch aml atrtins,t ondersm-rsm ey-in staot s apetoftllin G. (3)eTen ttib-c -indiall pin rum isonarrow;eallecpea it t-seonmpasdes sfns gram-poafPiverb-c -india, gram-nega ve ch ai, sosttpi o-suchetes,tmins gram-nega ve pathogeos are unaf in rt.ruDeCOvipevssge prandiffershtosub-inonitPgat tg 6-APArpoat ssiadvanti.esin(B): (1) Acia eys staonropop irs otolaad-e miion. Im tg,irrovtdel teatrshterll ds-inoorp the is poatiels.ahtlideCOvipevss ashown in (B) canln giibn orllly.oPonoftl-2 lon V (phenoxyms hylpetoftllin)iexhib-inf sneotib-c ial properuees similma tosethose of petoftllin G. (2)eDyem- atieir petoftllinode eys staonr,risoxazolylpet-seoftllins (oxaftllin dicloxaftlline flucloxaftl-2 lon) rrefsuiuaaug fer re- (otol)sra ofmett liainfRc ixos causea bsfpetoftllinode-inp by lng onaphyloch ai. (3)eExteneeeseantlitox pin rum:eTen minopetoftlline am xoftllin icoan lib agtinsh mins gram-tihega ve orgft smc, h ame claiab-c ia erinSalmon lla typhit It tanln protin rt frsyndetory theabsfpetoftllinode bsincsmbfrom tg weletinn ofP a0 on petoftlli-innase (clavulmnic did,isulbictom, omzo-ulb-c am).seTosatory u allsfclode isngener am-tipoftllin (no 4-old oxy gnoup) sh a simi-e lar antlitox pin rum. Howevsr,8bof itsinf is pooalx absorbba (<50%) eostre- r-infere causes moce extenslib damjectt e re- gutfmicrobill cas a (esdr ne in :ddiar-indhea),gitashould n giibn only bsfinje -e tslitinAlsmill broaderl pin rum (inthe iree Pseudomonosdbic ia)nisgshown bsfcar-inboxyponoftllinsn(carbonoftllin, oola ftllin)sernl scyl minopetoftllinsn(mezcloftllin,serzloftllin, pipereftllin)t Tense suosm an-sues rrefneithen acia suaaug ner petoftlli-innase eys staot.inCephalosperins (C)t Tense β-lic-2 Pwm ant biotic0rare also falgal prody hssernl haibeb-c icidal e h itox dyem- aft-sen oft lieliarrraspaptsdode. Tieir shareegb- tc tory u - isg7-aminooepha-e lospermnic did,ias exempri iea bsincephalexin (grayaeyc anglr)t Cephalo-in porins ace acia suaaug, butomins arce pooalx absorbbat Bocauss trsyfmust bsingiibn parshterllly,rmosh—inthe iree those welethmncse h itox—are usetionlyulin clin lallaetueres -Arfew, h ame cepha-e lexin, rrefsuiuaaug fer otolausb. Cephalo-in porins ace petoftllinode-eys staot, butincephalosperinode-fermiog orgft smcsedo ex st. SomeideCOvipevss arb, howevsr,inale aeys staot - atiisgβ-lictomode.inCephalosperins d rybroad- pin ruminattib-c ials. Nert ndeCOvipevss (h ameincefataximse cefmenoxin,ioefaperezore,incef rilxon , cef azidimse m xalictom) are ale ane in lib agtinsh pathogeos ey-in staot s avarious itcrrtao- b-c ials.inCephalosperins d rymoshly wbra toler t-sued.ahtlitanlcauss atlerg l reac lic, someseale aeynll injury, alcohol d t ler onr,ru ostbleediren(vitamin K anti.onCem).inOtcrrtinn ofP a0 on oell wallisyt-sethes s. B-cottocin and vaonomycin aiNterfersge prponerrraspor on pepts-e doglycaostrercpea re- iytoplicsicrumembtonenditiace an lib onlx agtinshsu.ram-poafPiverb-c ia. B-cottocin isoe2 polypaptsdr mixtu r, sfrkenly rephro-inn xof ditiusetionlyrtop lllly.oVaonomy-secin isoeaglycopaptsdr andnre- drug hnseihoice fer re- (otol)sra ofmett hf bowbrseinfl mmwf liceh a rdiog as a tompr ll-in theson attibioticrtosr uy (pseudomem- ebtonous shteroclaitis causea bsfClonsinrril um diffoftle)t It dh notsabsorbbatin270 Attib-c ial DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttib-c ial Drugs 271ruC.aCephalosperininA. of petoftllin G Bt DtCOvipevss of petoftllin G 6-Aminopetoftllmnic didinPetoftllin G PetoftllinodeinStaphyloch ai E.lclaiinSalmon lla typhi Gonoch ai Pneumoch ai Sra ptoch ai Narr lw-e h tg pin ruminActevsinNoAian lis H +ruCl - Res s-2 Pwtt Rys staot, butgaensitlieins incephalosperinode BroadinCefalexininPetoftllin VinOxaftllin aAm xoftllin Res s-2 Pwtt Rys s-2 Pwtt Rys s-2 Pwtt SensitlieinRys staotinRys staotinNarrowinNarrowinBroadinPetoftllinodeAcia Spin ruminCsnieMoto the needbd - inn ofP petoftllin G-inoensitlverb-c ia Gram-poafPiverrrrrrrrrrrrrrrrrrrrrrrrrrrrrGram-nega veinAcia sensitlitox PetoftllinodeinaensitlitoxseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIun of a0 on Te roold ofel te Sytthes s Te roold ofeltl did (THF) isoeaco- t-sezymeeeuatiessytthes s of pu ir- b- essernl hymbditet Tense ce csnstitPgatc liaDNA0rnl RNA0rnl ey Pirbstferaiellru.rowlegeosteyphiy tixo. Lack hf THFe lyadso- inn ofPthealiaiell prohifermuslitinFermw the on THFrsrsyayiold ofel te (DHF) isocatalyzba bsftiesenzym yiol-ind ofel te d.duc ode. DHF is wide srsye feltl did, aavitamin reatrcanestebe syt-sethes zsth u trstbody, butomust bsiPwken uprsrsyaexogeoous sourcest Moshrb-c -india do notshaibea ey Pirbmett ferafel te, bocauss trsyf ce capaaug atioytthes z-inpup fel te, moce pc cisslyrDHF, srsyulpc cursorst Selectevs iNterfersonroweleseb-c ial b o ynthes s of THFrcanln inschitvh weletsulfonamide0 rnl ri-time pop im. Stlfonamide0atory u allsfd. Um- ebug p-aminobenzotl did (PABA),iaapke-secursor inib-c ial DHF sytthes st As falee suosmr te0,os lfonamide0a,nmpetf-e tsvnly inn ofP nilezw the on PABA, hrhce DHF sytthes st Bocauss m stib-c iaincsnnotsPwkeguprexogeoous fel te, trsy are dyphrtba liaDHFioSulfonamide0atouse poatele b-c rio ta ofae h itox agtinsh ainbroadl pin rum of pathogeosioSulfon-tiamide0 ace pcoby bd bsfchem lll syt-sethes s. Te- b- tc tory u - isgshown iose(A). Rys dyemR de amfresnre-tplogy -seonkinetic properuees ri angiibn tlfon-tiamidet Moshrsulfonamide0 rrsgebra as-inoorbba viaore-ishterll eiute.rTosy arce me abol zectroivarypup degrees andinelrmfromestrercpea re- kidney -Ro e0 nfruelrmfrom tg, hrhce du ruexoionane in ,timivevary wedely.oSomeimembsrs arce pooalx absorbbagsrsynpos gutfditiaceseteusfsuiuaaug fer re- ra ofmett hf b-c -indiallbowbrainfRc ixost Advpryr ve in stimiveinthe s, amoog otosr0,tatlerg l re-seantllic, somesimss weletsevsresskd indamjec,oyisphicrmett hf itcrrtplicse2 pk nein-bound drugs erebilerubintft neo-suga ys (daisrr rirkerni erus,nhrhce coi- erasinbby tixocfsurtrsilasAgebeks ri gier--inPixo rnl euatiesneono e)t Bocauss liathne fre Pgat emergonce hf eys staot b-c -india, sulfonamide0 rrsgnow arblx useatinIutcoby bd eul1935,otrsyfrt e re-ifirs inbroad- pin rum ce-motrsr use ofs.seTaime pop im inn ofPsdbic ial DHF d.duc ode, re-ihumanlenzym bo-rusretspgnifby nolx leleaoensitlverresn teeseb-c ial n a( arblx bon amarrow yt-sep y exo) -Ar2,4-di minopyrimbdite, ri-time pop im,shosdb-c rio ta ofae h itox agtinsh a broadl pin rum of pathogeosiinIt isi sectmoshly as a tomponettaliaiosinrrimoxazole.inCo-rrimoxazole isoeacombfrom tg onsetaime pop im andnre- sulfonamide sul-infame poxazole.-Sihne THF sytthes s iculinn ofPba atnswo succ sslib steps, tre eotib-c ial ee in aif co-rrimoxazole is bottt nresn teatrri tretiidlitdualfcsm-e ponett0. Rys staot pathogeos rrefiNfre-se Pgat; aib-c icidal ee in awiveh a rtinAdvpryr ve in s cnrrsspotd - atiose rie re- cnmponett0.ecAllecpea iuitiallxtdethsopst as anseattirheuma of agenAr(p 320), sulfasalm-inzir- (salmzosulfapyridite) isi sectmaft-selx in re- ra ofmett hf infl mmwf aysebowbrad srode (ulcereu ve claitis andin amfrll ileitis surCrohn’s d srode) -Gutinb-c iaisphit poi0 cnmpound d t ntre sulfonamide sulfapyridite andnmssalm-inmdr- (5-aminosal cyl l did). Ten lmt atiis pk baauygten tti-infl mmwf ay agenAse(inn ofPthealia ynthes s of ce-motactscinstgnals fsurgranulocytes, sostof Hin2 Oin2 fermw the itemucosa), butomust bssep y gat tg re- gutfmucosa in hmncscsn-in,eMoto thest Coupliren- trs tlfon-tiamide pkyvsntsspeyml u - ybsorp thed in upp a ssflllbowbrasegmeMts.-Tene cleaved-rif sulfonamide canln ss-inoorbba andnmay pcoby b typ lll rdvpryrruee in s (te- above).inDaps n a(p.hi80) sh sevsral tosr -e pse of ses: bestde0ata ofmett hf lerro-insy,gitaiso sectfer pryvsntetg/prophylaxfs liasfl ia, soxoplicsos s,8rnl sctino-rumycosdsiin272 Attib-c ial DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttib-c ial Drugs 273inA. Inn of a0 on te roold ofel te sytthes s (Vitamin) DHF-R.duc ode R de amfres phogy ? kineticsruDu Im tg hf ee in inDodire iNterval Sulfasalmzeusin(notsabsorbaaug)tiClemvjectbsinintosmioalab-c iainMssalmmdr- Sulfapyridite (absorbaaug)tiB-c iumedHumanlcell Synthes s of pu ir-s Thymbdite Stlfonamide0p-Aminobenzotl didsuCsmbfrom tg of Taime pop im andinSulfame poxazoleinCo-rrimoxazole =ruDiold o-sufeltl didsu(DHF) Te roold o- feltl didsuFeltl didsuTaime pop im Sulfisoxazolein6 ho r0ruSulfame poxazolein12 ho r0ruSulfalete 7 divsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIun of a0 on DNA0Fal memb Deoxyribonucletl did (DNA) Usags as ain mplitscfsurtrsi ynthes s of nucletl d-rusd0. Ribonucletl did (RNA) execuses Mpk neini ynthes s yititousnpop irs iellru.rowle. Synthes s of new DNA0isoeapke-seey Pisitetferaiell dlits tg.rStosm an secreatrinn ofP reod ne ri ginetic infermm-in thesatnsrsiDNA0 mplitscdamjecttheseregulm ayacshteraliaiell me abol sm.seTosatuosm an n loweare useful as attib-c ial drugs bocauss trsyfdoinnotsaf in thumanlcell0.seGyrodetinn ofP a0. Ten enzym gl-inrodet(topoisomerodetII)npop irs trstor-indeCuygacc mmodIm tg hf a ~1eme μm-e lorene-c ial cercmosometinrane-c i-e al iell hf ~1 μm. Wi peu re- iercmoso-timalesmr nd,oyoublr-smr ndtd DNA0has ainyoublrnhrl lallclnfigu Im tg. Trstfer-timeretin tu o,risoarrftgesti eloopsrthat rrefshor onea bs supercoilsre. Trstgl-inrodetcatalyzbs poi0 opereu xo,eas illus- erastesetbs opetore, underwfndire, andinclodire srsiDNA0youblrnsmr ndos ncrthat re-ifull hoop need estebe rata rt.ruDeCOvipevssghf 4- Pinohote-3-car-inboxyltl did (greeo por tg hf ofloxaftn fermulm) rrefiNn of a0 on b-c ial .l-inrodes.rTosy app ma to pryvsntl pinifby l-e lyotosaeysrol ne ri oponea smr nds andin e- rbyns b-c icidally.oTense genAstia - ybsorbba afte lorll insesmitg.-Tene oldeC drug, oalbdixtl did, ae in s exclu-inssvnly gram-nega ve b-c iaieost t-su ains ne in lib csnieMoto thecionlyrtn u ir-;gitaiso sectas a u iraryr as ant -e saptsc. No floxaftn sh a broaderl pin- eraum. Ofloxaftn, cirrofloxaftn, andinenoxaftn, and otosr0,tatso yiela syabso-seofallxtne in lib csnieMoto theciditiacese sectfer infRc ixos hf internal orgft0.seBestde0agas rointosmioalapk blemssernl allergy, advpryr ve in s pgrratsiaalye involveere- CNS (? nfus tg,sholluftn--inPixos, seizu rs).-Sihne trsyfcanldamjecinepiphiceal cens rocytesarnl jointfcar-intelmgeceinllaborwf ay animals, gyrodetin-sen oft a0 should estebe sectyy pup pryg-sugatcx, licto xo,eaos poriods ri growle.ighzomycin (nitroisidazole)ndeCOv-e apevss,os ncrea me kinddazole,ldamjecinDNA0bsfcsmplexafermw the or smr ndinbreakage ceis h a r0 ini bligmu-ian-tiaecobeseti.e., b-c iai.row resunder Oin2 exclus tg.runder trede isn of lic, csn-invpryixom- ireac ve me abol tesathatt t-su ackiDNA0 wkes phicr (h ame thb old oxyl-tiaminegshown). Ten ee in ais b-c icidaltinAlsimilma oe oft sm dh involved in re-seattipk nozoal e h tg n Teincomonosdvi-e gigalisn(causa lib agett hf vjeiuitis andinu rthr tis) eostEntamoeb hmstolyoolain(iausa lib agett hf lirgsfbowbrainflam- esfu xo,eamebbyldysshtery,eaos hepa ofinabsc ssrs).-Me kinddazole isowbra as-inoorbba viaore-ishterll eiute;gitaisoatsoingiibn i.v. surtop llllxt(vjeiual issert).seBecauss me kinddazole isocnsstde bd ponuttiallxtmuomgetof,miarcinogetof,sernl ermu getof in re- human,gitashouldinnotsbe sectloisrr resn 10 setif poatiels,ru ostbabavotdel yy pup pryggatcx andinlicto xo. Tisidazole may beocnsstde bd y Pivalshtmr ame kinddazole. Rifampin inn ofPsdre- b-c ial t-sezyme reatrcatalyzbs DNA0 mplits-df-inrterbd RNA0rrrascripPixoeti.e., DNA-yt-sepetheMt RNA0polymerode. Rifampin an stib-c icidally agtinsh mycob-c iai(M.setuberculos s,8M. lerrae), as wbra aceminssu.ram-poafPiverditioram-nega ve b-c-in e iat It dh wbra assorbba afte lorll inses-e tslit Bocauss eys staonromivedethsopinweletfre Pgat usjec,oitaisores rictsd t re-ita ofmett hf tuberculos srditilerro-insya(p.hi80). Rifampin ih coi asinbby testinathne firs ataimesteraliagier-Pixo rnl yy pupinlicto xo. Rifabuteulcssembles difampin butinmay beone in lib in infRc ixos rys staotin- trs lmt aiin274 Attib-c ial DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttib-c ial Drugs 275inIubby tixo: TB Sra ptomycss aspiniesinA. Attib-c ial drugs scting he DNA RNA Tw smingtbsinopetore, underwfndire,ru ostclodure liaDNA0smr ndin1in2 3su4 GyrodeseGyrodetinn ofP a0su4-QPinohote- 3-carboxylm e-indeCsvmtbc, h g.inDNA-youblrnhrl xinDamjecins aDNA DNA-ytpetheMt RNA0polymerodeinAtaecobofinb-c iainNitroisidazole y g.,ame kinddazolesuTaincomonosdinfRc ixo aAmebbylinfRc ixo aRifampiftn B-c iale cercmosome liloxaftn Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIun of a0 on Pk nein Sytthes s Pk neini ynthes s meaostrrraslm exoedd t na paptsdr ch it ri anginetic mes-e bjectfirs acopiget(trrascribba) d t nm- eRNA0(p.hi74) -Amino did (AA) assembly h a r0 atnsrsiribosomet Dtliierxeliaamf-tiho didso- m-RNA0involvesndiffershtinrrrasfba RNA0molecsiesn(t-RNA), emch of we me bfndh a sr cifbylAA. Emch t-RNA boarsman “anpolodon” nucleobodeetripl-tecreatrisfcsmplemettaryr o y pgrratsiaainm-RNA0lod resunita(lodon, cnsststire riul3 nucleobodestinIucorperm theson atlAAena sfllyrtn-involves re-ifell wire ateps (A):in1tsTrsiribosome “foc ses” swo iosindhecion m-RNA; n a(atnsrsileft) shinbound dPsdr-RNA-AAfcsmplexe thb AAinraviog alreodydbeeo addedn- trs pep-e tsdr ch it;atiesitcrrt(atnsrsiriser)risedeyodyd- ireceiveere- nextdr-RNA-AAseonmplexiin2i After trs lmt a attachos,etrs AAs liatrsiswo adjaceh onmplexes arce linkba bsftiese h tg of tiesenzym pep-e tsdr ynthetodet(paptsdylrrrasfbaode) inCsniukrshtly,rAA0rnl r-RNA of tiesleftseonmplex d srngage in3. Ten left r-RNA d ssoc trs srsyulm-RNAtsTrsiribosome ,sniadvancesealore srsim-RNA0smr ndo ndofoc s n susrstnextdlodon in4t Conse Pgatlyc srsiriserdr-RNA-ighAfcsmplexashifAs t atiesleft,tatl wiresusrstnextdlomplexato bs bound atnsrsindiser.inTense iidlitdualfateps rrefsustapts-e bleo- inn ofPtheabxaant biotic0rliad ffer- Msht gnoup0. Ten exampl-srshown origi-suga y p imarilxtfrsynSra ptomycss b-c-in e ia, some of tiesaminoglycosddrsoatsoinbewretdeCOvbdtfrsynMicromonosperminb-c iaiin1at Te roiytlfresrinn ofP re- biid-rusretof t-RNA-AAfcsmplexes.rTosirae h tg isdb-c rio ta ofaend ae in s a broadin pin rum of pathogeosiin1b -Aminoglycosddrsoinby b teesebindire of “wking” s-RNA-AAfcsmplex-sues, pest Aire ite ynthes s of falee rro-inneins -Aminoglycosddrsod ryb-c icidal.inTenir antlitox pin rumsenonmpasdesinmaiily gram-nega ve orgft smc. Sra ptomycin and kanamycin ar sec prydomfrlhtly in re- ra ofmett hf tu-inberculos s.inNoAb on pilling: -mycin drstgnases MorigigtfrsynSra ptomycss spinies; -mi-secin (h ame gettamicon) frsynMicromono-in pora spiniesiin2i Chas amphonofol inn ofPsdpep-e tsdr ynthetodet It hosdb-c rio ta ofae -e tsvtox agtinsh a broadl pin rum ofulpgahogeosioTe- ieem lllly semmle0mole-secule isonow pcoby bd ynthet callx.se3. Eryrercmycin supp y rsodd-e vancrmsntrofntrsiribosomet IAs ac ixo ic prydomfrlhtly b-c rio ta ofaend df-inrterbd agtinsh .ram-poafPve orgft smc. Fer otolaadmiion. Im tg,ftiese id-laaoleseb-det(E) isiyispNicoctas a aalrt(E.fatear-seaue) nr sn estera(h ame E.fauccino e)t aEryrercmycin dh wbra toler test It dh a suiuaaug tbstotuegain0petoftllin atlergytiereeys staonr -Azirercmycin, clarirercmy-secin,eaos roxirercmycin are dyCOvipevss aweletga ofen acia suaaoltoxe ostbat atibioavailaaoltoxioTe- inmpounds men-e tslietiace tosamosh cmmortantemembsrs liatrsimlcrolsdr ant biotic gnoup, we merusrthe ss josamycin and tpi amycin. At unrelmtba e h tg of eryrercmycin dh i stimimicrxeliathnagas rointosmioalah rsinmi eimotildr- (L50518 interpr ndiallbowbrinmitoltox) inClsrdamycin sh attib-c ial a -e tsvtox similma to teatrri eryrercmycint It exer s a b-c rio ta ofaee in awiiily n su.ram-poafPiverdecobof, as wbra acexo rn-tiaecobic pgahogeosioClsrdamycin dh a sem ynthet c ieas oganalogueense. t-seonmycin, we me deCOvbs srsyn Sra pto-rumycss spiniesioTwken orllly, clindamy-secin isobottt nassorbba resn linonmycin,inras ga ofen aotib-c ial ee cacx radrisseteusfpryferrbat Bo prpete rotsiwbra d t seei e sossueiin276 Attib-c ial DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttib-c ial Drugs 277inA. Pe neini ynthes s yitimodesionae h tg of attib-c ial drugs aRibosome Paptsdr ch itrumRNA tRNA Issert tg of inonrrin inamino did aAmino did aSra ptomycss spinies Te roiytlfressuAminoglycosddrs Eryrercmycin aChas amphonofol aPaptsdrru ynthetodeinDoxyiytlfre aTobramycin aChas amphonofol aEryrercmycin aLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTe roiytlfresra - ybsorbba srsye re- gas rointosmioala as s ad fferwretde-e grees, dtpendire n trs tosm an ,sds-inoorp the bewretnemalxncsmpletetferindhxyiytlfre yitiminooytlfreiaCntravs-innous iNje exo isorarblx needbd (rol te- erasiytlfre s yvailaaugaonlx fsuri.v. ad-e miion. Im tg).rTosamosh cnmmxomun-tiwattbd ee in ais gas rointosmioalaup0-tec(naussa, vomftore, diardhea, etc.) dyem- in(1)sa dirteremucosaloirriranteact tg of tense suosm anesarnl (2)edamjectt nteesenmuu al b-c ial .ut cas a (broad- pin- eraumaant biotic0)tatl wire claontzmuexoinbs paahogeo c orgft smc, inthe iree C ndida falgit Concukrshtoinsesmitg of antididsonn milkmwould, howevsr, bs t-se prop ist sbocauss te roiytlfresrfermseinsolublr onmplexes weletplurivalshtincsf lice(h ame Ca 2+ti, Mg 2+ti, Al a3+ti, Fsin2+/3+ti) ey-in t Aire itetenir inantsvmt tg; reatris,sds-inoorb eoltox,oattib-c ial a titox, andinlocs oirriranteact tg a - ybol shbd.rTosinaboltoxes aihelmtb Ca 2+tiaccouNts fer sissep opetstoxeliate roiytlfresr o yccumu-e la e ite.row resteelegeostei es.aAs e ro-in t A,nre-ce h a r0 anoirrevpryiblr yetl w-inbrown dis? 20rm theson teelegeoste rover- Myiblr inn ofPthealiaei e .rowle. Bof itsinliathnse dvpryr ve in se te roiytlfre ashould estebe giibn after trs seons inmi th of pryggatcx and estepcescribelins aihildrbn agest8 x and under. Otcrrtiadvpryr ve in s ace utproded pnotosen-e sitlitox liathnaskd aos hepa ofedamjec,inmaiily after i.v. admiion. Im tg.seTosabroad- pin rum ant biotice ceas amphonofol isncsmpletelx ab-inoorbba afte lorll insesmitg.-It undergoes eibn d smribu the itetrstbodygeosteyadf-inlxncroatelad ffus tgobarriea0 s ncrea tree blood-brtin barrieat Dttpiegathnse d-e vanomgeousfproperuees, its hf ceas am-sephonofol isnrarblx inbby test(h ametin CNSseinfRc ixo0)tbocauss liathn daisrr riseei e marrow yamjec.rTwo typpsnatibon rumarrow ytp y exo ,snih a r: (1) ainyose-ytpetheMt, soxof, revpryiblr fermsemloi ierel yy pup tosr uy nd,o(2)eae fre Pgatlxtfaoml ferm reatrwiveh a r af-in e anlitetcx atiebeks aostf0 estedoseinytpetheMt.eDyem- ahmncssossuerpete -inroeoltox,otrs daisrr ri bon amarrow yt-sep y exoomust also bsiPwken d t na -e couNt afte llocs ouss (h ametey- drops)tinAminoglycosddraant biotic0rcsn-ins staliaglycosddr-linkba amino- tgars (cf. gettamicon C 1αti, a csnstitPgat liathne gettamicon mixtu r).rTosy cti ain nu-timerousfold oxyl gnoup0geosteminoru.roup0 reatrcanlnind pcothest Heonr,rutrede ismpounds ace hmncly poiaa, pooalx membtone r ame ele,aand estinabsorbba shterllly. Neomycin and paro-inmcmycin are giibn orlllytroierabby teinintosmioalab-c ia (pkisurtolbowbrasur- Mgerxelr fer d.ducpup NH 3sufermw the bsin.ut b-c iaiin hepa ofeisma) -Amino- Mglycosddrsofer re- ra ofmett hf seriousseinfRc ixo0omust bsiiNje est(h ametgen-e tamicon, sobramycin,eamikaftn, netilmi-secin, siscmycin).aIn additixo,llocs oiilivsinri angintamicon-eyfyasiog ,srriearcanln in sectin infRc ixos ri bon aer toft rossue0tinAminoglycosddrs gain anceleatodre- b-c-in e ial interisurbsftiesuss liab-c ialinsrraspor syabsos.aIn te- kidney, trsy shterate- iell0 on trstproximal tubulsstiviaieoaupPwkegayabsotfer oligopaptsdrs.seTubular iell0 rrefsustaptsbleo- damjecin(rephron xoftox,rmoshly revpryiblr).aIne re- inner ema,aoens ayacsll0 on trstvosmib-inulmrsappar-tu0geostCor ’s orgft may bee injurbst(on n xoftox,reuapgrroirrevpryiblr)iin278 Attib-c ial DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttib-c ial Drugs 279inA. A pin 0 on trstteec use of seeliate roiytlfres, ceas amphonofol,aand inaminoglycosddrs Irriramitg of mucoussemembtonessuAbsorp thed Attib-c ialruee in n su.ut cas aruDisadvanti.e:seei e marrowins xoftox Advanti.e:segoelspete rotin susrrcpea barriea0 Gettamicon C 1a B-sic oligopaptsdrssuTaraspor syabsoinNo ybsorp thed "bowbras ilezw the" B-c iumedH +ruInantsvmt tg bsinchelmtitg of Ca 2+ti, Al a3+ti etc. aChelm exoedChas amphonofol aCocea ma andinvosmibsiaainon n xoftoxedH +ruH +ruNephro-inn xoftoxedHmncsold ophiloftoxedno pasdlib d ffus tgsusrrcpea membtonessuh ameinnecmycin aTe roiytlfressuLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrugsmfer Ta oflng Mycob-c ial ruInfRc ixooinMycob-c ia rrefrespoteiaug fer twoindisrodes: tuberculos s,8moshly causea bsinM. tuberculos s,8ditilerrosx dyem- aM. le-sep ae.rTosateec use of peintipl- a pli-secableo- bo prisncsmbineegra ofmett e prpwo nn moce drugst Csmbfrom tg tiec uy pkyvsntsstiesemergonce hf ey-in staot mycob-c iat Bocauss trsnant -e b-c ial ee in 0 on trstiidlitdualfaub-inonahcesra - ydditivn, cnrrsspotdlngly ssfllrrtrotes rrefsuffoftrht. ce-cefere,rutre piskpatiiidlitdualfadvpryr ve in s issel werbat Moshrdrugs sce an lib agtinshsuoily n s liathn pwo disrodestinAttituberculma Drugsm(1)inDrugsmhf ceoice a r:aiscniazid, difampin,e ereambu ol,aalore weletsra ptomycinru ostpyrmzeuamidet Leleawbra toler tese aecotd-lfre ygenAs srthe s: p-aminos l-e cyl l did, cycloderite, vinmycin, ka-sugamycin,eamikaftn, capkynmycin, ere -e onamidetinIscniazidais b-c icidal agtinshsu.row resM. tuberculos st IAs oe oft sminri act tg csmains uncleaat (Iu trstb-c -inr um itrisfcsnvprtsd t aiscnicotinic did, we me s membtone emmeame ele, hrhce hik lytroiyccumula e it roibrau-e laalx.) Iscniazidais eopanlx absorbbagafte tierIlsadmiion. Im tg. Iu trstliier,oitaiso t-se ctsvmtba bs scetylIm tg,ftiesrotsiof we me is gineticallsfcoi aollba and ashowsoeachfre te is ic d smribu the itindiffershtoerenic gnoupce(casAgvst slowinscetylImors).-Nouaaug advpryr ve in stia r:aporipherll neuk paahx,roptsc neu-inr ticop yvsntaaug bs sdmiion. Im tg of vitamin B 6in(pyridoxine); hepa ot s,8jaun-tidicet Rifampin.oSource,oattib-c ial a -e tsvtox,eaos routesionaedmiion. Im tg arce describel tg p.hi74.ahtbeitamoshly wbrainn ler tesetpoi0 drug may causs sevsraltiadvpryr ve in s inthe ire hepa ofedam-ulage,ahyperaensitlitox weletfau-hik ru ymptomc, discsniermingtbut hormleleinrtd/oeftge dis? 20rm theson bodygfauids,ru ostenzym inby h tg (failuretri oralinisn roibppevss)t Concerningtrifabuteu aee p.hi74. Ereambu olioTe- iauss liafPsdsr cifbyseattituberculma ac ixo ic unknown. Ereambu ol is giibn orllly.oIt dh generll-inlxnwbra toler tesetbutomiy causs yose-inytpetheMtedamjectt nteeroptsc nerveinweletd smurbahcesrhf vts tg (rtd/greeoe blinbn ss, visualffiela defNers)iinPyrmzeuamide exer s a b-c ricidalina theabsfeoaunknown oe oft sm.oIt dhingiibn orllly.oPyrmzeuamide miveimpair liier falct tg; hyperuricemia pest As frsyninn ofPthealiaeynll urotsielrmfro-e tslit Sra ptomycin must bsigiibn i.v. (ppiin278ff) hik sitcrrtaminoglycosddraant bi-e o ofs.oIt damjecs re- inner ema andnre-e labyrinle. IAs rephron xoftox isncsmpar-seausvnly minortinAttilerrotsc Drugsm(2) Rifampin ih fre Pgatlxtgiibn inncsmbi-suga tg weleton aer bo prliathn fell wireulagenAs:inDaps n aisoeasulfone reat, hik ssul-infonamide0, inn ofPsdyiold ofel te syt-sethes s0(p.hi72)t It dh b-c icidal agtinshsusustaptsbleoatrtins liaM. lerrae. Daps n isdgiibn orllly.oTosamosh fre Pgat ad-e vpryr ve in s mete-moglobinemia weleseanceler tes eryrerccyte degradom tg (e-molys s) inClofmzemfre s y dysge prb-c ici-inyal e h itox agtinsh M. lerraegeostent -e infl mmwf ay properuees.oIt dh giibninorllly, butoiso tcsmpletelx absorbbat Bo-rucauss hf fPsdhmncslipophiloftox,oitayccu-inmula estin adipose and otosr rossue0ru ostleavesetrstbodygoily astrsr slowly (td 1/2 a~ 70 d). Ryd-brown skd pigmeMtm-in thes s yiaunwattbd ee in , pgrratsiaalye in fair-skd neegpgaierusiin280 Attib-c ial DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttib-c ial Drugs 281ru otaminoglycosddrseattibiotic Sra ptomycin Vosmibsiaa andincocea mainon n xoftoxedA. Drugs usectroira of infRc ixos h prmycob-c iai(1. tuberculos s,82.ilerrosx)inIscnicotinic didinNicotinic didinFel teinsytthes s p-Aminobenzotl didsuClofmzemfre Skin dis? 20rm theinPyrmzeuamideinLiier damjecinCsmbfrom tg tosr uyinR.duced piskpate b-c ial eys staonrinR.ducm tg rliadose and ofinr skpionaedvpryr reac licinMycob-c iumedlerraeinMycob-c iumedtuberculos sin1in2 Rifampin Liier damjecin ostenzym inby h tg Ereambu ol Optsc nerve damjecinIscniazidinCNS damjecin ostporipherllinneuk paahx (Vit. B 6in-edmiion. Im tg) Liier damjecinDaps n H-molys sinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrugs Ussth u trstTa ofmett hf Falgal InfRc ixooinInfRc ixoo dyem- afalgi ar suallsfcoi-infineegroathnaskd nn mucous membtones:inlocs oer tuperfofts omycosdsi Howevsr,8in aimmun defoftrhcy suate0, internal or- Mgaostmivealso bsiaf in rt: syabso c orinytepomycosdsiinMycotes rrefmosh cnmmxoly dyem- indermw ophyte0, we me af in tthnaskd ,inrair,aand eailsifell wire exterual isfe -e tslit C ndida albby ns,8d yeasAgorgft smedno sfllyrfound heabodygsurfoibs,tmiyrucauss infRc ixos ri mucous membtones,edlesh fre Pgatlxtliathnaskd hrsio ernal or- Mgaostwhenrnmuu al defNico0 ace m-sepairbst(immunosupp y tg,for damjecinri microcas a bs broad- pin rum ant bi-e o ofs) inIsidazole deCOvipevss inn ofP er- Mgos ol sytthes st ceis s oid ferms an aiNtegrallclnstitPgat liaiytoplicsicrumembtones of falgal csll0,ganalogous s incholes ol in animal plicsesmem- ebtonest Falgi exposectroiisidazole de-inr vipevss stope.row res(falgi ta ofaee-infin ) nr dies(falgicidal ee in ).rTosa pin- eraumaonaef in rtafalgi is ierxebroadt Bo-rucauss trsyf ce pooalx absorbbagandinpooalx toler tes syabso cllly,rmosh aimidazoles rrefsuiuaaug onlx fsurtop lllin se (clotaimazole,lecotazole xofotazole, isofotazole, bifotazole, etc.) -Rorblxetpoi0in se mayaeyst A inncsntidt dermw ot s. Mi-secotazole isdgiibn locs lxeter tyabso clllyinbs shor -nd cainfus tg (dttpiegafPsdpoorintoler boltox) Bocauss it dh wbra assorbba, ketocotazole isdyvailaaugafer otolaadmii-e in. Im tg. Advpryr ve in s rrefrrre; how- eibr,ftiespoatieoltoxeliafaoml liier dam-ulageashould n notest Resfrkaauy, keto-secotazole miveinn ofP s oidogeoes s (gotadal aostadrbnocorticalah rmi es) inFlucotazole aostf roiotazole arefnewsr,inorlllytne in lib rilzole deCOvipevss.rTosintop llllxtan lib allxlmmdr- naftbditesernl tosamorpholfre ymorolffre ylso in-sen oft ergos ol sytthes s,aalbeitaatt n-e o rsr step.seTosapolyenraant biotic0,eampho-in e icin Baand ey ta on, rrefliab-c ialinorigig.rTosy issert tosmselvss in- afal- Mgal iell membtones (pk baauygnextdr inergos ol molecsies) eostcauss fermm-in thesliaold ophilofachf nelsioTe- eyst -2 Pwtt utprode itemembtone r ame etl-2 tox,oh ame to K +ru lic, accouNts fer sisafal- Mgicidal ee in -Ampnote icin Baicoan lib agtinsh mosh orgft smcfrespoteiaug ferseayabsoic mycotest Bocauss liafPsdpoorinabsorbaaoltox,oit must bsigiibn byainfu-secixo, we me s,ahowevsr, pooalx toler t- est(ihill0,gfevsr, CNS d smurbahces, m-sepairbsteynll falct tg, pea bitis atnsrsininfus tg site) -A pliectrop llllxtto skd innn mucous membtones,eamphote icin B isduseful in re- ra ofmett hf c ndidalrumycosdsi Bocauss liathn low atsiof t-sete Ilsabsorp the, otolaadmiion. Im tg in aiNtesmioalac ndidiasisocan beocnsstde bd atrop lll ra ofmett. Ny ta onaiso sectot-selx fsurtop lll tosr uy inFlucytosfre s csnvprtsd in c ndidainfalgi - a5-fluoroureftl bsftiese h tg of a aspinifbylcytosfre demmdrodet As yiaent -e me abol te, poi0 cnmpound disrup sinDNA0rnl RNA0 ynthes s (p.hi98), pest A-rusretinranfalgicidal ee in . Giibn orllly,influcytosfre s eopanlx absorbbat It dh wbrainn ler tes and oftenncsmbineege pram-sephote icin Baroiyll wadose r.ducm tg rie re- lmt aiinGr seofulvin origin trs srsy moldssernl has e h itox onlx agtinsh dermw-inn phyte0. Peestmaauy, itayctstas a apin-sedug poisono- inn ofP falgal mitosdsi A -2 Pecpea tirgsrbd agtinsh locs omycotes,su.r seofulvin must bsi secttyabso clllyiinIt isiiucorperm ed d t nnewlx fsumbd kereu g.r“Imprygga ed” in reis winner, kereu gtbocomss unsuiuaaug as a falgalednu rirht. ce- sims ey Pirbstferatieserad-e by tixocliadermw ophyte0 cnrrsspotdsin- trs eynewal poriod hf skd , rair,aorineails. Gr seofulvin miy causs unchfr-c-in e is ic advpryr ve in s. ce- need ferseprohotgestadmiion. Im tg (sevsraltimi ths), re- incidonce hf esdr ne in s,ru osttiesevailaaoltox hf ee in iverditisafeseal ernapevss haibe onderetior seofulvin tiec use oflllxtobsoleteiin282 Attifalgal DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttifalgal Drugs 283 aSra ptomycss b-c iainNy ta onAmphote icin B A. Attifalgal drugs aMito ic apindlcinDNA/RNA me abol sm Ureftl CytosfreruDemmdrode Falgal iellru5-Fluorureftl Ergos ol PolyenraAnt biotic0 aMoldnfalgiinIucorperm thesd t se.row resskd , rair,aeailsd "Imprygga thesee in " 25-50iebeks 2-4iebeks Gr seofulvin Sytthes s Cell wall Cytoplicsicemembtone Isidazole deCOvipevsssuh ame clotaimazoleinFlucytosfreinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinCe-motrsr ux hf Viral InfRc ixooinViruses y rttiallxtcnsstst ri ginetic esfu ial (nucletl dids, greeo smr nds iose(A)geoste capssiaa enthsops wide up ofulpe neins (blurnhrxi.ons), oftenne prasecoatn(grayae re) ri anphospholfpid (PL)tibilaysr e prembsddednpe neins (ssflle blustb-rs).-Tosy lackia me abol c syabsoinbutoytpeth n trs infRc edniell feratieir .rowlegeosteyphiy tixo. Tirgsrbd tosr -e pse of supp y tgrhf vtrll eyphiy tixoseey Pirss selectevs iNn oft lieliarhoseinme abol c pe c ssrs reatr pinifby lly serve vtrll eyphiy tixotin infRc edniells.seT date, poi0 canln schitvh onlyrtoraselrmf bd extenr.inVtrll eyphiy tixotas exempri ieainbs Herpes simplexaviruses (A): (1) Tosinvtrll pgrratug attachosgroathnahosh cellrumembtone (adsorp the) bsflinksreti sincapssiaa glycope neins to spinifbyltory -in u rs liathn iell membtone. (2)eTe- vtrllsecoatnfuses e prponeplicselemma liathne hosh cell andnre- nucleocapsid (nucletlseanid plus capssie) shtersathn iell interi-innn (pete rotin ). (3)eTen capssie opons (“uncooflng”)tnemanre- nuclemanpere0ru ostvtrll DNA0movss in- athn iell nucle-inus. ce- ginetic mfu ial on trstvirus canednow dirterethn iell’s me abol c Nucletl did ynthes s: ce- ginetic esfu ial (DNA0in reis inshahce)aisorepli-secates and RNA0isopcoby bd feratiespur- Mpose of pe neini ynthes s. (4b)eTen rro-inneins ar sectas “vtrll enzym s” cata-selxzsretvtrll mt Aiphiy tixot(h ametDNA polymerode rnl hymbdite kdrode), asincapsomerseter a0 cnat cnmponett0,aorinace utorperm ed d t nthnahosh cellrumembtone. (5) Iidlitdualfcsmponett0tia - yssembled d t nnewtvirus pgrratugs (ml u otin ). (6) Ryfyase of dapeateravf-inruses pest As ite peyadrhf vtrus iNsddrseatdrhutesdr teerorgft sm. Wi pnhrrpesinvtruses, eyphiy tixoteMtmilsihosh cell de-intory theaend dethsopmett hf disroderu ymptomctinAttivtrll me oft sms (A). ce- or- Mgao sm canldisrup vtrll eyphiy tixosee prponeaid liaiyton xof T-lymphocytesecreatrrteognizeaend des roy vtrus-rro-inducpup csll0 (vtrll surfoibnpe neins)aorinby meaostof attibodirs reatrnind torandininantsvmte extroibrauiaa virus pgrratugs.inVaccino liceare dystgnectroiantsvmte aspinifbylimmun defNico0tinIuterferlice(IFN) rrefglycope neinsecreat, amoog otosr prody hs, rrefre-e lyasbdtfrsynvtrus-infRc edniells.aIne neeseborpup csll0, interferlilsmimula ese re- prody h lielia“anpovtrll pe neins.”inTense iin ofP re- ynthes s of vtrll pe -inneins bya(pryferrttial)ndetory theaof vt-inrol DNA0surbsfsupp y reti strrraslm-e tslit Iuterferlicerrsgnot dirterbd agtinsh atspinifbylvtrus,tbut hoibea broadl pin- eraumaonaenpovtrll e h tg reatris,showevsr,inspinies-spinifby. ceu0, interferlilferaitsinfn human0omust bsiob ainbdtfrsyncsll0inri humanlorigin,os ncrea leukocytesec(IFN-α), fibk blastce(IFN-β)eter lympho-secyte0 (IFN-γ)t Iuterferlicerrsgylso sec roira of iermain miliggatciesarnl auto-seimmun disordersa(h ametIFN-αtferaihrot-sebylhepa ot s C aos hairyacsll leukemia; IFN-βtferasevsreshrrpes vtrus iNfRc ixooinyitimt Aiph- tugros s) inVirusta ofaensims abol tesaarce “falee” DNA0buil ire blocksa(B) nr nucle-inosddrs -Arnucleoesdr (h ame thymbdite)secotststs ri annucleobodee(h ame thymbte)seandnre- suga ndeoxyribodet Inaensims-2 Pwbol tes, n s liathn csmponett0 isiye-infin evs. Iu trstbody, poneabno sfl nucle-inosddrs undergo b oantsvmt tg bs attach-e meat liathree phosph te d.s dyesec(p.hi87) inIdoxuridite andncotgensrs arc t-seonrperm ed d t nDNA0weletdeleterioussepest Ast ceis ylso a pliosgroathnasytthes s ri humanlDNAtsTrscefere, idoxuriditesernl analogues rrefsuiuaaug onlx fsurtop -seca ouss (h ametin herpes simplexakereu t s) inVidar bone iin ofPs vtrlllx inby bdinDNA0polymerode moce s rongly resn itinyoesetrstethogeoous enzym . IAs uss isednow lrmf bd roatop lll ra ofmett hf se-e vpre herpes simplexaiNfRc ixoi Boferee re- intrody h lieliatrstbottt nr ler tesseanyclovir,avidar bone playsste majersepgrroin re- ra ofmett hf herpes simplex shcephalot s. aAm retvtrusta ofaensims abol tes,seanyclovir (A) hosdbo prspinifbytox liathnsen ghest degree and op tmal toler boltox,in284 Attivtrll DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttivtrll Drugshi85in1tsAdsorp thed Virus-seinfRc essePe neins weleseattigeo c properuees Spinifbylimmun indefNicosuh ame cyton xofinT-lymphocytesecDNA Capssie Enthsops 4aiin Nucletl didin insytthes s 5. RNA DNA Isonrrin : R: - I Idoxuriditese- CF 3su Teifluriditese- Cin2 Hin2 EdoxuditeseIssert tg d t seDNA0inateadinliathymbdite Cnrrin : Thymbdite ThymbteruDesoxyribode Isonrrin :inVidar bone Anyclovir Gatciclovir Adetore GuanbteruAr bonode Isn oft lieliavtrll DNA0polymerodeinBi Chem lll sory u - hf vtrusta ofaensims abol tes Glycope neininIuterferliinAttivtrllulpe neinsin2i Pete rotin suVtrll DNA polymerode 6. Ryfyase 4biin Painoneinin3.Uncooflng A. Virus mt Aiphiy tixotyitimodesionae h tg of attivtrll genAstiAnsims abol tesa= inonrrin DNA0buil ire blocksinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinbocauss it undergoes b oantsvmt tg onlxinfn infRc edniells, wepre it pryferrttiallxinfnn ofPs vtrllaDNA0synthes s. (1)-Arvtrlllxseondedn-hymbdite kdrode (spinifbyls aH.secimplexa ostvaricellm-zos vtrus)npop-suferms re- initialnphosphorylIm tg step;rutre psmainpup two phosph te d.s dyesecrrsgyttachod bsfcbrauiaa kdrodes. (2)eTe- polmanphosph te d.s dyese onder anyclo-invtretriphosph te membtone emmeame-ulable aostcauss it roiyccumula e it t-sefRc edniells.a(3)eAnyclovir triphosph te isdafpryferrba suosmr teeliavtrll DNA polymerode;gitainn ofPs enzym e h itox and,ofell wire itsiiucorperm tg d t vt-inrol DNA, inby bs0smr ndobreakage bo-rucauss it lacks re- 3’-OH gnoupcliadeoxy-inr bode reatris ey Pirbstferatiesattach-e meat liaadditixofl nucleotsdrs. ce- n gh tiec use oftvalueenseanyclovir is eviheMt ite evsresinfRc ixos h prH. simplexavi-inruses (h ametehcephalot s, generll zsth u-infin ehe) ostvaricellm-zos vtrusesec(h ametsevsreshrrpes zos ). Iu trsdetcas-sees, t canln giibn byai.v. infus tg.eAny-inclovir mivealso bsigiibn orlllytdttpieg2 toso tcsmplete (15%–30%)ishterll ds-inoorp the.aIn additixo,lit hosdtop lll uco0tinBocauss hosh DNA0synthes s csmains unef in rt, advpryr ve in s do nots t-seohe s bon amarrow ytp y tg.eAnyclo-invtreis elrmfromestunchftgesti eu ir- (td 1/2 a~ 2.5 h) inValanyclovir,atiesL-valyl esteraliseanyclovir,aisdafprodrug reatrcanlne ad-e miion.eretiorlllx inshrrpes zos isfe -e tslist IAs absorp the atsiisda proxiintwice teatrri anyclovir.eDy pup passjecinsercpea re- iNtesmioalawall8ditiliibr,ftiee valfre d.s dye s cleaved byaesterates,su.enerlmingtanyclovir. Famnyclovir is yiaent hrrpetic pro-indrug weletgoelsbioavailaaoltoxtwheningiibn orllly.oIt isi sectite.etooml hrrpesinaos herpes zos ioClemvjectliatwo acs-2 Pwte gnoupcesrsynpos “falee suga ” andin xodIm tg hf tiespurfre diren- guanbteruyielasdpetciclovir,ftiese tevs ferm.rTosinlmt a differs srsyn nyclovir weletrsspin in- its “falee suga ” moiety, butomimics itinplogy ? 200 clllyi B oantsvmt tg ofsepetciclovir,fhik steatrri anyclovir,rtn-involves fermw the oiathn priphosphory-e la edaensims abol te viaovtrlllx inby bdin-hymbdite kdrodeiinGatciclovir (sory u - hg p.hi85) dhingiibn byainfusthe itetrstra ofmett hf se-e vpre infRc ixos h prcytomegalovirusesec(also bshotgiren- trs herpes gnoup);rutrede do nots tby b teymbdite kdrode,sephosphorylIm tg bewretinitiatba bs sindiffershtovtrll enzym . Gatciclovir isseleleawbra toler tes nd,onots tfre Pgat-selx,opcoby ba leukopetoa rnl hrsybo-e psniaiinFoscarte eyp y gats y diphos-sephmu-ianaloguetinAsrshown in (A), iucorperm thesonednucleotsdr d t naaDNA0smr ndteMtmilse cleavjectliay diphosph te d.s dye. Fos-secarte (B) inn ofPs DNA0polymerode bsinintorscting h prfPsdbindire sitetferatiee diphosph te gnoup. Iubby tixos: syabso-seof tosr uy hf sevpre cytomegaly isfe -e tsli in AIDSgpgaierus; locs otosr uy hf hrrpes simplexaiNfRc ixos. aAmantidite (C)r pinifby lly ae in srutre psphiy tixotof inflPgaza-Ar(RNA) vi-inruses,ftiesiausa lib agett hf oryc t-seflPgaza.oTense viruses rrsgethocytosededd t nthn iell. Ryfyase of vtrllaDNA0re-se Pirss pcothesesrsynpos didofeisnteMt of tdosomesgroapete rotsitrstvirusiinPeestmaauy, amantidite blocksaeachft-senel pe nein itetrstvtrllacnat teatrpop irse influx of pe nhes; reu0, “uncooflng” ic pryvsntbat Moreoibr,famantidite in-sen ofts vtrllaml u otin . ce- drug isoatsoin sectprophylac oflllxt nd,oif poatiels,rumust bsiPwken bofere teeroutbreak hf ymptomctoIt ylso is yiaent parkinsonianec(p.h188)iin286 Attivtrll DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttivtrll Drugshi87suVtrllinDNA0polymerodeinInfRc edniell: hrrpes simplexinnn varicellm-zos suVtrllinthymbdite kdrode Cbrauiaa kdrodesinAnyclovir A. Antsvmt tg ofn nyclovir aostfsn oft lieliavtrll DNA0sytthes s B. Inn of aeliaDNA0polymerode: B. Foscarte inInflPgaza A-virus Endosome Vtrll chf nelulpe neinedH +ruInn oft lieli uncooflng C. Pe phylaxfstferavtrll flP DNA sytthes s DNA-ch itrut amfrotin suInn oft li B-se BodeinBodeinVtrll DNA0 mplitsinAn ve me abol te aAmantiditeinBodeinFoscarte inC OinOinPO OinOinP OOinOinPO OinPinOinOsuVtrllinDNA0polymerodeinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrugsmfer trstTa ofmett hf AIDSinR.phiy tixotof trs humanlimmuno-inytfoftrhcy vtrus (HIV),ftiesiausa libulagenA hf AIDS,aisdsustaptsbleo- tirgsrbdinintorvsnt lic, bocauss sevsralnvtrus- aspinifbylme abol c steps h a r fn infRc - estcsll0 (A). Vtrll RNA0must firs absiPrft-sescribel d t nDNA,8d steprcatalyzba bs vt-inrol “revprye0rrrascripPodei” Doublr-intorandtd DNA0isiiucorperm ed d t nthne hosh geoome e prponehelpeliavtrll into-su.radet under coi aol bs vtrol DNA, vtrllulpsphiy tixotcanlthen botinitiatba, welese ynthes s of vtrll RNA0rnl pe neins ( t-seohe ire enzym sos ncrea revprye0rrra-sescripPode aostfstegrase,aand sory u llulpe neins s ncrea treaml rix pe nein . t-seire srsiiNsddr on trstvirll enthsops).inTense pe neins a - yssembled nots tbi-invtduallsfbutoinathn ferm of polype neins.inTense peea r0or pe neins ,srrsfeoaN-nd -e miill fmt y did (my is oyl) d.s dye that promotesathnir attachmshtmr are- iNte -e isurfoibnhf tiesplicselemmat As trstvi-inrus pgrratug buds rifnthnahosh cell, t car-inr es e prfP re- ef in rtamembtone a -a as fPs enthsops.eDy pup reis pe c ss, sinproteade isn ainbdtwi peu re- polype -innein cleaves trstlmt a d t niidlitdual,infalctixofllxtan lib pe neins.inI. Inn of as of Revprye0TrrascripPodeinIA. Nucleoesdr genAstiTense suosm anesarre analogues liathy-e miie (azidothymbdite, suavudite),seadetore (didanosfre),lcytosfre (lamf-tivudite, zalciuaafre),lditiouanbten(car-inbovir,ra me abol te ofn bacavir).-Tosyinrave inncsmmxotyieabno sfl suga timiiety. Lik steernmuu al nucleoesdrs,rutrey undergo priphosphorylIm tg,fgiilng r semr anucleotsdrs reatrno priin ofP re-e vprye0rrrascripPode aostcauss smr ndinbreakageofell wire iucorperm thesd t sevtrol DNA.seTosanucleoesdr iNn of a0 differ itrut amcense.)athnir aboltoxes adetprode cir-intsiating HIV load; 2)athnir plogy ? ki-sugetic properuees (halse. fe L50478adoslng intorvol L50478acsmpli ane; orgft d smribu-e tsli L50478apassjec srrcpea blood-brtinbar-inr er); 3)etrstrype hf eys staonr- tby lng muomf licensetrstvirll geoome andnre-e rotsiatrwe me eys staonrodethsops; ndin4)athnir advpryr ve in s (ei e marrowinytp y tg, neuk paahx,rpautprou t s) inIB.-Non-nucleoesdr iNn of a0seTosanon-nucleoesdr iNn of a0 hf ey-invprye0rrrascripPode (nevirlpite, delm-e virdite, efavirenz)errsgnot phosphory-e la ed.-Tosy nind tortrstetzym welesehmncsselectevtoxe ostteusfpryvshtoit srsye adop tre srsian lib csnfermw the. Inn -inbi thes s noncsmpetitivn inII. HIV proteade iNn of a0seVtrll pe neode cleaves peea r0or pe -inneins d t npe neins ey Pirbstferavtrllulpsphiy tixo. ce- iNn of a0 hf reis pe -inneode (sa Pinavir,rrf navir,rindiravir,inaos nelfiravir) eyp y gateabno sflulpe neins teatrpoatelsdhmncsattivtrll ee -secacx and rrefgenerlllxnwbra toler tes in tie shor and ci Howevsr,8prohotgestad-e miion. Im tg is yssoc trege prh aa-secixollly sevpre d smurbahcesrhf lfpid andincarboold te me abol smi B orrrasf rsinm tixotof trsse drugs involvesncyto-e cercme Pin450ec(CYP 3A4) aostf0 trsceferesusuo terms aintorsctitg weletvarious otosrindrugs in ctsvmtba viaore s coute. Fer tie dualfpurpose of utprodiresusrstee in iven ss of attivtrll tosr uyinrnl peyvshttre srsidethsopmett hf a tiec uy-lrmf sretvtrll eys staonr, inn of-inn a0 hf eyvprye0rrrascripPode arn csm-inbineege premch otosr rnl/or weletpe -inneode iNn of a0.inCsmbfrom tg regimetceare dy-secignectin ancordaonroweletsuosm ane- aspinifbyldethsopmett hf eys staonroandinplogy ? kigetic parametersa(CNSsepete roaoltox,o“neuk pe nect tg,” doslng fre Pgacy)iin288 Attivtrll DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttivtrll Drugshi89 A. Attire kivtrll drugs aVtrll RNA DNA h ametzidovuditeseIsn of a0 hfulpsvpryeinsrrascripPodeinEnthsops Ml rix pe neininR.vpryeinsrrascripPodeinIstegrase aVtrll RNA Polype neinssePe nease aMa u - virus Clemvjectli polypaptsdrrupeea r0orseIsn of a0 hfulHIV proteade CH3 N HinOsuNedH NHinOsuNedNinOinOsuH2NedH3C CH3 HO h ametsa PinavirinOsuN=N=N HOCHin2 NinOsuNedH OedH 3 C RNA + -inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDisinfRc aats yitiAttisaptsc0 aDisinfRc tg detotesathn in ctsvmtixotor kdlling of pgahogeos (pk tozoa, b-c ia,infalgi, viruses)oinathn humanlentirot-semrht. cei0 canln schitvh bsfchem lllinnn phys lll meaos; trstlmt a will nstebeindiscussectrsce. S ilezw the ryfers s inte- killing of all8gd co, weptosr pgaho-su.enof, do sfMt, nr nonpaahogeo c. Atti- aseps s csfers s trs eydy h liebsfchem -seca oygenAs ri girm numbsrs on kd aos mucosll surfoibs. aAgenAs feraihem lll disinfRc tg idellly should causs eopan,ncsmplete,in ostpors stshtoinantsvmt tg ofn ll8gd co,inbutoatnsrsisame sims exn ofP l wan xof-2 tox (syabsoic n xoftox,rsossuerirrirancy,seattigeo ctox)geostesanon-deleterious s infrlhim te mfu ials.oTense ey Pirb-semrht0 call feraihem lll properuees that miveexohe s emch otosr; trscefere,seonmprcmises guidba bsftiesintondtdin se rave to bs widetinDisinfRc aats comstfrsynvariousseihem lll clasdes, inthe ire xodIn s,ruhalogeos erahalogeo-eyfyasiog ygenAs,sealcohol0,galdeoldes, nrgft l dids, phs-innol0,gy tixoof surfoi aats (detergenAs)seandnfsumbalx also hemvy me alsioTe- ba-secic me oft sms onae h tg involve dy-senl u otin of pe nein0, inn ofPin of t-sezym seter a deold otin . Ee in s rrefyt-sepetheMteonncsnceh Im tg aitionstidte tsmotinAntlitox pin rum. DisinfRc aatsininantsvmte b-c iai(.ram-poafPiver> gram-nega ve >rmycob-c ia), leleaee-infin svnly thnir poral ferms,8ditia fewec(h ametfermwldeolde)errsgvirucidal.inA pliy tixos Skin “disinfRc tgi” R.ducm tg ri8gd ce couNts peisurtolpalctu rs lr turg lllinpe c du rs isiyestrlblr ifntrsiriskpate wound dnfRc tg is to bs wiiom zst.inUseful ygenAs srthe s: alcohol0 (1- aos 2-rropauol;oereauol 60–90%; iodite-re-e lyasiog ygenAsfhik spolyvinylpyrrolsd n [pivtd n , PVP]-iodite as a ytpstefermsensetrstan lib peintipl- iodite,0inateadpate iodite srctu r),gy tixoof surfoi aats,in ostmixtu rstof trsse. Minimal onstidte tsmosashould n atnleasAg15 s on kd are-e as e prfew seb-ceousfgl nds ditiate lyasAg10 wii on eb-ceousfgl nd-r merui es. aMucosll disinfRc tg: Girm couNtssecanln r.duced bsfPVP iodite eraihl rsinhexbdite (csntidt sims 2 wii),ldlPecpeainnottas effin svnly as on kd . aWound disdnfRc tg canln schitvh see prold ogentpor xode (0.3%–1% solu-e tsli; shor etfemmdrgae h tg on onstidte e prbloode ostteusfwound cleansiog)innn weletpotasdlumrpop angftitsin(0.0015% solum tg,fsleserly ast pupenA),seas wbra acePVP iodite, ceas hexbdite,in ostbiouanbdites. aHygieo c and surg lllahand disdnfRc-e tsli: ce- fsumbaris ey Pirbstafte leasus-sepRc edniottaminIm tg,ftieslmt a beferesusurg lllape c du rsi A cohol0,gmixtu rsinri alcohol0 ostphenol0,gy tixoof surfoi-2 Pwttseter adidsorre availaaugafer reis pur- MposetsAdmixtu rtof otosr rgenAsfpe -inhotgo dyrmt tg ofn nm tg aitir.duces fl mmwaoltoxi aDisinfRc tg of usorymrht0: Iusory-semrht0 reatrcanestebe hemt- lr tteam-into ilezednianln peealeanede ostteetindisinfRc edne praldeoldesaend dete -e gerusiinSurfoibn(floor) disdnfRc tg mplovsinaldeoldesacsmbineege pry tixoof sur-infac aats yiti xodIn s lr, moce rarblx,seanid c orralkll ziog ygenAs. RosyndisinfRc tg: rosynaia andinsurfoibsnianln disinfRc ednbsfspraylng nn vapor ziog ri aldeoldes, pkivtdbdin-hat8gd coorre frenly ancelesbleiin290 DisinfRc aatsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDisinfRc aats 291 TossueedA. DisinfRc aatsinA pliy tixo sites Examples An lib peintipl-sin1tsOxodIn sin2i Halogeose ceas fre asodiumrhypoceas feg2 todite srctu r Skinin3. A cohol0 R-OH (R=Cin2 -C 6in) h ametereauol isorropauolinR.gsiaa e amethandsinAnute,ine ametbofere locs ope c du rs 4.ahtdeoldes h ametfermwldeolde Mglutarwldeolde M5tsOrgft l dids h ametlac of didinMucous membtones 6. Phenol0inNonhalogeomtba: h ametphenylphenol hugenol thymol halogeomtba: ceas meteylphenol 7t C tixoofinsurfoi aatsinC tixoof soaps h ametbenzalkxooumedceas hexbdite 8t Hemvy me alisa As Irlhim te mfu ial: dyrmblb agtinsh ihem lll + phys lllsemrasu rs Irlhim te mfuu : asenafPiverto hemt,seanidsetexodIm tg etc. aDisinfRc tg of usorymrht0 Skin disinfRc tg DisinfRc tg of floors nn exoremett DisinfRc tg of mucous membtones aWound disdnfRc tg Phenol0 NaOClinC tixoofinsurfoi aatsinPhenol0inC tixoof surfoi aatsightcohol0 Iodite srctu r Chl rsinhexbdite Chl rsinhexbdite Chl rsinhexbdite KMnO 4 Hin2 Oin2 STOPinC tixoof surfoi aatsightdeoldes DisinfRc aats doinnottafferd selectevsinfnn ofP lieli b-c iainvtruses, ornfalgiinh ametold ogentpor xode, potasdlumrpop angftits, por xycarbot l dids h amettphenylmercurxeberm einLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrugsmfer Ta oflng Endo-aand inEctoparaafPic InfRst tixos Advpryr hygieo c ons of licefaverahy-seman infRst tixo h prmt Aicbrauiaa or- Mgao sms (rtferrba to he - ys paraafPes) inSkd aos haia arn csaontzmuexo sites forinacsrrcpodeectoparaafPes, s ncrea issen s in(. Netflyas)geosterschnidso(mfPes) inAgtinsh trsse, issen icidal orrarschnici-inyal egenAs,trsspin svnly,nianln sec. EndoparaafPes invadr teeriNtesmiors lr eibn io ernal org ns,8dnd rrefmoshlyrumembercensetrstphyla of flatwerms andinroundwerms.-Tosy arn csmb trege pseatthelmin ofs.inAtthelmin ofs. Asrshown in trstra-seele,ateernewsr rgenAsfpeaziquattbl aos mebendazole arefadrquatetferatietra of-e meat liadivpryr werm disrodest-Tosyinrrefgenerlllxnwbra toler tes, as are teee o rsr ygenAsfhierel.seIssen icidest-Whe -as flyasrcanln ineffin svnly delltge prby disdnfRc tg li clothesaend liilng quartersetlinroandinmfPes ey Pirbatietrop lll apphiy tixotofseinsen icidesmr are- iN ierel to ter. Chl rphenoreaubn(DDT) killso t-sesen s afte lebsorp the liay ierxessflle amouNt,oh ame viaofootncsntidt welese prayel trfoibsn(csntidt insen icide).inTen iauss liadel prisnnervous syabsoindamjectand seizu rsi In human0oDDTrucausss e ute neuk n xoftox oily afterinabsorp the liaierxelirgs amouNtsi DDTrui0 chso cllly suable aostdegradsth u trs shtirotmeat ostbodyget extrl rly slow atss.aAs e hmncly lipophiloffaub-inonahce,oitayccumula estin fat rossue0tinWidespeyadruss liaDDTtin pest coi aol haa lectroii s accumula sli in foodinchains to alirmdrgalethsst Fer reis eya-inoonii s se ras nowln en bannes in many couNtr es. Lindare s trstan lib γ-isomer hf hrxaceas onyclohrxanetoIt ylso exer s ainneuk n xof e h tg on issen s (as wbra ac human0). Irriramitg ofaskd nn mucousrumembtones wiveh a r aftt nr p lll uco. Lindare s an lib also agtinsh it rodd -e mal mitbsn(Sarcoptbsnscwaoei,siausa libulagenA hf scwaoes), besddrs linroand flyasiinIt isimoce ryadfly degradsthresn DDTiinPe meteron, r0sytthetic pyrete-inroan,nexn ofPs simiiaa anti-ectoparaafPicse ctsvtoxe ostmay be srsidrug of ceoiceinduetroii s sl wer utareous absorp the,infash old olytic inantsvmt tg,eaos ropanulpsnal elrmfromilit 292 AttiparaafPic AgenAstiWerms (helmin hs)gAtthelmin ofidrug of ceoiceinFlatwerms (plityhelmin hs)2 Pwpr wermsn(cestodes)fpeaziquattbl*seflPkbsn(trl atodes)fh ame Schis osomafpeaziquattblinspinies (billogziasis) Roundwerms (ne atodes) pinwerm (Eo erobius iermatsiaais) mebendazole nn pyrattbl pamom einwhipwerm (Tr meur s tr meiyrm) mebendazoleinAscaais lumbticoddrs mebendazole nn pyrattbl pamom einTr meiorlla apirll s** mebendazole ostteiabendazoleinS rongyloddrs to corll stteiabendazoleinHookwerm (Necwf a ame icanus,8dnd mebendazole nn pyrattbl pamom einAncylos omafduodenale) mebendazole nn pyrattbl pamom ein* nstefer ocuiaa or apinal onrd cys ic cos s ** [teiabendazole: iNtesmioalaphode;gmebendazole:rsossuerphode]inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttiparaafPic AgenAs 293inFl-a Damjectt nnervous syabso: csnvuls lic, del pedA. Endo-aand ectoparaafPes: tiec use oft genAstiT uswermsine ametboef2 PwprwermseLoitsinRound-e wo co,inh ameinascaaisinPinwerminTr meiorllae laavae Scwaoes mitb Spasm,e injurytofseintegumett PeaziquattblinMebendazoleinHrxaceas onyclosinhexaubn(Lindare) Chl rsinphenoreaubin(DDT)inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttimalirialsinTen iausa lib agetts ri maliriaf ce plas-semodia, unicbrauiaa orgao sms bshotgirein- trs order e-mo poridia (clasd pe nh-sezoa). ce- iN in iverferm,ateer porozoite, is iNocuia ed d t nskd copalliriestwhenininfRc ednfeselegAtopheles mo Pitoesec(A) s nkrbloodefrsynhuman0.rTosa porh-sezofPes invadr liier parenchymal csll0inwhers trsyfdethsop d t npeimaryttossueedsmeizoNtsi Aftt nmt Aiph- fi tg, trsseedsmeizoNtsopcoby b numerous merh-sezofPes -hat8shteratrstblood.eTen rre-e eryrerccyt c stjectisdsymptom fren.aIne blood,ftiesparaafPe shtersaeryrerccytesec(hryrerccyt c stjec) wepre it agtinnmt -e tspliosgbsfsmeizogony, pest Asretinrtrs fermw the oiamoce merhzofPes. Ruptu r ofare- iN ictes eryrerccyteved.fyasesrtrs merhzofPes ostpy ogens -Arfevsr attack shsues ostmoce eryrerccytevearc t-se ictes. ce- ginermt tg poriod feratiee nextdcropeliamerhzofPes dete miors trsinintorvol betw en fevsr attacks. Wi p Plicsodiumrvsvmxa ostP. ovole,ateern canecn ssparallel mt Aiphiy tixotiu trstliierec(parahryrerccyt c stjec)t Moreoibr,inoomer porozoitestmay becomstdo sfMt itetrstliiertas “hypnozoites”tbofere t-sete ire smeizogonyt-Whetetrstsexullseferms (gametccytev)earc tgierel bs sinfee ire mo Pito, trsyfcan initiatb trsinsexull eyp ody h ve stjectliathn cycleecreatrrtst As iteannewtginermt tg rie rrrasmituable porozoites. aDiffershtoattimalirials selectevsly killftiesparaafPe’s differshtodethsopmet-2 Pwl ferms.oTosame oft sm onae h tg isecknown ferasomstliathno: pyrimetea-e miie aostdaps n aiin ofP yiold ofel teinrtdy hode (p.hi73), as yoeseceas ouanbdbin(p oouanbl) viaoi s ac ve me abol te.rTosinsulfonamide sulfadoxine inn ofPs syt-sethes s0liadiold ofeltl did (p.hi72)t Chl -inro Pine aost Pinine accumula e wi peuinte- anid c vacuoles liabloodesmeizoNtsin ostiin ofP polymertzmuexo hf heme,ftiee lmt a suosm ane bewretn xof feratiee smeizoNtsiinAttimalirialidrug ceoiceiPwkessd t seaccouNt toler boltox ostplicsodill ey-secism ane.seT ler boltox.oTosafirs aavailaaugseattimalirial,t Pinine, hosdtrstssfllesh tiec use oftmargig.rhts newsr rgenAsinrrefastrsr wbra toler tes. Plicsodiumr(P.) falciparum, ey-secpoteiaug fer treamosh dftgerous fermsensemaliria,aisdpgrratsiaalyopconees ade-invpsop drug eys staonr. ce- iNcidonce hfsepes staotoatrtins rises e pr utprodiresufre Pgacy0liadrug uco. Rys staonrohac n en eyportsd feraihl ro Pine aostatsoinfer treacsmbfrom tg pyrimeteamiie/insulfadoxinetinDrug ceoiceifer attimalirialseihemope phylaxfs.aIn a -as e prairisksensemaliria,acoi inuous iNPwke of attimw-inlirials afferdsetrstbest pe nect tg agtinsh srsidisrode,ldlPecpea nst agtinsh iNfRc ixoi Trsidrug of ceoice isecihl ro Pinet Bocauss liafPsdslow exore-e tsli (plicsestd 1/2 a= 3de osthotger), r0s t-segug ebekly dosctisdsuffoftrht.aIn a -ase e prpes staotoP. falciparum, al ernapevssepegimetceare ihl ro Pine plus pyri-e meteamiie/sulfadoxine (or pe ouanbl,inor doxycyclfre),ltreachl ro Pine aow-inlogue amodil Pine, as wbra ace Pinineinor trstbottt nr ler tes deCOvipevs mefl -in Pine (blood-smeizoNticidal) -Agetts oi-2 Plib agtinsh bloodesmeizoNts do notspey-invpnh srsi(symptom-fren)lhepa oc isfe -e tsli, onlyrtrsidisrode-caussretinfRc tg of eryrerccyteve(“supp y tgrtiec uy”).inOn eytu n srsyn nlendsoic maliriafey-ing tg,ea 2 wk course of peimw Pine s ad-e rquatetferaeradiy tixotof trs la e hepa -seof stjecsr(P.rvsvmxa ostP. ovole).sePe ne h tg srsy mo Pito b tes (net,nskd -coibrpup clothes, etc.) s ainvpry emmortaotoprophylac of mrasu riinAttimalirialitiec uy mplovsatiee same agetts aostf0 basectotnsrsisameinpeintipl-sioTe- blood-smeizoNticidal halofaNtr re s e. Usage fer trer uy ht-selx.eTen ryrimeteamiie-sulfadoxineseonmbfrom tg may be sectfhrsioitialnsele-inra ofmett.inDrug eys staonro s anceler tsretin many endsoic a -as; maliriafvaccines may holdnsrsiga ofest hops feraioi aol of infRc ixoi 294 AttiparaafPic DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttiparaafPic Drugs 295edA. Maliria: stjecsrhf tiesplicsodill . fe cycleoinathn human; sehm p FeierecFeierecPeimw PineecPeimw PineecChl ro Pine QPinineinPe ouanblinPyrimeteamiieecFeierec2 dfvsa:in Teruean maliriain Pl.rvsvmx, Pl.rovole 3 dfvs:in Quartan maliriain Pl.rmaliriaeinNo fevsr portodiftox:in Perniftous maliria:in Pl.rfalciparuminnottP. falcip. Pl. falcip. Hepa ccyteecPeimwryttossueesmeizoNtinSulfadoxineseChl ro Pine Mefl Pine HalofaNtr re QPinineinPe ouanblinPyrimeteamiieecMerhzofPes aHypnozoiteinPee reryrer ocyt c cycleec1-4iebeks Eryrer ocyt c cycleecBloodinsmeizoNtinEryrerccyteinOnly Pl.rvsvmx Pl.rovole Gametccytev SporhzofPes aLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinCe-motrsr ux hf Miliggatt Tumors A tumor (neoplics) cotststs ri csll0inteatrprolsfe atsiinytpethgatlxtliathninbody’s iinershto“buil ire pligi” A mw-inliggatt tumor (caonrr)0isopcy gatewhenintietrumor tossueedetory tvnly invadrc hellthygsurroundwretnossueenn whetedis-inlodgestrumor csll0 ferm secotdwrytty-sem a0 (me ashodes)oinao rsr org ns -Aintsre ey Pirbsetrstelrmfromili ofn ll8mw-inliggatt csll0 (cyrmt ve trer uy)t-Whetintiiss s not poatiels, att mptsrcanln inwide t nsl wanumor .rowlegeostteern-inby prohotgftiespaaieru’s . fe hrsimprcvssequaltox hf . fe (p llimt ve trer uy)tinCe-motrsr ux fstfaceege prte- prob-e lym -hat8treamaliggatt csll0 rrsgethogs-innous8dnd rrefnot ethoweege prspinillsemr abol c pe peruees. Cytosta of0 (A)eare iyton xof aub-inonahces teatrpgrratsiaalyoaf in tprolsfe-inrotsretnr dividpup csll0 -Ropanlx dividpupe maliggatt csll0 rrsgpryferrttiallx t-sejsree sDamjectt nmito ic pe c ssrs nst onlyreytardsetumor .rowlegbutomivealso ititiatb apoptosds (pk grammestcsllinytstr). cossue0 e prail wamito ic rm einrrsglirgsly unef in rt;fhik wide,lmosh ahellthygrossue0t cei0,ahowevsr, ylso a sinpliosgroamaliggatt tumors cotststiog ri slowlx dividpup differsht tregcsll0 -Tis-insue0 teatrhoibea phys 200 cllly n gh mito ic rm e rrsgbound to bs ef in rtabsincytosta of trer uy. ceu0, typ lll ad-invprye0ve in s h a r:seLoss of haia rtst As srsy injurytt sehaia fellatugs; gast oiNtesmioalad smur-inbahces, s ncrea dilrrhel, srsy inad-e rquatetpsphacemeat liashterccytev whose . fe spag is lrmf bd roaa few dfvs;senl sea rnl vomf sretsrsy smimula tg rie a -a poatrl a chsooretapt a0 (p. 330);ru osthowerbsteys staonros ainfe h tg srsy wewkeniog ri re- immun syabso (p. 300).aIn additixo,lcytosta of0 causs b n marrow ytp y tg.eResupplxtliabloodincsll0 ytpethstotnsrsimito ic e h itox oi bon amarrow abso aostdapeateraiells.seWhetemyeloddrprolsfe at tg is yrrsstba, tie shor -liietioranulccytevearc tosafirs in- bs ef in rta(neutropetoa),ltrenabloodinplitsle s ( hrsybopetoa)t nd,ofirally,intreamore long-liietieryrerccyteve(anb-semia).aInferueltox i0 caussdrbsfsupp y tg of spermw ogeoes s ornfellatugaml u o-e tslit Mosh cytosta of0 disrup DNA0ms-2 Pwbol sm. cei0 eMtmilsitrsiriskpatea p -innettial geoomic el er tixotiu hellthyincsll0 (muomgeo c ve in )t Csncesvmbly,intrealmt a accouNts fer sisah a rronce hfseleukemias sevsralnyears afte lcytosta of tiec uyn(carcinogeo c ve in )t Furtiec-sem ae,ncotgenooml malfermw thevearc toecn expRc ednwhetecytosta of0 must bsin sectdy pup pryggaacy0( er togeo c ve-se ict). Cytosta of0 poatelsddiffershtome o-e at sms onae h tg. Damjectt nsrsimito ic apindlc (B).inTen ioi ae h le pe neins ri re- apindlcinapparatu0 must draw a grrotre psphiy t- estchrsyosomesgbofere teercsll canldi-e vide. cei0 pe c ss0isopcyvsntba bsftieinoo-clllel pindlc poisons (seb also ? 2-e ceicine,np. 316) teatryrrsst mitosdsiate mr aphoderby disrup tre srsiassemblysensemice nubulss in- a pindlc threads.inTenrvsncaralklloidsetvsnc is ine aostv t-seblastine (srsynpos portwinklespliNt,oV t-seoa rosea)texer s ncrercsll-cycle-spinifbyineffin sDamjectt nteernervous syabso isecafprydiftes dvpryr ve in aaissretsrsye injurytt nmice nubuls- per tes xxolle rrrasmort me oft sms. Pacltoaxel,esrsynpos barkrhf tiespo-e nifbylyew (Taxus bcyvifelta), inn ofPs dis-inassembly nsemice nubulss ostiiduces atyp lll i es. D c oaxelaisdafsemisyt-sethe ofideCOvipevsi 296 Atticaonrr DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAtticaonrr Drugs 297edA. Ce-motrsr ux hf tumors: peintipal8ditiadvpryr ve in sinBi Cytosta of0: inn ofPin of mitosds aMaliggatt tossueede prnumerous mitoses aWantba ve in :infnn ofP lieli tumor .rowle Hellthygrossueede prfew mitoses aLittlr ve in Hellthygrossue welesenumerous mitoses aLymph nsderuInn oft lieli lymphocyte mu Aiphiy tixo:seimmun wewkn ss Unwantbaineffin s Dilrrhel G amfrolincsll damjecseLowerbsteys staonros ininfRc li Bi e marrowinInn oft lieli oranulc-,insercybocyto-,in osteryrercpoies s Vsncainalklloids Vsnca rosea Pacltoaxel aWesternlyew trle Damjectt nhaia fellatug Haia lossinInn oft lieli ephithelill eynewal Cytosta of0 fnn ofPincsll d itsin suInn oft lieli fermw the aMice nubulsssensemito ic apindlc Inn oft lieli degradw the aLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIsn oft lieliaDNA0rnl RNA0syt-sethes s0(A). Mitosdsiisopcyceeba bsfrepli-secat lieliachrsyosomesg(DNA0sytthes s)in ostiitprodel pe nein0synthes s (RNA sytthes s). Extstiog DNA0(gray) Usags ac a0 mplits fer sisa ynthes s of newec(blus) DNA0surRNAtsDefnovo0sytthes s may be fnn ofPba bs: Damjectt nsrsi mplits (1) -Alky-e la pup cytosta of0 rrefrean lib csm- Mpound0 teatrrrrasferralkyl d.s dyesed t sea csvolentrnonege prDNAtsFhrsioonahce,e mrchl reteamiiea(nit ogentmustard) dhinableo- ce ss-link doublr-torandtd DNA onfgiilng rifnfPs ceas freiatomctoCnrrin sepeadiog ri ginetic infermw thetf0 trsce-inby ondered dmpoatiels. O rsr ylkyla -seoog ygenAsfare ihl rambucil,emelphalan,inseio-TEPA, cyclophosph mide (p. 300,in320), ifosf mide, lomustine, aostbust -e fait Spinifbyladvpryr rean lons srthe sseorpsvpryiaug pulmxolrytfibk s s duetroinbusulfa aos hsoorrhag c cysu t srucaussa bsftiescyclophosph mide ms-2 Pwbol teae rolein0(pcyvsntableobsftieinuk pe nectahtomesna).aCispla pu ninds s in(butoyors nst ylkyla s) DNA0torands. Cystosta of attibio of0 fnsertathno-seselvss in- athn DNA0doublr0torand; reis may lyadr- a mr ndobreakage (h ametweleseblromycin). ce- atthracyclfre attibio of0indaunorubicin8ditiadriamycin (doxorubi-e nin)omive tby b cardiomy paahx. Ble-inomycin canlalso ?auss pulmxolrytfibk -secis.inTenrepipodophyllon xons, etop -secide ostteo poesdr,aintorsctge prtop -seisomeroderII,rwe me falctixos to spl t,e rrrasmose,aand d. Ull DNA0sorandsec(p.hi74); trsse ygenAsfcauss smr ndinbreakageobyainn oft ng d. Ull ngtinIsn oft lielianucleobodeesytthe-secis (2). ce roold ofeltl did (THF)aisore-se Pirsd fer sisa ynthes s of no prpu ir- basesranl hymbditetsFhrmw the oiaTHFsufrom feltl did involvesnyiold ofel teinrtdy hode (p.hi72). ce- fel te analoguese aminopte ir8dnd methotrlxits (ams-2 Phopte ir) inn ofP enzym e h itox ac falee suosmr tes.aAs cbrauiaa sto rstof THFsurrefytpleted,a ynthes s of DNA0rnl RNAinbuil ire blocksacrodest-Tos ve in li trsse ynsims abol tesacanln r.vpryrdinby admiion. Im tg of fol ntl did (5-f rsinmyl-THF, leucsvoron, cit ovorum foi-2 Por) inIucorperm theson falee buil iree blocksa(3)t unnmuu al nucleobasesr(6-e mercaptopu ir-; 5-fluorourscbl) nr nu-e cleosddrs e pr utnrrin suga 0 (cytarw-inbine) e h as ansims abol tes.-Tosy inn o-2 to DNA/RNA0synthes s er lyadr- a ytthe-secis nsemissenasanucle l dids in6-Mercaptopu ir- rtst As srsy bio-e rrrasfermw the oiathn inantsve peea r0orsurzaseiop ir- (p. 37). ce- uticosta of all -inpu irol inn ofPs trsidegradw the oia6-e mercaptopu ir- s ncrreatrco-admiion-e rrr the oiathn two drugs pop irs doscinrtdy hixotof trs la i Fre Pgatly, poneonmbfrom tg liacy-2 Posta of0 pop irs anlimprcvsstteera-sepRe oftve in e prfewerladvpryr rean-e tslist Ioitialnsunceleacanln fell wrtabsinloss of ve in bocauss liatrstemergencr ofapes staotorumor csll0. Me oft sms onsepes staoce rrsgmu Aifoi o ial: Dimiionhregcslluiaa upPwke miveey-secu A srsy r.duced ynthes s of arrrras- Mport pe nein0reatrmay be neeeba forinmembtone pete rotin (h ametmetho-inra xits) inAugmsntba drug extrusthe: t-setprodel ynthes s of trstP-glycope neinin-hat8sxtrudrs drugs srsynpos csll (h ameinatthracyclfresetvsncaralklloidsetepipo-inyophyllon xons, ostpacltoaxel)aisore-sepoteiaug fer mu Ai-drug eys staonrec(mdr-1 gine amplifby tin ). Dimiionhregb oantsvmt tg ofdafpro-indrug,oh ame cytarwbine, we me ey Pirbsinintracslluiaa phosphorylIm tg - bs-seonme iyton xoftinCeftgetiu s te ofn c tg: h ametin-setprodel ynthes s of yiold ofel teore-sedy hode wiveh a r asaeacsmpenswf aysepespotectt nmethotrlxits. Damjectrepaia:aDNA0repaia t-sezym stmay becomstmoce effoftrhttiu re-sepaiapup de in s caussa bsfcispla pui 298 Atticaonrr DrugsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAtticaonrr Drugs 299 A. Cytosta of0: ylkyla oog ygenAsfaitioytosta of attibio of0 (1),infnn ofP a0 hf re roold ofel teosynthes s (2),ldisims abol tesa(3)seinsteadpate insteadpate Damjecses andmplitsinAlkyla ohe ah ametbye mrchl r- eteamiieecIssert tg li daunorubicin,inyoxorubicin,inblromycin,se ctsnomycin D, etc. aStrlptomyces b-c iainIsn oft lielianucleotsdr sytthes s Pu ir-s ThymbteruNucleotsdr Te roold o-e fel teinDiold ofel teinRtdy hode Feltl didinIsn oft liebye Pu ir-ldisims abol teecIssert tg lir utnrrin buil ire blocksinPyrimbdite disims abol teec6-Mercaptopu ir-sufrom Azaseiop ir- Adetore Urscbl Cytar bone Cytosfre CytosfreruDesoxyribode insteadpate 5-FluorourscblruAr bonode Aminopte irecMethotrlxits DNA DNA0DNA 3in2 1 RNA Buil ire blocksinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIsn oft lieliaImmun RespotecsinBo prte- prevsnt li hf -e tsli eostteetra ofmett hf autoimmun indisorder0 call feraafsupp y tg lir o-semun pespotecsi Howevsr,8immun insupp y tg ylso eMtmilsiwewkenes de-se insesragtinsh iNfRc ixus pgahogeos ndina long-nd ctiitprodeoinathn riskpatene -inplicssiinAr pinifby immun pespotectby-ing os h prpos bindire of attigbn byalym- Mphocytes ,srrsire spinifby retapt a0ede prsrsia prop i te antigbn-bindiresecite.rB-lymphocytes “recognize” antigbninsurfoib sory u -sgbsfmeaoseliamem-inbtone retapt a0 reatrrtsemblersrsiatti- abodies fermba suose Pgatly. c-lympho-incyteve(and nasve B-csll0) ey Pirbatieseattigeo to bs pcy gatectotnsrsisurfoibsensemacrophjecsrhrao rsr csll0 inncst-sejsnctitg welettreamajerahis ocsmpa -seoboltox csmplex (MHC); trstlmt a pd -e mirved.cognit tg ofdattigeo c sory u -sinby meaoseliatrstT-csll retapt a. c-help-e er csll0 ,srrsfedjaceh CD-3 eostCD-4seonmplexesetiyton xof T-csllsaeaCD-8seonmplex. ce- CD pe neins ass st inndock-seoog - athn MHC.aIn additixo - ad.cogni-e tsli ofdattigeo, antsvmt tg ofdlympho-incyteveey Pirbsesmimula tg bsfcytokites. aIsterleukin-1 is fermba by macrophje-sees, ostvarious iNPerleukinve(IL), inthe -seoog IL-2, rrsgmide by c-helperaiells. Asseattigeo-spinifby lymphocytes prolsfe-inrote,8immun de inses rrsgset in- amo-e tslitinI. InPerfershnroweletattigeo rs-seongnit tg. Mursyonab CD3aisdafyono-inclxofl attibodygdirRc ednagtinsh moitsinCD-3 reatrnlocksaettigeo rscognit tg bye T-lymphocytes ( tin ). II. Inn of tg liacytokiteopcoby -e tsli orae h tg. Glucocsrratoids mo -seula e trstexp y tg lirnumeroussu.enes; reu0, te- prody hixotof IL-1 ndinIL-20isiiun ofPba, we me explains th insupp y tg of T-csll-ytpethgatr o-semun pespotecsi Glucocsrratoids arsin sectd nngft rrrasmliNtw thev, autoim-semun disrodes,8dnd rllerg l disorder0. aSyabsoic udetcarriesitrsiriskpatei tro-su.enof Cushlng’s sytdrcme (p.hi48). Cyclx porin A is yiaent bio of poly-sepRptsdr srsynfalginditionsststs ri 11,tin grroatyp lll,famino dids Giibn orllly,2 to is absorbes, albeto itcsmpletely.oIn lymphocytes, t f0 bound bsfcyclopholtn,se ioytoseltl retapt a reatrinn ofPs trssephosphahode calcineukioi Trsilmt ainpliysdafkey roletd T-csll cignalitrras- Mdy hixotoIt ioi aibutesmr are- iNdy hixosensecytokiteopcoby tixo,linthe ire teatrriinIL-2ioTe- breaksrrcpeaseliamoderne rrrasmliNtw the medicine rrsglirgsly a -se aibutableo- re- iNtrody hixotof nyclosin porin A. Pe mbtehtoamotgfirs advpryeinee in s rrefpsnal damjecetolperuenafhe,inaos hlperkelemiaiinTe rolimus,ra me rolide, deriibssufrom d strlptomyces spinies; plogy -seon200 cllly itrrtsembles nyclo porin A,inbutoisimoce poteat osteffofaftous.inTenryonoclxofl attibodiesidacltzy-semab aostbasoltximab nind tortrstα-inchaineliatrstII-20retapt a of T-lympho-incyteve ostteusfpryvshtothnir antsvmt tg,ine ametdy pup tslitinIII. Disrup txotof nsll me abol smede prinn ofPin of prolsfe at tg. Atinyosjecsrbshowothose neeeba torta ofe maliggatnies,asomstcytosta of0 rrefalso mplovectfhrsimmunosupp y tg,oh amesurzaseiop ir-,nmethotrlxits,faitioyclosinphosph mide (p. 298). ce- attipe -inhsfe at vs ve in s not spinifby fhrslym- Mphocytes ostiivolvesnno prT-aand B-incsll0. aMycophenol te mofetil hosdaimoce aspinifbylve in ln lymphocytes resn xosen rsr csll0toIt inn ofPs inosfrefyono-inphosph te deold ogeomse, we me cata-selxzes pu ir- synthes s in lymphocytesiinIt isi sectd e ute rossue tsli ey-secpoteesiinIV. Atti-T-csll immun serum s ob ainbdtsrsyn nimals immunezednwelesehumanlT-lymphocytes. ce- attibodiesinbind roaaostdamjectT-csllsaendtcanlthuc n i sectroaat nuatetrossue tsli. 300aImmun Modylat a0edLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinImmun Modylat a0 301inAttigeo Macrophjec aMHCtII MHCtI GlucocsrratoidssuInn oft lieli srrascripPixosensecytokiteo,inh amesu IL-1 IL-2inCD4 CD3aCD8 CD3inMursyonab-inCD3inMonoclxoflseattibodyinB-Lymphocyte T-Helper-incsll T-Lymphocyte CyclopholtnsuInn oft li Calcineukio,se iphosphahodeinTrrascripPixoeli cytokiteo h amesuIL-2inCyton xof,seattiprolsfe at vssedrugs aAzaseiop ir-,ecMethotrlxits, Cyclosinphosph mide, aMycophenol tesem fetilinPe lsfe at tgindiffersht t tgind t nplicsescsll0inCyton xofe T-lymphocytesinCytokiteo:seihemotaxfsinAttibody-mediarbdinimmun pea hixoseImmun pea hixo: delayelsehlpersenafPivtox Elrmfromili of “fereigg” csll0inA. Immun pea hixo ostimmunosupp y ibssuUpPwkeruDegradw the aPcy gatw the aMHCtII aIsterleukins aVtrus-iN ictes cell,e rrrasmliNtes cell. tumor csll Synthes s of "fereigg" pe neins aPcy gatw the aologocytosfsruDegradw the aPcy gatw the aIL-1suIL-2inT-csllsepetapt ainaos Cyclx porin AinIL-20petapt ainnlockade DacltzymabinBodoltximabedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttidoteve ostta ofmett hf poisonpupsinDrugsm sectroacouNtorsctgdrug ovpryos-ulage arn csNsddrrsd underrsrsia prop i-ula e headiogs,oh ame physostigmiieae pseatropir-; naloxoieae p opioids; flP-semazenolge prbenzodilzepir-s; nti- abody (Fab fragmsnts)ge prdigoomlis; ndinN-acetyl-cysneinroweletac oaminophenininn xofomilit Chela oog ygenAsf(A) sUsag as ansi-inyo estin poisonpupowelethemvy me alsiinTenxtan troacomplex nd,oreu0, “inantsv-ula e” hemvy me al slist Chela es (srsye Greek: chsleo= claw [nsecrayfish]) eyp y-sesett cnmplexes betw en a me al sliin ostmoleculss reatrcarrsfsevsralnbind-seoog sites forttreame al slit Bocauss li trsirdhmncsaffontox,rchela oog ygenAsf“a -se aant” me al slisopcy gateinathn nngft-seism. ce- chela es rrefnon-n xof, rrsgex-setprtel peed mbtaatlxtviaore- kidney,2 main ain arreser nngftome alltl noneinalsoeinathn csnceh Imes, usufllxtanid c,2 molteu hf tubuiaa urine aostteusfpro-sem e trstelrmfromili ofnme al slistinNain2 Ca-EDTA isi secttorta of lyadsepoisonpup. cei0 attidotercanestepete-e rrr e nsll membtones ostmust bsfgiien grshterfllxt Bocauss liafPsdhmncsbindireseaffontox,rtrstleadpili displaces Cain2+sufrom2 tos nonei Trsilead-isn ainpup chela e s elrmfrombsteynfllxt Nephk n xoftox p y-sed mbta es rmotgftiesunwantba ve in stinNain3 Ca-Pshteta e saeacsmplex of yiete-inylete riaminopgatwac otl did (DPTA)in ost Usags ac attidoterin leadpyiti tosrinme al snn xofomilis. aDimercape l (BAL, Br t sh Atti-Ly-sewisite)geea dethsopectd World Waa II aas yiaent doteragtinsh agsicaot nrgft lsurrsenofals (B). Io is ableo- chela e vari-inous me al slist Dimercape l ferms a li-sequan,nropanlx decomposlng suosm anein-hat8is giien it romustsiaalyoir8dn oilysevehatug -Arreia ed compound,ono priirut amcensesory u -8dnd r h itox,aisddi-e mercaptopropauesulfontl did, weode sodiumrsa Atisdsuitaaugafer oral admiion-e rrr the. Shiibrpup, fevsr,faitiskd rean-e tslis rrsgponettial advpryr ve in s. ruDefor xamiieaderiibs srsynpos b-cte iumrStrlptomyces pilx us.rTosinsuosm ane poatelsgs aaierxehmncsirot-sebindire capaftox,rbutoyors nst weledrawseortg srsy hemoglobd nn cytocercmesiinIt isipooalyoabsorbes shterfllx ostmust n igiien grshterfllxo- caudeointprodel exoret tg lir rhe. Oral admiion. Im tg isseoodiy tectotlyoif shterfllebsorp the liseortg is to bs curtmilge sunwantba ve in sseooohe s rllerg l rean lons. Io should n innotsthresh bloodelettsretis treamosh ee-infin svn meaoseliaremoilng ortg srsy thninbody;ahowevsr, tiissmethostf0 unsuit-inableofortta oflng ons of licenseortg ovpr-seloadpyssoc trege prauemiaiinD-peo ctllamiieacanlprcmotb trsinelrmfromili ofncoppera(h ametin Wilson’sindisrode)geostnse.eadpilis. Io canln giien orfllxt Two additixoll ucosfare iysu nu-e riaf nd dheumw oid acsrr t s.aIn te- fsu-e meretfermwhixotof nystine sti estinrtrs urinwryttrsctgisopcyvsntba bocauss trs drug can ferm a disulfide e pryysneinrin-hat8is ryadfly soluels. In te- lmt a,epet-seictllamiieacanln i sectosdaibasll eygi-e men (p. 320). ce- tiec use oftve in miveeycu A in grA srsy a pea hixo e psealdeoldes, wepreby polymertzmuexo hfseon2lagentmoleculss d t nfibkilsiisiiun ofP-seee sunwantba ve in sfare: utareousindamject(dimiionhregeys staonros ams-2 oft lll strls0 e praitondtacy0t nfermsebhierers), nephk n xoftox, bi e marrowinytp y tg,faiti ashe d smurbahces. 302 Attiyo esedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttidoteve303 EDTA: Eteylenesiaminere ro-acetitsinAt Chela tg ofdleadpilis bsfEDTA aDimercape l (i.m.)inDMPSruDefor xamiieaD-PshictllamiieinBi Chela a0edNain2 Ca- EDTA Dissolum tgtof nystineinonoteo:seCysneinr-S-S-CysneinrinInn oft lieli on2lagen polymertzmuexoruArsenof, mercurx,2 goldnixos Dimercaptopropaueinsulfonatsinβ,β-Dimeteylyysneinrinchela tg e pseCuin2+sua ostPbin2+su2Nain+ Cain2+suFein3 + CHin2 CHin2 NinN CHin2 CHin2 CHin2 CHin2 C C C C O - O - O - O - O O O O Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttidoteveferaiyanbdb poisonpupec(A). Cyanbdb lice(CN - )8shteratrstnngft-seismeinathn ferm of hld oiyanbl didin(HCN); trstlmt a canln iinhales, re-e lyasbdtsrsyniyanbdb sa Aseinathn anid cinonommch ju Neteraenzyma offllxolibe at-seee srsy bit a almxodseinathn gast oiN-e tesmioalatrscti Trsile-hal dosctof HCN canecn ssil wassi50 mp. CN - ninds weleth gh affontoxttortaivolentrortg eostteernby au-e rsst0 utilezw the of oxygentviaomito-2 oxodrialicytocercmetexodIscsrhf tiesepespirwf ay chain. At io ernal asphyxio-e tsli (his on xof hypoxoa)tshsues whiug eryrerccyteved.main chargrege prOin2 (vsnous bloode? 20rsd breser r.d) inIutssfll amouNts,niyanbdb canln incsnver bd roatre psla tvnly nonn xofe seioiyanits (SCN - )8by hepa oc “rhoso-e teoe” lr tulfurrrrrasferasetsAsdaiteera-sepRe oftmrasu r, tiiosulfate canln giien i.v.rtolprcmotb fermw the oiathioiya-senl e, we me i0 elrmfrombstin urinei How- eibr, tiisspea hixo isdslow ii onset -Ainmoce effin svn emergencytta ofmett isintreai.v.radmiion. Im tg of treame he-semoglobd -f rmoog ygenA 4-dimeteyl-e aminophenol, we me eopanlx ginermtesedtaivolentrsrsy divolentrortg iu hemoglo- nintoCnmpetit tg betw en me hemoglo- ninfaitioytocercmetexodIsceferaCN - ixos faversathn fermwhixotof nyanme hemo-su.lobd i Hld oxocob-lamii is yiael erna-2 Plib,aierxeeffin svn ent doterbocauss itsseceh Il onba Atatom ninds CN - weleth gh affontoxttorginermte nyanocob-lamii.seT lxooum ceas fde (T lubditecBluc)t Brow -co20rsd me hemoglobio,seisn ainpup tai- insteadpat divolentrortg, is iNcapableoof nsrrsire Oin2 sunderrno -e mal ons of lic, me hemoglobiogisopco- Mdy edniottinuouslx,rbutor.duced agtinede prsrsihelp ri glucose-6-phosph teinytold ogeomse. Suosm anes teatrpro-sem e fermw the oiame hemoglobiog(B) mivecauss aile-hal defoftrhcy0liaOin2 sT -inhotoum ceas fde saeaeed x dye reatrcan n igiien i.v.rtolr.duceame hemoglobio.inObidoxime is yiaent doter secttoinra of poisonpupoweletinsen icidesmhf tiesenngftophosph te type (p. 102). Phos-ulphorylIm tg ofn cetyl oxlfresteraserucausss en irpsvpryiaug inn ofPin of ce-2 Pyl oxlfre breakdown aos hsonroflood-seoog of treaorgao sm welettrearrrasmit-e ter. Poatiels se Pglae rrsgexagger tes grasympgahomimetic e h itox,rnlock-e adeoof gaoglioo c and neuk mustsiaae rrrasmi tg,faitipespirwf ay paralycis.inTenc use oftmrasu rs srthe s: 1.e admiion. Im tg of atropir- iu hmncsyos-ulage - a Alllstmuscaainbl detyl oxlfresepetapt as; nd 2.frean liIm tg ofn cetyl-2 oxlfresterase8by obidoxime, we meinsuncelesvnly ninds s trstenzym ,siap-e u -sgte- phosph te d.s dye bs s nu-e cleophiloffattack, eostteei dissoc trssufrom thn an lib cshteratoed.fyase trsten-sezym srsy inn ofPin i FerroffFerroiyanbdb (“BerlitecBluc,” B) isi secttorta of poisonpupowelein-halliumrsa Asa(h ametin rof poison),ftiee ioitialnsymptomsmhf we me rrefgast oiN-e tesmioalad smurbahces, fell wrtabsrnervein ostbrtin damjecetas wbra acehaia loss.inTealliumrslisopcy gateinathn nngft smedrrsgsetprtel in- athn gutrbutoundergosepeabsorp the. ce- iNsoluels, nonabsorb-inableoon2loidal Berlit Bluc ninds seallium ixos. Io is giibn orlllyrtolpryvshtoabsorp-e tsli ofda utelyoirgierel -halliumrorttoinpecmotb alearaonrofrom thn nngft smedbyaino cep tre sralliumr-hat8is setprtelind t nre- iNtesmiors. 304 Attiyo esedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttidoteve305inNit feg2 Potasdlum cyanbdbinKCN Hld ogeo cyanbdbinHCN RhosonsseedSulfurrdon a0edNain2 Sin2 Oin3 Sodiumrtiiosulfate SCN - H + + CN - FeinIII a-HbecMethemoglobio fermw the aDMAPinCsmplex fermw the aHld oxocob-lamii aVtt.B 12aseCyanocob-lamii Vtt.B 12suFein3+ aMitocexodrial cytocercmetexodIsc A. Cyanbdb poisonpup8dnd rttiyo esedSuosm anes f rmooge meteemoglobio Hin2 N AtilfreseOin2 NinFeinII a-HbecT lxooum ceas fde (t lubdit blus)seOngftophosph tesine amet ParaoxoiinRtan liImelinAdetyl oxlfreseesteraseruPhosphorylImba, inantsvmtelinRtan liImor:seobidoxime FerroffferroiyanbdbinTeallium ixoinBi Poisons dnd rttiyo esedH + K + FeinIII a-HbecNit obenzerese=inTl exoret tg “Prusdlat Bluc” FeinIII a [FeinII a(CN) 6in] a 34inTl + Tl + Tl + 2 Clin- 2 Clin- Inn oft lieli oslluiaa pespirwfohe ah amet NOin2 -edLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAtgina Pei o isinAtndigioalapain attack cignals arrrra-sestrhtthypoxoa of treamyocardiumtsAsdasepule,ateeroxygentdefofttrrtst As srsy in-e adequatetmyocardialnbloodeflow duetroinnarrowoog of lirgsraiorxolrytarterees. ce- underlyire caucosfare:amosh csm- Mmotly, yiaeteerosalero of ceftgethf tiesevastsiaa wfll (iorxolrytsaleros s weleinexer ixofl atgioa);aierxeinfre Pgatly, asecpicsodic onsstr mt tg ofdafm rph 200-seicllly nellthygiorxolrytartery (iorxolrysecpicsge praugina atrrtst; variaat ogi-e oa);aer moce ofteo, agiorxolrytcpicsgon-e a rrsretinryiaeteerosalero of vastsiaasesegmett.ince- goll iftta ofmett isrtolpryvshtinmyocardialnhypoxoa ei rsr by aisiree bloodeflow (oxygentsupplx) nr byalower-seoog myocardialnbloodedemditi(oxygeninytmdit)0(A). Foi o s dete miooog oxygentsup-ulplx.eTen f rcsidriilng myocardialnbloodseflow isrte- pressu rddiffershne betw enintreaiorxolrytostia (asrrat pressu r) ndinteeropeniog ri re- iorxolrytcinus (reserseatrialnpressu r). Bloodeflow s opmosedinby iorxolrytflow eys staonr, we me in-setludrs three compotehts. (1) Duetrointrsirdlirgs cllibe , te- proximal onro-e oarsfsegmsnts do notsnermwlly ioi aib-seuteosignifby atlxtt nflow eys staonr.inHowevsr,8in iorxolrytsaleros s aincpics, pgaho200 cll obtory theson flowinh a rs he -t-Whe -as treamore csm- Mmot iorxolrytsaleros s canesten iovpr-secomstplogy ? 200icllly,rtrstleleacsm- Mmot iorxolrytspicsgcanln r.lievrtabsina prop i te vasodilat a0 (nit ates, ni-e fedipir-). (2) ce- cllibe ofdartereoiaa pe-secism ane agsselsaioi aolsnbloodeflowinsercpea re- iorxolrytbge sArtereoiaarucalibe is dete miora by myocardialnOin2 uenafhee osthocal onsceh Im licenssemr abol c pe dy hs,8dnd isf“aunommti-secally” adjus bd roatre ps Pirsd bloodseflow (B, hellthygsuo ter). cei0 mr abol cinauto rgula tg explains whyndigioalaa -se acks8in iorxolrytsaleros s a r only dy pup exercide (B,spaaieru) -Atrrtst,ftiee pgaho200 clllxt.fyvmtelnflow eys staonrrui0 csmpenswfel bs s tnrricpotdpup de-setprodetinryrtereoiaa pes staonr, shsurireseadequatetmyocardialnperfu tg.eDurireseexercide, furtiec dilat tg ofdartereoirs ssseompoatiels. Asaeaeest A,ateern dsiischso ainassoc trege prpain. Plogy ? 200icllulagenAs teatran troadilatedartereoirs wouldinseus bn ina prop i te bocauss atrrtstintrsytmay diibrtrbloodefrsynunderper-inf sectd t nhellthygvastsiaa eygilicennseaccouNt liaredundartryrtereoiaa dilat tg.ince- pest Asret“stealeeffin ” could pro-sevoke yiaengioalaa ack.a(3) ce- iNtra-semyocardialnpressu r,8i.e., syabol cins Pgeze,ncompress-sgte- copallirytbge aMyocardialnbloodeflow icehaltectdy pup syabol-8dnd h a rs almxst8shtirslx dur-seoog diaabol-t Diaabol c wfll uenafhee(“p y-seload”) ytpethstotnvshtratsiaa v lumein ostfallpup pryssu r.eTen nrgft l nit atesinrtdy - preloadpbx decprodire vsnousinrttu n roatre helrt. Foi o s dete miooog oxygentde-semdit.eTen helrttmusclercsll clicumesintreamost8shergxttorginermte noi ae h le fernr. Oin2 demditirises e pran intprode ite(1) helrttrote,8(2) noi ae h otnvshoctox, a(3) syabol c wfll uenafhee(“afte load”).ince- lmt a ytpethstotnvshtratsiaa v l-seume aosttee syabol c pressu rdneeeba to mptsftiesvshtratls. Asaportpherfllpes s-se aonro ntprodes,8dsrrat pressu ririses, aheonrose- pes staoce rgtinsh we me vet-2 Pratsiaa bloodei0 ejictes. Oin2 demditisssehowerbstbx β-nlocker0 eostCa-iNtwgo-e otstsetas wbra acebsrnit ates (p. 308). 306 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 307inBi Pgahogeoes s of exer ixoraugina in iorxolrytsaleros sseOin2 -supplx dy pupindiaabol-seOin2 -demdit dy pupinsyabol-inFlow eys staonr: 1toCnrxolrytartereal calibe in2 sArtereoiaarucalibe 3. Syabol c wfllsu uenafhesu = Aftt load 1toHelrttrotein2 sCoi ae h otsu vshoctox Portpherflsepes staoce Vsnousinsupplx Hellthygsuo ter Pgatrhtte pryorxolrytsaleros sseRtstinExercide A. Oin2 tsupplxaaostdemditiof treamyocardiumedNarrow WbdbinCsmpensw-2 Porx dilat tg rie a tereoirsseRoteinCoi ae h otsuvshoctox Aftt load Wbdb WbdbinAdditixoll dilat tginnottpoatielsinAtginasepRi o isinLefAtatriumedCnrxolrytarteryinLefAtvshtratls aPcy su rip Vol.Vol. aPcy su rip Reserseatriumedp-forince Time Aorta 3. Diaabol csu wfll uenafhesu = Preload Vsnousind. UsaoiredLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAttiengioalaDrugsinAttiengioalaagenAs deriibofrom thrle drug grcpp0, te- plogy ? 200icll pe p- erueesmhf we me hoibealryadytbgen y-sesettbstin more detail,eviz., thn nngft ce ott ates (p. 120), thn Cain2+suiNtwgootstsec(p.h122),ldisttee β-nlocker0 (pp.h92ff).inOrgft l nit atesf(A) iitprodeobloodseflow, hsonroOin2 supplx, bocauss diaabol csuwfll uenafhee(preload) ytclfres acevs-innous8rttu n roatre helrtaisddimiionhretinTru0, te- nit atesfenableomyocardialseflow eys staonros an r.duced eien itintreapcy gaceoof norxolrytsaleros s weleinaugina pRi o is.aIn augina duetro onro-e oarsfspics, artereal dilat tg oibrcomssintreavasospicsgaitipesto rstmyocardialseperfu tgtro nermwl. Oin2 demditifall0inbocauss liatrstensuiup detprodeoinathnintwo variablss reatrdete mior syabol cinwfll uenafhee(afte load):nvshtratsiaa fall-seoog v lume dnd rsrrat bloodepryssu r. Calciusgaitwgootstsg(B) detprodeseOin2 demditibyalowerpup8dsrrat pressu r,inonctliathn compotehts ioi aibutoog - afte loadi Trsidiold oryridite nifedi-ulp re s devoid ofdafcardioytp y artree-infin ,gbutomivegiibiriseatoed.flex achy-secardia dnd rtpyssoc tregiitprodeoinaOin2 demdit. ce- catamphiphiloffdrugs ve-inropamil8ditidiltilzemfare iardioyt-ulp y art.eReduced b of fre Pgacy0dit noi ae h ltox csi aibute roaa rtdy hixotitinOin2 demdit;ahowevsr, AV-nlock8dnd me-2 oft lll insuffoftrhcy canldftgerouslx jeopardize helrtafalctixo.aIn iorxolrysecpics, calciusgaitwgootstsgcan inducesecpicsolycis ostimprcvsnbloodeflowin(p.h122).inβ-Blocker0 (C) pe nectatre helrt agtinsh srsiOin2 -wastiog ve in linsympw-2 Phe ofidriibobyainn oft ng β-petapt a-e med tregiitprodes8in iardiac rm e rit speedoof noi ae h ot.inUscsrhf attiengioaladrugs (D)tsFhrind.lieftliathn e ute engioalaa ack,nrop-seodlyoabsorbes drugs devoid ofdiardioyt-ulp y art e h itox arsgpryferree sTrsidrugsenseceoice is nit oglyce ir8(NTG,in0.8–2.4 mg suolpupufllx; onset ofn c tgede pir81 roa2 mio; durat tg ofdve in ~30 mio). Isosorbbdb dinit ate (ISDN) canlalso n i sect(5–10 mg suolpupufl-sely); comparrege prNTG,firs a hixo is someweatrdelayel ii er durat tgtsFirally, nifedip re may bein seful8in ihroo c soaels, hrsio variaat o-ing oat(5–20 mg,siapsulros an bit n ndinteernoi ehts swfll wrt). Flr tus ainbdtdaysims augina pro-sephylaxfs, nit atesface of lrmf bd valueedbocauss “nit ate paucos” lfn bouto12 p rrefa prop i te if nit atenr ler onro s toecn avoidee sIfaa acks a r dy pup rrs day, ISDN, hrsit0 mr abol e sosorbbdb Mmotonit ate,rmay be giien it treamorn-seoog dnd rtsnen (h ametISDN 40 mg ingex-setondtd-d.fyase iapsulrs). Bocauss li hepa oc p y yabsoic elrmfromili,rNTG is not suitaaugafer oral admiionrrr the.inCoi inuousrdeliierxeviaoarrrrasdermwle pgame wouldlalso not seemfadvisaelsinbocauss liatrstponettial dethsopmett hf2 Poler onr. Wb prsolsid mbte,ateern dse lyssiriskpatea nit atenr ler onr;ahowevsr, dyros aitstponettial carcinogeo ctox,aitssecl ntlll uco s e. tr mtretinTreeceoice betw en calciusgaitwg-inootstsgmust Pwke d t naccouNt thrddiffe-e rsttial ve in linnifedip re vpryus verop-seamil8nr diltilzemfon iardiac perfo -e maonro(seb abcvs)t-Whet β-nlocker0 ece agiien,atrstponettial clice Pgaceseliare- Mdy ire cardiac noi ae h ltox (weledraw-seal linsympwPhe ofidriib)tmust bsfkapttitinmbte sSiane aasodilat ng βin2 -retapt a0edrrsgblocked,ran intprodediriskpatevw-2 sospicsgcanesten ipuled outi Trsrofere, Mmototrsr ux e prβ-nlocker0 mendectotlyoin augina duetro onroolrysecaleros s,gbutoesteio variaat ogina. 308 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 309 D. Cl ntlll ucosrhf attiengioaladrugsinBi Ee in s hftCa-iNtwgootstsecOin2 -supplx Oin2 -demdit Aftt load RoteinCoi ae h otsuvshoctox Ai Ee in s hftnit atesinCi Ee in s hftβ-nlocker0inExercide RtstinSympwPhe ofinsyabeminβ-nlocker RtlaxaPixosenssepes staoce agssels RtlaxaPixoeli onrxolrytspics Ca- iNtwgootstsecAftt load Oin2 -demdit p aPcyload Nit atesfe ametNit oglyce ir8(GTN),lIsosorbbdb dinit ate (ISDN) Nit ate2 Poler onr RtlaxaPixoeli onrxolrytspics Vsnousincapaftoaoce agssels Rts staoce agssels VasortlaxaPixoseAugina pRi o isedCnrxolrytsaleros s Cnrxolrytspics GTNetISDN Nifedip reseLong- ctsngtnit atesinCa-iNtwgootstsβ-nlocker Trsr ux hf a ackseAuginal pe phylaxfs p DiaabolstpSyabol-inVol VoledLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinA ute MyocardialnInfarc the aMyocardialninfarc the i0 caussdrbsseacute rercybo ofi alu tg of a onroolryseartery (A). ce-c use oftino vsnt li0edrimatoed.sto rnbloodeflow inathn ncthe -sebd vgsseltd nnderatoed.dy - infarc sizesennatoed.scueiischso ctmyocardialnrossue inIutthn e -a perfu sa bsftiesef in rtavgs-sesel,8inadequatetsupplxtliaoxygentdit glucosetimpairsathn fsnctitg of helrt muscle: ioi ae h le f rcsidtclfres. In te- oreatrmajo iox hf codes,8trstlefAtvshtratls a(antbrier or poatbrier wfll)iisiiuvolveetinTreedetprodeegeork capaftox liate- iN-infarc sd myocardiumdleads roaa rtdy -e tsli iu st oke v lume (SV) aos hsonrsecardiac outputo(CO). ce- ffll inabloodinpcy su ri(RR) taiggersed.flex an liIm tgsensetee sympwPhe ofisyabem. ce- pest -se aot smimula tg ri cardiac β-adrsto-2 apt a0 elicirs anliitprodeoinano prhelrt rm e rit f rcsilinsyabol c noi ae h ot, which,8in ionjsnctitg weletanlα-adrst-inotapt a-med tregiitprode in ortpher-seal pes staonr, leads roaa csmpenswf aysepideoinanloodepryssu r. In ATP-ytpletedincsll0 inathn infarc bnnderazote,aresmioginmembtone ponettial declfres weleta noicomf aateintprode in exftoaboltoxin-hat8may be furtiec exace bwfel bs scti-seiIm tg ofnβ-adrsto apt a0 sT geteer, no prpe c sses prom e trstriskpatefatwle vshtratsiaa lrrhythmias. Asaeaclice-sequgaceoof hocal ischso a,8sxtracslluiaa noiceh Im licens H + rit K + pideoinate- ef in rtaeygili, leadoog - aexftoaPixoeli to icep tvernervsafibers. ce- pest aatsesetsIm tg ofnpain, typ llllxt.x ortgacedinby trstpgatrhttas yinihilat ng,areinferces sympwPhe ofian liIm tgtinTreesunceleanseonfarc trsr ux cr t -secally ytpethstotnsrsileng p osetime betw en thn nnset ofntiesettack distteeinonlrtaiftta ofmettt-Whe -as somstteera-sepRe oftmrasu rsface oodiy tectotlyoafte inteerd gnosdsiisonoifirmba,i tosrs te-e celesta e prier exflu tg of noi aeoodi-secat lisrhracanln iinsu tutectotlyoin spe-e cilllxt.quippectfscbliuees. Wb poutoex-setepmili,rhowevsr, prompt a hixo isr o-sepe at vs. ceus,ra onlggerestta ofmettsecahtdyle hosdprcvsn sefultinTreeattiplitsle aagenA, ASA,aisda -semiionrerestat thrdfirs tuspRc ednsigncensseinfarc thei Pgin dyros aischso ao s ta of-sebd peed mbtaatlxtweletattiengioalsedrugs (h ametnit ates).aIn iase tr s ta of-semett fmilsi(notve in e pin 30 mio,da -semiionrrat tg ofdm rphbte,aif neeeba itinonmbfrom tg weletanlattiemetic tolpry-e vshtdm rphbte-inducetavomf ng,aisiiu- Mdiy tec sIfaECGnsigncenstmyocardialniN-infarc ixorarefabsenA, trstpgatrhttis soabo-selezednbs sttiengioalatrsr ux (nit ates, β-innlockers) distgiien ASA aos hspaaintinWhet teerd gnosdsihosdbgen cst-sefirmbanbs electrocardiogr uhy, at-e tempts rrsgsnlrtbd roadissolveathnintercybusfplogy ? 200icllly (rercybo-selytic trsr ux:ael eplice lr ttrlptoki-e oade)gnnatoed.moveathn obtory thesbye mrchft lll meaose(bfll li dila tg rrinaugioplicty)toHepaain is giibn tolpry-e vshtdatpoatielsgvastsiaa ey alu tg,8i.e.,ses asafeguard trstpgarhcy0liatiesef in rt agssel.eRegardleleansethn outcomstli trrcybolytic trsr ux nr bfll li dila-e tsli,ra β-nlockeraisda miionrerests asup-ulprls0 immbtehtoarrhythmias, unleleait isinnoi aeoodiy tec sTa ofmett hf lsfe-inthreateniog vshtratsiaa lrrhythmiassecallveferaanlattilrrhythmictliathn clicssenseNain+ -chftnel nlockers,oh ame lidocaineiecT timprcvsnlong-nd ctprcgnosds, uco se madeoof a β-nlockera(L50519eintidgaceoof ry-e infarc the dnd r ute cardiac mortaltox)in ostanlACE fnn ofP a0(pcyvsntixoeli vshtratsiaa enlirgsmett afte tmyocar- Mdialninfarc the)0(A). 310 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 311 to Ai Drugsmforttreara ofmett hf a ute myocardialninfarc the Ai Algo iohmmforttreara ofmett hf a ute myocardialninfarc the noyesedyesedSuspRc ednmyocardialseinfarc inAdetylsaltcyl cinadidinIschso ctptinedECGinTrrcybolysisinnoi aeoodiy tecedyesedAugioplictyinnoi aeoodiy tecedGlyce olatrinit ate FlrnrseSV RRseSV x HR = COseSV x HR = COseH + K + PtinedPcyload rtdy hixo:e ott ateecAftt load rtdy hixo:e ACE-fnn ofP ainAttiplitsle sedrugs, trrcybolyticulagenA, hepa irecIf neeeba:seattilrrhythmic: ah ametlidocaine Pors stett ptin:seopioids ostii teeeba:lattiemeticsinβ-nlocker Aoalggsic:seopioidsinIufarc inαinβββinExftoaboltoxinArrhythmiainSympwPhe ofinnervousrsyabeminPortpherflsepes staoce to Staodard trsr uxinβ-nlocker, ACE-fnn ofP a,i p ixofl hepa irecST-segmsntineleiIm tgselefAtbundlc nlockinTrrcybolysisinsunceleful to Augioplictyin p . GPIIb/IIIA-innlockeredyesedyesedto Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinHlperuenafheinArtereal olperuenafhe (hincsbloodeprys-insure)gginermlly yors nst impairathninwbra-beiog ri re- ef in rtaoodividual; howevsr,8in srsilotgftd ctit leads rosevastsiaa damject ost Uons lrytcsmpli-secat lisr(A). ce- rimahf attiolperuenafvnintesr ux isrtolpryvsht trstlmt a nd,inseus,rtolprclotgflsfet.x octahcytinHlperuenafheeinfre Pgatlyrrtst Assufrom dtotrsr disrode, s ncrasaeacits-2 oxlamiie-setprtoog -umor (pheocerc- Mmocytoma);ain mosh cas-sgte- couserucanesten idete miora: gssettial (p i-ulmlry) olperuenafhe. Attiolperuenafvnindrugs ace oodiy tectwhet bloodeprys-insuregcanesten isuffoftrhtly ioi aollsdrbssemeaoseliaweeser r.dy thesoraaflow- sa Atyiet.aIn p irciple, lowerpup8ofdvi rsrsecardiac outputooraportpherfllpes staoce may detprodeoblood pressu ri(cf. p. 306, 314,oblood pressu ridete mioants).rTosinavmilaaugadrugs influgaceoone lr no prli trsse dete mioants. ce- tiec use ofseut ltox hf attiolperuenafvns is dete -semiisa bsftieia ffofafxaaostPoler boltoxtinTreeceoice of a spinifbyldrug is dete -semiisa otnsrsibasos of arbinefit:riskpas-sesessmett hf se- peleiIntgdrugs,8in keep-seoog welettreapgatrht’s oodividual neees. aIsiinsu tutoog single-drug trsr uxin(mototrsr ux), thn fell wlng onssddrr-seatslis rpplx: β-nlocker0 (p.h92)face ofsevaluc in srsira ofmett hf juvenole hy-sepRruenafheewelettachycardia dnd h gh cardiac output;ahowevsr, in gatrhtsindismosedos anronchocpics, eien βin1 -se-e lyn lib nlocker0 ece noi aeoodiy tec inTriazbdb diure of0 (p.h162)face ponettial-sely wbra suitel ii olperuenafhe yssoc t-sebd e pryorgierlib helrtafmilure;ahow- eibr, tiey wouldln i nsuitaaugaii olpc- Mkelemic soates. Whet olperuenafhe isinaccompaniednbs stgina pRi o is,ftiee pryferreeeceoice wouldln ia β-nlockersennacalciusgaitwgootst (p.h122) rm he inteanla diure of. Asaforttreacalciusgai-se agootsts, t should n notsthresh verop-seamil, unlikennifedip re, poatelsgs car- Mdioytp y artre h itox.lα-Blocker0 mayecn ofnparratsiaa binefit in gatrhts weleinbinignlprcsta of olperplicia dnd o-sepairsd micturit tg. Atopcy gat,totlyoβ-innlockers8ditidiure of0 hoibeundergone lirgs-scaln cl ntlll trials, we me hoibseshown reatrrtdy hixotitoblood pressu rrui0 assoc trege prdetprodeegmorbbdtoxin ostmortaltox dyros ast oke ditionsgys-inrlib helrtafmilure. aIsimu Aidrug trsr ux, t f0 necys-inswrytto onssddrr we me rgenAs rat tgmllyseonmplemett emch otrsr -Arβ-nlockerse(bradycardia,fcardioytp y ixotduetroinsympwPhe ofinlockade)acanln ieffin svn-sely onmbfrrege prnifedip re (d.flexse achycardia),gbutoobviouslx nst wele ve-inropamil8(bradycardia,fcardioytp y -secin ). Mototrsr ux e prACE fnn ofP asec(p.h124) pe dy ss en adequatetrtdy -e tsli ofnblood pressu riito50% ofnpa-e tsenAs;ose- pespotectra e saintprodediroin90% by onmbfrom tg weleta (reiazbdb) Mdiure of. Whet vasodilat a0 s ncrasadi-seold alazbne lr minoxbdtl (p.h118) ece agiien,aβ-nlocker0 wouldlsUsag tolpry-e vshtdd.flex achycardia,fditidiure of0 roincouNtorsctgflubd8rttsntixotinAbrup te mioamili ofncoi inuousinra ofmett canln ifell wrtabsrreboundsehlperuenafhee(parratsiaalxtweletshort t 1/2inβ-nlockers). Drugsmforttreaioi aol of hlperuen-seciib crises ooohe s nifedip re (iapsulr,ses ab- chewrta ost wfll wrt), nit ogly-sete ir8(suolpupufllx), clxoidite (p.o. rrini.v., p. 96), diold alazbne (i.v.), diazoxbds a(i.v.), fenoldopam8(bxeinfu tg,8p.h114)in ost odiumrnit oprusdlde (p. 120,obyain-inf sin ). Treenoteclyn lib α-nlockersephentxlamiie (p.h90)iisiiudiy tectotly itepheocercmocytomatinAttiolperuenafvns forthlperuen-secixotitopryggatnx arsgβin1 -selyn libseadrsto apt a-nlockers,ometeyldopaec(p.h96), ditidiold alazbne (i.v.einfu tg) fer eclampcia (malesvn pideoinanloodinpcy su riweletCNSnsymptoms). 312 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 313inIutseibre cas-sgfurtiec onmbfrom tg wele Ai Artereal olperuenafhe ditiplogy ? tiec use offa proaches Diur eticsinβ -nlocker0inCa- iNtwgootstsecαin1 -nlocker0inACE fnn ofP asecATin1 -iNtwgootstsecIf tiec use ofseeycu A inadequate2 oftge - adrugsefrom dtotrsr grcppsenninonmbfreae psedrug from dtotrsr grcppseDrug selyn lnnseaccordoog - aons of licin ostneeesthf tieseoodividual gatrhtinIuitialnmototrsr uxede pronctliathn ffvnindrug grcpp0inAttiolperuenafvn trsr uxinHlperuenafheinSyabol c:nblood pressu ri>a160 mmHg Diaabol c:nblood pressu ri>a96 mmHg SUons lrytdisrodes: HelrtafmilureedCnrxolrytateerosalerosisin stgina pRi o is,fmyocardialse infarc the, lrrhythmiainAteerosalerosis ofncernbrfllagssels cernbrfllinfarc the st okeedCernbrflleemorrhjec aAteerosalerosis ofnpsnal agssels psnal fmilureedDetprodeeglsfet.x octahcy [mm Hg]ecα-nlockerseh amesuprazosine Ceh Ilecαin2 -wgootst ah ametclxoidite Vasodilat tginh amesudiold alazbnesemiioxbdtl Rtserp reseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinHlpouenafheinTiesvshousrsidctliathn circula tg,oex-sethe ire tee pulmxolrytcircula tg,oan-e onmmodatesf~ 60% ofnsrsirotalnbloodsev lume; bocauss liatrstlow vsnousinpressu ri(meaof~ 15 mmHg) t f0 plrtaifinteerlow-pressu risyabem. ce- artereal vastsiaa bees, eyp ysettire tee h gh-inpressu risyabemi(meaofpressu r,in~ 100 mmHg), csn ainf~ 15%. ce- artere-seal pressu riginermtes teerdriilng flrnrseforaporfu tg of rossueonditinngfts. aBloodedrainpup from thn lmt a collscAseininteerlow-pressu risyabem8dnd isfpumpedinback by trsthelrtai t nre- h gh-pressu rrusyabem.inTreeartereal blood pressu ri(ABP)inytpethstot:e(1) re- v lume ofnblood perseuuit osetimer-hat8is flrnrd by trsthelrtind t nre- h gh-pressu risyabem—cardiacinoutputotnrricpotdpup t nre- pe dy haifinst oke v lume aos hslrttrote8(b ofs/semii), st oke v lume beiog dete mioraind t a alia by vshousrfallpup pryssu r;8(2)inteernouNtorf rcsilpposlng thn flow ifinblood,8i.e., portpherfllpes staoce, we mein saeafsnctitg of yrtereoiaa calibe .inChroo c hlpouenafhe8(syabol c BP <a105 mmHg). Peimlry bdtopwPh c hlpo- uenafheeginermlly hosdno cl ntlll ompor-se aonr sIfasymptomsms ncrasalicsitudein ostdizzbness a r,ra prcgramahf phys -secal exercide insteadpat drugs isfadvis-inable. SUons lrythlpouenafhe8 saeasign rie an underlyire disroder-hat8should n inra ofectfirs sIfast oke v lume isrtoorlow, aas iu helrtafmilure,dafcardiac glycosbds acanln giienos aintprode myocardialsenoi ae h ltox ost t oke v lume. Whetinst oke v lume is detprodeegdyros ainsuf-sefiftrhtnblood v lume,nplicsessuosm -setutesmwallln helpful8in ta oflng bloodseloss, wepreasaeldonreroieadefoftrhcy re-sequi rsfadmiion. Im tg of a minermlocsr-e tstoid (h ametflud oisrrasor-). Thsilmt ainis teerdrup8ofdceoice fer orthosta of ol-inpouenafhe8dyros aautonomic fmilure.-Ain grasympgaholytic (er electricll p ce-2 maker)acanld.sto rniardiac rm e ininbradycardiatinA ute hlpouenafhe. Fmiluretliaor-e thosta of rgula tg -Ar oftge srsy thninrecumbsht t trstertermposltsli (ortho-inonls s)mwalllcauss blood e pin teerlow-inpressu risyabemis asinkis wardsathn feetinbocauss re- veinsoinanody partsrbshowinteerhelrtawallln d stetdba,idespi e r re-seflex vshoonsstr mt tg, by trstweeser ifinteerc lumi ofnblood in teerblood vgs-sesels. ce- ffll inast oke v lume is partlyseonmpenswfel bs s pideoinahslrttrote.rTosind.mainlng r.dy thesoi cardiac output acanln nouNtorbanbs elevatire tee pe-e rtpherfllpes staoce, enabllng bloodeprys-insuregditinngft perfu tgtro be maiN-e tainbd. At orthosta of malfsnctitg isinpresrhttehen csuNtor- rgula tg fmilsin ostcernbrfllbloodeflow fall0,iweletpest -se aot symptoms, s ncrasadizzbness, “black-out,” lr eien loss ofncoiscious-e teos.aIn te- sympgahotoo c f rm,nsympw-2 Phe ofmlly med tregcircula ay d.flexe0edrrsgd t naffiedn(more prchouacedintachycardia dnd pideoinaportpherfllpes s-se aonr,8i.e., diaabol cnpressu r);ahowevsr, teern dsifmiluretroacompenswfemforttreare- Mdy hixotitovshousrrttu n. Pe phylac ofsera ofmett weletsympgahomimetics teernfere wouldlholdnltotle prcmisr. In-inonead,fcardiovastsiaa fitness trainpupedeouldlappslr more omportart.e At io-setprodetinrvshousrrttu n may beinachievrtain two ways.aIncprodire NaClseinPwke augmsnts sa Atrit flubd8rt Usagsin os, hsonr,nblood v lume (ioi aeoodi-secat lis: olperuenafhe, helrtafmilure).inCoistr mt tg ofdvshousrcapaftoaoce vgs-sesels miser b- pe dy banbs diold orr-segooamine. Whetrsr tr s ve in couldlal-2 soln iachievrtabs st α-sympgahomi-seme of rmains debataaug.aIn te- veryinrarefasympgahotoo c f rm,nuss liasympw-2 Phomimetics wouldlcertainlyan r.ason-inable. In gatrhts welethlpouenafhe8duetroinhincsPhoae ic spioalacordrrrrasyn lnnsec(pest AsretinryiagssettiallytcsmpleteinsympwPhe ofidineriIm tg), loss ofnsym-e pgahe of vasom nnacoi aol canln noo-sepenswfel bs sdmiion. Im tg of sympw-2 Phomimetics. 314 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 315 Ai Ta ofmett hf hlpouenafheinHelrtinKidney aIstesmiors Sksle alnmuscleedLuupedBrtinedLow-pressu rinsyabeminH gh-pressu rrusyabem Vsnousind.tu n St oke v l. xtrotein= cardiac output aBlood pressu ri(BP)inPortpherfllpes staoce α-SympwPhc- Mmimetics Artereoiaarucalibe β-SympwPhcmimetics Cardiacinglycosbdss aPgrasym-e pgaho2ytics Red staibutoli ofnblood v lumeinIuitialnons of liinCoistr mt tg ofdvshousrcapaftoaoce agssels,oh ame diold orrgooaminetii a prop i te, α-sympgahomimetics Intprode ofnblood v lumeinBP SaseltedNaCl + Hin2 Oin0,9%edNaCledNaCled+ Hin2 OinMinermlo-e onrtstoidinBP BP Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinGout aGout is yiainheritel mr abol c disrodein-hat8rtst As srsy olperur mso a,8yiagl- eiahixotitoteerblood nseur m did, thninetd-pe dy haif purine degrada the. ce-2 Pyp lll gout ettack onssdsts of arhinclyseptinful8inflammw the oiathrdfirs mr a-se ars phalftgell joinPe(“podagra”). Gout aa acks areftaiggerel bs preciptoaPixoeli odiumrurmte nryabal0 inathn synovialsefluid ofdjoinPs. aDy pup rrs eaalxtonlgeanseonflammw-e tsli,rurmte nryabal0 ace phagocytossdrbssepolym rph nualear leukccyteve(1) reat ahnguliathn cryabal0 bsftieia ameboid cl-intoplico ctmovemsnts (2). Thsiphago- cytof vacuolstfuses e pra lysosome (3).ince- lysosomal enzym 0 ace,ahowevsr, unableo- degrads re- odiumrurmte. Furtiec ameboid movemsnt dislodgssintreanryabal0 aitioaucosfrup uretliatiee phagolysosome. Lysosomal enzym 0edrrsglibe atel in- athn grraulccyte, re-e st AsretinriAs detory thesby self-digys-inrlhe ditidamject- athn adjacsht tossue inIuflammw ay med tors, s ncrasaprcs-se aglftdins dnd chsoooac oftfsctors, ece ad.fyasedn(4). Morn grraulccyte0 ace at-e tae hrta ost ufferasimiiaa detory the;intreainflammw the d t naffies—thn gout aa ack fla rsfup.inca ofmett hf thn goutsettack dimsses ad t arup treainflammw ay d.spotectinTreedrup8ofdceoice isonolchic re, anlalkw-e loid from thn autumi crocus (Colchicumedautumiale). Io is known asaea“spiodleedpoison” bocauss it lrrsst0 mitocis tsemr aphasbobyainn oft ng noi ae h le spiodle pe neios. Ios attigoutse h itox isindyros ainn ofPin of ioi ae h le pe neios itethn neut ophils, wepreby ameboid Mmob ltox ostphagocytotic e h itox ece apcyvsntba. Thsimosh csmmot advpryr ahe in s hftnolchic rerarefabd mbtalapain,sev mf ng,a ostdilrrhea, probably8duetroininn ofPin of mitocestinrtrs eopanlx di-sevidpup gast oiNtesmioalaepi rslialnosll0.inColchic rerisi sufllx giibn orlllyr(h amesu0.5 mg houalxtuttilapain suosidesmhr gas-e taoiNtesmioalad smurbahces a r; maxi-ulmlladaily yode, 10 mg).inNoisteroidal atti-inflammw aysedrugs, s ncrasaiodomete die ditipls-innylbutazote,aarefalso effin svn.aIn sy-e vsre cas-s, glucoonrtstoids8may be iu- Mdiy tec Effin svn pe phylaxfs of goutset-se acks8ps Pirssrurmte bloodelevels ro besehowerbstro leleateanl6 mg/100 mL. aDiet.aPurine (csll nualei)-r me foodsseshouldln iavoidee,oh ame nngft m ofs aMilk,adaiay pe dy hs,8dnd eggs ace low in apurines dnd r rir.commendec sCoffiein osttea ace pe mit ednsionrose- mete-seylxatthiieacaffiine dors nst shterapu-e rine mr abol sm.inUr mosta ofs detproderurmte pco- Mdy tg -Allopurinol, as wbra aceirs a cu-e mula ng mr abol e fll xatthiiea(oxy- apurinol),ainn ofP xatthiieaexodIsc, which catalyzssrurmte fermw the fromsehlp xatthiieaviaoxatthiie. Thsselpry-e a rsor0 ece ryadfly elrmfrombstviaotrs urine -Allopurinol is giibn orllly a(300–800 mg/d). Ex aptmfortinfre Pgatseallrrgof ra hixos, t f0 wbra Poler teceddnd isfteerdrup8ofdceoice fer goutspro-sephylaxfs. Atore- nlrtaifttrsr ux, goutset-se acks8may a r,rbutotiey canln pry-e vshtel bs noicurrett admiion. Im tg of on2chic rer(0.5–1.5 mg/d). Ur mosur ms, s ncrasaprcbinedid, benzbromarone (100 mg/d), lr tulfinpyrazote,apro-sem e psnal exoret tg nseur m did. Thsysecaturmte thn nngft c didrrrrasport syabemiinrtrs proximal psnal tubulrs,2 maksretitounavmilaaugafer urmte peab-2 sorp the. Whet underyoded, tiey inn o-seottotlyothn adidrsetprt ay syabem, we meinhasaeassfllerrrrrasport capaftox. Uroteinelrmfromili isfteenainn ofPrta osta gout aa ack is poatiels. In gatrhts weleturoteinonoteoiinrtrs urinwryttae h,eur mosur msedrrsgnoi aeoodiy tec in316 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 317 Ai Gout dnd iAs tesr uxinAll xatthiie Xatthiie Hlp xatthiieinUr m didinNualeusinLysosome Phagocyte Chsoooac ofinfacP asec1in2 3 aGout a ackseColchic re 4inAtsli (urote)sepeabsorp theinAtsli setprtoheinUr mosta ofinUr mosur medPccbinedid Xatthiie OxodIsc AllopurinoledLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinOabeoporos sseOabeoporos s is deffrregasaeaginermlezedinyttprodeoinanore malea(oabeopenoa)treat aae in s nore mataix8dnd minermlrnoi ehtinequally, giilng riseatoefae hu rsfofdvsrts-2 brfllbodies e prnore pain, kyphosis,2 ost horteniog ri re- P aso. Fae hu rsfofinteerhipldisttee d smal padfusaarefalsoe onmmoe. ce- underlyire pe c ss is yindiss Pilibrium betw en nore fermw the abytosteoblictonditinore rsorp therbsseosteoclicto.inClicsifofahixo: IdtopwPh c oabeopor-seosisftype I, a rrsretinrpoatmenopaucalsefesfles;osype II, a rrsretinrseoescshtinmflestrit fesfles (>70 y)toSUons lryseosteoporos s: assoc trege prpeimlryindisnndersms ncrasaCushiig’s disrode, rrinindy banbs drugs, h ametchroo c trsr uxede prglucoonrtstoids8orthspaaintaIn te-srseforms,8trstcauss canln ielrmfrombs. aPoatmenopaucal oabeoporos sseeyp ysettsaeaportod nsea celer tec losssensenore male. Thsilowerrtrs preexfsmioginnore male, rrs eaalierrtrs cl ntlll signcinbocome oloifesm. Resktfsctorsfare:ap rma uretmsto-2 pauco, phys lll ine h itox,rcigaretteinomok ng,a lcohol abuco, low nodyinwbeser, aitioalcius-ponr diet. aPc phylaxfs: Admiion. Im tg of es-e taogen can pe nectaagtinsh poatmeno-2 paucll loss ofnnore male. Fre Pgatly,senoijug tec etorogensaaref sect(p. 254).inBocauss etorogennmototrsr uxaintprod- es trstriskpateutereieacaonrr,ra gierageninneeestro be giibn noicurrettlyr(hx apt afte hynrerectomx), asfe ametinryiaoralsenoi ae ep tverp r gratsli (p. 256).inunderrtr s trsr ux, mNicosmwalllcoi in- ur.eTen riskpatetrrcyboembol c disor-seder0 iveintprodedidistteatenstmyocardiale infarc the probably8howerbs. Hormone ra ofmett canln iextetdbaafer 10 y rrinlotgsr -Bnfere menopauce,adaily cal-2 ciusginPwke shouldln ikapttate1 g (ioi-e tainbd ir81 L of milk), diti1.5 g trsreaf-e ter.inTrsr uxtsFhrmw the oianewnnoreinmftaix8isiiudy banbs flus fde. Admiion-e terregasa odiumrflus fde, t smimula esedosteoblictotsFlus fdetis suosm tutectforinold oxyl d.s dyes iu hld oxya gattetroinformrflus a gatte, thn lmt a beiog moresepes staotatoed.sorp therbs osteoclicto. Toinsafeguard adequatetminermlezaPixoeli tewnnore, calciusgmust bsfsuppliba itinsuffoftrht amsuNts. Howevsr, simul a-seneousradmiion. Im tg wouldleycu A in apcyciptoaPixoeli nonabsorbableooalciusseflus fdetinathn intesmiors. Wb pr odium Mmotoflus ophosph tertr s problemiisinnircumvsntba. Thsitewnnore fermedinmay hoibeintprodedirys staonros anoo-seprelesvn,gbutoestetors tgml, st aintdit gradoxifmlly nore frag ltox may io-setprode. Bocauss treaioi of liceunder which nore frag ltox is detprodeegre-2 mait unalear,rflus fde trsr ux is nst in aroutooef se. Calcitoo i (p. 264)ainn ofPs osteo-sethict e h itox,rhsonronore rsorp the. As aapop tds it neeestro be giibn byain te-inrlhe ( a,iel ernat vsly, asaeanacll spray).inSalmxnid isfmore ponettateanlhuolorucalcitoo i bocauss liafPs slowerrelrmfro-inrlhe.inBisphosphonmtes tory urllly amioic endogenousrpyrophosph te, which inn ofPs pcyciptoaPixoe ostdisso-e lutoli ofnbore minermle. Thsy d.tardinnore d.sorp therbs osteoclicto nd, in aparr, also yttprodeonbore minermlezaPixo inIudicat lisrooohe s: -umor osteolysis,sehlpercalcso a,8yid Paget’s disrode.inCl ntlll trialsge preAidronmte,radmiion-e terregasaae d t mit ehtdd.gimen,ahoibseyieldbaafavs ableortst As d nabeoporo-secis. Wb prthn newerrdrugs clodronmte, apamidronmte,raostalendronmte,rinn of-e tsli ofnosteoclicto peed mbtates;oa cst-se inuousrd.gimen wouldlseus appslr toecn frodible. Bisphosphonmtes irrsta e es phage-seal distgastr mgmucus membtones;osab-2 lePs shouldln i wfll wrt e pra r.ason-inable amsuNteliawa a (250 mL) distteeinpgatrhttshouldlkeeptinryiaupresermposl-e tsli fer 30 mio fell wlng drug inPwke in318 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 319inNormwl soate Oabeoporos sseOngft c nore mataix, Oabeoid Bore minerml: hld oxya gatte Ai Bore: nermwl soate ditinabeoporos sseInrpoatmenopauce Etorogen (+ Gieragen) Calcius-sa Asec1 –i1.5g Cain2+superrdayecPhys 200icllulonsst turht:ecPyrophosphor m didinB. Oabeoporos s:rdrugs forape phylaxfs distta ofmettseOsteoclictoOsteoblicto Flrmw the Resorp theinProm ixoeli noreinfermw the aInn ofPin of noreinresorp theinFlus fdetinnsecNaF:e An liIm tg of osteoblicto, Flrmw the of Flus a gatte Calcitoo iinPop tdsulonssfsmiog of 32 aminoinadids Bisphosphonmtesinh ametalendron m didinHO P OinC P OOH (CHin2 ) 3 aNHin2 OH OHOH HO P OinO P OinOH OHOH Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinRheumw id Artrrof sinRheumw id artrrof srhrachroo c poly-seartrrof sr saeaprcgrelesvn inflammw aysejoinPedisroder-hat8d t mit ehtlyoa acks MmoregditimoregjoinPs, peed mbtaatlxe thosctliathn ffngers8dititoee. Thsiprob-inable causs liarheumw id artrrof sris yinpgaho200 cll ra hixotliathn immunrrusyabem. cei0 malfsnctitg canln pro-sem edgnnataiggerel bs variousrcoodi-sehixos, nthe ire ginet c disposltsli,ulage–rtlatregeslr ostteaa,ihlpouhe -semia,8yid infe tg -Ae d itialnioxbousinsmimulu0 elicirs anliiflammw the oirusynovial membtonesr-hat,8in suri,ulleads road.fyase hf attigensasercpea which treainflammw ay pe c ss is2 maittainbd. Inflammw the oiathrdsyn-seovial membtone i0 assoc trege prl o-see Im tg of iuflammw ay med tort to-inonlhces -hat,8amsog otiec a hixos,2 osoooac ofmlly smimula e misrw the a(d pedes s)mhf phagocytat bloodeosll0 a(grraulccyte0,rmacr phages) in- athnrusynovial tossue Thsiphagocyte0 pe dy bsedetory tve enzym 0 -hat8prom e tis-insueidamjec.eDuct- athn pe dy hthe oiruprcstaglftdins dnd leukctrtgaes (p.ec196) distotiec fsctors, treainflammw-e tsli spreads roarrs ehtirsgjoinP. Asaeaee-e st A, joinPecarraljectis damjecd distteeinjoinPeisi lmimitsly immob ltzedgnnafu sa. Phagy ? tiec uy. A ute d.lieftlie inflammw ay symptomsmcanln inachievrtabs prcstaglftdindsynthode itn ofP as;enoteteroidal atti-inflam-2 ma ay drugs, nnaNSAIDs, s ncrasadiclof-e enac,aiodomete die, piroxifmm,8p.hiem),2 ostglucoonrtstoids8(p. 248). Thsiinbvi-sehably8chroo c uss liaNSAIDseisilikelyotoe oauss advpryr effin e. Nvi rsraNSAIDsedtortglucoonrtstoids8canlhaltathn pe - orelesvn detory thesofdjoinPs. ace- uss liadisrode-modifyireseagenAs may d.dy - treare Pirsmett forinNSAIDs. ce- uss liasume rgenAs dors nstsemeaor-hat8d t vsntixoeitnsrsibasoc pw-2 Phoginet c mrchft smsm(albvi hopedinfor)iisiachievaaug.aRateer,adisrode-modi-sefypup rrsr ux pe mits a utels sctireseagenAs to n i sectasaadd-lisrhraas re-sequi rt. ce- csmmot fro uretliadisrode-sem dffier0 ivetieia delayel effin , we meindethsopstotlyoafte ira ofmett foraseibrllulweeks. Amsog poatielsgmrchft smsmrie amt tg, inn ofPin of macr phage e h i-seoty8yid inn ofPin of d.fyase hr e h itoxsenselysosomal enzym 0 ace beiog dis-incussbd. Inohe sd in tei0 categorytarr: tulfacllazbne (anainn ofPor ose. poxyge-e oadenditioyclooxygenode, p. 272),lchlo-e roquine (lysosomal bitdpup), goldlcoo-sepounds (lysosomal bitdpup; i.m.: au-e r tiioglucose,8aur tiiomalate; p.o.: au-e ranofii, less effin svn), as wbra aceD-pen-seicillamiie ( osla tg ri me aln liceneee-sebd fer enzym e h itox,rp. 302). Fre Pgatseadvpryr ra hixosfare:adamject- ask iinditimucous membtones, psnal toxiftox, aditinloodedyscricias.aIn additixo, uco se madeoof cytosta ofs dnd omunrasup-ulprls0ants s ncrasametectrexote8(howinyode, oice weekly) dnd leflum mbctasinwbra harmaccytokinlattibodies (inflixi-ulmlb) dnd soluble cytokinlretapt a0ed(e anertapt). Metectrexote8exer s dnseatti-inflammw ay effin , aplrtafrom itsseatti-auto omunraac the dnd,enexttroinsulfacllazbne,iisonoisddrrbstro hoibeteeinmosh favs ableorisk:binefit rw th.aIninmosh seibre cas-sgcytosta ofs s ncrasseazwPh op innditioyclophosph mfdetwallinhave to n i sec.inSur0 cll rmoval lintreainflamedinsynovial membtone8(synovectomx) fre-sequgatlyoprcvidesmlong-nd ctd.lief sIfafro-seciels, tei0 a proach is pryferreeebocausssealliplogy ? tiec use offmrasu rsfei-e tail signifofatt advpryr effin e. 320 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 321 Ai Rheumw id artrrof srdnd iAs ta ofmettseGinet c disposltsli Environmettal fmcP asecA ute taiggerinSynovif sinIomunrasyabem: ra hixotagtinsh arratsiaa tossueinIufyn lnnsetraumw Chsoo-se ac ofinfacP asecInflammw the PtinedInflammw the Carraljecsedetory theinProstaglftdinsinPormraboltoxintlaljecnodesedPhospho. podesedPop tdodesedBoreindetory theinIL-1 TNFecαinNon-eteroidalseatti-inflammw aysedrugsed(NSAIDs)edGlucoonrtstoids Metectrexote, p.o. /s.c.ulweekly yodireseSulfacllazbne p.o. aGoldlparrNtorslsePneumonitfs, naussa,sev mf ng,amyhsosupp y ixoseallrrgof ra hixo,enephrotoxiftox, agast oiNtesmioalad smurbahcesedLes licensemucous membtones, kidney,ask i,inloodedyscricias Months Yeaasec123456 Rtlieftliasymptoms “Remi ixo” aDiscoi inua tg bocauss li: rsidcteffin e rrrininsuffoftrht ffofafxseSidcteffin e:edLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinMisrwiie Misrwiie8 saeasyndrom- chaae hrrezedinbsrrecurrett a acks f d t naerhele-seachenditinaussatteaten a r at8dr rgularind t aval0 aitihict foraseibrll houas.aIninclicsoffmisrwiie, treaa ack is typ llllx herlldrtabs st “aura” accompaniednbs spreadoog hom nymous visufl field yt-ul in s e pryoas ednshaap edgsse(“fnrtsfi-secat li” spRc ra).aIn additixo, treapgatrhtrucanestefocus tg certain oo ters, hosdae ravshousrappsattetforaparratsiaa foods,eddnd isfhlpersetsi tve s aodorsf(hlpercs-semoa)toraleserm(photophobia). Thsiexacte oauss lintresetcsmplaitt0 iveunknown; howevsr,8aad smurbahce in crineal bloodseflow is trstlikelyounderlyire paPhogi-senet c mrchft sm.aIn additixoos aag riten inheritel peedisposltsli, pcyciptoaPiresefsctorsfareare Pirsdrtolprcvoke diset-se ack, h ametpsychic ttrlle, lacktliasleep,sete tain foods. Phagy ? tiec uy of mi- orwiie8hosdtwo dims: ttopppup rrs a ute aa ack ditipcyvsnting suoce Pgattotes.inca ofmett hf thn a acktsFhrinsymptoma of rlief, heldaches ece ara ofectweletanalggsicsm(aceoamino-sepheg,oanetylsaltcyl c did), ditinaussatis ara ofectweletmetoclopr mfdet(p. 330)sennadomperidone -Sionrose-re is delayel agast ic emptyire dy pup rrs a ack,ndrugseabsorp the canln markedly d.tarded, heonroeffin svn plicseslevels areanstseobtainbd. Bocauss metoclopr mfdeinsmimulmtes gast ic emptyire, t pro-sem es absorp the f d giercd dialggsicindrugs andlseus fscbliumtes pain d.lief ecIf anetylsaltcyl c didaisda miion-e terregi.v.eas trstlysine sa A,firs bioavmil-inab ltox is csmpletei Trsrofere, i.v.ein te-inrlhe may be advisaelstinry ute a acks.inShouldlanalggsicsmprcvsninsuffo-2 cigatlyoeffin svn, hrgooaminetor onstli tre 5-HTin1 , dgootstsgmay helpacoi aol teeiny ute a ackain mosh cas-sgorapeyvsht dnseimmbtehtoa acktsThsiprobable csmmote mrchft smahf a hixo isra smimula tg riseserotoo i retapt a0 hf thn 5-HTin1Ded(hrinperhaps also thn 1B diti1F) suosypetinMereovsr,8hrgooaminethosdaffontox forindopamire d.tapt a0 (L50478 naussa, eme-secis), as wbra aceα-adrsto apt a0 diti5-seHTin2inrecapt a0 (L50518gvastsiaa tore, L50518inplitsle aagg rgIm tg). Wb prfre Pgatseuce,ate- vastsiaa sidcteffin egmay gfvninriseatoeseibre portpherfllischso ao(rr-segoo sm). Oibruss (>oice perrweek) risehrgooaminetmay prcvoke “rebound” aheldaches, A from prr-ses stett vasodilat tgtsThcpeaddifferett itinohaae hrr (uenafhe-sype heldache), trsse prompt furtiec onnsump tg risehrgooamine. ceus,ra viciousrcircugadevel-seops e pryhroo c abuco of ergooaminetorseotiec analggsicsm-hat8may enctweletdr r-e vsrtielsgd smurbahces f portpherflinbloodeflow dnd opairmett hf psnalinf nctitgtinA miionrerestorllly,8hrgooamine2 ost umataiptag,oele aiptag,ongrataip-se ag,orezaPaiptag,o ostzolmf aiptagahoibseotlyolrmftel bioavmil boltoxt Diold orr-segooamine may be giibn byai.m. lr thowini.v.ein tetsli, umataiptag suo utate-e ouslx lr nyanacll spray. aPc phylaxfs. caken rgulaalxtovsrdae lotgsraportod,ra hete ogineousrgrcpp risedrugs comprisire pe pranolol, nadolol, aa enolol, ditimetoprclol (β-nlockers),seflungrizbne (Hin1 -h stamiie, dopamire,eddnd calciusgaitwgootst), pizoo fei (po-2 zooyliie, 5-HT-aitwgootst), meteysrr-segfdet(parrall 5-HTinID -wgootst ditinlice-selyn lib 5-HT-aitwgootst,8p.h126), NSAIDsed(p.hiem), aitioalcitoo i (p. 264)amay de-setprodeathn fre Pgacx, t nafox,r ostdu-e raPin of miorwiie8a acks. Amsog thn β-innlockers8(p.h90),totlyothosctlacksretin-e tainsofisympgahomimetic e h itox ecetef-ul in svn. 322 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 323 Misrwiie8a ack: HeldacheinHlpersetsi tvtoxsenssenlfa hixo,egusoaPixo,edduditixo, visixoseNaussa, v mf nginAdetylsaltcyl c dida1000 mgsennaaceoaminophega1000 mgse(Diold o)-ulErgooamine2 Sumataiptageddnd otiec taiptags Meto-sethopr mfdeininn ofPrta celer tecindelayel imprcvsd Rtlieftlisemosrwiie Psychos sseNaussa,sev mf ng Plitsle seagg rgIm tgecαin1 + αin2 Vaso-ulonsstr mt tgulErsegooamineecαin1 + αin2 Sumataiptag dnd otiec taiptags A. Misrwiie8and iAs ta ofmettseGast ic emptyireseDrugseabsorp theinMisrwiie orse6 mg 100 mg 1 mg 1-2 mgse5-HTin1Ded5-HTin1AseDin2 5-HTin2se5-HTin1Ded5-HTin1AseDin2 5-HTin2seWhet teec use offve in inadequate2 Neu oginiciniiflammw the,ullocal edema,sevasodilat tginLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinCsmmot tladinTreecsmmot ? 2d—colloquimlly thn flu,secatlrrh, nnagrippe (str mtly speak ng,ateeinrarer infe tgtweletdnflugaza virusss)—in saenry ute infe tusliiflammw the oirutrs upperrd.spirw ay tae h. Ios sym-e ptoms, sneez ng,arunniog nosct(duetroinrhd itis), hoarseoess (laryngitis), diffo-2 cu Ayoin swfll wiog dnd sorefthroat a(plogyngitis8dititotsillitis), ccpeadasso-e c trege prfirs te ousfteenamucous sputum (uracheitfs, nronchitis), soresemuscles,8dnd ginerml malaiss canln inpresrhttoodividuallx lr noicurrettlyritinvogy ng nombfrom tg orasequgace. ce-2 Pd ctabems from dt oldlpopsiaa beliefin-hat8tresetcsmplaitt0 rrsgnausbanbs ex-seposuretroachallpup oa dampteos.ace-2 nausa svn paPhoginsaarefdifferett virus- es (rhd o-,rade o-,r gradnflugaza v.)treat amay be rrrasmit ednbs sercsol d opletsinpr dy banbs ccpeaiog dnd sneez ngtinTrsr use offmrasu rs. Firs at-e tempts of arcaucll ra ofmett cnssfsm oiruzanamavir, anainn ofPor oseviral neura-semiiodIsc,8yiagnzym necysswrytforavirusseadsorp the yid infe tgrmaccsll0. How- eibr, sionrosymptomsmhftnommot ? 2dseabote8spottateouslx,ose-re is n anoo-sepellpup neeetroauco drugs sConvsntixoflsepemed rsface ootetdbaafer symptoma of ad.fief ecRhd itis. Nacll dischirgs couldlbe apcyvsntbaabs pgrasympgaholytics;ahow- eibr, otiec at opiie–likeneffin eg(pp.ec104ff) wouldlhave to n i ceptec inTrsrofere, pgrasympgaholytics ece ahardly eieri sec,iel hcpeadaotnrri-sespotdpup a hixo isrprobably8exploitel iiintreanase hf Hin1 attio stamiies, anaingre- Mdiett hf oloy ? 2d pemed rs. Lofmlly op-sepliba (nacll d ops) vasoonsstr mt up α-insympwPhomimetics (p.h90)ideyorgierintreanacll mucosa dnd drytpp setprtohes,2 learpup rrs nacll passjec.eLong-nd cseuceamay causs damject- anacll mucoussemembtonesr(p.h90).inSorefthroat, swfll wiog prob-inlemst Demulcsht lozergie csn ainiresesu fa e8anierhe ofs s ncras eteylamino-sebenzoote8(b nzocaine)gnnateuracwiie (p.hie8)tmay prcvfdetd.fief;ahowevsr, tee riskpateallrrgof ra hixos8should n inbornstinrmindtinCspea -Sionroccpeaiog Usagstroin.x ol exoess tracheonronchill setpr-sehixos, supp y ixo hf thisrphys 200iclluld.flex isrjusoffiednotlyoehen csueaiog isindftge ousf(afte isu ge y)gnnaunpr dy -inrlib bocauss liaabsrhttsetprtohes sCo-sedeiie8and noscapiie (p.h212) supp y incouncsbs s ceh Il a hixotinMucous airway btory the. Mu-ulonlytics, s ncrasaedetylcyabeiie, split di-setulfidronords d mucus,rhsonrod.dy - itsseviscostox ostprom e learpup ofnbron-inchill mucus. Otiec .x octorants (h amesuhsten ibrlges, pooa iusgiodide,raosin ocac) smimula e pe dy hthe oiawa ay amucus. Adetylcyabeiieiisiiudiy tectitinoyaboftfibros s gatrhts yid innalregasaae aercsol. Whetrsr mucolytics ece oodi-secated in teernommot ? 2d yid whetrsrin.x octorants likenbromohexinetor am-2 broxolsteffin svnly8hower viscostox of nronchill setprhixos8may be qugshixoec inF ibr. Attipyretic enalggsicsm(ace-inrylsaltcyl c did,aaceoaminopheg,8p.h198)edrrsgd diy tectotlyoehen se-re is hincsfr-e vsr. Feieriisaeana urll pespotectyid uce-seful8in monitorpup rrs cl ntlll couasstli anliife hixotinMuscle aches eostptins,rhele-seache. Attipyretic enalggsicsmeceteffyn libsein d.lievpup rrssrosymptoms. 324 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 325 Ai Drugsmusbanin commot ? 2dseLofml uss li α-sympgahomimetics (nacll d ops oraspray)seH 1 -Attio stamiies Cauhixo: sbaat tginVirfllinfyn lnnseCaucll rrsr uxedompoatielsinAdcumula tg inryirwayssensemucus,rinadequate2 .x ulstherbs ccpea Adetylsaltcyl cinadid AdetaminophegedDetorgierln of mucoussemembtonesinSoreny inHeldachein rFeierinSnifflrs,2 runny noscinCsmmot ? 2dseFluinSorefthroatinCspea Airway torgierln inSurfa e8anierhe ofs Cauhixo:inrisktliasetsi tza theinAtt tulesvn:inMuco2ytics Adetylcyabeiie Glibsewarmrfluids BromhexineinCsdeiie Pooa iusedoodide2 solutoliinEx octorants: Stimula tg ri nronchill setprtoheinDextrom-t rphaginLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAllrrgof Disnnders IgE-med tregallrrgof ra hixos8(p.h72)ininvolve maltccsllad.fyase hf o stamiieec(p.h114) ostprody hthe oiaotiec med -inr a0 (s ncrasaleukctrtgaes,8p.h196). Re-e st Aahtdd.spotecsrooohe s: rtlaxw the oiruvastsiaa smoo prmuscle, asfevfdeaced lo-e omlly ny vasodilat tg (h ametnoijunn liIlulonsgierln )gnnasyabemiomlly ny hlpouen-secixot(as iu enaphylac of8shock);fei-e haaced capillary pe mraboltoxae pserrrasuda tg ri fluid in- atossueo—inswellpup of ioijunn liI ditimucoussemembtonesrhf thn upperryirwayse(“hayecfeier”), cutateousoehefl flrmw the;senoi ae h tg ri nronchill smoo prmuscle—innronchill althma; smimula tg ri intesmi-e oal smoo prmuscle—dilrrhea.ec1 -StaboltzaPin of maltccsllo.inCromolynapeyvshts IgE-med tregre-selyase hf med tors, el hcpeadotlyoafte inchroo c ta ofmett. Mornovsr,8byainte -seferpup8welettreaa hixos8hf med tort to-inonlhces onliiflammw ay csllo, t oaucos aamoregginerml inn ofPin of allrrgof in-inflammw the. Io is appliba lofmlly to: cst-sejunn liI,anacll mucosa, nronchill ta s a(innalIm tg), iNtesmioalamucosa (absorp-inrlhe almxltcnil8weletorml inPwke).aIndiy -sehixos: pe phylaxfs of hay fevsr,8allrrgof aasthma,8dnd food8allrrgoes.in2. Blockade hf o stamiie d.tap-inr a0 -Allrrgof ra hixos8ace peed mb-e oattlyrmed tregbyaH 1 recapt a0. Hin1 attio stamiies (p.h114) rsimoshlyoussd orllly.ace-ir teec use offve in is riten disappoiNt ngt Iudicat lis:8allrrgof arhd itis (hay fevsr). 3. F nctitgal attdgootstsghf me- Mdiat a0 hf allrrgy.aa) α-SympwPhcmi-seme ofs, s ncrasanaphazoliie, oxymr a-sezoliie, ostte aeold ozoliie, regdp-sepliba top llllx roarrs noijunn liIlraosinnacll mucosa tolprcdy - local vasoons-inonr mt tg, dnd detorgierln ditito dry pp setprtohes8(p.h90),te ametinrhay fevsr.inSionrose-yamay causs mucosal damjec, teeiri se shouldln i hort-nd c.inb) Epiiephriie, giibn i.v., is trsinmosh omportart drug inose- menagemettsehf ataphylac of8shock: t onsstr mtsnbloodsevgssels,od.dy -s capillary pe mraboltox,in ostdilmtes β 2 -SympwPhcmimetics, s ncrassend butaliie, fenote ol,raostalbute ol,race aemploybanin nronchill althma,imoshlyinbsrinnalIm tg, eostptrrNtorsllyrit emer-segeac rs. Eibn afte iinnalIm tg, effyn libseamsuNtsacanld.ach treasyabemiogcircula-inrlhe aitioauco sidcteffin eg(h ametpalptoa-sehixos, ta mulousness,ld.stlessness,lol-inpokalrmia). Dy pup yhroo c admiion. I-e tsli,rtreasetsi tvtox ri nronchill muscu-ullo uretisilikelyoto detliie.ind)ace- phylliierbshongs roarrsseme hylxatthiies. Whereasacaffiine (1,3,7-tr me hylxatthiie) peed mb-e oattlyrsmimulmtes treaCNSnditionsstr mtssete nbrfllbloodevgssels,ote- phylliie (1,3-d me hylxatthiie) poatgssesaaddi-sehixoml marked nronchodilat a,fcardio-insmimulmnt, vasortlaxwnt,fditidiure ofoan-e tohes sTrssroeffin egace attaibutediroinboth inn ofPin of phosphod rstorsscin(→ c AMP elevatitg,8p.h66) distattdgo-e o smaatrade osire d.tapt a0.aIn nronchi-seal dlthma,ite- phylliie canln giien orllly forape phylaxfs oraparrNtorsllyrroincoi aol teeoa acktsMloifesmahixos8hfseoveryodjectioohe s too c-clxoif8seo-2 zu rsfaitioardiac lrrhythmias asfeaalxsecigts. ae) Iprat opium (p.h104) canln ii-e haleetroaiudy b nronchodilatthe;ahow- eibr, it osten lacks suffoftrht ffyn lib-e teos iu ellrrgof nronchospasm.inf) Glucoonrtstoids8(p. 248)ahoibsesignifofatt atti-allrrgof e h itox eit robably8inte fere8weletdifferett eragessenseteeoallrrgof rspotect Iudicat lis:8hayecfeier, nronchill althma8(pryferably8hocllulapplicIm tg of aomlogues e prhincspry-e syabemiogelrmfromili,te ametbetlomete -e sore, be ssxnidr);aataphylac of8shock a(i.v.einrhincsyodjec)—arprobably8norgi-e tomic e h tg ri immed tr otect. 326 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 327 Ai Atti-allrrgof rrsr uxedAttigeng(h ametpollsg,8pinicallpu G) IgE Attibodies aInn ofP a0 hfselyukctrtgaedsynthes s:inh ametzilyutheinR.fyase hfinhistamiieecHistamiieecd.tapt ainR.a hixotliatirgsteosll0 aVastsiaa smoo prmuscle, pormraboltoxinMucous membtonessensenosctdnd eyn:ineedteos swellpup, setprtoheinSkio:inehefl flrmw theinCircula tg:in oaphyl.8shock aBronchill musculo ureedGlucoonrtstoids Vasodilat tg Edema α-SympwPhc- Mmimetics:inh amee oaphazoliie EpiiephriieinCoi ae h tg aBronchill althmainTrs phylliie β2-SympwPhcmimetics:inh amee nd butaliieseH 1 -Attio stamiies Leukctrtgaes Leukctrtgae d.tapt ainattdgootst:inh ametzafirlukaerinCOOHSinCH3inOH NCledCH3inLeukctrtgaeecd.tapt ainOinOinNseH NedCH 3 aH 3 aC NedNseH NedHinOH OH HOedCH 3 aCH 3 aCH 3 aCHO OOOinCOOOOC O O OH CHin2 CHin2 MaltccsllastaboltzaPin inbssetpomolynedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinBronchill AlthmainDefontoixo: arrecurrett,aepisodici hort-e teos ri nrea pryausbanbs nronchoons-inonr mt tg lrisire from dirway inflammw-e tsli aos hlper ra hiitoxtinAlthma8 gatrhts tetdtroaunderesmi-e mmte thn trueeseibrtox ri tieia disrode.inTrsrofere, self-monitorpup by trstuss li hom- peak .x irw ay flow mete sris yn essettial plrtaif thn teec use offpe - oram. Wb prpe pec .dy atixo, treapg-e tsett canldeteermeaalxtoigtstliadetereora-inrlhe aitioan adjusormed cIm tg e pin tee frameworkpatea phys lian-d recttd teer use offd.gimen. aPwPhcphys 200y.aOnctliathn main apaPhoginet c fsctorsf saenryllrrgof in-inflammw thetliathn nronchill mucosa. Flrnins aonr,8leukctrtgaes -hat8ace afermed dy pup enrIgE-med tregim-2 mure d.spotect(p. 326) exer s chsoo-se ac offve in onliiflammw ay csllo. As treainflammw thetdethsops, nronchitbe-ulonmefhlpersetsi tve s aspasmoginicinsmimuli. ceus,rsmimuli otiec thaor-he origigal attigen(s) canlactaas taiggers (A);fe ametbrea ppup of io2d yir is yiaio-seportart taiggerrit exercide-iudy ba aasthma. Cyclooxygenodeainn ofPorsed(p.h196) exemplify drugs sctiregasaaste-sema8taiggerstinMenagemett. Avoidahce atealthmaintaiggers is yiaioportart pe phylac ofsemrasu r,atecpea nst alwaysefrodible. Drugsm-hat8d n ofP yllrrgof inflammm -inr aygmrchft smsmrrod.dy - nronchillsehlper ra hiitox, viz., glucoonrtstoids, “malt-csllastaboltzers,” dnd leukctrtgaeinattdgootsts, ettack orucial plPhoginet cselinks. Bronchodilat as, s ncrasaβ 2 -sym-e pgahomimetics, te- phylliie,8yid ipra-inr opium, prcvfdetsymptoma of rlief. ace- abep schsori(B) allun. Imes s n-uloelesvn levels hf phagy ? tiec use ofsemanagemett at8dncprodire degrersfofindisroderseibrtox. Firs ta ofmett hf ceoice fer teeiny ute a ackaace hort-sctire, sercsolezedinβ 2 -sympgahomimetics, e ametsalbutamol, aalbute ol,rnd butaliie, fenote ol,raosseotiecs.ace-ir a hixotl a rs e pin min- ute0 aitihicts fora4 s a6 h ecIf β 2 -mimetics have to n i sec Mmoregfre Pgatly thaor-hrer mimesdae week,amoregseibre disroderis prysett. Arintris srage, menagemetttioohe ss atti-e inflammw ay drugs, s ncrasa“malt-csllinonlboltzers” (in childrstmrrojuien le pg-e tsetts)gnnaelse glucoonrtstoidst IunalI-sehixoml ta ofmett must bsfa miionreresecd.gulaalx, imprcvsmett beiog evfdeatseotlyoafte iseibrll weeks. Wb prpe pecseuceahf glucoonrtstoids8undergooog hiea prysyabemiogelrmfromili,tnoicernlabout asyabemiogadvpryr effin e iveunwarrant- ee sPoatielsglocal advpryr effin e arr: s ophogyngefl cftdidiaais8ditidyspho-e o a. To minrmfze trstriskpatecftdidiaais,sedrugradmiion. Im tg shouldln a r be-ulfere mornpup oa yvsh ng mrals, nnabe afell wrt bsrrinsoog ri re- s ophogynx.edAtti-inflammw ay tiec uy is trstmoreses noeleful8trstleos uco s madeoof as-e teedbaaβ 2 -mimeticrmed cIm tg.inSeibre cas-sgmay,ahowevsr,are Pirs anliit naffiednnronchodilat a ta ofmettseweletsyabemiogβ 2 -mimetics er tee phyl-seline8(syabemioguceahtly; low tiec use ofseiudex; monitorpup hf plicseslevelse teedba)toSalmete ol is amlong-sctiregii-e hala svn β 2 -mimeticr(durahixo: 12 h; ns-inoste~20 mio)tteatensfers teeoadvattdgstli a8hower syabemiogexposure. Io is sec Mpe phylac ofmlly ot bedmime forano ur-e oal asthma. Zafirlukaer is amlong-sctire, sele -inrlib, eostponettaleukctrtgae d.tapt ain(LTD 4in, LTE 4in) attdgootsttweletanti-in-inflammw ay/attiallrrgof e h itox eittef-ul ofafx inose- meiit naonrose-r ux hfinchroo c asthma. Io is giibn boletormllxseditinsrinnalIm tgtsThsiotectahf a hixo isinolow (3 to 14 a)toPe necttve effin e agtinsh innalregLTD 4inhict up to 12rroin24 h ecIprat opium may be effin svn itinsom- pgatrhts ysaenrydjunn atti-aste-sema of,gbutohosdga ofer e oltox inapeyvsht-e ing nronchospas offvpisodes iu chroo cinnronchitis. 328 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 329edAttigens,seinfyn lnns,seozote,inSO 2 , NO 2 Bronchillsespasm aDyst,seno2d yir,sedrugsedA. Bronchill althma,ipwPhcphys 200y distteer use offa proach aMild althma8Seibre althmaModermte althmainM dffiedoafte inINTERNATIONALinCONSENSUS REPORTh1992edGlucoonrtstoids syabemioedGlucoonrtstoids B. Bronchill althma ta ofmett algorpthminNoxbousrsmimuli "or" "or/atd"edGlucoonrtstoids PgrasympgaholyticsinAllrrgegs Avoid Mexposureinca ofiniiflammw the aDilate2 nronchi Maltccsll-inonlboltzer” a ainglucoonrtstoids “edAttiinflammw ay ta ofmett,rinnalIm ib, chroo cmllxseBronchodilattherasaneedba: hort-sctirerinnalIm ibgβ 2 -mimetics Maittainbd nronchodilatthe 4 x/day4 x/day4 x/day3 x /week<ed–inTrs phylliie p.o./? 2 -mimetics p.o. aoralong-sctireg? 2 -mimetics innalIm ibedInflammw the Bronchill hlper ra hiitox <ed–in<ed–in<ed–inoraleukctrtgae attdgootstsedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinEmes sseInremes srtreastomancrempties iu arret-e rcgradeoolorsr. Thsipylor m sphioote inis closbanwh le treanardia eittes pha- ousrd.laxos aallow tie gast ic noi ehts toecn pe pellestorldnbs s forceful,dsynchro-e tousrcoo ae h tg ri abd mbtalawfllsemusclesfditidiaphragm. Closuretoiatiee glottis8ditielevatitg ri re- softtpalate2 peyvsht eh x hf v mf usliiroarrs . I-e chsa ditinasophogynx. Asaeaeuls, teereinisrprodromal salivatitg rr yawn ngt Co-seordina tg botw en rrssrodifferettinonlgie deperds onose- medullary cei-e tec foa ymes s, we me canln an liImedinbsrdivpryr smimuli. cessrorrsgnoiveyel aviaotrsevgstibsiaa a pgratus,rvisufl, nl-infsctorx,r ostgusoaP ay inputs, es wbra aas viscercsNicorytafferetts from thn ppperrylimettaay tae h. Furtiecmore, apsychic .x ortgac-sgmay also an liIme treaemeticrcrNtor. Thsimrchft sms underlyire m ixoesickoess (kiietosis,2 ssatsickoess) distv mf ng dy pup peyg-e oatcx ecetstits unalear. aPoiaa suosmlhces canested.ach tre aemeticrcrNtor itself bocauss it isrpro-e tectregbyathn nlood-b aintbarrior. How- eibr, tiey canld directly8excite thn cei-e tec by an liImpup yhemorecapt a0 ior-he ecearpoat rmamrrod.tapt a0 hn portph-see Il vagal nerve endpups.edAttiemeticrtiec uy. V mf ng cyn n a seful8 ra hixot nablpup rrs nodytroin.lrmfromb an orlllyrd giercd poison.edAttiemeticrdrugs sref secttolpryvsht kb-e oetosis, peygoatcx v mf ng,acytotoxifsedrug-iudy ba orapottope Im ve v mf -e ing, as wbra acev mf ng dye to padfw the tiec uy.inM ixoesickoess. Effin svn pe phy-ulloxis canln anhievrtawelettreapgrasym-e pgaholytic scopolamiie (p.h106) distHin1 attio stamiies (p.h114) ri re- dtphenyl-semete ie sype (h ametdtphenold amire,edmetlizbne)i Attiemetic e h itox is nst a Mpe perox shaaednbs sll pgrasympgaho-ullytics er attio stamiies. Thsieffofafx oirutrs drugs msntixoed deperds onose- an-e tull situatitg ri re- oodividual (gast icul ollpup, ete iol onnsump tg),tenviron-semettal ons of lice(h ametrrs nehavior osecfellow travsllrrs), aitirrs .ype hf mo-inrlhe .x ortgac-t. ce- drugs should n intaken 30 mio bnfere te- nlrtaifttravslseditirepe tec eibrya4 s a6 h Scopola-semiie appliba rrrasdermmlly thrcpeadae adhes vn paPme canlprcvfdeteffyn libsepe nectili fer up to 3 a. Peygoatcx v mf ng isrpronetroinn a r inose- firs taimestec;lseus phog-sema? tiec uy wouldltoincfdetwath tre aportod nsemaximal fe alnvulnermboltoxaroinchemiomlein ury. A cordingly, attiemet-e icsm(attio stamiies, oraneu olop tcs ifecd. Pirsd) shouldln i sectotlyoehenincoi inuousrv mf ng -hrea ens roadis-inmurb electrolytctdnd wa a balaonros ayindegrer -hat8places treafe us attrisk. Drug-iudy ba v mf ng. To pry-e vshttv mf ng dy pup atticaonrr2 osoooiec uy (espRcimlly e pryisplI-sehig),teffin svn uss canln imadeoof 5-HTin3 -ecd.tapt a attdgootstsg(h ametns ltectrhe,ulgrraiectrhe, aitir opiectrhe), alonetor itinoombfrom tg e prglucoonrtstoids (me hylpeedaieolore, dexamete sore).edAtticipaP ay naussatdistv mf ng,aee-e st Aire from inadequatelyacoi aollesinnaussatdistemes srin gatrhts undergo-e ing cytotoxif osoooiec uy, canln at-e tenua ednbs s benzodiazepiie s ncrasselorazepam. Dopamire dgootst-iudy ba anaussatin grkiisxnian gatrhts (p.h188)edcanln csuNteae hrtaweletDin2 -d.tapt ainattdgootst0 -hat8pinetrmte ponrly8intorutrs CNSn(h ametdomperidone, s lpi fde).edMetoclopr mfdetis effin svn it naussaseditiv mf ng hf gast oiNtesmioalaorigig (5-HTin4 -d.tapt a dgootsm) distat hiea yodjectalso iu chsoooiec uy- distpadf-seam tg-iudy ba sickoess (low ponetcyinattdgootsmaatr5-HTin3 - distDin2 -d.tap-inr a0)toPhenothilziies (h ametlevomeprom-seazbne,itaimepr zbne,iperphen zbne)tmaye stpp y naussa/emes srtrat fell wssete tain .ypecensesu ge ytor is dye to opo-2 id analggsics, gast oiNtesmioalairrsta-e tsli,ruremia,8yid disrodes accompaniedinbsrelevatbanintae rineal p y ure. ace- ayntheticrcanembonoids8dronmb-e inol ditinabolonethove attioau-inosatt/attiemetic effin e -hat8may bine-ul ot AIDS aitioancsrapgatrhts. 330 Trsr ux hf Selecttd DisrodesedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinTrsr ux hf Selecttd Disrodes 331 Ai Emetic smimuli distattiemeticrdrugs Peygoatcxsev mf ng Kiietosesinh ametssatsickoess Psychoginicinv mf ng Seser Olfa hixoinTastbedIntaemucosal sNicorytnervee endpups8in mouth, phogynx,2 ost tomanc Vgstibsiaa syabem Chsooretapt a0ed(drug-iudy bainv mf ng)edAcearpoat rmainEmeticrcrNtor Chsoo-seretapt a0edScopolamiieseH 1 -Attio stamiies Dtphenold amireedMeclozireedDopamire dttdgootstsedDomperidoneedMetoclopr mfde Os ltectrhe 5-HTin3 -dttdgootst NedNNinOinNseH OinNseH CledPgrasympgaholyticsinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAtsFhundahixos8ditinasoc princfplrsfofinplogy ? 2000seHardolo JG, Limbfrd LE. Goodolo &edGiColo’e. Thsiplogy ? 200iomlebaais8oirutrsr use ofe. 9rutr ee sNew York: McGraw-Holl;h1996.inLevire RR.cology ? 2000:rdrugaa hixosseditirea hixos. 5rutr ee sNew York: Partri-e ton Publpsppup Grcpp;h1996.inMuisxn PL, Musllrr RA, Brerse GR.corio-setfplrsfofiplogy ? 200y.eLondxo: Chdp-seolo & Hall;h1995.inMutschlrr E, Deretdorf Hi Drugoan-e tohes—nasoc princfplrsfdistteer use of aaspin e. Stuttgart: Medplogy SctrhtifofedPub.; BocaaRatxo: CRCcoress;h1995.inPage CR Aturtis8MJ, Sut a MC, Walkor MJA, Hoffolo BBt Iutegr teciplogy -ulon200y.eLondxo: Mosby;h1997. Peatt WB, Taylor P.coriotfplrsfofidrugoan-e tohe—trsibasosfofiplogy ? 200y.e3 rdinec inNew York: Churchall Livpupstore;h1990 ecRaup HP, Dale MM, Rit a JM, Gardinor P.cology ? 2000. 4rutr ee sNew York: Churchall Livpupstore;h1999. B. Cl ntlll plogy ? 2000seDtpiro JT, Talber RL, Yer GC, Matzke GR,2 Wsllo BG, Posey LM. Phagy ? tiec -e py–aipwPhcphys 200tlll a proach.e3 rdinec Norwalk Atlno: Appletoo & Lftge;ec1997. Kuemmerle H, Shibsya T, Tallsmett JP. Huolo plogy ? 2000: trsibasosfofitlii-e icll plogy ? 2000. Amstecdam: Elsbvi-seec;l1991.inLaureonroDR ABeniett PN. Cl ntlll plog-sema? 2000. 8rutr ee sEdinbu gh: ChurchallinLivpupstore;h1998.edMelmxn KL, Mortlli HF, Hoffolo BB,2 Nieretberg DW. Cl ntlll ology ? 20- oy—nasoc princfplrsfit teec use ofs.e3 rdinec New York: McGraw-Holl;h1992. ace- Med cIl Let a xn Drugs andlTiec -e pse ofs.eNew Ro oslle NY: ce- Med cIlinLet a Inc.; publpspel bi-weekly.inCl ntlll ology ? 2000—Electronicrdruguld.fergace. campa,8Flor da: GoldlStai-e dard Mulmimed Inc.; upd tec eibry 4 months. inCi DrugoiNteae hixos8ditiadvpryr effin eseD’Arcey PF, Griffon JP. Iat oginic disrod-sees. Oxford: Oxford Univprytoxaoress;ec1986.inDavies DM. Textbookpateadvpryr druguld.a hixos. 4rutr ee sOxford: Oxford Univpr-inotoxaoress;h1992. aHateten PD, Horn JRi DrugoiNteae hixos,2 oalysis ditimenagemett. Vatcouvsr, WA: Appliba Teec use ofs Inc.; 1999; ppd tec eibrya4 months.inDi Drugsminapeygoatcx aitihictw the BriggsmGG, Frerolo RK, Yaffe SJi Drugssein peygoatcx aitihictw the: arrefergace oui s to fe alnditineonmtll pisk. 5rutr ee Balmimore:aWollpacon& Wolkiis;h1998.edRubon PC.aorescribirerin peygoatcx.eLon-e dhe: Brof sh Med cIl Jouroal;h1987inE. Phagy ? kiieticsinRowlftd M, Toz a TN. Cl ntlll plogy -ulonkiietics:tnoicepts yid applicIm tgs. 3 rdinec Balmimore:aWollpacon& Wolkiis;ec1995.inF. Toxi? 2000seAmdua MO, Doull J, Klaasset CDi Casa-serett ditiDoull’s toxi? 2000: trsibasocinsctgac-fofipoisons. 5rutr ee sNew York: McGraw-Holl;h1995. 332 Furtiec ReadooginLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin333 Drug Iudexes Nometclo ure. Thsind condn svn agenAseditiplogy ? etdeoigtote8suosmlhcesin-hat8rrsgnapable hf modifyiree. fn pe - cgssesadr rspin svn oiawhetrsr treaef-ul in 0 elicired8may bine ot s ology -he orgft smsmnoicernec By thisrdefontoixo,2 toxio isralso aiplogy ? e. caken iu a anarrower sNico, aiplogy ? e mransdae suosmlhcem-hat8dsmusbanfer teer use of apurposes -Ae un. Pivocal Pd ctfer sunc a8suosmlhce s med cioaladrugtinAidrugocanln idrhtifoednbs differettindeoigtot lis:ed– thn chemiomlena rig– thn ginericr(tonpe pri.tary)ena rig– a taadeoor btondena rigce- drug diazepam may Usaggasaae allun. Imtve examplei Chemiomlly, tei0inoompound is callest7-chloe -1,3-d hy-ulde -1-me hyl-5-phenyl-2H-1,4-benzo- Mdiazepii-2-one, a Pd cttooaunwieldx forineibrydayouss -A simplerena r is diaze-e pgm. cei0 is nst a legmlly pe nectba ana r butoa ginericr(tonpe pri.tary) ana r -Ae INN (=oiNteatot lialnionpe - pri.taryena r)iisia ginericrna r reat ahosdb en agrerd upherbs anliit ato-sehixoml commi ixo. Peypgrat licecsn ainire diazepame wer- firs markered8underarrs . Ide na r Valium nsri egmanufa hurer, Hoff-seolon–La Ro os, Inc. cei0 na r is arreg-e onrerest. Idemark -Afte ipanettape nec-inrlhe fer teegmanufa hurefofidiazepam-incoi ainire drug peypgrat lice.x ired, otiec companies wbregfree tolprcdy -2 peypgrat licecsn ainire thisrdrugt Eanc invsntbaaa pe pri.tary na r fer itsse“owi” peypgrat li. Asaeaeest A, teereinnowe.xtst0 a pletecrafofipe pri.tary lI-sebels fer diazepam peypgrat lice(as8oiru1991,amoregthaor50)toSom- lintresetrod-seily d.vealttreaa hivn itgeediett,rbocaussseteernomploy na r is simplyaaddedirointhn ginericrna r, e ametDiazepam- (noo-seploy’s na r). Otiec deoigtot lis8ace anew cprohixos, as fer example, Vivol.inSimilaalx, som- otiec commercimllxses noeleful8drugs srefsoldlunderamoresethaor20tdifferett btondelabels. Thsinum-2 berfofipe pri.tary na rs, teerefore, aga ofly8excerds treanumberfofiavmil blsindrugs Flrnte- akefofitlartox, otlyoINNstorseginericr(tonpe pri.tary)ena rs8ace ausbanin tei0 a Pharto deoigtote8drugs,ses nheas trstna r “diazepam” ior-he ebove examplei Uceahf Iudexes Thsi iudexes rsimeart to helpatrstrele-seer:ec1 -idrhtifs s commerciml peypgrat li forina giibn drugt cei0 inflrmw the is foundsein re- oodex “GinericrNa r → P pri-seetary Na r.” a2. obtain inflrmw the aboutttreaplog-sema? 200tlll pe peroiesrhf thn a hivn it- orediett iu arcommerciml peypgrat li.aIninnnder to fiitirrs ginericr(tonpe pri.-se ary)ena r,rtreaseons oodex “Pe pri.-se aryrNa r → GinericrNa r” canln inonnsultee sPjectrefergacesiper ainire torutrs drug canlthen bsglookrd up inose- In-e dex. Thsilfsm oiipe pri.tary na rs giien bshowtwall necysswrily n iicsmpletee dye to te-ir mulmitudetsFhr8drugs reat a rsimarkered8underaseibrll btond na rs, tee taadeona r ri re- s igigalseoloufa hurertwall bsilfsmed; in teernsscinnsesom- fre Pgatly prescribed ginerics,sesom- pe pri.tary na rs oiaotiec mlou-infscturerstwall also bsilfsmed. Brond na rsm-hat8alearly d.vealttreadrug’sseidrhtioxahove b en omit edt Combfro-inrlhe peypgrat licehove nsten en iuohe - ee,tbarriup a few8excepm tgs. Mloy a btondena r is nst lfsmed iiintreaoodex “Pe pri. aryrNa r → GinericseNa r.”aIn tresetcas-s, it wall bsi seful8roincoisu A treapgckagirerinflrmw the,ineh me shouldllfsm rrs ginericr(tonpe - pri.tary)ona r rroINN.inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin334 Drug Iudex Drug Na r TaadeoNa rig(* denote0 invgstigot lialndrug soaPuslii USA)edAedAbacavir ZiagenedAbciximab ReoPe AdarbosctPeycoscinAcebutclol Monitag,oSRc ralinAcenocoumarpu (=oNicoumalone)-Siotrom Adetaminophegasee Paraceoamol AdetazolamideoDiamox, Glaupax Adetylcyabeiie Airbrhe, Fab ol,rMucomyst,8Parvolex Adetyldigoxio AcylanidinAdetylsaltcyl c didaAspir i,iArtrros i,iAsadriie, Ecctrte,inEotropheg,8Pyrheoval, SupasainAdiclovir Zovirax ACTH Ac-har AtlrtrophiiinActiromycio DAtlsmegenedAoyclovir Zovirax ADH (=oVasop y in) Pit y in,aoresynedAdpsnaligasee epiiephriieinAdpiamycio See doxorub cioinAjmaliie Cardiorhythmino; GilurytmalinAlbute ol See SalbutamolinAlcuronium htsoferpuinAldoeteroie AldoonrtenedAlendronmte8Fosamax Alfettanil8Alfetta Alfuzosir8Alfonet, Xa ralinAtsopy puol htsopr i,iNovopy ol,rUros i,iZysopr m,iZysoricseAlpr zolam Xanax Alprenolol Aprobal,rApm ie, Gub atol Alprostadil8(=oPGE1) Prostir8VR,rMinpe ginAlteplice Ac-ivsscinAlumiioum old oxideoAldrox, Alu-Tab, Amphojel,8Fluagel AmdttddinooSolu-Coi ehthe, Virofral, Symmet yl Ambroxol Ambril, Bronchopront,rMucosolvag,oSurfa tol Amikacio Amik i,iBricl i,iNovamin Amilor deoArumil AtlaRc ril AMidamor ANiluridinAmilor deo+ Hld ochloe thilzideoMcdyre seε-Aminocapro c didaAmiomr AAfibr i,iCapr molinε-Aminocapro c dida+ Aromboplictir8Epsolon-TachostyptagedAminome hylbenzo c didaGumbix,8Pamba 5-Aminosaltcyl c didaPe pasa, Rez podedAmiodaroie tlrdarex, tlrdaroneedAmf aiptyliie Amf ail AElavil AEudep AEuovil ALevatb AMevaailedAmodiaquiie Camoquie, FlavoquieeedAmoxiftllpu Amoxil Atlamoxyl AMoxacio,iNovamoxioinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 335e d-Amphetamiie Dexedriie, SynmtlgedAmphotericpu B Amphozote, F ngil i,iF ngizote, MorxoflseAmpiftllpu Amftll, Omnipeg,8Penbrof g,8Polyftllpu,coriotfpeg,8Tota-e ftllpuseAm puon- Inoonr, Wiicsrame Ancrod*oArv i,iArwie, Vipr iex Angiot nafn II Hlpert nafn Apr idiie Amfdxofl,iAspeghe, FibociledAndeparpu Nlrmifl Artstwiie8Uluracwii,rUbfsmeafn AabemizolstHismenaledA enololaorenlrmite, TenlrmitedA orvssoaPir LiptoorinAuracurium Tae riusedAt opiie At opisol,rBoe t opiiedAuranofon RidauraedAur thioglucoce Ayreotag,oAur myoco, SolgenaledAzapropazoteaPe lixlgedAza ppopr ie Azanig,oImuran,oImurekedAzfdx hymfdire RctrhviredAzfthrcmycio Zfthrcmax Azloftllpu Azlpu,cSecur pegedAzt yxofm Aza tosedB Baciuracir8Aluracir,rBaciguett,rTopiuracir Bacsofer Liod. aledBasoliximab Simulecte Betlomete soie Aldecir,rBetlovett,rBeonsIsc,8Beontide,rPe paderm, VaiceriledBen zepr l Lot nafn BNicorlzideoMadopar (pluslLevodopa) BNiza ppne-Pinicallpu G Biftllpu,cMegaftllpu,cTardoftllpuseBNizt opiie CogintpuseBNizbromaroie Desuric,iNaromricio,iNormurat,rUricovacseBNizocaine Anaierhes i,iAmericaite, Anacwiie BetaxololaBetop of,gKerloie Bezafibrmte Befizfl,iBezalip,iBezatol,rCedyr BifnsIzolstAmycnr, Bedriol,rMycnspnr, MycnspnrlgedBiperider Akiietoi,iAkinophyledBis ? dyl Bifol, Broxalax, Dy olax, Dylcolax, Laxwn i,iLaxbine,2 Nigalax, Pyrilax, Telrmii,rUlcolaxedBismuletsubsaltcylmte Papt -BismoledBisoprclol Coicnr, Det nafel,8Emcnr, Isonet, Soprcl,iZebeta Btoolte ol Effin sg,8ToatolIme Blecmycio Blenoxaie Botulpuum Toxio Type A Oculpuum Bromazepam Dy azanil ALectopam ALexotlgedBromhexineoAuxit,rBisolvoi,iOphthosoledBpomocaiptineoParlodel,8Pravfdel, Seroi -BagregedBrotizolam Letdorm (A), LetdormpuseBuciodolol* BextraedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinBe ssxnidr Pulmionrt, SpiroonrtinBemr anidr Bemrx, Bur iex, Foi ego, FordiurlgedBunitrololaBetriol,rSt y he BupranololaBetadrar,rBetadrstol ALoocor,8Panrmft Buprenlrphiir Beprene, TemggsicinBepropion Wsllbatrte, WsllbutrpuseBucorelpu Sprecur, Suprefa tseBucpiroir Bespaa BesulfanAMielucio,iMtoosar,rMyler g,oSulfabutpuseButizidaSaltucir N-Butyl-scopolamiie Bescop g,oHyoccir-N-ButylbromidinC Calcifediol Caldercl,iDedr000l,iHidr0fercl Calcitoo i Calcimor,8Calsynar Atibacalcio,iKaailedCalcitriol Ro altrcl Calcium darbonmte8Calsai,iCaltrmte,iNu-Cal Camazepam Albego Canrenlie Kanrenll, Soldsctone, Ven ctone Can ssartarof acond Caprecmycio CapssoaP,iCaprolpuseCaptopril8Acediur,8Acepail AAlop y i,iCaponet, Cesplog,oHyperoil, aLopir i,iTNicobnnseCar zolol Coidy hog,oSue rnnseCarbachol Doryl AMiosoaP,iLintpuseCarbamazepiie Eptool AMazepiie,oSirtal,iTNgreool ATimonilseCarbinicallpu Anabactyl (A), Carpudapeg,8Geopeg,8Py pegedCarbinoxoloir Biogast oie,oBioplex, Neogil, SanodpuseCarbidopaa+ Levodopa Isionm,iNaonm,iSiieme seCarbimIzolstNeo-Meromzols, Neo-ThyrecsoaPseCarbopliPir ParapliPirseCarteolol Arteop of,gCaltidrst, Carteol AEudak, Ocup y ,iTNialpuseCasageilol CoreginCefalexingKeflex, KeftabinCefazolii Ancef, Ketzcl Cefixime SupraxedCefminoxime Biercall, Cefmax, Crmix, TacefinCefope IzoteaCefobid,aCefobi ,iTomabefinCefotaxime tlafnrlgedCefoxof gcMefoxioinCeftazidime Fortaz, Fortum, TacicefinCeftriaxoneoAfattex, Ro ephiiinCefuroxime axeoilaCefPirseCslluloce Avicel CephalexingCepexing(A), Cepnrex, Keflex, Lnspnrll CerivssoaPir Baycnl Chsnodeoxychol c didaChsnixedChloealold ate8Lorpual,iNoctec, SomnosedChloeambucilaChloeaminophege,iLiukerlgedChloeamphegifolaChloecmyce sg,8Chloecp of,gLeukcmycio,8Paraxit, Sopa-semyce sg,8SpersagifoledChloehexidire Baxedsg,8Chloe-hex, Hibidil, Hibitate,8Plak-out a336 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 337edChloemddinoneoaceoate8GesmafnrtsgedChloeoquiee Aralsg,8Avloclor,8QuieachloeedChloepromaziee Larga hil, Hibanil AMegapheg,8TecrazireedChloepropamideoDiabiieseedChloepro ppxgae Taractag,oTarasai,iTruxaledChloete lidoneoHygro nnseChlaRcalcife ol D-Tabs, Vigenool AVigorsaginClorazepate8Novoclopmte,iTaanxgaeinCilazaprilaInn oaceinCimetidire Papt l ATagame seCiprofl xacio Ciprobay,aCiproseCisaprideaPe ulstdseCispliPir PliPirex, PliPiroledCitalopr m CelexainClartohrcmycio BiaxioinClavulmn c Adida+ Amoxiftllpu AugmintpuseClrmictire Tavtst Cl ndamycio Clrocio,8DolIcit, SobeliginClobazam Fros um Clodronmte* tlasteoi,iOssinet, Osmac Clofazimiee LampregedClofibrmte At omid-S Atlaaipex, SkleromexeedClometeiIzolstDon. Ineu it, Hrmiieu itedClomtphene tlomid,8Dyneric, Omifio,8Pergomime, SeropheneedClonazepam Clonopii, Iktorpvil ARivctrtledClonidire CatapresetDixartoedClopidogrel PlivixedCloetebol Me rnbit, SteaenaboledClotiazepam Clozai,iRize,iTienlr,iTaRcalmo, Verat aginClotaimIzolstCanierst, ClotaimIderm, Gyne-Lotaimio,iMycelex,incaimystegedCloxaftllpu Clovapeg,8TNg pegedClozapiie ClozartledCsdeiieAtldicepm,8PaibrlledCslgstipolaChslgstabyl AChslgsttdseCslgsty amire8Quen. In AtuemidinCnrtstot opii Ac-har Atlrtigil, tlrtrophiiintlrtisol (Hld oclrtisone)-Aloonrt, tlrtmte,itlrtef, tlrtenema, Hlderm, Hyoonrt,inR. hoonrt, UnionrtinClrtisone tlrtelIn Atlrtogin AtlrtoieinCotaimoxazolstBac rim,iNovotaimel,8Prctrte SeptraedCromoglycote8(Cromolyn) Iutal,iNalcrnm,iOp ofrnm,iRynafrnm,iV stacrom Cyanoonbalampu Anacnbit, Bedoz, Rubooi,iRubramin Cyclofen l Ferocdyr,iOodogyte,8Oodonid,8Sanocros i,iSexovidinCyclopegthilzideoNavfdrix, SylimidinCyclophosphamideoCytoxai AEudoxai APrccytoxinCyclospnrire8Neoral, Sftdimmure, Sftg-35e CyproheptddinooAnarex l ANuran,oPerian sg,8Periool AVimionne Cyproteroie-aceoate8Androcyr Cytarabiie Ud cil, tyoosaredLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDinDatlizumab ZNiapax Dactiromycio See Actiromycio D Dalteparpu Fragmin D oapar id Orga aginD otrclene D otr um Dapsoie Avlosulfoie,oEporal, Dtphenasore, Udolac Daunorub cio Cerub diie,oDaunoblictir,8OodenainDeferoxamiie DesfbrlledDelivirdire RcscaiptoeedDesip amire8Perocfran,oNoepramin Desmop y in DDAVP,rMinir i,iStimIme Desogierrel + E ppnylen. Idiol MasaglheinDexamete sore Decadrhe, Deroiil, Hexadrcl,iSpersadex DexeoimideoTaRmblex Dex. In Hyskhe aDiazepam Apau it, At nafneetDiasoaP,iDizac, Er dai,iLembtol, aMeval,iNoai,iTNicium, Valium, Va. In AVivol aDiazoxideoEudemite, HypersoaP,iMutabIsc,8Prcg. Nm Diclofenac htsvo In ADiclophlogont,rRhumalgIn AVoltarst, Voltarol aDicloxaftllpu Diclocil, Dynapeg,8PwPhcciledD daiosire (ddI)AVidex Die hylstitben. ol Honvol aDigitoxio Crystldigio,8Digicnr, Digimerck, DigIcit, Lagifor, Lagoxit, Legoxit, Novodigoxio aDigoxio immure FAB Digibiid aDiold alaziee Diolzit, Nep y ol,aoressunicinDiold oergomamire8Angionlrm, D.E.H.45, DioldergoP,iDivegml AEudophl.-sebaginDiltiazem CardizNm Dimenold fromb Dimetab, Dramamire, Dymenatb AMarmireedDinoprostrMinpe ctir8F2α, Prostarmon, Prostir8F2 htphaedDinoprostoteaPeepidil, Prostir8E2 Dtphenold amire-Allrrdryl ABen dryl AInsommal,iNautamiieecDtphenoxylomb Diarsee,tLom il AR.tardio aDisopyr mfdetNoepanr,8RythmodaginDobutamiie Dobutrex Doceoaxel TaxotereinDolicet oi8Anzeme seDomperidone*oEucitoo AEvoxit, M ilium, Nauzelsg,8Peridhe aDopamire DopasoaP,iInt opiiedDorzolamideoTrusop seDoxacurium Nurcmax Doxazosio Cardura, CarduraiedDoxepii Adapii, Siiequai,iTriadapiiedDoxorub cio Adpiblictir,8AdpiamycioedDoxyoycliieAt-Pak, Doxiftn AVibramycioedDoxylamiie DecaprynedDronmbpuol MariroledDe peridhlaInapsire, D olop aied338 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 339 E EcnsIzolstEcnsoaPir, Gyno-PevaayledEcctppopmte PhospholiieAIodide2 EtolIprilaVasotec, Xanif2 Etfluraie E praie En xacio Bac dai,iCompreftn AEn rame En xaparpu LovetoxinEn acopone*oCom aiedEpiiephriie Adpsnalig, Bronchaid,8Epifio,8Epiiml AEpiPeo,8Epitrmte,edLyophrii, Simplere, Supraren i,iVoponefriie Ephedriie Bofedrcl,iEfedrci,iVo-t o-roledEprosartaroTevetegedEptifobatide Iutegriliie Ergocalcife ol DrosdoledErgomet ire (= Ergouovine)-Ergotrmte Maleatb AErmmlIme Ergouovine-Ergotrmte Ergotamiie Ergomar AGynergin AMigrtledEryahomcyir8E-mycio,8Eryc, EryohrcmidinEryohrcmycio-en.olomb Dowmycio,8Ilosore, NovoryohrcinEryohrcmycio-e hylsuccfromb EES, Eryohrccio,8WyamycioedEryohrcmycio-propionmte8Cimet iredEryohrcmycio-stearmte Erymycio,8EryohrccioedEryohrcmycio-succfromb MoromycioedEryohrcpoie sg (= epoe sg alfa) EpogenedEsmololaBreviblocedEs. Idiol Es. IceinEs. Idiol-benzomte Pr000ton BinEs. Idiol-valermte Delen. ogin ADioval, Femogix, Pr000tovainEs. Itriol = Es. iol TheglhledEtatercepmAEnb yl E pacryn c didaEdec it, Hld omedsg,8Recmax E pambutcl E ibi,iMyambutcl E ppnylen. Idiol Ectiryl, Feminone,tLynnrll E ppxofmideoTaRcatoeedEthopropaziee Parytoao,8Parsitcl E posuximideoPe sgimid,8SuxinuPir, ZaroitpuseE idocaine Duraiest E idronmte8Calcimux ADiodronel, DtphosedE ilefriie Apotprtoo,8Effoitpl,8Effortpl,8E hyl8Adpianll, Circuphe,inKer a in,aoulsamio,iedE odolac Lodiie Etcmidate8Amidate EtcposidctTcposar AVePestdseEtprtooate8Tegison,iTiga he F Fam idire Papcid,8Papdul Felbamate8Felbatcl Felodipiie Plendil Felyp y in Octapresafn Fetfluramiie Gaiml APonderml APondimioinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinFetofibrmte Liptdyl, TricorinFetoldopamAtlrlopmminFetoprofeniNalfon,iNalggsicinFetote ol Berotec, PartusistegedFettanyl8SublpmazeedFettanyl8+ De peridhlaIntovarinFooaeterideaPe Rcim, ProscarinFaRcainidr TambocorinFlucloxaftllpu FlucloxinFlucnsIzolstDiflucyn Flucyoosire-Alonbar,8Anontil Flud oclrtisone8Alfloeote, F-tlrtef, Flor nif2 Flumazenil8Anexatb ARomazionne Flunarpziee Dinaplex, Flugerml ASibelium Flunisol deoAerobid,aBrxoflide,rNacllide,rRhiimlarinFaunitrazepam* Hypnoscdon,iNarcozep ARohypnol FluoxeoiteaPe zac 5-Fluorouracil8Adpucpl,8Effudex,8EffurixinFlupegtixol Depix l AFluanxol Fluphen zbneoMcdinet, Pe lixine Flurazepam* DaColoee FlutamideoD oginil,8Eulexine Flutic sore Cu liIme AFlix sIsc,8Fl sIsc,8Fl vettinFluvssoaPir Lescol Fluvoxamiie Fl xifral, Faibrit, Luvox Fll c didaFlldiie,oFllvite,iLiucovorine Foscarnet FoscaviredFosiropril8MoroprtledFurcsNmideoFusie,tLa ix, Seguail AUritcl G GabIpegtiniNeu oitpuseGallamiie FlaxedslseGallopamil htgoonr, Corgfl, Proonrum, Wingom Gaidiclovir tyoovere, Vitra UstinGeliPir-cell ids8Gelifundsg,8Haey ?cel Gemfibroz l LoptdseGettam cio Cidhmycio,8Garamycio,8Refnbacit, SulmycioedGlibetclomideo(= glybu fde) Daoiil, DiaBeta,8Euglucoo,8GlysIsc,8MofrnnsscinGlimepi fde8AmaayledGlipizideoGlucotrcl Glyceaylt iritrmteo(= nitroglyceain) Ang-O-Sp g,oNitrocop,oNitrogard,oNitroglys,iedNitrolpupufl, Nitrong,aNitrosoaPseGlycopyrrolomb Rnbitul Gnnsdorelpu Fac rel, Kryptocur, R.fyfa tseGocorelpu Zolodex Gram cidpu Gr moderm Graaiectrhe KytrtledGroseofulviu Fulvicio,8Grosov i,iLikudeoedGuenabenz8Wyt nafn Gueneteidire Ismelsg,8Visut nafl Guenfacite8Teiex 340 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 341seH Halofant ire Halfan HaloperidhlaHaldol, Serenace Halote ie Fluote ie,iNarkotlgedHCGo(= chorionicrgnnsdot opii)AChsrex, thorci,iEotromoie,oFllluteio,8Gonic,iedPeygoe in,aoregryl, Profa iedHeparpu Calciparpu, Hepaleai,iLiqueminedHeparpu, low mlaRcsiaa Fragmin, FraxiparpuedHetssoarch (HES) HesplgedHexachloe pe ie see L ndaieseHexnbarbital Evipal Hld alaziee Al zbne,iAp y oliieseHld ochloe thilzideoAprozide,rDiaqua,rDiuchloe,iEsidrsx, Hld omfl, Ne - Csdema, Oret cseHld omlrphore Dilaudie,tHymlrphlgedHld oxoonbalampu Ac -B12, htpha-redi ol,aSyoobex Hld oxychloeoquiee Pla Pgail Hld oxye hyl soarch HesplgedHld oxype geeteroie capromte DuraluPir, Geeterol L.A.,tHyluPir, Hy oxot, Pe -DepoedHloscyamiie sulfate8Cystlsplz-M ALevbid,aLevafn I IbuprofeniAc propheg,8Advil AMctrte, Nupr i,iTretdarinIdoxu fdiie Dendpie,tHerplex, Kereftd,8StoxilecIfosfomideoIfex IloprostrLmtlgaprost Imip amire8Dynaprig,oImpail AJanrmfte, Melsp amir,iTofranil, aTyp amireedIudapomideoLozide,rLoz l ANItrilixinIudinavir CrixliIninIudomete cio Ammuno,iIndoftd,iIndoftn,iIndome, MetacenedInfliximab RemiomdeedIusulpu Humalog,aHumulio,8Ilrtoo,8Novolsg,8Velosulfn Inte feron-α2 Berofer atpha 2 Inte feron-α2biInt oo A Inte feron-α2a Roferon A3 Inte feron-β Fibliferon 3 Inte feron-β-1a Avoiex Inte feron-β-1brBetasernnseInte feron-γiAc mmureecIprat opium At ovett,rIt opecIrbssartarofvaproseIsocnsIzolstGyno-Taavogin ATaavoginseIsoete riie Arm-a-Mee,tBisoriie, Brxokoscl,iDey-LutbedIsofluraie Foraie IsxniazidaArmazid, Isonamire, Lamiazid, Nld azid, Rrmffon,iTe.-sebacoo i Isxppsnaligeo(= Isxppoterenol)-Aludrig,oIsup yl, Ne 8Epiiit, Savettriie IsxsorbideodiritrmteoCedocard,oCorldus,rCoeotex, Isordil, Sorbitrmte 5-IsxsorbideomoioritrmteoColsb AElanoao,8IsmoseIsotprtooopu Acutate Ro os, Ro ?cutlgedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin342 Drug Na r → TaadeoNa redIsoxsupr ie Rolssox, Vasodilan,oVasop iie Is Idipire8DynaCirc ItrocnsIzolstSpnrlgox K Klgamycio Aofmid,iKantrex, KlsbciledKaolii + Pin sgo(= a apulgite)iKa Rctmte,iDonnagel-MB, Pin okaye Ketamiie KetalarinKetocnsIzolaNiznrll Ketorolac Acsiaa,8ToaadoledKetotifeniZadinetedL LabetalolaNormodyte,8Taandate Lsctuloce Cephsiaf,gChroosiaf,gDuphalac Lamivudiie (3TC) EpiviredLam igige Lami tol Lansop Izolstorev didinLeflunom deoAravainLepi udii8RefludlgedLeuprorelpdeoLuprogedLevodopa Larodopa, Dopar, DopaidlgedLevodopa + BNicorlzideoMadopar, Pe lopaedLevodopa + CarbidopaaSiieme seLevomepromaziee Levoprome, NozielgedLidocaine Dalcaite, Lidopeg,8Nulicaite, Xylocwii,rXylocwrdinLiicsmycio Albio of,gCtllpmycio,8LiicscioedL ndaie Hexit,rKwbra,rKild ie,iScabene Lix hyroiineoCytomel,8TriosoaPseLisiropril8oriopvil AZen. ilinLisproninsulpu HumaloginLisu fde Cuvalit, Doprrgoi,iEuiml ALysenylinLithium darbonmte8Carbolite,iDunrllith, EskllithinLithium darbonmte8Lithate, Lithobid,aLithotabsinLomustineoCeeNu aLoper mfdetImodium, Ka Rctmte II aLorat dire ClartoioedLorazepam Alzapam AA liIo,8LorazedLorcainidr Lop gtrol ALorivox, Remivox Lermetazepam Ergocalm,8Loramet,iNoctamidinLosartaroCozaaredLovssoaPir Mevaonr, MeviracorinLyp y in Diapid,aVasop y in SftdozedM Mlonitol Isonol AOsmitrcl MaprotiliieoLudiom l MaziodolAMazonlr,iSanorex MebetdazolstVecmox Mechloeete miie MusoarginseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 343edMeclpziee (meclozire) Attivert, Attrizbne,iBxofmine,iWheibrtedMeclofenamate8MetlomenedMed oxype geeteroie-aceoate8Amin ADepo-P overa, OrlgietedMefloquiee LarimminMelphalao AlkerlgedMen dixoe SynkayvitedMeperidiie Demercl MepiidololaBetagon,iCarpdiIn AtlriidollgedMepivacwiie8Carbocaite, Isocwiie 6-Meromptopur ie Pur ieaholedMesalamiie (Mesalazire) As ? l,8Pentasa, RowasainMesna Mesnex, UrcmitexlgedMeeterolone8Androviron, Pe vironedMeetranol MenophIsc,8Nor Pga, OvssooledMetamizola(= Dipyroie)-Algocalmig, Bonpyrio,8Divariie, Feibrlll AMetilog,oN - valgio,8Paralgio,8SulpyrioedMetappoterenol-Alupett,rMetappeledMetformpuoDiabex, GlucophIgeedMethadoneoD lophfte, Methadosc,8Physxsapt needMethamphetamiie Desoxys,iMethampex MethimIzolstTapIzols Methohexital Brevitol Methotrexmte8Folex, Mexmte Methoxyfluraie Pentpraie,iMethofane Methyl-Dopa Aldomet,iAmodopa, Dopamet,iNovomedopa, P y iol, aSembtina Methylcslluloce Celevaf,gCellothyl,gCttrucil, tllogil, Le ril,rMuroceledMethylergomet ire (Methylergouovine)-Metrsrgfte, Metenarpu, Methylergobrevio,8Ryegouo- vio,8Partrrgoi,iSpametrio-MedMethylphegidate8RitalpuseMethylprylou NlludlrseMethyltesmoeteroie Android,aMetandrst, Tierred, VirilouseMethysrrgode SansbrtedMe pranololaOp opranololedMetoclopr mfdetClopr ,8Emex, Maxer g,oMaxolai,iRetlomide,rRegllgedMetoprclol Betalof,gLop y orseMetroiidazolstClont, Femmzols, Fla00l,iMetroiid,8PrctosoaP,iSat iculMexilrtoo Mexitil Mezloftllpu MezlpuseMiansbrio Bllvidon,iNorvsl Mibefradil8PosicorinMicnsIzolstMicIm t, M otstaPseMidazolam VpryrdseMifepaistoteaRU 486 aMil puon- PaimIcorinMinooycliieAMinoosg,8Vect iredMinoxidil Loninet, Rogwiie MisoprcsooloCytoteculMtohramycio MtohraciredMitoxait oieiNovait oieedMivacurium Mire rnnseMoclobNmideoAur rixinMolstdomiieAtlrvstoo ADuracorci,iMolstdolaPseLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinMoi elukaer SpupulairedMlrphiir hld ochloeideoMcrphiteculMlrphiir sulfate8Aetramlrph ADuramlrph AEpimlrph ARoxaiol,rStatexinMuromoiab-CD3 OrPhcclone8OKT3edMycophenolomb MofeoilaCellCept NedNabolonetCesame seNadolol Corga dseNaftifoniNafPirseNalbuphiir NubairseNalidix c didaNegr m,iNograme NaloxoneoNaromrseNaltrexoneoNalsrex, Revia,iTrexmrseNandrolone8Anabolir,8Androlone, Deca-Durabolir,8Hybolir Decauo- mte,iKabolirseNaphIzoliieAAlbalhe, Degiet-2,corivfte, Vasoonne NappoxeniAleve ANIprcsyn,iNaxene Narontigeo(= Noscapine)-Coscopsg,8CoscotabinNadrcparpu* FraxiparpueinNedocrcmil TalmdeedNelfinavir Vire ept Necmycio Mycifradin,iMyciguett NecstigmiteaPe stigmit Neoilm cio NetromycioedNevirapire8ViremureecNinardipiie8CardereecNinlosamfdetNiclocide,rYomesaginNifedipiie AdmlIm, ProoardiainNimodipiie NimotopecNi oldipiie Ssiaa Nitrazepam At mpol AMogwdhe aNitrendipiie Bayot nafn,rBayp y edNitroglyceain See Glyceayl t iritrmteedNitroprussidctsodium Nipride,aNitrop y edNizat dire AxidinNor-Diazepam Taanxilium N,8VegesaginNoaadpsnaliga(= Norepiiephriie) Arterstol ALevophedinNorethieteroie Mofrnnorin= Nore ppnd oieiNorluPir, Nor-Q D Norfl xacio Noroxio aNoscapinea(= Narontige)-Coscopsg,8CoscotabinNlrtriptyliie PameloeedNysoaPir KornsoaPir, MycnsoaPir, Mykirac ANilsoaP,iNysoex, O-V aStiPirseOseOc rentide SftdostiPirseOfl xacio Tarivfd Olanzapiie Zyp yxainOmepr zolstLosec, Prilosecul344 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 345 Os ltectrhe Zofran Opium Tiooturef(laudanum)8ParegoricseOrcippsnaligeo(= Metappoterenol)-AlupettseOrnip y in POR 8ruOxaftllpu Bac oftll, ProstaphlirseOxatom deoTiose seOxazepam Oxpam ASer x, Zapex OxicnsIzolstOxtstaPseOxprenolol TaasicorinOxymetazolire Af it, Allrrest, tlr cidpu, Drosoao,8Ne -Synephriie, aSinaresPseOxy oftn Pitoosg,8Syntoosghe aPinPaclioaxel TaxoledPgmidronmte8AminomuxedPgncuronium Pavulhe aPenoopr zols* Penoolac PapIibritetCerebid,aCeresplg, DelapIi, Myobid,aPapIcoo,8Pavabid, Pavadyr,iVa aledParaceoamol =oaceoaminophegaAcepheg,8Anacio-3, Brxm -Seltzor,8Da ail AT mpr , aTylstol AVmlIdol AVmlorine Parxm mycio Humatine ParxxeoiteaPaxilecPenbutclol LevatolecPendiclovir DenaviredD-Pinicallamiie Cupr mire, DepegedPinicallpu G Biftllpu,cCryspin ADeltapeg,8Lanaftllpu,cMegaftllpu,cPog-seftllpu,cPNicorb,8Pentids,8Permapeg,8PfizorpiiedPendillpu V Betapeg-VK, Bopeg-VK, Coftllpu-VK, Lanaftllpu-VK, Le-e derdillpu VK,iNadopeg-V,iNovopeg-VK, PNiapar VK,ecPenbec-V,iPeg-Vee K,8Pfizorpeu VK,iRnbiftllpu-VK, Uti-seftllpu-VK, V-Cillpu K, VeetidsecPentazocite8Fortral, TalwiiedPentnbarbital Butylore, Nembutal,iNovarectal,8PentancaedPentnxifyllire Trettol PergolideoPermax Periudopril8Coversum Permetrron Elimite,iNix,8PermanoieedPeteidire = Meperidiie Demercl, DolaitpusePhenoyclidinooSernylinPheni amire8Dateral AInhistotinPhennbarbital Barbita, Gardeiml ASolfonotinPhennlphthaleio Alopheg,8tlrrectcl,iEspotabs AEvac-U-gin AEvac-U-Lax,inEx-Lax,oMcdate,8PeulstinPhennxybenzamire8DibetzyliiesePhenprocoumoniLiquamar AMaroumarsePhentolamiie Regof g,8RogitpusePhenylbutazone8Algoibrite,8Azolie,tButagin AButazolidin,iMalggsicinPhenytopuoDilaitpusePhysxstigmiteaAttilir um Phytomen dixoe Konmkthe Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinPilocwrpiie Akwrpiie, Almocwrpiie AI-Pilopiie AMiocwrpiie AIsop - Cwrpiie APilokairedPiidololaViskegedPiperaftllpu PopraciledPipecuronium hrduagedPiretzepiie Gast ozepiiedPiroxifam FeldegedPizotifeni= Pizotyliie Litec, Moseglr,iSandomigran Plicamycio MtohraciredPolidocanol Thes t Peanlukaer*8UluairedPravasoaPir PravacholedPrazepam Cettrax Prlziquai el Bilt icide2 Prlzosio Minip y edPeedaieolore Artstuloce Atldelscl,itlrtmlone, Delua-tlrtef, Deluastab, Ecnsop yd, Hldeltrmscl,iInflamace AKey-P yd, Metmlone,seMetretoi,iPed p yd, P ydmte,iP ydonr, P yloie Peedaieoie Met clrten, Orlsore, Penmscl,iWinpeedinPrilocwiie8Citatest, Xylorest Peimaquiie Peimaquiie PeimidoneoMyidone, My oliie ASertlgedProbenedidaBenemid,8PrcbalaoedProbufolaLovelcoedProcwiie8Novocaiie PeocaiiamfdetPeocan SR,8Prcmire, Prorest0l,iRhythmin Peocarbaziee NatulaoedProoyclidinooKemadriiedProgabideoGabret(e)edProgeeteroie Femot oie,oProgeeta UstinPrcmethaziee Anergao,8Ganpheg,8Mallergao,8Pentazire, Phen zbne,inPhenergao,8Prcmeth,8Prcrix, Pr0vigai,iRemsedinPrcpafenlie RhythmoledPropofol DiprivaoedPropranololaDet nacl,iIndbrlledPropyl ppxuracil8Propyl-ThyraciledPyrai el Pgmoate8AnoiminthinPyraziiamfdetAldiiamide,rTebrlzidinPyridxstigmiteaMesmiooi,iRegouolinPyridxxineoBee- ix, Hexa-Betalpu,cPyroxioeinPyrimete miie DarapriminPyrimete miie +oSulfadxxineoFlteidlrseQseQuazepam Dnrll Quieacriie AtabrpueinQuieapril8Accup il Quieidire Cardioqpu,cCpu-Quie, Quiealai,iQuieidix, QuieoraedQuieine Quieaminoph, Quieamm, Quiee,iQuieiteed346 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 347 RecRal xifene EvtstaecRamip il httace Rantoidire ZanoacinR.mifettanil8UluivainRepaglinidr Actul i,iNovoNlrm, Peandio aR. Uspiie Sandril, Serpalai,iSerpasil AZeppueinRibavirpu Virmzols, RebetolinRifabutpu MycnbutpuseRifampon Rifadin,iRimIctlgedRitodriie YutoparedRitonavir NorviredRocuronium ZemurnnseRolite. Icyclii Rever i,iTrlteoycliie,8VelIcycliieinRopiiirols* ReQuipinRoxtohrcmycio Rul dinSinSalazosulfapyridire = sulfasalaziee Azalite,8Azulf diie,oS.A.S.-500, SylazopyrioedSalbutamolo(= Albute ol) Provettil,iNovosalmol AVentolioedSaltcyl c didaAcnex, Sebcur, Soluvsr,iTrlte-Ver-Sll Same e ol Sed.vettseSaquiiavir Fortovsss, InvirascinScopolamiieiTrltederm Scop,8Tript needSelegeliie Carbex, Dep yryl, EldepayledSenna BlIck Drauser, Fletcher’s Cssooria,iGenna,iGentls No ure,iNytilax, SenokoP,iSenoloxedSertsgdols* Serle tseSibutramiie Redy hil SildegafilaViagraedSimeteicnse Gas.X,rMylicoo,8Phazyme, SilaioedSimvasoaPir ZocorinSimoeterol Simo-Lande2 SotalolaSotacorinSpin sromycio Trob cioinSpiram cio Rovamycio,8SelectomycioedSpironoloctonetAld ctone Stavudiie (d4T) ZertoedSt ypt kirase Kabikirase,rSt yptascinSt ypt mycio St ypolir,8St ypt soledSt ypt zocit ZanosaredSuccfrylcholiieAAnectiee,iQuelicio,8SuccnsorioedSucralfate8Carafmte,iSulcrmteedSufettanil8SufettaedSulfa etamideoAK-Sulf Forte Atetamide,iSulamyd,iSulair,oSulfex, SultenedSulfa ytiie RenoquidedSulfadiaziie MofrnsulfoiedSulfadxxineo+ Pyrimete miie ProklaredSulfamethoxIzolstGammzols, Ganoaool,iMethanoxaioledSulfapyridire DaginaiedSulfssoxIzolstGattriafn,rGulfasioinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinSulfasalaziee Azalite,8Azulf diie,oSylazopyrioedSulf npyrazone8Anturan,oAprazoneedSulprostoteaNmlIdoredSulthil r OspolooedSumatriptan Imitrex T t-PAo(= alteplice) Ac-ivsscinTacriie Cogiex TacrolimusoPrograf Tam xifen Nllvadix, Tam fenedTemazepam Euhypnos, ResooriledTeniposidctVumonedTerlzosio HyorioedTerbutalpu Bre ppne,iBricanylinTe fenddinooSeldaieseTesmoeteroie cypionmte8Androcyp,8Andronatb ADuratest, Tesmoje tseTesmoeteroie inaioate8Andro, Delatestryl AEve oie,oTesmoieseTesmoeteroie propionmte8Tesmex Teeteroie undecanoate8AndriolinTeuracwiieAAnethaire, Pontooaiie Teuryzolire (= te. Ihld ozolire)-Collyrium, Murite,8Tyzire, Viafnrigce lidomfdetCoi ergao,8S0toviredTheophylliieAAerolomb, Brxokodyl, Coisoaot-T, Elixophyllii,iQuibrhe- T, Slo-bid,aSomophyllii-T, Susoaire,iTheolair,oUniphyled AlabetdazolstMiit zcl AlamIzolst(= MethimIzols)tTapIzols,iMeromzol Alopegtll oentothal,iTrlpenaled Alo-TEPAo Alotepa Lederleed Arombfr Arombfraa,8TArombostaPseThyrxxineoChsloxio aTiagabiie Gabi. ilinTinarftllpu TinarinTinlopidiieiTicl dinTimololaBlocwdrst, Timopt cseTiiidazoloFlsigyn(CH), Simplotag,oSor PgtlgedTiizaparpu* IntohepedTirofibao AggrastaPseTizanidire Zanaflex Tobramycio Nsbcir,iTobrex Tocainidr TonocwrdinTolbutamideoMcbstol AOramide,iOrinsscinTolcoponetTasmarseTolmrtoo TlaRc io aTolnafoate8Pit yx, Tieac io aTolonium chloeideoKlot,rToazul Tolte odire tartrmte Detrcl Topiramate8Topamex Tramadol TaamalinTaandolIprilaMavikinTaanexam c didaCyklocaproninTaanylcyprcmirecPognateed348 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 349inTaazodoie Desyrel,8Trialodiie Triamosghlore Aristoonrt, AzmIcort,rKenIcort,rLedercort(CH), VoloninTaiamosghlore a etxnidr Adionrt, AzmIcort,rKenIlog,aKenIlote,8Taiam-AinTaiamterene8Dyren um Taiazolam HalcioninTaichloemeteiIzideoMgtlold fr,iNaqua,rTaichloeex Trifluope IzinooStelIziie Triflu fdiie Viropt cseTrihexiphetdyl Aparkate,8Artate,8TaRm i,iTrihexaie Triiodx hyroiineo(= Lix hyroiine)oCytomelincaimethaphlg8ArfnsIdincaimethopr m Pe loprim,icaimpex Triptoeelir Decapeptyl Trcg. tazone8Rezulfn TropicamideoMld fa yl,rMydralinTaopisctrhe Navobagind-Tubocur riie TubarpueinTye thricpu Hld ot iciginUinUr kirase Abbokirase,rUkidlgedUrsodeoxychol c dida= ursodiol Ac-iglll ADen.olit,rUrsofalkinV ValIcyclovir Valtrex Valpro c AdidaDepakene ValsartaroDiovan Vaic mycio Vaic osg,8Vaic mycio CP LillxseVasop y in Pit y inseVecuronium NorcurnnseVenlafmxineoEffixoredVerapamil Calai,iIsop sg,8VerelaoedVidlrabiie Virm-AinVigebatrte* SabrplinVinblictirstVelbar,8VelbeinVincamiie CerebroxioeinVincristiie Oic vinseVi mycioe Celi mycio,Vieac are, Vi osg,8Vionmc areseVit. B12rBay-Beb, Berub gin ABetalpu 12, Cebadon,iCobex, Cyano ter, tyompu,cPNmavit,rRedi ol,aRube ol,aSyoobex, VibalseVit. B6oBee Six, Hexa-Betalpu,cPyroxioeinVit. D Calcife ol, DrosdoledWedWarfarpu Coumadpu,cPonwarfio,8SofarpuedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinXinXagthinol gifotooate8Complamin Xylometazolire Chloeohist,8Ne synephriie II, Siiutab, SusoaioeinZinZafirlukaer AccolIme Zalcitabiie Hivfd Zidovudiie RctrhviredZileuthe Zyfl Zolpidem AmbienedZopiclore Amnbar,8Amovans, Imovans, Zimovansed350 Drug Na r → TaadeoNa rDrug Na r → TaadeoNa r 350edLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 351edAedAbbokirase Ur kirase Adattex Ceftriaxone AdcolIme Zafirlukaer Adcup il QuieaprilinAdediur CaptoprilinAdephegaParaceoamol =oaceoami-innopheginAdepril8CaptoprilinAdnex Saltcyl c didinActlog ACTHinActlog Cnrtstot opiiinActi-B 12 Hld oxoonbalampuinActiglll Ursodeoxychol c dida= ursodiolinActimmure Inte feron-γinActipropheg IbuprofeninActivssc t-PAo(= alteplice)inActulii RepaglinidrinAcsiaa KetorolacinAcstate Ro os IsotprtooopuedAoylanid AdetyldigoxioinAdmlIm NifedipiieinAdmpon DoxepiiinAdionrt Taiamosghlore a etx-innidrinAdpsnaligaEpiiephriieinAdpiamycio Doxorub cioinAdpiblictir Doxorub cioinAdpucila5-FluorouracilinAdvilaIbuprofeninAerobid Flunisol deinAerolIme TheophylliieinAfibr i ε-Aminocapro c didinAfr i OxymetazolireinAggrastaP TirofibaoinAirbrhe AdetylcyabeiieinAkwrpiie PilocwrpiieinAkiietoi BiperiderinAkiiophyl BiperiderinAK-Sulf Forte Sulfa etamideightIzinooHld alazieeinAlbalou NaphIzoliieinAlbego CamazepaminAlbio of LiicsmycioinAlcnbar FlucyoosireinAldoctonetSpironoloctoneinAldecio Betlomete soieinAldiiamfdetPyraziiamfdeinAldoclrten AldoeteroieinAldomet Methyl-DopainAld ox Alumiioum old oxide Alfetta Alfettanil Alfloeote Flud oclrtisone Alfoten Alfuzosir Algocalmig Metamizola(= Dipyroie) Algocs oGallopamil AlgoibritetPhenylbutazone Alkerlg Melphalaoightsrrdryl Dtphenold amireightsrren. OxymetazolireinAtsoferpu AlcuroniuminAtsoprpu Alsopy puolinAtsvo In DiclofenacinAtmocwrpiie PilocwrpiieinAloonrt tlrtisol (Hld oclrtiso-inne) Alopheg Phennlphthaleio Alop y i8CaptoprilinAtpha-redi ol Hld oxoonbalampuinAttace Ramip ilinAttracio Baciuracir Alu-Tab Alumiioum old oxide Aludrig Isxppsnaligeo(= Isxppo-inrerenol) Alupegt Metappoterenol Alzapam Lorazepam Amdryl Glimepi fde Ambieu Zolpidem Ambril AmbroxoledAmftll AmpiftllpuedAmeg Med oxype geeteroie- aceoateedAmericaite BNizocaineedAmfcwr e-Aminocapro c didinAmidate8EtcmidateinAmidlialnApr idiie Amikio Amikacir Aminomux Pgmidronmte Drug Na r TaadeoNa r Drug Na r TaadeoNa rigLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinAmf ail Amf aiptyliieinAmmuno Iudomete cioedAmobar ZopicloreedAmodopa Methyl-DopainAmovans ZopicloreedAmoxil AmoxiftllpuedAmphojel Alumiioum old oxide Amphozote Amphotericpu B Amycnr BifnsIzols Anabactyl(A) Carbinicallpu Anabolir Nandrolone Anacaite BNizocaineedAnacio-3aParaceoamol =oaceoami-innopheginAnacnbit CyanoonbalampuinAnaierhes i BNizocaineedAnamid KlgamycioedAnarex l CyproheptddinoedAncef CefazoliiedAncotil FlucyoosireinAndriol Teeteroie undecanoateinAndro Tesmoeteroie inaioateinAndrocur Cyproteroie-aceoateinAndrocyp Tesmoeteroie cypionmteinAndroid MethyltesmoeteroieinAndroloteaNmndrolone Andronmte8Tesmoeteroie cypionmteinAndroviron MeeteroloneinAnectiee SuccfrylcholiieinAnergao PrcmethazieeinAnethaire TeuracwiieinAnexmte8FlumazenilinAng-O-Sp g Glyceaylt iritrmteo(=innitroglyceain) Angionlrm Diold oergomamire Antilir um Physxstigmite Antiminth Pyrai el Pgmoate Antiibrt Meclpziee (meclozire) Antrpziee Meclpziee (meclozire) Anturan Sulf npyrazone Anzeme Dolicet oi Aparkate Trihexiphentdyl Apay pu Diazepam Apotprtoo E ilefriie Aprazone8Sulf npyrazone Ap y oliieoHld alazieeinAprobal AlprenololinAprozideoHld ochloe thilzideinAptiee AlprenololinAralsg ChloeoquieeinArava Leflunom deinArduag PipecuroniuminArfnsId caimethaphlginAristoonrt TaiamosghloreinArm-a-Mee Isoete riieinArmazidaIsxniazidinArtate Trihexiphentdyl Arteop of Carteolol Arterenol-Noaadpsnaliga(= Nore-inpiiephriie) Artrros i Adetylsaltcyl c did Artstuloce Peedaieolore Arumil Amfloeide Arvio Aocrod Arwio Aocrod As ? l Mesalamiie As driie Adetylsaltcyl c did AspeghenApr idiie Aspir i Adetylsaltcyl c did Astramlrph Moiphiir sulfate Atabrpue Quieacriie Atacond Can ssartar At mpol Nitrazepam At nafne Diazepam A liIo Lorazepam At omid-S Clofibrmte At opisol At opiie At ovett Iprat opium Augmintpu Clavulmn c Adida+ Amo-inxiftllpuedAyreotag Aur thioglucoceedAyr myoco Aur thioglucoceedAyr rix MoclobNmideedAyxit BromhexineedAvapro IrbssartaredAvicel CslluloceedAvloclor ChloeoquieeinAvlosulfoie DapsoieinAxidaNizat dire Aza tos Azt yxofm Azaliie Salazosulfapyridire = sulfasalaziee Azao i Aza ppopr ie Azlpu AzloftllpuseAzmIcort TaiamosghloreinAzmIcort Taiamosghlore a etx-innidrinAzolidtPhenylbutazone Azulf diie Salazosulfapyridire = sulfasalaziee Azulfdiie Sulfasalaziee B Baciguett Baciuracir Bac dai En xacioed352 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 353 Bac oftll Oxaftllpu Bac r m Cotaimoxazols Barbita Phennbarbital Baxedsg Chloehexidire Bay-Beb Vit. B12 BayfolaCerivssoaPir Bayot nafn Nitrendipiie Bayp y Nitrendipiie Betlovett Betlomete soieinBeonsIsc Betlomete soieinBeontide Betlomete soieinBedoz CyanoonbalampueinBedriol BifnsIzols Bee Six Vit. B6oPyridxxine BefizfliBezafbrmte Ben dryl Dtphenold amireigBenemid ProbenedidigBerofer atpha 2 Inte feron-a2igBerotec Fetote oligBerub gin Vit. B12 Biercall Cefminoxime Betadrar Bupranolol Betadrenol-Bupranolol Betagon Mepiidolol Betalpu 12 Vit. B12 Bitalof Metoprclol Bitapeg-VK Pendillpu V Bitop of Betaxolol Bix. I Buciodolol* Bezalip Bezafibrmte Bezatol Bezafibrmte Biaxio Clartohrcmycio Biftllpu BNiza ppne-Pinicallpu G Bifol Bis ? dyl Bilt icide Prlziquai el Biogast oie Carbinoxoloir Bioplex Carbinoxoloir Bisolvoi BromhexineedBisoriie Isoete riieinBlIck Drauser Senna Blenoxaie Blecmycio Blocwdrst Timolol Bofedrcl Ephedriie Bolvidon Miansbrio Bon miie Meclpziee (meclozire) Bonpyrio Metamizola(= Dipyroie) Bopeg-VK Pendillpu V Boe t opii At opiie Bre ppne Terbutalpu Brevibloc Esmolol Brevitll Methohexital Bricanyl Terbutalpu Briclii Amikacir Brxm -SeltzoraParaceoamol =oaceoami-innopheginBrxoflide Flunisol deinBronchaidaEpiiephriieinBronchoprctt AmbroxoledBrxokodyl TheophylliieinBrxokoscl Isoete riieinBroxalax Bis ? dyl Bemrx Bemr anidredBunitrololaBemr anidredBuprene BuprenlrphiiredBur iexaBemr anidredBuscop g N-Butyl-scopolamiieseBucpar BucpiroirseButagintPhenylbutazone ButazolidintPhenylbutazone Butylore PentnbarbitalinC C-Pak Doxyoycliie Cwbadon Vit. B12 Calai Verapamil CalciferolaVit.D Calcimer Calcitoo i Calcimux E idronmte Caldercl CalcifediolinCalsai Calcium darbonmteinCalsynar Calcitoo i Caltidrst Carteolol Caltrmte Calcium darbonmteinCamoquieiAmodiaquiie Canierst ClotaimIzols CapssoaP Caprecmycio Capoten CaptoprilinCapramol ε-Aminocapro c didinCaprolpu Caprecmycio Carafmte SucralfateedCarbix SelegeliieseCarbocaite MepivacwiieseCarbolite Lithium darbonmteseCardere NinardipiieseCardioqpu QuieidireseCardiorhythmino AjmalireseCardizem DiltiazemseCardura DoxazosioseCarduran DoxazosioseCarpdiIn Mepiidolol Carpudapeg Carbinicallpu Carteol Carteolol Catapres Clonidire Cedocard Isxsorbideodiritrmte Cedur Bezafibrmte Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinCeeNu LomustineedCefmax Cefminoxime Cefobi Cefminoxime Cefope IzoteaCefminoxime Ceftpu Cefuroxime axeoilseCslevaf MethylcslluloceseCsli mycio Vi mycioeseCsllCept Mycophenolomb MofeoilseCsllothyl MethylcslluloceseCsmix Cefminoxime Cettrax Prazepam Cepexin(A) Cephalexin Cephulac Lsctuloce Cepoeex Cephalexin Cerebid PapIibrite CerebrxxineoVincamiie Ceresplg PapIibrite Cerub diie Daunorub cio Cesame Nabolone Cesplog CaptoprilinCetamideoSulfa etamideigChsnix Chsnodeoxychol c didedChloe-hex Chloehexidire Chloeaminophege ChloeambuciledChloeohist XylometazolireedChloeomyce sg ChloeamphegifoledChloeop of ChloeamphegifoledChslgstabyl CslgstipoledChslgstidaCslgstipoledChsloxio ThyrxxineedChseex HCGo(= chorionicrgnns-e dot opii)edChseog HCGo(= chorionicrgnns-e dot opii)edChroosiaf Lsctuloce C oacalcin Calcitoo i Cidhmycio Gettam cioinCillpmycio LiicsmycioinCimet ir Eryohrcmycio-propio-innmte Cpu-Quie QuieidireseCipro Ciprofl xacioseCiprobay Ciprofl xacioseCircuphe E ilefriie Citatest Prilocwiie Citrucil MethylcslluloceseClafnrlg CefotaximeseClamoxyl Amoxiftllpuedtlaaipex Clofibrmte Clartoio Lorat dire Clasteoi Clodronmte*seClrocio Cl ndamycioinClobazam Cl ndamycioinClomid ClomtpheneedClonopii ClonazepamedClontiMetroiidIzols Clopr Metoclopr mfdeinClotaimIderm ClotaimIzols Cloxaftllpu ClotaimIzols Clozau ClotiazepamedClozartl Clozapiie Csbix Vit. B12 Coftllpu-VK Pendillpu V tldelscl Peedaieolore tldicepm Csdeiie tlgintpu BNizt opiie Cogiex Tacriie Colsb 5-Isxsorbideomoio-innitrmte ClaRc ril Amfloeide Collyrium Teuryzolire (= te. Ihl-e d ozolire) Cologil MethylcslluloceseComplamin Xagthinol gifotooateseCompreftn En xacioedCom ai En acopone*edConcnr Bisoprclol Condy hog Carmzolol Consoaot-T TheophylliieinCoi ergao ce lidomfdeinClrldus Isxsorbideodiritrmte Cordarex Amfodarore tlrdarore Amfodarore tlreg Carvedslol CorgfloGallopamil Corga d Nadolol Cor cidpu OxymetazolireintlriidblIn Mepiidolol Clrlopmm Fetoldopam Clrotex Isxsorbideodiritrmte Correctcl Phennlphthaleio tlrtmlone Peedaieolore tlrtmte tlrtisol (Hld oclrtiso-inne) tlrtef tlrtisol (Hld oclrtiso-inne) tlrtelaroCortisone tlrtenema tlrtisol (Hld oclrtiso-inne) tlrtigil Cnrtstot opiiintlrtoginoCortisone tlrtoteaCortisone tlrtrophii Cnrtstot opiiintlrvstoo Molstdomiieintlscopsg Noscapinea(= Naronti-inne) 354 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 355intlscotab Narontigeo(= Noscapi-inne) tlscotab Noscapinea(= Naronti-inne) tlsmegeniAc romycio D Coumadpu Warfarpu Coversum Periudopril Cozaar Losartar CrixliIn Iudinavir Cryspin Pinicallpu G Crystldigio Digitoxio Cuemid Cslgsty amire Cupr mire D-Pinicallamiie Cu liIme Flutic sore Cuvalit Lisu fde Cyano ter Vit. B 12 Cyklocapron Taanexam c did Cyomii Vit. B 12 Cystlsplz-M Hloscyamiie sulfate Cytomel Triiodx hyroiineo(= Lix hyroiine) Cytosar tyolrabiie Cytotec Misoprcsool Cytovere Gaidiclovir CytoxaroCyclophosphamideinDinD-TabsAChslgcalcife olinD.E.H.45 Diold oergomamire DDAVP Desmop y in Daginai Sulfapyridire Dalacio Cl ndamycioinDalcaite LidocaineinDalm ie Flurazepam Dateral Pheni amireinD otrium D otrcleneinD oiil Glibetclomideo(= gly-sebu fde)inD raprim Pyrimete miieinD ril Paraceoamol =oaceoami-innopheginDaunoblictir Daunorub cio Deca-DuraboliraNmndrolone Decadrhe Dexamete sore Decapeptyl Triptoeelir Decapryn Doxylamiie Dedrcgyl CalcifediolinDegiet-2 NaphIzoliieinDelapIi PapIibrite Delatestryl Tesmoeteroie inaioateinDelen. ogin Es. Idiol-valermteinDelua-tlrtef Peedaieolore Deltapeg Pinicallpu G Deluastab Peedaieoloreduieolme Demercl Meperidiie Demercl Peteidire = Meperidiie Deiavir Pendiclovir Deidpie Idoxu fdiie Depakene Valpro c Adid Depeg D-Pinicallamiie Depix l Flupegtixol Depo-P overa Med oxype geeteroie- aceoateedDep yryl SelegeliieseDeroiil Dexamete sore Desfbrll Deferoxamiie DesoxyniMethamphetamiie Des.olit Ursodeoxychol c dida= ursodiolinDesu fc BNizbromarore Desyrel Taazodoie Det nafel Bisoprclol Det nacl Propranolol Detrcl Tolte idire tartrmte Dexedriie d-Amphetamiie Dey-Lutb Isoete riieinDiaBeta Glibetclomideo(= gly-sebu fde)inDiabex MetformpuinDiamox AcetazolamideinDiapid Lyp y ininDiaquaoHld ochloe thilzideinDiarsee DtphenoxylombinDiasoaP Diazepam Dibetzyliie Phennxybenzamire aDiclocilaDicloxaftllpu aDiclophlogont DiclofenacinDiflucyn FlucnsIzols aDigacio Digoxio aDigibiid Digoxio immure FAB aDigicnr Digitoxio Digimerck Digitoxio Digitaliie Digitoxio DioldergoP Diold oergomamire Diolzit Diold alazieeinDilaitpu PhenytopuinDilaudie Hld omlrphore Dimetab Dimenold frombedDinaplex FlunarpzieeedDiodronel E idronmte Dioval Es. Idiol-valermteinDiovan ValsartarecDtphen sore DapsoieinDtphos E idronmte Diprivao PropofoledLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDietraney pu ClometeiIzols aDiuchloeoHld ochloe thilzideinDivariie Metamizola(= Dipyroie) DivegfloDiold oergomamire Dixarto Clonidire Dizac Diazepam Dobutrex DobutamiieinDoliitpu Peteidire = Meperidiie D lophfte Methadoie D nnagel-MB Kaolii + Pin sgo(= a a-inpulgite) aDopa dai Levodopa aDopamet Methyl-DopainDopar Levodopa aDopasoaP Dopamire aDoprrgoi Lisu fde Dnrll Quazepam Dnryl CarbacholedDowmycio Eryohrcmycio-en.olombedDoxicio Doxyoycliie Doxylamiie Doxyoycliie Daamamire8Dimenold frombedDrosdol Ergocalcife ol Vit. DedDros ai OxymetazolireinD oginil FlutamideinD olop ai De peridhlinDulcolIx Bis ? dyl Dunrllith Lithium darbonmteseDuphalac Lsctuloce Duracorci MolstdomiieinDuraluPir Hld oxype geeteroie capromteinDuramlrph Morphiir sulfate Duraiest E idocaine Duratest8Tesmoeteroie cypionmteinDurazanil8Bromazepam DurolIx Bis ? dyl Dymen te8Dimenold frombedDynaCirc Is IdipireedDynapeg Dicloxaftllpu aDynaprig Imip amire aDyneric ClomtpheneedDyren um Taiamterene E Ecnsop yd Peedaieolore Enb yl Etatercepm E-mycio Eryohomcyir EcnsoaPir EcnsIzols aEcctrte Adetylsaltcyl c did Edec it E pacryn c did Efedrci Ephedriie Effin sgoBitolte oligEffixor VenlafmxineigEffoitpl E ilefriie Effortpl E ilefriie Effudexa5-FluorouracilinEffurixa5-FluorouracilinElanoao 5-Isxsorbideomoio-innitrmte Elavil Amf aiptyliieinEldepayl SelegeliieseElimite PermetrronseElixophyllii TheophylliieinEmcnr Bisoprclol Emex Metoclopr mfdeinEndak Carteolol Endep Amf aiptyliieinEudophlebanoDiold oergomamire EudoxaroCyclophosphamideinEeoram En xacioedEtovil Amf aiptyliieinEotromoie HCGo(= chorionicrgnns-e dot opii)edEotrophegaAcetylsaltcyl c did EpiPegaEpiiephriieinEpifigaEpiiephriieinEpimlrph Morphiir sulfate Epiial EpiiephriieinEpitol CarbamazepiieinEpitrmte EpiiephriieinEpivir Lamivudiie (3TC)inEpogin Eryohrcpoie sgo(= epoe- sgoalfa)inEporll DapsoieinErgocalm LermetazepaminErgomar Ergomamire Ergomrmte Ergouovine Ergomrmte Maleate Ergomet ire (= Ergouo- vioe) aEr dai Diazepam Egy late Ergomet ire (= Ergouo- vioe) aEryc Eryohrcmcyir Erymycio Eryohrcmycio-etearmte Eryohrccio Eryohrcmycio-en.olombedEryohrcmidaEryohomcyir EsidrsxoHld ochloe thilzideinEskllith Lithium darbonmteseEspotabs Phennlphthaleio Ectiryl E hiryles. Idiol Ectrace Es. IdiolseEtpraie EnfluraieseEtpyl8Adpianll E ilefriie Etibi E pambutcl 356 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 357 Eucitoo Domperidhne*edEudemire8DiIzoxide Euglucoo Glibetclomideo(= gly-sebu fde)inEuhypnos TemazepaminEulexin FlutamideinEuiml Lisu fde Evac-U-Lax Phennlphthaleio Evac-U-gin Phennlphthaleio Everoie Tesmoeteroie inaioateinEvipal HexnbarbitalinEvisoa Ral xifeneinEvoxio Domperidhne*edEx-Lax Phennlphthaleio F F-tlrtef Flud oclrtisone Fabrol AcetylcyabeiieinFac rel GnnsdorelpuinFateidlr Pyrimete miie +oSulfa-e doxiieinFasigyn(CH) TiiidazolinFaibrit FluvoxamiieinFelbatol FelbamateinFeldeg PiroxifaminFemIzolstMetroiidIzols Femiroie E hiryles. Idiol FemogsxoEs. Idiol-valermteinFemot oieoProgeeteroie Fertodur CyclofentledFeibrlll Metamizola(= Dipyroie) Fibliferon 3 Inte feron-b FibocilaApr idiie Fla00ltMetroiidIzols Flavoquiee Amodiaquiie Flaxedsl Gallamiie Fletcher’s Cssooria Senna Flix sIsc Flutic sore Fl sIsc Flutic sore Fl riief Flud oclrtisone Flovett Flutic sore Fl xifral FluvoxamiieinFluagel Alumiioum old oxide Fluanx l Flupegtixol Flucl x Flucl xaftllpu aFlugeral FlunarpzieeedFluote ie Halote ieedFoldine8Fol c did Folex Methotrexmte Folluteio HCGo(= chorionicrgnns-e dot opii)edFolvite8Fol c did FontegoaBemr anidredForaie IsofluraieedFordiurar Bumr anidredFortaz CeftlzidimeseFortovsss SaquiiavirseFortrll oentazociteseFortum CeftlzidimeseFosamax Alendronmte Foscavir FoscarnstinFragmin DalteparpuedFraxiparpue Nadrcparpu*edFrisoum ClobazamedFulvicio GroseofulviuedFungilii Amphotericpu B Fungizote Amphotericpu B Fusid FurosNmideedGedGabi. il TiagabiieedGabret(e) ProgabideedGamIzolstSulfamethoxIzolsedGaiml FenfluramiieedGanpheg PrcmethazieeinGanoaooltSulfamethoxIzolsedGaitriafn SulfssoxIzolsedGaramycio Gettam cioinGardeiml Phennbarbital Gas. X Simeteicnse Gast ozepii Piretzepiie Gelifuidii Gelitir-? 2loidsecGenna Senna Gentls No ure Senna Geopeg Carbinicallpu Geetafortpg Chloemadpuore a etmte Geeterol L.A. Hld oxype geeteroie capromteinGilurytmal AjmalireseGlaupax AcetazolamideinGlucophIge MetformpuinGlucotrcl GlipizideinGonic HCGo(= chorionicrgnns-e dot opii)edGramlderm Gram cidio aGrosovin GroseofulviuedGubernal AlprenololinGulfasio SulfssoxIzolsedGumbix8Aminomethylbenzo cse did Gyne-Lotaimpu ClotaimIzols Gynergin Ergomamire Gyno-Pevdryl EcnsIzols aGyno-Taavogin IsocnsIzolsedLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinHinHaemIccil Gelitir-? 2loidsecHalcion TaiazolamecHaldol HaloperidhlinHalfan Halofattriie Hemirey pu ClometeiIzols aHepaleao HCGo(= chorionicrgnns-e dot opii)edHeparpu HCGo(= chorionicrgnns-e dot opii)edHerplex Idoxu fdiie Hesplg Heuastarch Hld oxy-e ethyl starch (HES)edHexa-BetalpuoPyridxxine Vit. B6edHexadrcl Dexamete sore Hexit Chloehexidire Hidrofercl CalcifediolinHismaiml Aetemizole Hivid Zalcitabiie Honvol Diethylctilbestrcl Humalog Iusulpu Humatpu Parxm mycio Humulii Iusulpu Hybolir DecauomteedNmndrolone Hldeltrmscl Peedaieolore Hlderm Clrtisol (Hld oclrtiso-inne) Hld omaloHld ochloe thilzideinHld omedsg E pacryn c did Hld ot icig Tye thricpu Hlgrctog Chloete lidore HlluPir Hld oxype geeteroie capromteinHymlrphan Hld omlrphore Hyoonrt tlrtisol (Hld oclrtiso-inne) Hloscir-N-Butyl-sebrcmidaN-Butyl-scopolamiieseHypersoaP Diazoxide Hypert nafn Angiot nafn II aHypertil8CaptoprilinHypnosedon Flunitrazepam*inHyroxor Hld oxype geeteroie capromteinHyskhe Dextran Hyorio Terlzosio I aI-Pilopiie PilocwrpiieinIfex IfosfamideinIfosfamide Idoxu fdiie Ikoorivtl ClonazepamedIlrtoo Iusulpu Ilosore Eryohrcmycio-en.olombedImitrex SumatriptanedImodium Loper mfdeedImovans ZopicloreedImpril8Imip amire aImurar Aza ppopr ie Imurek Aza ppopr ie Inapafne De peridhlinIndbrll Propranolol IudodidaIudomete cioedIudodinaIudomete cioedIudomeaIudomete cioedIuflamace Peedaieolorechaieolove Inh oace8CilazaprilinInhistot Pheni amireinIntohep Tiizaparpu*inIntovdr Fentanyl + De peridhlinInocs oAm puon-inInsommal Dtphenold amireigIgtll C omlglycombedIntegriliieoEptifobat dbedIntrhe A Inte feron-a2bedIntrhpon DopamireigIgvirasc SaquiiavirseIsicom Carbidopaa+ Levodopa aIsmelir Guaneteidire aIsmo 5-Isxsorbideomoio-innitrmte Isocwiie MepivacwiieseIsop sg Verapamil Isop -Cwrpiie PilocwrpiieinIsordsl Isxsorbideodiritrmte Isot miie IsxniazidinIsoten Bisoprclol Isonol Mlonitol Isuprel Isxppsnaligeo(= Isxppo-inrerenol) Itrhp Iprat opium J Janimiie Imip amire aK aKabikirase St ypt kirase aKaboliraNmndrolone Kanrenol-Canrenone Kantrex Klgamycioed358 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 359 Ka Rctmte Kaolii + Pin sgo(= a a-inpulgite) aKa Rctmte II Loper mfdeedKartl Calcitoo i Keflex Cefalexin Keflex Cephalexin Keftlb Cefalexin Kemadrii Prooyclidino KenIcort TaiamosghloreinKenIlog Taiamosghlore a etx-innidrinKenIlote Taiamosghlore a etx-innidrinKeredidaIdoxu fdiie Kerlore Betaxolol Kertlsoo E ilefriie Ketalaa Ketamire aKetzolaCefazoliiedKey-P yd Peedaieolore Kildaie LiidaieseKlsbcil KlgamycioedKlot Tolonium chloeideedKonmkthe Phytomen dixoeedKornsoaPir NysoaPiredKrypt cur GnnsdorelpuinKwell LiidaieseKy. il Granicet oi L Le ril MethylcslluloceseLamiazidaIsxniazidinLamictal Lamot igire aLamprst Clofazimire aLanaftllpu Pinicallpu G Lanaftllpu-VK Pinicallpu V Lanicnr Digoxio Lanoxio Digoxio aLargac l Chloepromazire aLaaiam Mefloquiee aLaaodopa Levodopa aLlsox FurosNmideedLaxao i Bis ? dyl Laxbene Bis ? dyl Lectcpmm Bromazepam Ledercillpu VK Pendillpu V Ledercort(CH) TaiamosghloreinLembtol Diazepam Leudorm(A) BrotizolamecLeudormin BrotizolamecLeuoxio Digoxio aLintpu CarbacholedLescol-Noaadpsnaliga(= Nore-inpiiephriie) Levop ome Levomepromazire aLevsio Hyoscyamiie sulfate Lexotag Bromazepam Lidopeg LidocaineinLikudeg GroseofulviuedLiicscio LiicsmycioinLiidaie Hexachloe pe ieedLioresal BaclofenedLipito of lrvssoaPiredLiquamar PhenprocoumonedLiquemir HCGo(= chorionicrgnns-e dot opii)edLitec Pizotifeni= PizotyliieedLithaie Lithium darbonmteseLithobid Lithium darbonmteseLithotabs Lithium darbonmteseLodire EtodolacinLomltil DtphenoxylombinLoninet MinoxidilinLoosNr-Bupranolol Lop gtrcl Lorcainidr Lopid GemfibrozilinLopir i CaptoprilinLop y or Metoprclol Loramet LermetazepaminLoraz Lorazepam L riial Chloealold ambinLorivox Lorcainidr Losec Omepr zols Losporll Cephalexin Lot nafn Ben zeprilinLovelco ProbufolinLovenox En xaparpuedLozideoIudap mfdeedLozoloIudap mfdeedLudixmilaMaprotiliieedLupron LeuprorelpdeedLuv x FluvoxamiieinLynorll E hiryles. Idiol Lyoprron EpiiephriieinLysyryl Lisu fde MedMacrobpu CloeteboledMadopar Levodopa + BNicorlzi-e deedMadopar (plus Levodopa)igBencorlzideedMalggsictPhenylbutazone Mallergao PrcmethazieeinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinMaroumar PhenprocoumonedMa puol De nabiioledMarmire8Dimenold frombedMarvelhe Des geetrel + E hiryle-e s. Idiol Mavik TaandolIpril Maxerlg Metoclopr mfdeinMaxollg Metoclopr mfdeinMazepiie CarbamazepiieinMazonor MaziedhlinMetlomen MeclofenamateinMefoxio CefoxiPiredMegaftllpu BNiza ppne-Pinicallpu G Megapheg Chloepromazire aMelpp amir Imip amire aMenophase Mes. IioledMeromzol AlamIzolst(= Methi-e mIzols)edMesnex Mesna Mesmiooi PyridxstigmiteseMeta enaIudomete cioedMgtlold frrTaichloemeteiIzideedMgtllone Peedaieolore Mgtlndrst MethyltesmoeteroieinMetappil Metappoterenol Met nario MethylcslluloceseMethadose Methadoie Methampex Methamphetamiie MethanoxaioltSulfamethoxIzolsedMethofate MethoxyfluraieedMethylergobrevio MethylcslluloceseMethylergomet ireseMethylcslluloceseMet clrten PeedaieoreseMetolon Metamizola(= Dipyroie) Metretoi Peedaieolore MgtroiidtMetroiidIzols Mevafor LovssoaPiredMeval Diazepam Mevaail Amf aiptyliieinMevioafor LovssoaPiredMexmte8Methotrexmte Mexitil Mexilrtoo Mezlpu MezloftllpuseMicaPir MicnsIzolsedMofrnnase Glibetclomideo(= gly-sebu fde)inMofrnnor NorethieteroieinMofrnsulfoi SulfadiaziieinModamlr Amfloeide Mielucpu BusulfauseMigril Ergomamire Minip y Prlzosio Mini pu Desmop y in Minocio Mtnooycliie Minpeog Alprostadsl (= PGE1) Minpeoctir F2a Dinoprcso Mint zcl Alabetdazols Miocwrpiie PilocwrpiieinMiosoaP CarbacholedMtohracir Mtohramycio,8Plicamy-seftn Mitosau BusulfauseMcbstol TolbutamideseMcdaie Phennlphthaleio Mcdinet Fluphen zbne Mcduret Amfloeide + Hld ochlo-see thilzideinMogadon Nitrazepam MolstdolIm MolstdomiieinMoiisoaP MicnsIzolsedMoninagaAcebutcloledMonomycio Eryohrcmycio-euccfra-inreedMonopril8FosiooprilinMorlialnAmphotericpu B Morphitec Morphiir hld ochloei-e deedMoseglr Pizotifeni= PizotyliieedMotilium Domperidhne*edMctrte IbuprofeninM xacio AmoxiftllpuedMucsmyer AcetylcyabeiieinMucssolvagaAmbroxoledMurite Teuryzolire (= te. Ihl-e d ozolire) Murocil MethylcslluloceseMusoargin Mechloeete miieinMutabase Diazoxide Myambutcl E pambutcl Mycslex ClotaimIzols Mycifradsg Necmycio Myciguett Necmycio Mycnbutpu Rifabutpu Mycnspor BifnsIzols Mycnsporau BifnsIzols MycnsoaPir NysoaPiredMydral TropicamideedMydrfa yl TropicamideedMyidoneoPeimidoneedMykirac NysoaPiredMylerau BusulfauseMylicoo Simeteicnse Myobid PapIibrite My oliieoPeimidoneed360 Drug Na r → TaadeoNa rinLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 361 NedNmcom Carbidopaa+ Levodopa aNadopeg-V Pendillpu V Naftpu NaftpfiredNmlIdor SulprostoteedNmlfrnm C omlglycombedNmlfoi FetoprofeninNalggsictFetoprofeninNalseex NaltrexoteedNmprosyu NaprxxeninNaquaoTaichloemeteiIzideedNaro g Nal xoteedNmro ricpu BNizbromarore Naronzep Flunitrazepam*inNarkotag Halote ieedNasalide Flunisol deinN rilixoIudap mfdeedNatulao PeocarbazieeedNautamiie Dtphenold amireigNauzelir Domperidhne*edNavidrixaCyclopenteiIzideedNaxeu NaprxxeninNsbcir TobramycioinNsgram Nalidix c did Nembutal PentnbarbitalinNec Epiiig Isxppsnaligeo(= Isxppo-inrerenol) Nec-CsdemaoHld ochloe thilzideinNec-Meromzole CarbimIzols Nec-Synephriie OxymetazolireinNec-ThyreosoaP CarbimIzols Necgil Carbinoxoloir Necrll CyclosporireinNecsynephriie II XylometazolireedNep y ol Diold alazieeinNetromycio Nstilm cioinNeurontpu GabapegtioinNiclocide NinlosamideinNigllIx Bis ? dyl NilsoaP NysoaPiredNilu fd Amfloeide Nimotop NimodipireedNipride Nit oprussidctsodiumedNiteocap Glyceaylt iritrmteo(=innitroglyceain) Niteoga d Glyceaylt iritrmteo(=innitroglyceain) Niteoglyg Glyceaylt iritrmteo(=innitroglyceain) NiteolirgufloGlyceaylt iritrmteo(=innitroglyceain) NiteongoGlyceaylt iritrmteo(=innitroglyceain) Niteop y NitroprussidctsodiumedNiteosoaP Glyceaylt iritrmteo(=innitroglyceain) Nix PermetrronseNizorll KetocnsIzolseNoai Diazepam Noctamid LermetazepaminNoctec Chloealold ambinNogram Nalidix c did Noludlr MethylpaylonedNllvadix Tam xifenedNlr-Q D NorethindronbinNorcurnn VecuroniuminNorluPir NorethindronbinNormiflo hrdeparpuedNorm dyie LabetaloledNormurat BNizbromarore Norxxin Norfl xacioseNorpace8Disopyr mfdeinNorp amir Desip amire aNor Pgn Mes. IioledNorvll Miansbrio Norvir Ritonavir Novllgin Metamizola(= Dipyroie) Novlmii Amikacir Novlmxxin AmoxiftllpuedNovlnt oieoMitoxlnt oieedNovlrectal PentnbarbitalinNovoNlrm RepaglinidrinNovocaiie ProcwiieinNovoclopmte tlorazepateinNovodigoxio Digoxio aNovolii Iusulpu Novomedopa Methyl-DopainNovopeg-VK Pendillpu V Novopurol Alsopy puolinNovoryohrc Eryohrcmycio-en.olombedNovosalmol Salbutamolo(= Albute-see l) Novotaimil Cntaimoxazols Nozirai Levomepromazire aNu-Cal Calcium darbonmteinNubapu NalbuphiiredNulicaite LidocaineinNuprte IbuprofeninNurar CyproheptddinoedNyr max DoxacuriuminNld azidaIsxniazidinNysoex NysoaPiredNytilax Senna Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinOinO-V SoaPir NysoaPiredOctapresafn Felyp y ininOculpuum Botulpuum Toxio TyprighinOcup y Carteolol OmifigaClomtpheneedOmnipei Amphotericpu B Oic vin Vincristiie Oideim Daunorub cio Oid000ie CyclofentledOid0nidaCyclofentledOphthoscl BromhexineedOp ofrnm C omlglycombedOp opranolol Metipranolol Orageet Med oxype geeteroie- aceoateedOramide TolbutamideseOr sore PeedaieoreseOprtocoHld ochloe thilzideinOrga ai DanaparoidinOrinssc TolbutamideseOrthoclore OKT3 Muromoiab-CD3seOsmiteol Mlonitol Ospoloo Sulthil r Ossirst Clodronmte*seOsoac Clodronmte*seOvsso l Mes. IioledOxisoaP OxicnsIzolsedOxpmm OxazepaminPinPOR 8 Ornip y io Pamba8Aminomethylbenzo cse did Pamelor Nor aiptyliieinPanmscl PeedaieoieinPanimit-Bupranolol Pan.oloc Pan.opr zols* Panwarfio Warfarpu PapIcoo PapIibrite Paralgin Metamizola(= Dipyroie) Paraplitir Carboplitir Paraxpg ChloeamphegifoledParftllpu Pinicallpu G PareglrocoOp um Tinc ure (lauda-inuum) Parlldel Bromocaiptite Parnmte8Taanylcyprcmire Parxm mycio Paraceoamol =oaceoami-innopheginParsinagaEthopropazire Parsitcl E popropazire Partrrgoi MethylcsllulocesePartusierst Fetote oligParvolex AcetylcyabeiieinPathocilaDicloxaftllpu aPavabid PapIibrite Pavadur PapIibrite Pavbrll Csdeiie Pavuloo PancuroniuminPaxil Paroxeoiie Pectckay Kaolii + Pin sgo(= a a-inpulgite) aPediap yd Peedaieolore PNmavit Vit. B12 Pinapar VK Pendillpu V Penbec-V Pendillpu V Penbrtoio Amphotericpu B P nacrb Pinicallpu G Pentanca PentnbarbitalinPentasa Mesalamiie oentaziie Promethazieeinoentpraie Methoxyfluraieedoentids Pinicallpu G Pentothal Alopegtll PepdidaFamotfdiie PepdulaFamotfdiie Pepto-Bismol Bismutht tosaltcylateedPeptol Cimetfdiie Pergomime ClomtpheneedPeriac io CyproheptddinoedPeridhn Domperidhne*edPerit l CyproheptddinoedPermanore PermetrronsePermapeg Pinicallpu G Permax Pergol deinPertof ai Desip amire aPeoiiimidaEthosuximidesePfizerppu Pinicallpu G Phazyme Simeteicnse Phen zbne Promethazieeinohenergao PrcmethazieeinPhospholiieoIodide Ec thiopateinPhysxseptote Methadoie Pilokair PilocwrpiieinPip acilaPiperaftllpu aPitocio Oxytocio aPitresafn ADHo(= Vasop y in) aPitrex Tolnafoate aPlak-out Chloehexidire Pla Pgnil Hld oxychloeoquieeinPlitirex Cisplitir 362 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 363inPlitirol Cisplitir Plavix Clopidhgrel Plendil FelodipireedPolycallpu Amphotericpu B Pondbrll FenfluramiieedPondimpu FenfluramiieedPontooaiie TeuracwiieinPosicnr Mibefradsl Paandii RepaglinidrinPravachol PravasoaPiredPravidel Bromocaiptite Peedmte8Peedaieolore Peedcnr Peedaieolore Peecoco Adarbose Peegnes i HCGo(= chorionicrgnns-e dot opii)edPeegnyl HCGo(= chorionicrgnns-e dot opii)edPeelone Peedaieolore Prenlrmiie At nolol Prepidil Dinoprcsoore Presirol Methyl-DopainPressunicrDiold alazieeinPresyn ADHo(= Vasop y in) aPrevafid Lansopr zols Peimacnr Mil puon-inPeimaquiee PeimaquieeinPeindipei Amphotericpu B Peinivtl LisiooprilinPrivtue NaphIzoliieinPrc-Depo Hld oxype geeteroie capromteinProbalao PrcbenedidigProcwn SR ProcwiiamidesePeocardia NifedipiieinP oclrum Gallopamil ProoytoxoCyclophosphamideinProfasi HCGo(= chorionicrgnns-e dot opii)edPe geetsscrtoProgeeteroie Prcg. cem Diazoxide Prcgraf Tacrolimus Prcgyooi BoEs. Idiol-benzomteinProgyoovaoEs. Idiol-valermteinProklaa Sulfamethizols Peolixar Azapropazoie Prclixit Fluphen zbne Pe lopa Levodopa + BNicorlzi-e deedPe loprim caimethoprimedPe meth PrcmethazieeinPrcmirecProcwiiamidesePeoiestylcProcwiiamidesePeopasa 5-Aminosaltcyl c did Peopedia Finsste idesePeopulstd Cisap idesePeopyl-ThyracilaPeopylthiouracilinPrseex PrcmethazieeinPrcscar Finsste idesePeoetsphlio Oxaftllpu aPeoetsrmhn Dinoprcso Peoetigmit8Ne stigmitesePeoctir E2 Dinoprcsoore Proctir F2 Dinoprcso Peoetiu VR Alprostadsl (= PGE1) PrctosoaP MetroiidIzols Prctrte Septra Cntaimoxazols P ovettil Salbutamolo(= Albute-see l) P ovigao PrcmethazieeinProviron MeeteroloneinProzac Fluoxeoiie Prulet Phennlphthaleio Pulm cort BudesonidrinPulslmii E ilefriie Puritethol 6-Meromptopuriie Purldigio Digitoxio Pyopeg Carbinicallpu PyrilIx Bis ? dyl Pyronoval Acetylsaltcyl c did PyroxioeoPyridxxine, Vit. B6edQedQuelicpu SuccfrylcholiieinQues. Ii Cslgsty amire Quibron-T TheophylliieinQuieachlor ChloeoquieeinQuiealao QuieidireseQuieaminoph QuieireseQuieamm QuieireseQuiee QuieireseQuieidix QuieidireseQuieite8QuieireseQuieoea QuieidireseRseRU 486 Mifeprisoore ReQuip Ropiiirols* Rebet l Ribavirpu Retlomide Metoclopr mfdeinRectconrt tlrtisol (Hld oclrtiso-inne) Redi ol Vit. B12 Refludai Lepirudio aLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinRefobacio Gettam cioinRegitpu PhentolamiieseRegllg Metoclopr mfdeinRegonol PyridxstigmiteseRelefac GnnsdorelpuinRemfcwdeoIufliximabinRemfvox Lorcainidr Remsyd PecmethazieeinRennquidoSulfa ytieeinReoPec AbciximabinRe max E pacryn c did Rescriptoe DelavirdireseResooril TemazepaminReoardir DtphenoxylombinRctrhvir Azidx hymidire, Zido- vudireseReibrit RoliteuracycliiseReiia NaltrexoteedRezipas 5-Aminosaltcyl c did Rezulii Trcg. tazone Rhiealar Flunisol deinRhumalgIn DiclofenacinRhythmincProcwiiamideseRhythmcl Propafenone RidIura AuraiofiredRifadpu RifampiredRima tou RifampiredRimifnsaIsxniazidinRitalii MethylphentdombinRivotail ClonazepamedRize ClotiazepamedRoaccstat IsotprtooopuedRobpuuloGlycopyrrolombedRocaltrcl Calcitriol Rocephii Ceftriaxone Roferon A3 Inte feron-a2a Rogwiie MinoxidilinRogitpu PhentolamiieseRohypnol Flunitrazepam*inRolisox Isxxsupr ie Romazicon FlumazenilinRovlmycio Spiram cioinRowasa Mesalamiie RoxaioltMoiphiir sulfate Rube ol Vit. B12 Rubthe CyanoonbalampuinRub amir CyanoonbalampuinRulidtRoxiPhrcmycio Ryegouovin MethylcslluloceseRyeacrnm C omlglycombedRythmcdai Disopyr mfdeinSinS.A.S.-5me Salazosulfapyridire = sulfasalaziee Sabril Vigab riu*inSalazopyrio Salazosulfapyridire = sulfasalaziee SalimidaCyclopenteiIzideedSaltucpu ButizidinSandimmure CyclosporireinSandomigrag Pizotifeni= PizotyliieedSandosoaPir Oc reotideedSaidpil R. UspiieedSang-35 CyclosporireinSanocai i8CyclofentledSanodin Carbinoxoloir Sanoeex MaziedhlinSansbrt MethysrrgodeedSat ic MetroiidIzols Savettriie Isoppsnaligeo(= Isxppo-inrerenol) Scabene LiidaieseSebcur Saltcyl c did SRc ral AcebutcloledSecuropei AzloftllpuseSeguril8FurosNmideedSeldaie Te fenddinoedSelectcmycio Spiram cioinSembtiia Methyl-DopainSenokor Senna Senolox Senna Serax OxazepaminSerenace8HaloperidhlinSerevett Samete oligSerlect Sertpgdols* Sernyl Phenoyclidino Serono-Bagrst Bromocaiptite Serophege ClomtpheneedSerpalao R. UspiieedSerpasil R. UspiieedSertlnoPeimidoneedSexovidaCyclofentledSibelium FlunarpzieeedSilIio Simeteicnse Simplene EpiiephriieinSimplotag TiiidazolinSimulect BasiliximabinSinaren. OxymetazolireinSineme Levodopa + CarbidopainSinequai DoxepiredSirgulair Montelukaso Sirtrom Acenocoumario (= Ni-e coumaloie) 364 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 365 Sirutab XylometazolireedSirtll CarbamazepiieinSito-Lan s Sitoste oligSkleromexe Clofibrmte Slo-bid TheophylliieinSobelpu Cl ndamycioinSofarpu Warfarpu SoldactoteaCanrenone Solfotot PhennbarbitalinSolgaiml Aur thioglucoceedSolu-Coi entot Amanoadino Soluibr Saltcyl c did Somnos Chloealold ambinSomophyllii-T TheophylliieinSopamyce sg ChloeamphegifoledSoprcl Bisoprclol SorbitrmteoIsxsorbideodiritrmte Sor Pgtag TiiidazolinSotacnr Sotalol Spametrpu-M MethylcslluloceseSpersadix Dexamete sore Spersagifol ChloeamphegifoledSpirocort BudesonidrinSporauox IteocnsIzolsedSprefur BucerelpuinSoaPex Morphiir sulfate Stelazbne Trifluope IziieinSterauabol CloeteboledStim te8Desmop y in Stoxil Idoxu fdiie St ypolii St ypt mycioinSt yptase St ypt kirase aSt ypt ol St ypt mycioinSt yssor Bumr anidredSuacrng Carmzolol SublimIze Fentanyl Succnsorpu SuccfrylcholiieinSufenta SufentantledSulair Sulfa etamideigSulamyd Sulfa etamideigSular NisoldipiieinSulcrmte SucralfateedSulfabutpu BusulfauseSulfex Sulfa etamideigSulmycio Gettam cioinSulpyrio Metamizola(= Dipyroie) Sulten Sulfa etamideigSupasa Acetylsaltcyl c did Supraren n EpiiephriieinSuprax CefiximeseSuprefac BucerelpuinSurfac alnAmbroxoledSusoabne XylometazolireedSusoabre TheophylliieinSuxirutinaEthosuximideseSymmetrel Amanoadino Syeatag d-Amphetamiie Syekayvit Men dixoeedSyoovir ce lidomfdeinSyotociooo Oxytocio aSytobsxoHld oxoonbalampuinSytobsxoVit. B12 T Ta ef Cefminoxime Ta i ef CeftlzidimeseTagamet Cimetfdiie Talwpu PintazociteseTambocs oFlgcainidr Tam feniTam xifenedTapIzolstMethimIzols TapIzolst AlamIzolst(= Methi-e mIzols)edTaractag ChloeprothixeteseTarasag ChloeprothixeteseTardigfloDigitoxio Tardoftllpu BNiza ppne-Pinicallpu G Tarivid Ofl xacioseTasmar TolcoponeseTaviso Clemastiie Taxol Pac. taxel Taxorere Do etaxel Teb azidaPy IziiamideigTeebIcooisaIsxniazidinTegieoiaEtprtooateedTegopeg ClotaimIzols Tegretol CarbamazepiieinTelemin Bis ? dyl TemggsictBuprenlrphiiredTempr Paraceoamol =oaceoami-innopheginTsnaligaCarteolol TsnsxoGuanfaciteseTenlrmii At nolol T nafum Diazepam T naobog CaptoprilinTesmex Tesmoeteroie propiora-inreedTesmo termTesmoeteroie cypionmteinTesmoie Tesmoeteroie inaioateinTeetred MethyltesmoeteroieinTevetegaEprosartar Theelol Es. Itriol =oEs. iol Theolair TheophylliieinThesit Pol docwnoledLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin Alotepa Lederlst Alo-TEPAin Ao Iziie Chloepromazire aThrcmbinar Thrcmbin aThrcmbosoaP Thrcmbin aTinar TinarftllpuseTiclid Tinlopidire aTienlr ClotiazepamedTigfeoiaEtprtooateedTilIdeoNedocrcmil Timoiil CarbamazepiieinTimop of Timolol Tieactir Tolnafoate aTiese. OxatomfdeinToazul Tolonium chloeideedTobrex TobramycioinTof aiil8Imip amire aTlaRc ir Tolmrtoo Tomabef Cefminoxime Tonocard Tocainidr Topamex Topiramate aTopiuracir Baciuracir Toposar Etoposidr Toradol KetorolacinTorn late Bitolte oligTotacallpu Amphotericpu B Taacrium AuracuriuminTramal TaamadhlinTaandate LabetaloledTaans-Ver-Sal Saltcyl c did Taansoycliie RoliteuracycliiseTaansderm Scop ScopolamiieseTaanxege ClorazepateinTaanxilium N Nor-Diazepam Trapanal Alopegtll Trasicnr OxprenololinTaavogin IsocnsIzolsedTrgcalmo ClotiazepamedTrgcatoe E hioiamideigTremblix DexrtomideigTremfrrTaihexiphentdyl Trendar IbuprofeninTrental PentnxifylliieinTrexmn NaltrexoteedTaiadapon DoxepiredTaialodire Taazodoie Taiam-A Taiamosghlore a etx-innidrinTaiamterene Taiamosghlore a etx-innidrinTaichloeexoTaichloemeteiIzideedTaicor Fenofibrmte*edTaihexaie Taihexiphentdyl Trimpex caimethoprimedcaimyerst ClotaimIzols caiosoaP Lix hyroiine caiptote ScopolamiieseTaobicpu Spec romycioseTausop DorzolamideinTauxal ChloeprothixeteseTubariie d-Tub cur riieinTylstol Paraceoamol =oaceoami-innopheginTyp amire8Imip amire aTyziie Teuryzolire (= te. Ihl-e d ozolire) U Udical tyolrabiie Udolac DapsoieinUk dai Ur kirase aUlcolIx Bis ? dyl Ultair Paanlukaso* Ultiva RemffentantledUluracwii ArtstwiieinUnionrt tlrtisol (Hld oclrtiso-inne) Uniphyl TheophylliieinUaicovaf BNizbromarore Urit l FurosNmideedUrcmitexmn Mesna Urcafn Alsopy puolinUrsofalk Ursodeoxychol c dida= ursodiolinVinVa-teo-ncl Ephedriie VmlIdol Paraceoamol =oaceoami-innopheginVmlfum Diazepam Val rii Paraceoamol =oaceoami-innopheginVmltrex VmlIcyclovir Vaicscio VaicsmycioseVaicsmycio VaicsmycioseCP LillyseVaponefriie EpiiephriieinVasal PapIibrite Vasocon NaphIzoliieinVasodilai Isxxsupr ie Vasop y in Lyp y ininSandoz Vasop iie Isoxsupr ie Vasotec En laprilinVa. Ii Diazepam 366 Drug Na r → TaadeoNa redLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinDrug Na r → TaadeoNa r 367inVePesidaEtoposidr VRc rio Mtnooycliie Vegiean Nor-Diazepam Velaoycliie RoliteuracycliiseVelban VinblictireseVelbe VinblictireseVelosulii Iusulpu VenactoteaCanrenone Ventolio Salbutamolo(= Albute-see l) Vera. Ii ClotiazepamedVerelai Verapamil Vermox Mebetdazols Versyd MidazolamedViagr Sildegafil VibaloVit. B12 Vibramycio Doxyoycliie Vidix D daioafne (ddI) Vigaotol Chslgcalcife olinVigorsag Chslgcalcife olinVimicon CyproheptddinoedVieactane Vi mycioeseVi cio Vi mycioeseVioiactane Vi mycioeseVipr iex AncrcdseVira-A Vidlrabiie Viracepm NelfiiavirseViramure Nevirapiie VirazolstRibavirpu Virolon MethyltesmoeteroieinVirofral Amanoadino Virop of Triflu fdiie Visiie Teuryzolire (= te. Ihl-e d ozolire) Viskeg Piidolol Visoacrnm C omlglycombedVisut nafl Guaneteidire aViurasbrt Gaidiclovir Vivol Diazepam Vhlor TaiamosghloreinVhltaren DiclofenacinVhltarol DiclofenacinVumon Teniposidr W Wellb riutBupropior Wellbu riutBupropior Wheibrt Meclpziee (metlozire) Wiicsram Am puon-inWiigom Gallopamil Winpeyd Peedaieon-inWyamycio Eryohrcmycio-en.olombedWyt nafn Guanabenz X Xanax AlprazolamedXanef En laprilinXa ral Alfuzosio Xylocwii LidocaineinXylocwrd LidocaineinXylotest Prilocwiie Y Yomiean NinlosamideinYutopar Ritodriie Z Zadinet KetotifenedZanaflex Tizanidire aZaioaaa St ypt zocio aZanoac Ranitidire aZapex OxazepaminZarontpu EthosuximideseZebeta Bisoprclol Zemurnn RocuroniuminZinapax Dac. zumabinZepiie R. UspiieedZerit Soavudiie (d4T)edZestail LisiooprilinZiageniAoacavir*inZimovans ZopicloreedZiPhrcmax AziPhrcmycio Zocs oSimvasoaPiredZof ai Oidaicet oi Zoladix GocerelpuinZovirax Aciclovir Zyflo ZileutouinZyloprim Alsopy puolinZylo ic Alsopy puolinZyprexm Olaizapiie Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinA aoacavir, 288 aociximab, 150inAbel, John J., 3 aolrtifacients, 126 aosoepf li, 10, 11, 46, 47inspeyd of, 18, 46se dcsmmcdaf li, eye, 98se dcumulaf li, 48, 49, 50, 51se dcumulaf li equilibrium, 48seACE, see Angiot nafn-ons- vertpgg etzy righCE inh oito s, 118, 124e diuprtocondit, 158seheart failu e t yatment, 132 hypert nafli t yatment, 312, 313 myocardial infarctior therapy, 310 acebutclol, 94 aceoaminophei, 198, 199 biomrmnsformaf li, 36e common ? 2d t yatment, 324, 325 intnxicaf li, 302 migraiie t yatment, 322 aceoazolamide, 162 N-acetyl-cyabeiie, 302 acetylcholiie (ACh), 82, 98, 166, 182 bindiigms agifotooic re-incepmor, 64 eeter hld olysis, 34, 35 musclstrelaxlnt effin s, 184–187inreleasb, 100, 101, 108sesynthesis, 100sesee also choliiocepmors acetylcholiieeterase a(AChE), 100, 182 inh oit li, 102 acetylcoetzy r A, 100seacetylcyabeiie, 324, 325 acetyldigoxio, 132 N-acetylglucocamire, 268 N-acetylmuramyl did, 268 acetylsaltcyl c did (ASA), 198, 199,hiem biomrmnsformaf li, 34, 35e common ? 2d t yatment, 324, 325 migraiie t yatment, 322 myocardial infarctior therapy, 310 plitelet aggregaf li is- h oit li, 150, 151, 310 acipimlx, 156se drolsio, 298se dromegaly, 242, 243 actior pot ntial, 136, 182, 186 active prindiple, 4 acyclovir, 284, 285, 286, 287ina ylaminopinicallpus, 270ina ylmrmnsferases, 38seAddi on’s di easb, 248seadinohypophy ealo(AH)edhorm nes, 242, 243 adenylate cyclasb, 66 adpsnal clrtex (AC), 248sepusufficiency, 248seadpsnal medulla,agifotooice s.imulaf li, 108, 109, 110 adpsnalige, see epiieph-seeiie adpsnrrgoc synapsb, 82 adpsnocepmors, 82, 230 agoiisos, 84, 86, 182 totypes, 84 adpsnocortstwl trophy, 250 adpsnocortstwl supp y -e s li, 250 adpsnocortstot opic hor-e moie (ACTH), 242, 243, 248, 250, 251se drfamycio,8298se dsorbett powde s, 178se dverse drug effin s, 70–75 aerosols, 12, 14 affinity, 56seinaioioceaRc ivity, 62 agitaf li, 106 agoiisos, 60, 61 inverse, 60, 226 partial, 60 agrmnulooytosis, 72 AIDS t yatment, 288–289 ajmalire, 136 aka ppsia, 238se kiieeia, 188 albumio,8drug bindiig, 30 albute ol, 326, 328 alcohol dehld oginase a(ADH), 44 alcohol eliminaf li, 44 alcuronium, 184 aldoeteroie, 158, 164, 165, 248, 249 anoagoiisos, 164 deficiency, 314 py gaf ve use dit, 172 alendronmte, 318 alfuzosio, 90 alkaloids, 4 alkylitirg oytostaf cs,8298se llergic reactiors, 72–73, 196, 326–327se llopy puol,8298, 316, 317se lloste ic noagoiism, 60 alloste ic synergism, 60 α-blooke s, 90 alprostanil, 118 alteplasb, 146, 310 Alzheimer’s di easb, 102 amanoadino, 188, 286, 287inamikacir, 278, 280inamiloeide, 164, 165 6-amino-pinicallan c did, 268 γ-aminobutyr c did, see GABA ε-aminocapro c did, 146se minoglycosidrs,8267, 276–279 368inIndbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIndbx 369 p-aminomethylbenzo cse did (PAMBA), 146se minopte io,8298se minopyrioe, 198se minoquieueide, 258se5-aminosaltcyl c did, 272 p-aminosaltcyl c did, 280inamicdaroie, 136se mi aiptyliie, 230, 232, 233 amodiaquiie,8294 amo olfiie,8282 amoxiftllpu, 168, 270, 271 cAMP, 66, 150inamphetamiies, 88, 89, 230 see also spedific8drugsinamphotericpu B,8282,8283 ampiftllpu, 270inampules, 12inam puon-, 118, 128, 132 auabolic steroids, ann aualggsics, 194–203 anoipyrrtoc, 4, 196–199, 202–203, 324 see also opioidsecanaphylactic reactiors, 72, 73, 15n t yatment, 84, 326, 327inancrcd, 146, 147inAncylostcma duodeimle, 29n aud ogins, ann auemia, 138–141, 19n megaloblictic, 19n pernicaous, 138 auesthesia balaoced, 216, 217seons ucf li, 204e dissociaf ve, 220 infilmrmf li, 90, 204e p ymedscaf li, 104, 106, 226 regioial, 216inspiial, 204, 216insurface, 204e total irtravetous (TIVA), 216insee also gsnrrwl ny -e thef cs; locwl ny thef cs augiia pec oeis, 128, 306–308, 311, 31n prophylaxis, 308, 311 t yatment, 92, 118, 120, 122, 308, 311 angiot nafn II, 118, 124, 158, 248seanoagoiisos, 124 biomrmnsformaf li, 34, 35e formaf li, 34 angiot nafn-onsvertpggseinzy r (ACE), 34, 124, 158insee also hCE inh oito s angiot nafnasb, 34 Anopheles mosquitoes, 294 anoeexiants, 88seanoacids, 166–168seanoagoiisos, 60, 61 antpraquiioie de ivaf ves, 170, 174, 176, 177 anoiadpsnrrgocs, 95–96, 128 anoiauemics, 138–141 anoiarrhythmics, 134–137 eaRc rophys l200stwl c- sors, 136, 137 anoibacterial8drugs, 266–282 csll wlll synthesis inh o- ito s, 268–271 DNA funcf li ish oito s, 274–275 mycnbacterial8infectiors, 280–281 proteio synthesis inh oi-into s, 276–279 te. Ihldrofolomb synthe-e s s inh oito s, 272–273 anoibiomics, 178, 266 broad-spedtrum, 266 cyabostaf c,8298senarrow-spedtrum, 266 see also anoibacteriale d ugs; anoifungal8drugs; anoiviral8drugsinanoibodies, 72, 73 moiocloral, 300seantstwocer8drugs,8296–299seantstholiiergocs, 188, 202 antstoagulants, 144–147 antstonvulslnts, 190–193, 226 antsdep y sants, 88, 230–233 t icyclic, 230–232 antsdlabef cs,8262,8263 antsdlarrheals, 178–179 antsdluprtoc horm ne a(ADH), see vasop y in antsdotes, 302–305 antseme ocs, 114, 310, 330–331 anoiepilep ocs, 190–193 anoiflatulents, 180seantsfungal8drugs,8282–283 anoigins, 72, 73 anoihelmiif cs,8292 antshietamiies, 114–116in llergic di orde t yat-e ment, 326, 327incommon ? 2d t yatment, 324, 325 mof li sickny prophy-e laxis, 330 pep oc ulce t yatment, 166–168sesedmt ve ac ivity, 222 antsy larials,8294–295 antsparasitic8drugs, 29n–295 antsparkiisxnian8drugs, 188–190 anoipyrrtoc aualggsics, 4, 196–199, 324 thermo egulaf li dit, 202–203 anoisep ocs, 290, 291 anoithrcmbin III, 142, 144 anoithrcmbomics, 142–143, 148–151 anoithyroid8drugs,8246, 247 antsviral8drugs, 284–289 AIDS t yatment, 288–289 inte ferons, 284, 285 virustaf c anoimetao- olites, 284–287 anxiety states, 226 anx l2ymics, 128, 222, 226, 228, 236se polipoproteios, 154, 155se poptosis, 296se protooin, 146se pprtomb supp y sants, 88 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinarachidon c did, 196, 201, 248inarea pnsorema, 110, 130, 212, 330 area unde the curve a(AUC), 46se eecolire, 102 artrrooisinchron c polyartrroois, 320 rheumatoid, 302, 320–321 Artrus reactior, 72 artstwiie, 208, 209 Ascar s lumbticoidrs,8292, 293 aspir i, see acetylsaltcyl c e did aspir i icthma, 198se etemizole, 114–116in cthma, 126, 127, 326–329 β-blooke s dit, 9n t yatment, 84, 104e asorpugents, 178se symmetr c Nind , 62 at nolol, 94, 95, 322 atherosclsrosis, 154, 306 a lrvssoaPir, 156se uracurium, 184 atrial8fibrallaf li, 130, 134 atrial8flutnd , 122, 130, 131, 134 atropiie, 104, 107, 134, 166, 216inlackenseceaRc ivity, 70, 71 poi oniig, 106, 202, 302 auraiofir, 320 aur thioglucoce, 320 aur thiom late, 320 autonom c iervous syabem, 80seAV blook, 92, 104e axolemma, 206 axoplism, 206 azapropazoie,hiem aza ppopr ie, 36, 300, 320 azidx hymidire, 288 aziPhrcmycio, 276 azloftllpu, 270inazcmycio, 274e Be B lymphocytes, 72, 300sebaciuracir,8267, 268, 270inbaclofen, 182 bacterial8infectiors, 178, 266,8267 resierwoce, 266,8267 see also anoibacteriale d ugs bacterididal8effin , 266, 267 bacteriostaf c8effin , 266, 267 balaoced auesthesia, 216, 217 bamipiie, 114 barbituratrs,8202, 203, 220, 222 depeideice, 223 baro ecepmors, gifotooe8ef- fin s, 110 barrie s blood-oissub, 24–25 csll membtanes, 26–27 external, 22–23 basiliximab, 300seBatrolo funcf li, 46sebathmctropism, negaf ve, 134 betlomete sore, 14, 250, 326seben zepril, 124 benign prostaf c8hyperpli-e s a, 90, 252, 31n bencorlzide, 188 bNiza pplzide, 162 bNiza ppre, 268 bNiza ropiie, 106, 107, 188 bNizbromarore, 316 bNizotwiie, 208, 209, 324 bNizodiazepiies, 182, 220, 226–229 anoagoiisos, 226 depeideice, 223, 226, 228 epilepsy t yatment, 190, 192 myocardial infarctior t yatment, 128 plogy ? kiie ocs, 228, 229 ecepmors, 226, 228 sleep di turbaoces dit, 222, 224 bNizopyrrie, 36 bNizo ppldiaziies, see thi-e lzide diuprtoco bNizylpinicallpu, 268 Berlpu Blue, 304 β-blooke s, 92–95, 128, 136se ugiia t yatment, 308, 311 hypert nafli t yatment, 312–313 migraiie prophylaxis, 322 myocardial infarctior t yatment, 309, 310 inus tachycardia t yat-e ment, 134 types of, 94, 95 bNzafibrmte, 156sebifnsIzols,8282 bile acids, 18m billogziasis, 292 bindiigma says, 56sebindiigmcurves, 56–57sebindiigmforces, 58–59sebindiigmsites, 56sebioavailability, 18, 42 absolute, 42 dete minaf li of, 46 relaf ve, 42 bioequivaleice, 46sebiogen c miies, 114–118 biomrmnsformaf li, 34–39 bNizodiazepiies, 228, 229 pu l ver, 32, 42 biperiden, 188, 238sebiphosphonatrs,8318 bis ? dyl, 174 bisoprclol, 94 bladde atoo a, 100, 102 bleomycio,8298seblood p y supr, 314 see also hypert nafli; hypot nafliseblood sugarionst ol, 260, 261 blood-braii barrie , 24 blood-oissub barrie s, 24–25 370 Indbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIndbx 371 bns s,8types of, 58, 59sebotulpuum toxio, 182 bowel atoo a, 100, 102 bradycardia, 92, 104, 134 bradykooin, 34 brain, blood-braii barrie , 24 brao, 170inbromocaiptite, 114, 126, 188, 242, 243 bronchiwl cthma, see cthma bronchiwl narftnoma, tx-inb dcs sm kiig dit, 11n bronchiwl mucus, 14 bronchitis, 324, 328inchron c obsorucf ve, 104e tob dcs sm kiig dit, 11n bronchoconsorpcf li, 196, 198sebronchodilaf li, 84, 104, 127, 196, 326sebronchodilafo s, 126, 328 brotizolam, 224 buccal8drug admiiis. I- sor, 18, 19, 2n Buchheim, Rudolf, 3 budesonidr, 14, 250, 326sebufot nio,8240inbulk gels, 170, 171 bumr anidr, 162 buprenlrphiir, 210, 214 bucerelpu, 242, 243 buspiron-, 116sebusulfau,8298seN-butylscopolamiie, 104, 126sebutyropheg nes, 236, 238sebutyryl choliieeterase, 100seC cabergol de, 126, 188, 242 caffiiie, 326 calcifediol, 264 calcineur i, 300secalcitoo i, 264, 265,8318, 322 calcitriol, 264 calcium anoagoiisos, 122–123, 128 angiia t yatment, 308, 311 hypert nafli t yatment, 312–313 calcium chlorel blooke s, 136, 234 see also calcium anoago-innisos calcium chelafo s, 142 calcium homeostasis, 264, 265 calmodulpu, 84 caocer,8296–299sesee also carftnomaseCandida albstwos,8282 canrenone, 164 capallary beds, a4 capreomycio,8280secapsules, 8, 9, 10secaptopril, 34, 124secarbachol, 102, 103secarbamatrs,8102 carbamazepiie, 190, 191, 192, 234 carbinicallpu, 270incarbinoxoloir, 168incarbidopa, 188 carbimIzols, 247 darbon c dids,hiem darbon c nold ase (CAH), 162 inh oito s, 162,8163secarbovir, 288 carboxypinicallpus, 270incarftnomasebronchiwl, 11n prostaf c, 242 cardiac rren., 104, 134 cardiac drugs, 128–137 anoiarrhythmics, 134–137 glycosidrs,8128, 130, 131, 132, 134 modes of actior, 128, 129 cardioaccelermt li, 104 cardiodep y s li, 134 cardioceaRc ivity, 94 cardioc.imulaf li, 84, 85 ca minaf ves, 180, 181 ca otid b dy, gifotooe8ef- fin s, 110 case-onst ol tudies, 76 casoor oil, 170, 174 catechol miies actiors of, 84, 85 sorucfupr-ac ivitytrela- sorships, 86, 87 see also epiiephriie;innorepiiephriieincatecholmii-O-methyl- rmnsferase (COMT), 82, 86, 114 inh oito s of, 188 cate rmics, 170, 172 csfminoxiu, 270incefope Izoie,hi70incefotaxime,hi70inceftlzidime,hi70inceftriaxone,hi70incell membtane,hiee membtane stabilizaf li, 94, 134, 136sepermeaf li, 26–27 cells,hiee cslluloce, 170incephalexin, 270, 271 cephalosporirasb, 270, 271 cephalosporirs,8267, 268, 270, 271 ce ivasoaPir, 156sece uletide, 180incesoode parasites, 292 cetr zite, 114–116inchllk, 178sechlrcowl, medsciial, 178sechelitirg agents, 302, 303sechemotherapeuf c agents, 266sechenodeoxychol c dida (CDCA), 180inchirality, 62 chloeal old amb, 222 chloeambucil,8298sechloeamphegifol,8267, 276–279 chloeguanidr, 294 chloeide chlorels, 226 chloemadinore a etamb, 254 chloeoquiie,8294,8295, 320 chloephegiramiie, 114 chloephegote ie (DDT), 29n,8293 chloepromazire, 208, 236, 238 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinlackenseceaRc ivity, 70, 71 chloeprothixete, 238sechloete lidonr, 162 chslgcalcife ol, 264 chslgcyabokooin, 180inchslgkiie ocs, 180inchslglithiasis, 180inchslgre ocs, 180inchslgstasis, 238sechslgste ol, 154–157segallstoteaformaf li, 180inmetaoolism, 155secholiie, 100secholiie acetyl rmnsferase, 100secholiiergoc synapsb, 100secholiiocepmors, 98, 100, 184seanoacid effin s, 166seanoagoiisos, 188 musc riiic, 100, 188, 230innifotooic, 64, 65, 100, 108, 182 chron c polyartrroois, 320 chronotropism, 84senegaf ve, 134 chylomofrnns, 154seftlazapril, 124 cimetfdiie, 116, 168inciprofl xacio, 274e cisap ide, 116secisplitir,8298secitrmte, 142 clariPhrcmycio, 168, 276seClark, Alexmnde J., 3 clavulan c did,hi70inclea aice, 44inclemastiie, 114 clemizole, 268 cl ndamycio,8267, 276 clinical8tesmiog, 6 clinical8trials,876 clob zam, 192 clodronmte, 264, 318 clofazimire, 280, 281 clofibrmte, 156seclometeiIzols, 192 clomtphene, 256seclonazepam, 192 clonfdiie, 96, 182, 31n clopidhgrel, 150incloetebol, ann Cloet fdium botulpuum, 18n Cloet fdium difficile,hi70inclotiazepam, 222 clotaimIzols,8282 clottirg fac o s, 142 clozapiie, 238, 239,8240inco-taimoxazols,hi7n,8273 toagulaf li cascwde, 142, 143 toated taolets, 8, 9, 10secotwiie, 88, 89, 208secsdeiie, 210, 212, 214, 324, 325 ? 2chicire, 316, 317se? 2ds, 324–325 ? 2esmipol, 154 ? 2esmyramiie, 130, 154 ? 2ic, 104, 127incommon ? 2d, 324–325 ? mprtom ve anoagoiisos, 60, 61 ? mplemett ac ivaf li, 72, 73 ? mpliaice, 48secsn Ninrmt li mime course, 46–47, 68, 69 dur ig ir egular irtake, 48, 49 dur ig repeated dosiog, 48, 49 csn Ninrmt li-bindiig curves, 56–57secsn Ninrmt li-effin curves, 54, 55secsn Ninrmt li-effin trela- sorship, 54, 55, 68, 69 csnformaf li chloge, 60 csngeet ve heart failu e, 92,8128, 130, 158, 31n conjugaf li reactiors, 38, 39, 58 conjunc ival decsngeet li, 90 csnsmipaf li, 172, 173 a ropiie poi oniig dit, 106 see also laxlf ves csntac dermatoois, 72, 73, 28n cont olled trials,876 corliary sclsrosis, 306, 307secsrpus luteum, 254 ? rtstot opin, 242 c rtstot opin-releasiig horm ne (CRH), 242, 250, 251seclrtisol, 36, 248, 249, 250, 251se ecepmors, 250inclrtisoie, biomrmnsforma- sor, 36e coryza, 90 cotaimoxazols,h178secough, 324, 325 coumarios, 142, 144, 145 covaleit bns s,858 c aiial ierves, 98secreams, 16,h17secromlglycomb, 116secromllyn, 14, 116, 326 cross-ove t ials,876 cur re, 184 Cushing’s di easb, 220, 248, 300, 318 prevett li of, 248incyanidr poi oniig, 304, 305 cyanoonbalampu, 138, 304, 305 cyclic endoperoxides, 196 cyclofentl, 256secyclooxyginases, 196, 248sepuh oit li, 198, 200, 328incyclophil i, 300secyclophosphamide,8298, 300, 320 cyclosbrioe,8280secyclosporir A, 300secyclo pplzide, 162 cyprcteroie, ann cyprcteroie a etamb, 254 ?ysmiour a, 302, 303secyabostaf c anoibiomics, 298secyolrabiie, 298secyoochrome P450, 32secyookiies, 300secytomegaloviruses, 286secytostaf cs,8296, 297, 299, 300, 320 cytostaf cs,8alkylitirg, 298secyootnxic reactiors, 72, 73 372 Indbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIndbx 373 D dac. zumab, 300sedlnt oleno, 182 dapsoie,hi7n,8280, 281, 294 daunorub cio, 298sedealkylitiors, 36 deaminaf li, 36 decarbamiioylaf li, 102 decsngeetants, 90 defe oxamiie, 302, 303sedehaloginaf li, 36 delavirdire, 288 delirium oremins, a36 dem ntia, 102 N-dem thyldiazepam, 228 demulcents, 178sedeoxyribnsucls c did (DNA), 274e synthesis inh oif li, 298, 299sedepeideice bNizodiazepiies, 223, 226, 228 hypno ocs, 222, 223e laxaf ves, 172, 173 opioids, 210–212 dephosphorylaf li, 102 depolar zitg musclstrelax-seanos, 184, 186, 187 deprenyl, 88 dep y s li, 226, 230inendogetous, 230–233 man c-dep y s ve illny , 230int yatment, 88, 230–233 dermatl200st agents, 16, 17se s8drug vehicles, 16,h17sedermatlphytes, 282 descendiigmantpuo i ep- svb syabem, 194 d. Unsitizaf li, 66 d. fluraie, 218 desip amire, 230, 232, 233 desmop y in, 164, 165 desogeetrel, 254 desulfuraf li, 36, 37sedexamete sore, 192, 248, 249, 330 dexazosio, 90 dexrtomide, 62, 63 dextrao, 1nn dlabefes mellitus hypoglycemia, 92sepusulpu replacem nt therapy, 258sepusulpu-depeideit, 260–261 nli-pusulpu-depeideit, 262–264 dia ylglyceaol, 66 dlarrhea, 178seantsdlarrheals, 178–179 chologen c, 172 dlaste eomers, 62 dlazepam, 128, 228 dlazoxide, 118, 31n dscaf li c, 268 dlclofenac, 200, 320 dlcloxaftllpu,hi70ind daioafne, 288 dietelysmilbeetrol, 74 dieteylether,8216 dlffuaflisebarrie ms ,hiee membtane permeaf li, 26,hi7 dlgitalis, 130, 131, 302 digitoxio, 132 Nind ohepaf c cycle, 38sedigoxio, 132 diold alaziee, 118, 31n dshldroergomamiie, 126, 322 dshldropyridires,8122, 308 dshldrotesmoeteroie, ann diltiazem, 122, 136, 308 dsm nhldrinomb, 114 dsm rcaprol, 302, 303sedsm rcaptopropanesulfns- c did,h302, 303sedsm teicnse, 180, 181 dsm teieteroie, an4 2,5-dsm teoxy-4-eteylinamphetamiie,8240in3,4-dsm teoxyampheta-e miie,8240indsm tiideib, 114 dsnoprcso, 126 dsnoprcsooie, 126 dsphenold amiie, 114, 222, 230 dtphenolmete ie de iva- svbs, 170, 174, 177 dtphenoxylomb, 178sedipole-dipole inte actior, 58sedipole- li iste actior, 58sedipyridamole, 150indipyroie, 198, 199 disiofin anos, 290, 291 disiotegraf li, nsetaolets aud capsules, 10indisopyr mfde, 136sedi orientaf li, a ropiie poi oniig dit, 106 Disse’s spaces, 24, 32, 33 dissolut li, nsetaolets dit ecapsules, 9, 10indist ibut li, 22–31, 46, 47indiuprtoco, 158–165,8313sepudscaf lisafor, 158seloop, 162,8163seosmof c, 160, 161 potasafum-spariig, 164, 165 sulfoiamide8type, 162, 163 tpplzide, 132, 162,8163, 312e dobutamiie, inaioioceaRc- svity, 62 do etaxel, 296sedo osahexaenomte, 156sedomperidhne, 322, 330 L-dopa, 114, 188 DOPA-decarboxylose, 188 dopamiie, 88, 114, 115, 132 agoiisos, 242seanoagoiisos, 114 in norepiiephriie syn-e thesis, 82 mime ocs, 114igParkiisxn’s di easb dit, 188 dopamiie ecepmors, 114, 322 agoiisos, 188 blookwde, 236, 238sedopamiie-β-hld oxylase, 82 dopiig, 88, 89 dorzolamide, 162 dobjectforms, 8 dobjectschedule, 50, 51sedobe-liiear kiie ocs, 68, 69 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotindobe-d. plicstrelat li- ship, 52–53indobiig ir egular, 48, 49seove dosiog, 70, 71 repeated, 48, 49sesublimiial, nn double-bl nd t ials,876 doxorub cio, 298sedoxyoycliie,hi77, 278, 294 doxylamiie,822e d omctropism, negaf ve, 134 dronmbpuol,8330 droperidhl, 216, 236sedrops, 8, 9e d ug iste actiors, 30, 32seantstonvulslnts, 192e d ug- ecepmor inte actior, 58–69e d ugs active prindiple, 4 admiiis. If li, 8–19 e dverse effin s, 70–75 apprcval prccy , 6 barrie sms ,hi2–27 biomrmnsformaf li, 32, 34–39 csn Ninrmt li mime course, 46–47, 48–49, 68, 69 development, 6–7indist ibut li ii b dy, 22–31, 46, 47inlibermt li of, 10 proteio bindiig, 30–31 reoarded releasb, 10, 11 ites of actior, 20–21 ources, 4 see also eliminaf li ofe d ugs; spedific8types seof8drugsinduodeiml ulce s, 104, 166 dusmiog powde s, 16 dynlrphiis, 210 dyskiieeia, 238sedysminorrhea, 196sedyabonia, 238seEseEmax, 54seE. ? 2i, 270, 271 EC50, 54, 60 ecnsIzols,8282 ec thiopate, 102 ecstasy,8240inec oparasites, 292 edema, 158, 159seEDTA, 142, 264, 302, 303seefavirNiz, 288 effirves Nin taolets, 8 effscacy, 54, 60, 61 Ehr. h, P., 3 s cobjnoids, 196ses cobjpegtlenomte, 156seeaRc romechloical coupliig, 128, 182 eaRc rostaf c att actior, 58, 59 eaiminaf li of8drugs, 32–43, 46, 47inβ-blooke s, 94 biomrmnsformaf li, 34–39, 42 chloges dur ig drug therapy, 50, 51seexponential rmte ppo-incy es, 44, 45 hldrophil c drugs, 42, 43sepu kidney, 40–41, 44 pu l ver, 18, 32–33, 44 lipophil c drugs, 42, 43sel rsis, 330–331 emulsiors, 8, 16 en lapril, 34 en laprilat, 34, 124seinaioiomers, 62, 63 inaioioceaRc ivity, 62 endooytosis, 24se ecepmor-medsated, 26, 27 endoneurwl space, 206 endoparasites, 292 β-endorphii, 210, 211, 212 endothelfum-de ived re-e laxirg fac o (EDRF), 100, 120inenfluraie, 218 enkephaliis, 34, 210, 211 enol c dids,hiem enoxacio, 274e egtlcopone, 188 Ettamoeba eietl2ymica, 274e Eind obius ve micularis, 29n Nind ohepaf c cycle, 38, 39seinzy r is ucf li, 32 Nphedriie, 86, 87 epilepsy, 190, 191, 226 antsepilep ocs, 190–193 childhocd, 19n t yatment, 162 epiiephriie, 82, 83, 260ecanaphylactic shook t yat-e ment, 84, 326, 327inβ-blooke s dit, 9n cardiac rren. t yatment, 134 locwl ny theeia dit, 206 gifotooe8dit, 108, 109, 110 sorucfupr-ac ivitytrela- sorships, 86, 87 epipodophyllotnxins, 298seepoxiditiors, 36 epoxides, 36 Epsom salts, 17m ep ofibatide, 150inergocorniie, 126 ergocrisoiie, 126 ergocrypoiie, 126 ergolides, 114igergometrpue, 126, 127 ergoste ol, 282,8283 ergom alkaloids, 126 ergomamiie, 126, 127, 322 eryohrcmycio, 34, 267, 276,hi77 eryohrcpoiesis, 138, 139 eryohrcpoietpu, 138 eeter hld olysis, 34 eet Idiol, an4, an5, 257seestriol, 2n4, an5seestrogen, 2n4, 318 estroie, an4, an5see pacryn c did, 162 e pambutcl, 280, 281 ete icl, 202, 203, 224 eliminaf li, 44 teinyleet Idiol (EE), an4, 255, 256se teinyltesmoeteroie, an5see pioiamide,8280se teieteroie, an4 ethosuximide, 191, 19n eteylaminobenzomte, 324 eteylenedsamiiete. Ia et- c did (EDTA), 142 374 Indbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIndbx 375see ilefriie, 86, 87 etofibrmte, 156seetomfdamb, 220, 221 etoposidr, 298seetprtooate, 74 euphoria, 88, 210 expec oelnts, 324, 325 exponential rmte ppocy es, 44, 45 extracsllular fluid volu rig(EFV), 158seextracsllular space, 28seextrapyr mfdal di tur-inb nces, 238 eye drops, 8, 9e F fac o VII, 142 fac o XII, 142 famcyclovir, 286 famotfdiie, 116, 168infatty dids,hie filbamatr, 190, 191 filodipiie, 122 filyp y in, 164, 206 fenes. If lis, 24sefenfluramiie, 88sefenoldopam, 114, 312sefenote ol, 86, 87 llergic di orde t yat-e ment, 326 cthma t yatment, 328e tocolysis, 84, 126 fentanyl, 210, 212–216 ferr c ferrocyanidr, 304, 305 ferr tpu, 14e fiver, 202, 203, 324sefexofenddino, 114–116infibrallaf li, 122 atrial, 130, 131, 134 fibrao, 34, 142, 146infibranogen, 146, 148, 149sefibrano2ymic therapy, 146inFick’s Law, 44 fiiaste ide, ann first-orde rmte ppocy es, 44–45 first-pass hepaf c elimina- sor, 18, 42 fish oil supplemettaf li, 156sefleas, 292,8293 flgcainidr, 136sefloxaftllpu,hi70influcosIzols,8282 flucytosins,8282 flud oclrtisoie,8248, 314 flukes, 292 flumazenil, 226, 302 flunarpziee, 322 flunisol de, 14, 250 fluoeide, 318 5-fluoeouracil,8298sefluoxrtoie, 116, 230, 232, 233 flupegtixcl, 236, 238, 239 fluphen zire, 236, 238, 239 flutamide,8252 flumicasoie dipropioramb, 14, 250 fluvasoaPir, 156, 157 fluvoxamiie, 232 fol c did, 138, 139,hi7n, 273 deficiency, 138 follicle-c.imulaf rg hor-e moie (FSH), 242, 243, 254 deficiency, 252 supp y s li, 256 follicular maturaf li, 254 fosc riet, 286, 287infosioopril, 124seFrazer, T., 3 frusemide, 162 funcf liwl noagoiism, 60 fungal8infectiors, 282–283 fungididal8effin , 282 fungistaf c8effin , 282 furosNmide, 162,8264 G G-proteio-coupled re ep- ors, 64, 65, 210 modeenseope If li, 66–67 G-proteios, 64, 66 GABA, 190, 224, 226 GABA ecepmors, 64, 226 gab pegtin, 190, 191, 19n Galei Atlaudius, 2segallamiie, 184 gallopamil, 122 gallstotes, 180indissolv rg of, 180, 181 gaidiclovir, 285, 286 gaiglia gifotooe8dctior, 108, 110 paraverteb al, 82 preverteb al, 82 gaiglion c blooke s, 108, 128 gasorpc secprtoli, 196 gasorpc ulce s, 104, 166 gasorpn, 166–168, 242segasorpois, troph c, 138 gelaPir, 152 gels, 16 gemfibrozil, 156 genrrwl ny thef cs, 216–221 inhalaf lial, 216, 218–219 pu teraole, 216, 220–221 genrr c drugs, 94 gettam cio,hi76, 278, 279 gesoodei, 254 g rgival hyperplieia, 19n Glauber’s salts, 17m glaucoma, 106 t yatment, 92, 102, 162 β-globuliis, drug bindiig, 30 glomerular filmrmf li, 40 glucagoi, 242seglucoc rtstoids,hiem, 248–251 llergic di orde t yat-e ment, 326 cthma t yatment, 328e cyookiie inh oif li, 300segout t yatment, 316 hypercalcemia t yat-e ment, 264 rheumatoid artrrooisint yatment, 320 glucosN metaoolism, 260, 261 see also dlabefes mellit-e us glucosN-6-phosphate de- hldroginase deficiency, 70 glucuron c did, 36, 38, 39seLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinβ-glucuron dases, 38seglucuron daf li, 38 opioids, 212seglucuron des, 38seglucuronyl8trmnsferases, 32, 38seglutamatr, 64, 190 ecepmors, 190seglutamiie, in ? njugaf li eactiors, 38 glybueide, 262 glycrrwldehlde inaioiom- ers, 62 glyceaol, 20 glycire, 64, 182,8183sepu conjugaf li reactiors, 38 glycogetolysis, 66,884 glycosur a, 162 cGMP, 120ingoite , 244, 245, 247ing 2d ? mpounds, 320 goiadorelpu suprrwgoiisos, 242segoiadot opin-releasiig horm ne (GnRH), 242, 243, 252, 256 gocerelpu, 242segout, 316–317 GPIIB/IIIA, 148, 149, 150inanoagoiisos, 150ingrmnicet oi, 116, 330 Graves’ di easb, 246, 247 gri eofulv r, 282,8283 growth horm ne (GH), 242, 243 growth horm ne re ep- ors, 64 growth horm ne releasbsepuh oit rg horm ne (- GRIH), 242 growth horm ne-releasiig horm ne (GRH), 242 guaneteidire, 96 guanylate cyclasb, 120ingynecomastia, 164, 168 gyrase inh oito s, 274, 275seHseHahneolor ASamuel, 76 half-life, 44inhallucinaf lis, a ropiie poi oniig dit, 106 hallucinogins, a40, 241 haloflnt iie,8294,8295 haloperidhl, 236, 238, 239 halote ie, 218, 219 haptins, 72, 73 hay fiver, 326 HDL particles, 154 heartinβ-blooke s dit, 9n cardiac rren., 104, 134 cardiac drugs, 128–137 cardioaccelermt li, 104 cardiodep y s li, 134 cardioc.imulaf li, 84, 85 see also angiia pec oeis; myocardial infarctior; myocardiuminheart failu einβ-blooke s dit, 9n csngeet ve, 92, 128, 130, 158, 31n t yatment, 118, 124, 132, 158inHelpcnbacter pylo i, 166 e Idicmt li of, 168, 169 hemlglobpu, 138 hemllysis, 70, 72 hemlsidrrosis, 140 hemlstasis, 142, 148 heparii, 142–146, 309, 310 hepaf c elimina sor, 18, 32–33, 44 exponential kiie ocs, 44inhepafocytes, 32, 33, 154 heroii, 212inHerpes simplex viruses, 284, 286 hexameteonium, 108 hexobarbital, 222 hese blood p y supr, see hypert nafli herudii, 150inhietamiie, 72, 114, 115, 166, 326 anoagoiisos, 114 inh oito s of releasb, 116 ecepmors, 114, 230, 326sesee also anoihietamiiesinHMGAtlA e ucfasb, 154, 156, 157 Hohenoeim, Theophrastus voi, 2 homa ropiie, 107 homeopathy, 76, 77 hookworm, 292 horm ne replacem nt therapy, 254edhorm nes, 20 hypophy eal, 242–243 hypothalampc, 242–243 see also spedific8hor-e moies huolo chorion c goiado- ropii (HCG), an2, 256 huolo immunodeficiency virus (HIV), 288–289 huolo minopausal gora-indot opin (HMG), an2, 256 hldrochloeo pplzide, 162, 164 hldroclrtisoie,8248 hldrogil, 16,h17sehld olysis, 34, 35 hld omorphoir, 210, 214 hldrophil c ? 2loids, 170, 171 hldrophil c ?ream, 16 hldrophil c drug elimina- sor, 42, 43sehldrophobic iste actiors, 58, 59sehld oxyapaf te, 264, 318 4-hld oxycoumarios, 144sehld oxyeteyl star h, 152 hld oxylaf li reactiors, 36, 37se17-β-hld oxyprogeeteroieincaproamb, 254 5-hld oxytrypoamire a(5HT), see cerotoo i hypercalcemia, 264 hyperglycemia, 162,8258, 260 hyperkalemia, 186 hyperlipoproteioemia, 154–157set yatment, 154 hyperpyrrxia, 202 hyper Unsitivity, 70 376 Indbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIndbx 377 hypert nafli therapy, 312–313 α-blooke s, 90 hCE inh oito s, 124, 312seβ-blooke s, 92, 31n calcium anoagoiisos, 122, 312e diuprtoco, 158, 31n in pregnaicy, 31n vasodilato s, 118, 31n hyperthermia, a ropiie poi oniig dit, 106, 202 hyperthyroidism, 244, 246–247 hypertonia, 226 hyperur cemia, 162,8316 hypno ocs, 222–225 depeideice, 222, 223e hypoglycemia, 92, 260 hypokalemia, 162,8163, 172, 173 hypophy is, 242–243, 250 hypot nafli, 118, 119, 314 t yatment, 90, 314–315 hypothalampc releasiig horm nes, 242, 243 hypothalamus, 242, 250, 251sehypothermia, 238 hypothyroidism, 244 hypovolemic shook, 152 I ibuprofen, 198, 200 idiopathic dilated cardio- myopathy, 92sepdoxu fdiie, 286 ifosfamide,8298 iloprcso, 118 imidazolstde ivaf ves, 282, 283 imip amire, 208, 230–232, 233 immune ? mplex vascu-e loois, 72, 73 immune modulato s, 300–301 immune d. plics, 72, 73, 300seimmunogins, 72seimmunosupp y s li, 300–301, 320 indiiavir, 288 iidomete cio,hi00, 316, 320 infertplity, 242 inflammaf li, 72, 196, 326se cthma, 328, 329seglucoc rtstoid therapy, 248, 249 rheumatoid artrroois, 320 inflammafory bowel dis- easb, 272 influNiza virus, 286, 287, 324 infuafli, 12, 50 inhalaf li, 14, 15, 18, 19 pu teriors, 12, 18, 19 puoafne moiophosphatesedehldroginase, 300sepuoaftol t isphosphate, 66, 84 inctropism, 92senegaf ve, 134 iostericidrs,8292 poi oniig, 304, 305 iisxmnia, 224, 226 pusulpu, 242, 258–259 dlabefes mellitus t yat-e ment, 260–261, 262 p yparatiors, 258, 259 egular, 258seresierwocems ,hi58sepusulpu ecepmors, 64sepusulpu-depeideit dla-inbefes mellitus, 260–261 inte ferons (IFN), 284, 285 inte leukiis, 300sepute stooial8fluid, 28seputesoiial8epithelfum,822e irtramuscular ir terior, 18, 19 putravetous ir terior, 18, 19 putriis c d ivity, 60 inaioioceaRc ivity, 62 putriis c fac o , 138 putriis c sympathomime oc activityt(ISA), 94 putubaf li, 216 puulpu, 28 inverse agoiisos, 60, 226 puverse enaioioceaRc ivity, 62 podiie, 246, 247 deficiency, 244 podized salt prophylaxis, 244 pon c currents, 136sepon c iste actior, 58seip atropium, 14, 107 llergic di orde t yat-e ment, 326 bronchodilaf li, 126, 328 cardiaoaccelermt li, 104, 134 iron ? mpounds, 140 iron deficiency, 138, 140 iron ove load, 302 i ocosIzols,8282 i ofluraie, 218 i onilzid, 190, 280, 281 isope ie, 258 i oppsnalige, 94 psoproterenol, 14, 94, 95 sorucfupr-ac ivitytrela- sorships, 86, 87 psosorbide dinitrmtet(ISDN), 120, 308, 311 5-psosorbide moionitrmte a(ISMN), 120inpsotprtooo c did, 74 psoxazolylpinicallpus, 270inptracosIzols,8282 J jocamycio, 276 juvenile licst dlabefese mellitus, 260 K K + chlorels, see potasafum chlorel ac ivaf li kanamycio, 276,8280sekaolpu, 178sekaraya gum, 170inketamiie,8220, 221 ketanse io,8116 ketocosIzols,8282 ketotifen,8116 kidney, 160, 161 drug eliminaf li, 40–41, 44 kinetosis, 106, 330, 331 kyphosis, 318 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinLseβ-lactam riig, 268, 270inβ-lactamases, 270inlactaf li, drug tnxicity, 74, 75selactuloce, 170inlampvudiie, 288 lamotresiie, 190, 191inLlogendorff p yparatior, 128 Llogley, J., 3 lansoprazole, 168 laryngitis, 324 lawensemass actior, 3, 56selaxaf ves, 170–177 bulk, 170, 171 depeideice, 172, 173 irr tant, 170, 172–174, 175, 177 lubticant, 174 misuse of, 170–172seosmof c lly ac ive, 170, 171 LDL particles, 154–157selead poi oniig, 302, 303seLennox-Gasoaut synd omb, 192 leprcsy, 274, 280seleuenkephalii, 212inleukotreenes, 196, 320, 326, 327, 328e NSAIDS dit, 200, 201inleuprorelpu, 242, 243 levrtomide, 62, 63 levodopa, 188 levomepromazire, 330 . N, 292,8293 lidotwiie, 134, 136, 208, 209 biomrmnsformaf li, 36, 37 dlgitnxin intnxicaf liset yatment, 130 myocardial infarctior t yatment, 309, 310 ligdit-gated li chlorel, 64, 65 ligdit-ope Ifed inzy rs, 64, 65 linccmycio, 276 l ndanN, 292,8293 liicoed, 170inlipid-lowerirg agents, 154 lipoc rtsn,8248 lipolysis, 66,884 lipophil c ?ream, 16 lipophil c drug elimina- sor, 42, 43selipophil c ointment, 16selipoproteio metaoolism, 154, 155selipoxyginases, 196seliquid paraffpu, 174seliquid p yparatiors, 8, 9e lisioopril, 124selisu ide, 114, 188 lithium iors, 234, 235, 246, 247inlive biomrmnsformaf li, 32, 42 blood supply, 32 drug eliminaf li, 18, 32–33, 44 drug exchloge, 24seinnd ohepaf c cycle, 38, 39selipoproteio metaoolism, 154–157seloadiigmdoce, 50 locwl ny thef cs, 128, 134, 204–209 chemicwl sorucfupr, 208–209 dlffuaflinditieffin , 206–207 mechloism of actior, 204–206selomusoiie, 298 loop diuprtoco, 162,8163seloperamide, 178, 212inloratidiie, 116inlorazepam, 220, 330 .ormeoazepam, 224 loriors, 16,h17selovasoaPir, 156, 157 low blood p y supr, see hypot nafliseLSD, see lysergic did di-e eteylamide Lugol’s solut li, 246inluteiniz rg horm ne (LH), 242, 243, an2, 254 deficiency, 252 lymphocytes, 72 lymphokiies, 72 lynes. enol, 254 lyp y in, 164 lysergic did, 126 lysergic did dieteylamide (LSD), 126, a40, 241 M macrophages, 300seac ivaf li, 72 magieeium sulfate, 126 maistenwocemdoce, 50 majs oeietl? mpaoibility ? mplex (MHC), 300sey laria,8294–295 malignait neurolep oc syn-e d omb, 238 man a, 230, 234, 235 man c-dep y s ve illny , 230inoloritcl, 160, 161, 170inm protoliie, 232 margii of8safety, 70 mass actior, lawens, 3, 56semast cells,h72 inh oito s of hietamiie releasb, 116 stabilizaf li, 326, 328 ma rix-type taolets, 9, 10inmaturity-licst dlabefese mellitus, 262–264 mazirdole, 88 mebeidIzols,8292,8293 mebhld oliie, 114 mecamylamiie, 108 mech.ore pamiie, 298 mecl zite, 114, 330 medsciial chlrcowl, 178semed oxyprogeeteroie a e- amb, 254 mefloquiie,8294,8295 megakaryocytes, 148 megaloblictic auemia, 19n melphalau,8298semembtane permeaf li, 26–27 membtane stabilizaf li, 94, 134, 136sememory cells,h72 minsorual cycle, 254 mensoruatoli, 196 378 Indbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIndbx 379 meperidiie, 126, 210, 214, 215 mepivatwiie, 209 6-m rcaptopuriie, 298 mesalamiie,8272 miscalire, 116, a40 miste oloie, ann mes. Inol, 2n4, an6inmetamizole, 198 metasoases, 296inmetenkephalii, 212, 213inmetenoloie, ann meteoeism, 180inmetformio,8262 l-methadoir, 210, 214, 215 me pamphetamiie,886, 87, 88 methemlglobpu, 304, 305 m teimIzols, 247 meteohexital, 220 meteo. examb, 298, 300, 320 m teoxyfluraie, 218 m teoxyverapamil, 122 4-methyl-2,5-dsm teoxy-inamphetamiie,8240inmethylaf li reactiors, 36, 37 m thyldigoxio, 132 m thyldopa, 96, 114, 312semeteylenedsoxy me pam- pletamiie (MDMA), 240inmethylergometrpue, 126inmethylp ydnisolore, 330 17-α-methyltesmoeteroie, 252inmethylxantpiies, 326inmethysergide, 322 metoclopramide, 322, 330 metoprclol, 94, 322 metron dazole, 168, 274e mexilrtoie, 134, 136semezcloftllpu, 270inmianse io,8232 mibef Idil, 122, 308 micosIzols,8282 Micromlnospora bacteria, 276 micturitoli, 98 m dazolam, 220, 221, 228 m feprisooie, 126, an6inmigraiie t yatment, 116, 126, 322–323 milieu iste ieur, 80semil puon-, 132 minrrwloc rtstoids,hi48, 249 minsy l alveolar csn Ni- rmf li (MAC), 218 minspall, an6, 257seminooycliie,hi78 minoxidil, 118, 31n mpsoprostcl, 126, 168, 169, 200semites, 292,8293 mixed-funcf li oxidises, 32 mixfuprs, 8 moclobNmide, 88, 232, 233 molsidomiie, 120, 308 mlnoamiie oxidise (MAO), 82, 86, 88, 114 inh oito s of, 88, 89, 188, 230,8232 moiocloral anoibodies, 300semood chloge, 210 morniig-after pall, an6 morphiir, 4, 5, 178, 210–215, 310 anoagoiisos, 214 in?reased sUnsitivity, 70 metaoolism, 212, 213inove dosage, 70, 71 S rmub tail phenominor, 52, 53inMorton, W.T.G., 216 motoliie, 276 mof li sickny , 106, 330, 331 mofs oeidplomb, 182 gifotooe8dit, 110 mofs osyabems, drugs act- rg oi, 182–193 mounoaii sickny , 162 moxalactam, 270inmucocoliary mrmnsport, 14inmuco2ymics, 324, 325 mucosal admiiis. If li, 12, 14, 18,822e mucosal blook, 140 mucosal disiofin li, 290, 291inmuprpu, 268 mupomlnab CD3, 300seyusc riiic choliiocepmors, 100, 188, 230seyuscimol, 240seyusclstrelaxanos, 182, 184–187, 226 my cthen a gravis, 102e mycnbacterial8infectiors, 274, 280–281 M. leprae, 280seM. tuberculocis, 280semycnphenolmtetmofe il, 300semycoses, 282–283 mldriaf cs,8104 myocardial infarctior, 128, 148, 226, 309–310 myocardial insufficiency, 92, 132 myocardiumincont actior, 128, 129 oxygin demand, 306, 307seoxygin supply, 306, 307 relaxatior, 128, 129 myometrpal relaxanos, 126 myometrpal c.imulanos, 126 myospu kinase, 84 N Na chlorel blooke s, 128, 134–137, 204senabilore, 330 NaCl reabsorptior, kidney, 160, 161 iadolol, 322 naftfdiie, 282 nalbuphiir, 212, 215 nalfdix c did,hi74senaloxoir, 210, 211, 214, 215, 302 nal. exoir, 214senand oloie, ann naphazolige, 90, 326sen proxete, 200senasal decsngeet li, 90 Naunyn, Bernlogd, 3 nausea, 330–331 see also anoieme ocs; mof li sickny nazatidiie, 116inLlmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinnebulize s, 13, 14inNecafs oameticanus,8292 nedocromil, 116senegaf ve bathmctropism, 134 negaf ve chronotropism, 134 negaf ve d omctropism, 134 negaf ve inctropism, 134 nelfiiavir, 288 neoloode parasites, 292 neomycio,8278, 279 neoplisms, see caocer; ncarftnomaseneostigmiie, 102, 103, 184 iephror, 160, 161 ie ilm cio,hi78 neupohypophy eal (NH) horm nes, 242 neupohypophy is, 242, 243 gifotooe8effin s, 110 neurolep aualggsia, 216, 236 neurolep auesthesia, 216 neurolep ocs, 114, 216, 240inepilepsy dit, 190 man a t yatment, 234 schizophren a t yatment, 236–238 thermo egulaf li dit, 202, 203 neuromuscular mrmnsmis- afli, 182,8183seblookiig, 184 ieur tic di orde s, 226 ieutrwl noagoiisos, 60 ieutrophils,h72 nevirapiie, 288 gifotooe, 108–113 effin s oi b dy func- sors, 110–111 gaiglion c dctior, 108 gaiglion c mrmnsmiss li, 108, 109innifotooic did, 118, 156innifotooic choliiocepmors, 64, 65, 100, 108, 182 nifedipiie, 122, 123, 126, 308 hypert nafli t yatment, 312 man a t yatment, 234 nsyodipiie, 122, 234 nstrmtettslgraice, 120innstrmtes, organ c, 120–121 nstrmzepam, 222 nstrendipiie, 122 nstric did, 120 nstric oxide (NO), 100, 116, 120, 148 nstroglyce io,8120, 308, 311, 31n nstroimidazols, 274, 275senstrostigmiie, 102senstrous oxide (N2O), 218, 219innizatidiie, 168 uo i epmors, 194, 196 nli-pusulpu-depeideit di-e abefes mellitus, 262–264 nlicovaleit bns s,858 nlidepolar zitg muscls relaxanos, 184, 185 nlieteroidal8anoiinflam-inmatory drugs (NSAIDS), 38, 198, 200–201segout t yatment, 316 plogy ? kiie ocs, 200serheumatoid artrrooisint yatment, 320 noradpsnalige, see norepi- iephriie nordazepam, 228 norepiiephriie, 82, 83, 88, 118 biomrmnsformaf li, 36, 37 locwl ny theeia dit, 206 geur nal re-uptake, 82, 230sereleasb of, 90, 91insorucfupr-ac ivitytrela- sorships, 86, 87 synthesis, 82, 88 noreteieteroie, an4 norfl xacio, 274e nortaiptyliie, 232 nosc piir, 212, 324 nosN drops, 8, 9e suclslsidr inh oito s, 288, 289 nysoaPir, 282,8283 Oseobesity, dlabefes mellitus dit, 262,8263inobidoxime,h304, 305 oct yotide, 242 ofl xacio, 274e ointments, 12, 13, 16,h17seolanzapiie, 238seomeprazole, 168 ondancet oi, 116, 330 opioids, 178, 210–215, 302 effin s, 210–212 metaoolism, 212, 213inmodeenseactior, 210 tslgraice, 214seopium, 4 tin?fupr, 4, 5, 178seoral admiiis. If li, 8–11, 18, 19,822e dobjectschedule, 50seoral cont acep oves, 2n4, 256–257sebiplos c p yparatiors, 256, 257seminspall, an6, 257semoiophos c p ypara- sors, an6, 257semorniig-after pall, an6 oral reold am li solut li, 178seorciprsnalige, 86, 87 organ p yparatior tudies, n4 organophosphate iosteri-incidr poi oniig, 304, 305 organophosphates, 102e ornip y in, 164, 165 osmof c diuprtoco, 160, 161 oeteoy lacia, 19n oeteopinia, 318 oeteoporosis, 264, 318–319inouabaio, 132 ove dosage, 70, 71 ovulaf li, an4 inh oif li, 256 stimulaf li, an6 oxaftllpu,hi70, 271 oxalate, 142 oxatomfde, 116inoxazepam, 228 nxicosIzols,8282 380 Indbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIndbx 381 ox dases, mixed-funcf li, 32 oxiditior reactiors, 36, 37seoxymeoazolige, 326seoxytocio, 126, a42, 243 P p-aminobenzo c did (PA-inBA), 27n,8273 pac. taxel, 296, 297 pain, 194, 195 see also analggsics pallpaf ve therapy, 296 pamidronmte, 318 pan?reaf c enzy rs, 180, 181 pan?reozy in, 180inpan?uron um, 184, 185 pantoprazole, 168 Papaver sxmniferum, 4 papaveriie, 210igParacslsus, 2separacstamol, see acstami- inphenseparaffpuomas, 174separaoxoi, 36, 102, 103separasit c isfectiors, 292–295 parasympathrtoc iervous syabem, 80, 98–107 natomy, 98 drugs act rg oi, 102–107 d. plicssms ac ivaf li, 98, 99 parasympatho2ymics, 104–107, 128, 134, 324 cont apudscaf lisafor, 106 parasympathomime ocs, 102–103, 128sedirin , 102, 103sepudsrin , 102, 103separathili, 102 biomrmnsformaf li, 36, 37 parathorm ne, 264, 265 paraverteb al gaiglia, 82 parinnd al admiiis. If li, 12, 13igParkiisxnism antsparkiisxnian drugs, 188–190inpseudoparkiisxnism, 238 t yatment, 88, 106, 114 paromcmycio,8278 paroxrtoie, 232 partial agoiisos, 60 pastes, 12, 13, 16,h17sepaoieit ? mpliaice, 48sepec pu, 178sepinbutclol, 94sepindiclovir, 286 D-pinicallamiie, 302, 303, 320 pinicallpuasb, 270, 271 pinicallpus, 267–270, 271 eliminaf li, 268 pinicallpu G, 72, 266, 268–270, 271 pinicallpu V, 270, 271 Pinicallpum nooaPum,8268 pinoazociir, 210, 212, 214, 215 pinoobarbital, 223 biomrmnsformaf li, 36, 37 pep oc ulce s, 104, 106, 166–169 pep odases, 34 pep ode synthrtasb, 276 pep odlglycoi, 268 pirchloeate, 246, 247 pergol de, 114, 126, 188 pirirdopril, 124sepirireur um,8206 perisoalsis, 170, 171, 173 permetrron, 292 pernicaous auemia, 138 pirphen zire, 330 peteidire, 210igplogy ? dyiamics, 4igplogy ? genrtoco, 70igplogy ? kiie ocs, 4, 6, 44–51 ccumulaf li, 48, 49, 50, n1 csn Ninrmt li mime course, 46–49, 68, 69 proteio bindiig, 30 see also eliminaf li ofe d ugsigplogy ? 2000,oeietlry of, 2–4igplogyngitis, 324 α-phose, 46inβ-phose, 46inphose I reactiors in drug biomrmnsformaf li, 32, 34inphose II reactiors in drug biomrmnsformaf li, 32, 34inphenacetpu, 36sephencyclidire, 240sepheniramiie, 114 phenobarbital, 138, 190, 191, 19n, 222 inzy r is ucf li, 32, 33 phenolphthalepu, 174sephegotei zires, 236, 238, 330 phenoxybenzamiie, 90 phenoxymethylpinicallpu, 270 phentolamiie, 90, 31n phenylbutazoie,hi00, 316 phenylephriie, 86 phenytoio, 130, 136inepilepsy t yatment, 190, 191, 19n fol c did absorptior dit, 138 phobic di orde s, 226 phosphodiesterase, 66 inh oito s, 128 phospholspase A2, 248 phospholspase C, 66,8100, 150 phospholspid bilayer, 20, 26se s8barrie ,822e phospholspids, 20, 26e phosphoric did, 20 physostigmiie, 102, 103, 106, 302 pilocarpiie, 102sepirdolol, 94, 95 pinworm, 292,8293 pipecuron um, 184 piperaftllpu,hi70inpiperazire, 236, 238inpirNizepiie, 104, 107, 166 pirNtanidr, 162 pirnxicam,hi00, 320 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinpizotifen,8322 placebo8effin , 76, 77 placebo-cont olled trials, 76 placenoal8barrie ,824igPl noago, 170inplisma volu r expmnde s, 152–153inplismalemma, 20 plismii, 146 inh oito s, 146 plismiiogen, 144, 146 ac ivafo s, 146 Plismodium falciparum, 294 Plismodium ovale, 294 Plismodium vivax, 294 plomblet ac ivaf rg fac o (PAF), 148, 150 plomblet cyclooxyginase, 150, 151 plomblet fac o 3 (PF3), 142 plomblets, 148, 149, 196 inh oito s of aggregaf li, 150, 151 plicamycio,8264 poi oniigseantsdotes, 302–305 a ropiie, 106, 202, 302 polidotwicl, 208 polyartrroois, chron c, 320 polyeoe8dioibiomics, 282, 283 polymyxins, 266,8267 portal8vepu, 32, 33 potasafum (K + ) chlorel ac- svaf li, 66 potasafum-spariig diuprt- cs, 164, 165 pot ncy, 54, 60, 61 pot ntiaf li, 76 powde s, 12, 13, 16,h17sepramipexole, 188 pravasoaPir, 156 praziqudioel, 292,8293 prazosio, 90 preclinical8tesmiog, 6 p ydnisolore, 36, 248, 249 p ydnisore, biomrmnsfor-inmatili, 36 pregnaicy drug tnxicity, 74, 75 hypert nafli t yatment, 312 vomimiog, 330, 331 pregnaidiol, 2n4, an5sepremidscaf li, 104, 106, 226 preverteb al gaiglia, 82 prilocaire, 208, 209 biomrmnsformaf li, 34, 35seprimaquiie,8294,8295 primary boliary cirrhosis, 180 primidhne, 138, 192 pro-opiomelanoonrtsn, 210, 211 probenedid, 268, 269, 316, 317seprobuco2, 156 procair mfde, 134, 136seprocaire, 134, 208, 209, 268 biomrmnsformaf li, 34, 35seprodrugs, 34inprodynlrphii, 210igproenkephalii, 210, 211 progabide, 190igprogeeteroie, 2n4, an5, 257igprogeetin p yparatiors, 254seoral cont acep oves, 2n6seproguanil,8294,8295 pr kiie oc agents, 116seprolactiu, 242, 243 prolactiu releasb puh oit rg horm ne (PRIH), 242 prolactiu-releasiig hor-e moie (PRH), 242 prome paziie, 114 propafenore, 136sepropofol, 220, 221 prop Inolol, 94, 95,8322 biomrmnsformaf li, 36, 37 inaioioceaRc ivity, 62 propylthiluracil,8247 propyphen zoie, 198 prospec pve t ials,876 prostaoyclii, 116, 118, 148, 150, 196 prostaglaidin synthasb pu- h oito s, 320 prostaglaidins, 126, 168, 196, 197, 320 NSAIDS dit, 200, 201inprostate bNiign hyperplieia, 90, 252, 31n carftnoma, 242 hypertrophy, 106 protamiie, 144 protease inh oito s, 288, 289 proteio bindiig, of8drugs, 30–31 proteio kinase A, 66 proteio synthesis, 276 inh oito s, 276–279 proteio synthesis- egulaf- rg ecepmors, 64, 65 pr tirelpu, 242sepseudocholiiesterase defi-inciency, 186 pseudoparkiisxnism, 238inpsilocpu, 240inpsilocybii, 116, 240inpsychedel c drugs, 116–118,8240, 241 psychl200stal depeideice, 210–212 psychlmime ocs, 240, 241 psychlplogy ? 200stals, 226–241 psychlsoma oc uu- coupliig, 232, 236 purgaf ves, 170–177 depeideice, 172, 173 pyr ziiamide,8280, 281 pyridostigmiie, 102sepyridylcarbpuol,8156 pyrime pamiie, 294,8295 pyrogins, a02, 203 Q quiiapril, 124sequiiidiie, 136, 295 quiiine, 294 4-quiiolore-3-carboxyloc acid,hi74, 275se382 Indbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIndbx 383 R acemates, 62, 63 rwloxifen,8254seramipril, 124sermnitfdiie, 116, 168inrapid eye movem nt (REM) sleep, 222, 223e reactive hyperemia, 90, 91in ecepmor-medsated endo- cytosis, 26,hi7 ecepmors, 20 drug bindiig, 56setypes of, 64–65 rin al admiiis. If li, 12, 18, 19 ri ucf li reactiors, 36, 37sersnal failu e, prophylaxis, 158serenal tubular secprtoli, 40serenio, 124, 158serenio-angiot nafo-aldoste- roie (RAA) syabem, 118, 125, 158seinh oito s of, 124–125 ri Uspire, 96, 114 resierwoce, 266,8267 d. piratory t act,822e irhalaf li of8drugs, 14, 15, 18, 19 rioarded drug releasb, 10, 11 rioeplasb, 146 etrospec pve t ials,876 reverse mrmnscaiptasb, 288 inh oito s, 288, 289 Reye’s synd omb, 198 rheumatoid artrroois, 302, 320–321 rhinitis, 324 ribnsucls c did (RNA), 274e synthesis inh oif li, 298, 299seribnsomes, 276 r ciools c did, 174, 175 rifabut o, 274e rifampio,8267,hi74, 280, 281 risk:benefit If l, 70ig isperidhne, 238, 240seritodrpue, 126inritoiavir, 288 rocuron um, 184 olite. Ioycliie,hi78 ropiiirole, 188 rosig. tazoie,hi62 rough endoplismic re ocu-e lum (rER), 32, 33 roundworms, 292,8293 Se salazosulfapyridire,8272 salbutamol, 86, 328 salicylates, 200sesalicyl c did, 34 see also acetylsalicyl c acidsesalmeterol, 328 Salmoiella8typhi, 270, 271 saluprtoco, see diuprtoco saquiiavir, 288, 289 slrcoplismic re oculum, 182 Slrcopfes scabiei, 292 slrtans, 124seSceietlsoma, 292 schizophren a, 118, 236, 237seScemiedeberg, Oswald, 3 scopolamiie, 106, 107, 240, 330 sea sickny , 106, 330, 331 sedaf li, 222, 226 scopolamiie, 106 seizuprs, 190, 226 seaRc ivity, lack of, 70, 71 seaRgoliie, 88, 188 senna, 174, 176 sensitivity in?reased, 70, 71 variaf li, 52 sUnsitizaf li, 72 serotoo i, 88, 116–118 ac iors, 116 geur nal reuptake, 230seplomblet ac ivaf li, 148, 150 ecepmors, 116, 230, 322 serotoo i-seaRc ive reup- ake inh oito s (SSRI), 230,8232 sertprdole, 238insertraliie, 232 Sertlmann,me ,8F.W., 4 serum sickny , 72 sibutramiie, 88sesidr effin s, 70–75 signal8trmns ucf li, 64, 66 lithium ior effin s, 234 ssm teicnse, 180 ssmile prindiple, 76 simvasoaPir, 156 afous bradycardia, 134 afous taohycardia, 92, 134 afscmycio,8278 skiise s8barrie ,822e disiofin li, 290, 291 protectior, 16,h17setrmns d cal drug del v- eryosyabems, 12, 13, 18, 19 sleep, 222, 223e di turb nces, 118, 222, 224 sleep-wake cycle, 224, 225 slow-releasb taolets, 10 smokiig, 112–113 see also gifotooe smooth endoplismic re oc-e ulum (sER), 32, 33 smooth muscls acetylcholiie effin s, 100, 101inadpsnocepmor ac ivaf li effin s, 84 drugs act rg oi, 126–127 relaxatior of, 104, 120, 122, 326sevascular, 118, 120, 122, 196, 326sesodium chlorel blooke s, 128, 134–137, 204sesodium chloeide reabsorp- sor, kidney, 160, 161 sodium cstrmte,8264 sodium meteohexital, 221 sodium moiofluoeophos- plmte, 318 sodium nstroprussidr, 120, 31n sodium p cobulfate, 174 sodium thiopenoal, 221 solut lis, 8, 17secsn Ninrmt li of, 28 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinpu teraole, 1n soma oc iervous syabem, 80 soma ocrinpu, 242sesoma osoaPir, 242sesoma o ropic horm ne (STH), 242, 243sesopoeifocs, 222sesorbitcl, 160, 170 sore throam, 324, 325 sooalcl, 136 spismo2ymics, 126, 127 spisticity, 226 sperma ogenrsis stimula- sor, 252 spiramycio, 276 spironolactnse, 164, 165 stage freser, 92seerwoozolol, 252 Staphylococcus bacteria, 270seerwtins, 156 status epilep ocus, 190, 192seerwvudiie, 288 abeady s amb, 48 abeal8effin , 306 stereoi ometism, 62 sterilizaf li, 290 steroid ecepmors, 64sesteroids, anaoolic, 252 Strmub tail phenominor, 52, 53ins. epookiiasb, 144, 310 S. epoomyces bacteria, 276,hi77, 300, 302 s. epoomycio, 276,8280, 281 s. e , sleep di turb nces dit, 224, 225 sorokb, 148 S. ongyloides stercoralis, 29n sorychniie, 182 tocu aueous ir terior, 18, 19 sublimiial dosiog, 52 subl ngual drug admiiis- rmf li, 18, 19,822e succinylcholiie, 186 sucralfate, 168, 169 bulbactam, 270inbulfadoxiie, 294,8295 bulfam teoxazols, 27n, 273 sulfapyridire,8272 sulfasalazire,8272, 320 sulfinpyr zore, 316 sulfoiamidesseantsbacterial,8267,hi7n, 273 diuprtoco, 162,8163sesulfoiylupra,hi62 sulfotrmnsferases, 38 sulfoxiditiors, 36 sulprostcue, 126insultei mr, 162 suma rip au, 116, 322 suppoaftories, 12, 13 suspensiors, 8 swallowiog proolems, 324 sweat glaids a ropiie poi oniig dit, 106 sympathrtoc iniervaf li, 80 sympathrtoc iervous syabem, 80–97 drugs act rg oi, 84–97 d. plicssms ac ivaf li, 80, 81insorucfupr of, 82 sympatho2ymics α-sympatho2ymics, 90, 91inβ-sympatho2ymics, 92, 93, 94, 95 nli-seaRc ive, 90 seaRc ive, 90 sympathomime ocs, 90, 91, 128, 132, 314 llergic di orde t yat-e ment, 326 cthma t yatment, 328e bronchodilaf li, 126 ? mmon ? ld t yatment, 324, 325 dsrin , 84, 86sepudsrin , 86, 88, 89 putriis c d ivityt(IS), 94 afous bradycardia dit, 134insorucfupr-ac ivitytrela- sorships, 86, 87 synapse adpsnergic, 82 choliiergic, 100sesynapsir, 100sesynovec omy, 320 syrups, 8 T T lymphocytes, 72, 300setaolets, 8–10sevagiial, 12, 13 taohycardia, 134ina ropiie poi oniig dit, 106 t yatment, 92, 122, 134 taohyphylaxis, 88setaoriie, 102setaorolimus, 300setamoxifen,8254setape worms, 292,8293 oard ve dyskiiesia, 238 tazobactam, 270inbemmzepam, 222, 224 ten posidr, 298setera ogenicity, 74seterazosio, 90 terbutaliie, 84, 86, 326, 328 tesmiog clinical, 6 p yclinical, 6 tesmoeteroie, 34, 242, 252, 253 eeters, 252 tesmoeteroie heprwooamb, 252 tesmoeteroie propioramb, 252 tesmoeteroie undecwooamb, 34, 252 tetaous toxio, 182,8183sete. Ioaire, 208, 324 te. Ioycliies, 266,8267, 276–279 te. Ihldroclorabpuol,8240sete. Ihldrofol c did (THF), 272, 298, 299sete. Ihldrozolige, 90, 326sethalidomidr, 74sethallium salt poi oniig, 304setheophylliie, 118, 126, 127, 326, 328 thermo egulaf li, 196, 202–203se384 Indbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NicotinIndbx 385 tei mIzols, 247 pplzide diuprtoco, 132, 162,8163, 31n tpplzolidiredi nes, 262–264 thio-TEPA, 298sethioamides, 246, 247 thiopenoal, 220 thioupratde ivaf ves, 246 thiouprylenes, 246 thioxantperes, 236, 238 thromb cthen a, 148 thrombii, 150inthrombocytopinia, 72inthromboses, 142, 148, 158seprophylaxis, 142–143, 146, 148–151inthromboxaie, 148, 150, 196inthymete ocs, 230,8232 thymidire kinase, 286 thymolep ocs, 230,8238 thyroid horm ne re ep- ors, 64 thyroid horm ne therapy, 244–245 thyroid hyperfuncf li, 202 thyroid perox dase, 246 thyroid c.imulaf rg hor-e moie (TSH), 242, 243, 244 thyro ropii, 242sethyro ropii-releasiig hor-e moie (TRH), 242 thyroxiie, 244, 245, 246 tiagabii, 190inticarftllpu,hi70inticlopidiie, 150inteser juncf lis, 22,824igmimed-releasb capsules, 10intemidazols, 274intemclol, 94setin?fupr, 4setirofibai, 150intissue plismiiogen ac iva- or (t-PA), 146 tizaiidiie, 182 oobacco smokiig, 112–113 see also gifotooe oobramycio, 277,8278 tocainidr, 136setocolysis, 84, 127setocolymics, 126 tslbutamide,8262 oolon um chloeide, 304, 305 Toluidire Blue, 304, 305 tcustllptis, 324 topiramatr, 191, 19n topoi ometose II, 274intooal putravetous ny the- afa (TIVA), 216 tsxico200stal puvestiga- sors, 6 t aoheptis, 324 tramadhl, 210intrmndhlapril, 124setrmnexam c did, 16setrmnscytosis, 24, 26setrmns d cal drug del very syabems, 12, 13, 18, 19 es. ogen p yparatiors, 254setrmnsferrpu, 14e mrmnsmitter toerwoces, 20 choliiergic synapse, 100sesympathrtoc, 82 mrmnspep odase, 268 inh oif li of, 268, 270inmrmnsportsemembtane permeaf li, 26,hi7 mucocoliary, 14inmrmnsport proteios, 20inmrmnylcypromiie, 88, 232 travel sickny , 106 trials,8clinical, 76 triamcinoloie, a48, 249 triamterene, 164, 165 triazolam, 222, 223, 224, 226 triazolstde ivaf ves, 282 Trichiirlla8spiralis, 292, 293 trichloem teilzide, 162 Trichomlnas vagiialis, 274, 275 Trichuris t ichiura, 292 t icyclic8dioidep y sanos, 230–232 t ifluperazire, 236, 238, 239 t iflupromazire, 236, 238, 239 t iglyce ides, 154–156, 248 t iiodothyroniie, 244, 245 t imeprazire, 330 trime pape i, 108 trime poprim,8267,hi7n, 273 rip orelpu, 242setrogl tazoie,hi62–264 trolnicet oi, 330 tropiset oi, 116 tuberculocis, 274, 276,8280sed-tubocurariie, 184, 185 tumours, see caocer; carft- inmasety amire, 232 L-ty osins,882 my osins kinase d ivity, 64 my otrrocio,8266,8267 Ue ulce s, pep oc, 104, 106, 166–169 ulmrmleite, 2n8 ur cosoaPics, 316, 317seur cosur cs, 316, 317seur ns,8drug eliminaf li, 40seurokiiasb, 146seursodeoxychol c did (UDCA), 180seVsevaccinaf lis, 284 vagiial taolets, 12, 13 vagus ierve, 98 v lacyclovir, 286 v lproamb, 190, 192, 234 v lpro c did, 191, 19n van der Waals’ bns s,858, 59 vanccmycio, 267,hi68, 270invanillyColodel c did, 82 varicoafties, 82 vasculoois, 72 vasoactive putesoiial8pep- ide (VIP), 242 vasoclietricf li, 84, 90 gifotooe8dit, 110 serotoo i ac iors, 116 vasoclietricfors, locwl n- es.heeia dit, 206 vasodilat li, 84 locwl ny theeia dit, 206 Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotinserotoo i ac iors, 116 vasodilato s, 118–123, 31n calcium anoagoiisos, 122–123 organoc istrmtes, 120–121 vasop y in, 148, 160, 164, 165, 242 gifotooe8dit, 110 vecuron um, 184 vegetaole fibe s, 170inverapamil, 122, 123, 136seangiia t yatment, 308 hypert nafli and, 312 man a t yatment, 234 vNinricular rmtetmodifi-incaf li, 134 Vibrio cholerae, 178sevodarabiie, 285,8386 vigaba rin, 190, 191 vinblictiie, 296 vincrisoiie, 296 vicmycio, 280seviral8infectiors, 178, 284–289 AIDS, 288–289 ? mmon ? ld, 324–325 virusoaPic8dioimetaoolites, 284–287 vitamii Atde ivaf ves, 74invitamii B12, 138, 139 deficiency, 138 vitamii D,8264 vitamii D horm ne, 264, 265 vitamii K, 144, 145 VLDL particles, 154 volu r of8dis. ibut li, 28, 44 vomimiog drug-is uced, 330 pregnaicy, 330, 331 see also anoieme ocs; mof li sickny Von-Willeb andt fac o , 148, 149 W Wepfe ,8Johlor Jakob, 3 whipworm, 292 Wilson’s di easb, 302 wound disiofin li, 290, 291inX xantpiie ox dase, 316, 317sexantpiiol gifotooamb, 156 xinor, 218 xylomeoazolige, 90 Z zafirlukast, 328e zalcitabiie, 288e zero-orde kiie ocs, 44inzidovudiie, 289inzinc pusulpu, 2n8 Zollpuger-Ellpson syn-e d omb, 168inzolpidem, 222 zoiulae occludeites, 22, 24, 206 zopicloie, a22 386 Indbx Llmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotin