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 mediated largely by presynaptic receptors that facilitate transmitter release from excitatory aminoacidergic (glutamatergic) nerve terminals in the cerebral cortex. Nico- tine increases vigilance and the ability to concentrate. The effect reflects an en- hanced readiness to perceive external stimuli (attentiveness) and to respond to them. The multiplicity of its effects makes nicotine ill-suited for therapeutic use. 110 Nicotine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotine 111 A.Effects of nicotine in the body Antidiuretic effect Vigilance Respiratory rate Sensitivity Partial depolarization of sensory nerve endings of mechano- and nociceptors Partial depolarization in carotid body and other ganglia Release of vasopressin Partial depolarization of chemoreceptors in area postrema Partial depolarization of baroreceptors Epinephrine release Emetic center Emesis Partial depolarization of autonomic ganglia Para- sympathetic activity Sympathetic activity Darmt?tigkeitHerzfrequenzVasoconstriction Blood pressure Defecation, diarrhea Blood glucose and free fatty acids Glycogenolysis, lipolysis, “silent stress” Bowel motilityVasoconstriction Nicotine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Consequences of Tobacco Smoking The dried and cured leaves of the night- shade plant Nicotiana tabacum are known as tobacco. Tobacco is mostly smoked, less frequently chewed or tak- en as dry snuff. Combustion of tobacco generates approx. 4000 chemical com- pounds in detectable quantities. The xenobiotic burden on the smoker de- pends on a range of parameters, includ- ing tobacco quality, presence of a filter, rate and temperature of combustion, depth of inhalation, and duration of breath holding. Tobacco contains 0.2–5 % nicotine. In tobacco smoke, nicotine is present as a constituent of small tar particles. It is rapidly absorbed through bronchi and lung alveoli, and is detectable in the brain only 8 s after the first inhalation. Smoking of a single cigarette yields peak plasma levels in the range of 25–50 ng/mL. The effects described on p. 110 become evident. When intake stops, nicotine concentration in plasma shows an initial rapid fall, reflecting distribu- tion into tissues, and a terminal elimi- nation phase with a half-life of 2 h. Nic- otine is degraded by oxidation. The enhanced risk of vascular dis- ease (coronary stenosis, myocardial in- farction, and central and peripheral is- chemic disorders, such as stroke and intermittent claudication) is likely to be a consequence of chronic exposure to nicotine. Endothelial impairment and hence dysfunction has been proven to result from smoking, and nicotine is under discussion as a factor favoring the progression of arteriosclerosis. By releasing epinephrine, it elevates plas- ma levels of glucose and free fatty acids in the absence of an immediate physio- logical need for these energy-rich me- tabolites. Furthermore, it promotes platelet aggregability, lowers fibrinolyt- ic activity of blood, and enhances coag- ulability. The health risks of tobacco smoking are, however, attributable not only to nicotine, but also to various other ingre- dients of tobacco smoke, some of which possess demonstrable carcinogenic properties. Dust particles inhaled in tobacco smoke, together with bronchial mucus, must be removed from the airways by the ciliated epithelium. Ciliary activity, however, is depressed by tobacco smoke; mucociliary transport is impair- ed. This depression favors bacterial in- fection and contributes to the chronic bronchitis associated with regular smoking. Chronic injury to the bronchi- al mucosa could be an important causa- tive factor in increasing the risk in smokers of death from bronchial carci- noma. Statistical surveys provide an im- pressive correlation between the num- ber of cigarettes smoked a day and the risk of death from coronary disease or lung cancer. Statistics also show that, on cessation of smoking, the increased risk of death from coronary infarction or other cardiovascular disease declines over 5–10 years almost to the level of non-smokers. Similarly, the risk of de- veloping bronchial carcinoma is re- duced. Abrupt cessation of regular smok- ing is not associated with severe physi- cal withdrawal symptoms. In general, subjects complain of increased nervous- ness, lack of concentration, and weight gain. 112 Nicotine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nicotine 113 A. Sequelae of tobacco smoking Nitrosamines, acrolein, polycyclic hydrocarbons e. g., benzopyrene heavy metals Sum of noxious stimuli "Tar" Nicotiana tabacum Nicotine Number of cigarettes per day 5 4 3 2 Platelet aggregation Epinephrine Coronary disease Annual deaths/1000 people Bronchial carcinoma Annual cases/1000 people Inhibition of mucociliary transport Years Months Chronic bronchitis BronchitisFree fatty acids Fibrinolytic activity –40–20–100 >40 >4015-401–140 Ex-smoker Duration of exposure Damage to bronchial epithelium Damage to vascular endothelium Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Biogenic Amines — Actions and Pharmacological Implications Dopamine A. As the precursor of nore- pinephrine and epinephrine (p. 184), dopamine is found in sympathetic (adre- nergic) neurons and adrenomedullary cells. In the CNS, dopamine itself serves as a neuromediator and is implicated in neostriatal motor programming (p. 188), the elicitation of emesis at the level of the area postrema (p. 330), and inhibi- tion of prolactin release from the anteri- or pituitary (p. 242). Dopamine receptors are coupled to G- proteins and exist as different subtypes. D 1 -receptors (comprising subtypes D 1 and D 5 ) and D 2 -receptors (comprising subtypes D 2 , D 3 , and D 4 ). The aforemen- tioned actions are mediated mainly by D 2 receptors. When given by infusion, dopamine causes dilation of renal and splanchnic arteries. This effect is mediat- ed by D 1 receptors and is utilized in the treatment of cardiovascular shock and hypertensive emergencies by infusion of dopamine and fenoldopam, respective- ly. At higher doses, β 1 -adrenoceptors and, finally, α-receptors are activated, as evidenced by cardiac stimulation and vasoconstriction, respectively. Dopamine is not to be confused with do- butamine which stimulates α- and β-ad- renoceptors but not dopamine receptors (p. 62). Dopamine-mimetics. Administra- tion of the precursor L-dopa promotes endogenous synthesis of dopamine (in- dication: parkinsonian syndrome, p. 188). The ergolides, bromocriptine, pergolide, and lisuride, are ligands at D- receptors whose therapeutic effects are probably due to stimulation of D 2 recep- tors (indications: parkinsonism, sup- pression of lactation, infertility, acrome- galy, p. 242). Typical adverse effects of these substances are nausea and vomit- ing. As indirect dopamine-mimetics, (+)- amphetamine and ritaline augment do- pamine release. Inhibition of the enzymes involved in dopamine degradation, catechol- amine-oxygen-methyl-transferase (COMT) and monoamineoxidase (MAO), is another means to increase actual available dopamine concentration (COMT-inhibitors, p. 188), MAO B -inhibi- tors, p. 88, 188). Dopamine antagonist activity is the hallmark of classical neuroleptics. The antihypertensive agents, reserpine (ob- solete) and α-methyldopa, deplete neu- ronal stores of the amine. A common ad- verse effect of dopamine antagonists or depletors is parkinsonism. Histamine (B). Histamine is stored in basophils and tissue mast cells. It plays a role in inflammatory and allergic reactions (p. 72, 326) and produces bronchoconstriction, increased intesti- nal peristalsis, and dilation and in- creased permeability of small blood ves- sels. In the gastric mucosa, it is released from enterochromaffin-like cells and stimulates acid secretion by the parietal cells. In the CNS, it acts as a neuromod- ulator. Two receptor subtypes (G-pro- tein-coupled), H 1 and H 2 , are of thera- peutic importance; both mediate vascu- lar responses. Prejunctional H 3 recep- tors exist in brain and the periphery. Antagonists. Most of the so-called H 1 -antihistamines also block other re- ceptors, including M-cholinoceptors and D-receptors. H 1 -antihistamines are used for the symptomatic relief of allergies (e.g., bamipine, chlorpheniramine, cle- mastine, dimethindene, mebhydroline pheniramine); as antiemetics (mecli- zine, dimenhydrinate, p. 330), as over- the-counter hypnotics (e.g., diphenhy- dramine, p. 222). Promethazine repre- sents the transition to the neuroleptic phenothiazines (p. 236). Unwanted ef- fects of most H 1 -antihistamines are las- situde (impaired driving skills) and atro- pine-like reactions (e.g., dry mouth, con- stipation). At the usual therapeutic dos- es, astemizole, cetrizine, fexofenadine, and loratidine are practically devoid of sedative and anticholinergic effects. H 2 - antihistamines (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers. 114 Biogenic Amines Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Biogenic Amines 115 A. Dopamine actions as influenced by drugs “H 1 -Antihistamines” ChlorpromazineDiphenhydramine DopamineAcetylcholine mACh-Receptor Dopamine receptors Sedation, hypnotic, antiemetic action H 2 -ReceptorsH 1 -Receptors H 2 -Antagonists e.g., ranitidine H 1 -Antagonists e.g., fexofenadine Histamine D 2 -Agonists e.g., bromocriptine Dopamin Receptors Dopamine Dopaminergic neuron Striatum (extrapyramidal motor function) Area postrema (emesis) Adenohypophysis (prolactin secretion ) D 1 Bronchoconstriction HCl Parietal cell Vasodilation permeabilityBowel peristalsis D 2 -Antagonists e.g., metoclopramide D 1 /D 2 -Antagonists Neuroleptics D 2 Inhibition of synthesis and formation of false transmitter: Methyldopa Destruction of storage vesicles: Reserpine Increase in dopamine synthesis L-Dopa B. Histamine actions as influenced by drugs D 1 -Agonists e.g., fenoldopam Blood flow Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of histamine release: One of the effects of the so-called mast cell stabilizers cromoglycate (cromolyn) and nedocromil is to decrease the re- lease of histamine from mast cells (p. 72, 326). Both agents are applied topi- cally. Release of mast cell mediators can also be inhibited by some H 1 antihista- mines, e.g., oxatomide and ketotifen, which are used systemically. Serotonin Occurrence. Serotonin (5-hydroxytrypt- amine, 5-HT) is synthesized from L- tryptophan in enterochromaffin cells of the intestinal mucosa. 5-HT-synthesiz- ing neurons occur in the enteric nerve plexus and the CNS, where the amine fulfills a neuromediator function. Blood platelets are unable to synthesize 5HT, but are capable of taking up, storing, and releasing it. Serotonin receptors. Based on bio- chemical and pharmacological criteria, seven receptor classes can be distin- guished. Of major pharmacotherapeutic importance are those designated 5-HT 1 , 5-HT 2 , 5-HT 4 , and 5-HT 7 , all of which are G-protein-coupled, whereas the 5-HT 3 subtype represents a ligand-gated non- selective cation channel. Serotonin actions. The cardiovascu- lar effects of 5-HT are complex, because multiple, in part opposing, effects are exerted via the different receptor sub- types. Thus, 5-HT 2A and 5-HT 7 receptors on vascular smooth muscle cells medi- ate direct vasoconstriction and vasodi- lation, respectively. Vasodilation and lowering of blood pressure can also oc- cur by several indirect mechanisms: 5- HT 1A receptors mediate sympathoinhi- bition (L50478 decrease in neurogenic vaso- constrictor tonus) both centrally and peripherally; 5-HT 2B receptors on vas- cular endothelium promote release of vasorelaxant mediators (NO, p. 120; prostacyclin, p. 196) 5-HT released from platelets plays a role in thrombogenesis, hemostasis, and the pathogenesis of preeclamptic hypertension. Ketanserin is an antagonist at 5- HT 2A receptors and produces antihyper- tensive effects, as well as inhibition of thrombocyte aggregation. Whether 5- HT antagonism accounts for its antihy- pertensive effect remains questionable, because ketanserin also blocks α-adren- oceptors. Sumatriptan and other triptans are antimigraine drugs that possess agonist activity at 5-HT 1 receptors of the B, D and F subtypes and may thereby allevi- ate this type of headache (p. 322). Gastrointestinal tract. Serotonin released from myenteric neurons or en- terochromaffin cells acts on 5-HT 3 and 5-HT 4 receptors to enhance bowel mo- tility and enteral fluid secretion. Cisa- pride is a prokinetic agent that pro- motes propulsive motor activity in the stomach and in small and large intes- tines. It is used in motility disorders. Its mechanism of action is unclear, but stimulation of 5HT 4 receptors may be important. Central Nervous System. Serotoni- nergic neurons play a part in various brain functions, as evidenced by the ef- fects of drugs likely to interfere with se- rotonin. Fluoxetine is an antidepressant that, by blocking re-uptake, inhibits in- activation of released serotonin. Its ac- tivity spectrum includes significant psy- chomotor stimulation, depression of ap- petite, and anxiolysis. Buspirone also has anxiolytic properties thought to be me- diated by central presynaptic 5-HT 1A re- ceptors. Ondansetron, an antagonist at the 5-HT 3 receptor, possesses striking effectiveness against cytotoxic drug-in- duced emesis, evident both at the start of and during cytostatic therapy. Trop- isetron and granisetron produce analo- gous effects. Psychedelics (LSD) and other psy- chotomimetics such as mescaline and psilocybin can induce states of altered awareness, or induce hallucinations and anxiety, probably mediated by 5-HT 2A receptors. Overactivity of these recep- tors may also play a role in the genesis of negative symptoms in schizophrenia (p. 238) and sleep disturbances. 116 Biogenic Amines Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Biogenic Amines 117 A. Serotonin receptors and actions LSD Lysergic acid diethylamide Psychedelic 5-HT 1D 5-HT 3 5-HT 1A 5-HT 2A Serotoninergic neuron Ondansetron Antiemetic Buspirone Anxiolytic Fluoxetine 5-HT- reuptake inhibitor Antidepressant Sumatriptan Antimigraine Propulsive motility Entero- chrom- affin cell Cisapride Prokinetic 5-HT 2B Platelets Constriction Endothelium- mediated Dilation 5-HT 2 5-HT 4 Hallucination Emesis Blood vessel Intestine 5-Hydroxy-tryptamine Serotonin Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Vasodilators–Overview The distribution of blood within the cir- culation is a function of vascular caliber. Venous tone regulates the volume of blood returned to the heart, hence, stroke volume and cardiac output. The luminal diameter of the arterial vascula- ture determines peripheral resistance. Cardiac output and peripheral resis- tance are prime determinants of arterial blood pressure (p. 314). In A, the clinically most important vasodilators are presented in the order of approximate frequency of therapeu- tic use. Some of these agents possess different efficacy in affecting the venous and arterial limbs of the circulation (width of beam). Possible uses. Arteriolar vasodila- tors are given to lower blood pressure in hypertension (p. 312), to reduce cardiac work in angina pectoris (p. 308), and to reduce ventricular afterload (pressure load) in cardiac failure (p. 132). Venous vasodilators are used to reduce venous filling pressure (preload) in angina pec- toris (p. 308) or cardiac failure (p. 132). Practical uses are indicated for each drug group. Counter-regulation in acute hy- potension due to vasodilators (B). In- creased sympathetic drive raises heart rate (reflex tachycardia) and cardiac output and thus helps to elevate blood pressure. Patients experience palpita- tions. Activation of the renin-angioten- sin-aldosterone (RAA) system serves to increase blood volume, hence cardiac output. Fluid retention leads to an in- crease in body weight and, possibly, edemas. These counter-regulatory pro- cesses are susceptible to pharmacologi- cal inhibition (β-blockers, ACE inhibi- tors, AT1-antagonists, diuretics). Mechanisms of action. The tonus of vascular smooth muscle can be de- creased by various means. ACE inhibi- tors, antagonists at AT1-receptors and antagonists at α-adrenoceptors protect against the effects of excitatory media- tors such as angiotensin II and norepi- nephrine, respectively. Prostacyclin an- alogues such as iloprost, or prostaglan- din E 1 analogues such as alprostanil, mimic the actions of relaxant mediators. Ca 2+ antagonists reduce depolarizing in- ward Ca 2+ currents, while K + -channel ac- tivators promote outward (hyperpolar- izing) K + currents. Organic nitrovasodi- lators give rise to NO, an endogenous activator of guanylate cyclase. Individual vasodilators. Nitrates (p. 120) Ca 2+ -antagonists (p. 122). α 1 - antagonists (p. 90), ACE-inhibitors, AT1- antagonists (p. 124); and sodium nitro- prusside (p. 120) are discussed else- where. Dihydralazine and minoxidil (via its sulfate-conjugated metabolite) dilate arterioles and are used in antihyperten- sive therapy. They are, however, unsuit- able for monotherapy because of com- pensatory circulatory reflexes. The mechanism of action of dihydralazine is unclear. Minoxidil probably activates K + channels, leading to hyperpolarization of smooth muscle cells. Particular ad- verse reactions are lupus erythemato- sus with dihydralazine and hirsutism with minoxidil—used topically for the treatment of baldness (alopecia androg- enetica). Diazoxide given i.v. causes promi- nent arteriolar dilation; it can be em- ployed in hypertensive crises. After its oral administration, insulin secretion is inhibited. Accordingly, diazoxide can be used in the management of insulin-se- creting pancreatic tumors. Both effects are probably due to opening of (ATP- gated) K + channels. The methylxanthine theophylline (p. 326), the phosphodiesterase inhibi- tor amrinone (p. 132), prostacyclins (p. 197), and nicotinic acid derivatives (p. 156) also possess vasodilating activity. 118 Vasodilators Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Vasodilators 119 B. Counter-regulatory responses in hypotension due to vasodilators A. Vasodilators Nitroprusside sodium α 1 -Antagonists ACE-inhibitors Nitrates Dihydralazine Minoxidil Ca-antagonists Venous bed Vasodilation Arterial bed β-Blocker ACE-inhibitors Angiotensin- converting enzyme (ACE) Vasomotor center Vasodilation Blood pressure Blood- pressure Angiotensin II Angiotensinogen Aldosterone Vasoconstriction Vasoconstriction Angiotensin I Cardiac output Blood volume Heart rate Sympathetic nerves Renin-angiotensin-aldosterone-system Renin Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Organic Nitrates Various esters of nitric acid (HNO 3 ) and polyvalent alcohols relax vascular smooth muscle, e.g., nitroglycerin (gly- ceryltrinitrate) and isosorbide dinitrate. The effect is more pronounced in venous than in arterial beds. These vasodilator effects produce hemodynamic consequences that can be put to therapeutic use. Due to a de- crease in both venous return (preload) and arterial afterload, cardiac work is decreased (p. 308). As a result, the car- diac oxygen balance improves. Spas- modic constriction of larger coronary vessels (coronary spasm) is prevented. Uses. Organic nitrates are used chiefly in angina pectoris (p. 308, 310), less frequently in severe forms of chron- ic and acute congestive heart failure. Continuous intake of higher doses with maintenance of steady plasma levels leads to loss of efficacy, inasmuch as the organism becomes refractory (tachy- phylactic). This “nitrate tolerance” can be avoided if a daily “nitrate-free inter- val” is maintained, e.g., overnight. At the start of therapy, unwanted reactions occur frequently in the form of a throbbing headache, probably caused by dilation of cephalic vessels. This effect also exhibits tolerance, even when daily “nitrate pauses” are kept. Excessive dosages give rise to hypoten- sion, reflex tachycardia, and circulatory collapse. Mechanism of action. The reduc- tion in vascular smooth muscle tone is presumably due to activation of guany- late cyclase and elevation of cyclic GMP levels. The causative agent is most likely nitric oxide (NO) generated from the or- ganic nitrate. NO is a physiological mes- senger molecule that endothelial cells release onto subjacent smooth muscle cells (“endothelium-derived relaxing factor,” EDRF). Organic nitrates would thus utilize a pre-existing pathway, hence their high efficacy. The genera- tion of NO within the smooth muscle cell depends on a supply of free sulfhy- dryl (-SH) groups; “nitrate-tolerance” has been attributed to a cellular exhaus- tion of SH-donors but this may be not the only reason. Nitroglycerin (NTG) is distin- guished by high membrane penetrabil- ity and very low stability. It is the drug of choice in the treatment of angina pec- toris attacks. For this purpose, it is ad- ministered as a spray, or in sublingual or buccal tablets for transmucosal deliv- ery. The onset of action is between 1 and 3 min. Due to a nearly complete pre- systemic elimination, it is poorly suited for oral administration. Transdermal de- livery (nitroglycerin patch) also avoids presystemic elimination. Isosorbide dinitrate (ISDN) penetrates well through membranes, is more stable than NTG, and is partly degraded into the weaker, but much longer acting, 5- isosorbide mononitrate (ISMN). ISDN can also be applied sublingually; how- ever, it is mainly administered orally in order to achieve a prolonged effect. ISMN is not suitable for sublingual use because of its higher polarity and slower rate of absorption. Taken orally, it is ab- sorbed and is not subject to first-pass elimination. Molsidomine itself is inactive. Af- ter oral intake, it is slowly converted into an active metabolite. Apparently, there is little likelihood of "nitrate tole- rance”. Sodium nitroprusside contains a nitroso (-NO) group, but is not an ester. It dilates venous and arterial beds equally. It is administered by infusion to achieve controlled hypotension under continuous close monitoring. Cyanide ions liberated from nitroprusside can be inactivated with sodium thiosulfate (Na 2 S 2 O 3 ) (p. 304). 120 Vasodilators Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Vasodilators 121 5-Isosorbide mononitrate, an active metabolite t1 2 ~ 240 min A. Vasodilators: Nitrates “Nitrate- tolerance” t1 2 ~ 30 mint1 2 ~ 2 min NONO Inactivation Route: e.g., sublingual, transdermal Glyceryl trinitrate Nitroglycerin Route: e.g., sublingual, oral, transdermal Isosorbide dinitrate Blood pressure Prevention of coronary artery spasm Preload O 2 -supply Afterload O 2 -demand Venous blood return to heart Venous bed Arterial bed Vasodilation “Nitrates” Peripheral resistance Consumption R – O – NO 2 Release of NO Activation of guanylate cyclase GTP cGMP RelaxationSmooth muscle cell SH-donors e.g., glutathione Active metabolite Molsidomine (precursor) Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Calcium Antagonists During electrical excitation of the cell membrane of heart or smooth muscle, different ionic currents are activated, including an inward Ca 2+ current. The term Ca 2+ antagonist is applied to drugs that inhibit the influx of Ca 2+ ions with- out affecting inward Na + or outward K + currents to a significant degree. Other labels are Ca-entry blocker or Ca-channel blocker. Therapeutically used Ca 2+ an- tagonists can be divided into three groups according to their effects on heart and vasculature. I. Dihydropyridine derivatives. The dihydropyridines, e.g., nifedipine, are uncharged hydrophobic substances. They induce a relaxation of vascular smooth muscle in arterial beds. An effect on cardiac function is practically absent at therapeutic dosage. (However, in pharmacological experiments on isolat- ed cardiac muscle preparations a clear negative inotropic effect is demon- strable.) They are thus regarded as va- soselective Ca 2+ antagonists. Because of the dilatation of resistance vessels, blood pressure falls. Cardiac afterload is diminished (p. 306) and, therefore, also oxygen demand. Spasms of coronary ar- teries are prevented. Indications for nifedipine include angina pectoris (p. 308) and, — when ap- plied as a sustained release preparation, — hypertension (p. 312). In angina pec- toris, it is effective when given either prophylactically or during acute attacks. Adverse effects are palpitation (reflex tachycardia due to hypotension), head- ache, and pretibial edema. Nitrendipine and felodipine are used in the treatment of hypertension. Ni- modipine is given prophylactically after subarachnoidal hemorrhage to prevent vasospasms due to depolarization by excess K + liberated from disintegrating erythrocytes or blockade of NO by free hemoglobin. II. Verapamil and other catamphi- philic Ca 2+ antagonists. Verapamil con- tains a nitrogen atom bearing a positive charge at physiological pH and thus rep- resents a cationic amphiphilic molecule. It exerts inhibitory effects not only on arterial smooth muscle, but also on heart muscle. In the heart, Ca 2+ inward cur- rents are important in generating depo- larization of sinoatrial node cells (im- pulse generation), in impulse propaga- tion through the AV- junction (atrioven- tricular conduction), and in electrome- chanical coupling in the ventricular car- diomyocytes. Verapamil thus produces negative chrono-, dromo-, and inotropic effects. Indications. Verapamil is used as an antiarrhythmic drug in supraventric- ular tachyarrhythmias. In atrial flutter or fibrillation, it is effective in reducing ventricular rate by virtue of inhibiting AV-conduction. Verapamil is also em- ployed in the prophylaxis of angina pec- toris attacks (p. 308) and the treatment of hypertension (p. 312). Adverse ef- fects: Because of verapamil’s effects on the sinus node, a drop in blood pressure fails to evoke a reflex tachycardia. Heart rate hardly changes; bradycardia may even develop. AV-block and myocardial insufficiency can occur. Patients fre- quently complain of constipation. Gallopamil (= methoxyverapamil) is closely related to verapamil in both structure and biological activity. Diltiazem is a catamphiphilic ben- zothiazepine derivative with an activity profile resembling that of verapamil. III. T-channel selective blockers. Ca 2+ -channel blockers, such as verapa- mil and mibefradil, may block both L- and T-type Ca 2+ channels. Mibefradil shows relative selectivity for the latter and is devoid of a negative inotropic ef- fect; its therapeutic usefulness is com- promised by numerous interactions with other drugs due to inhibition of cy- tochrome P 450 -dependent enzymes (CYP 1A2, 2D6 and, especially, 3A4). 122 Vasodilators Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Vasodilators 123 A.Vasodilators: calcium antagonists Smooth muscle cell Ca 2+ Arterial blood vessel Nifedipine (dihydropyridine derivative) Membrane depolarization Na + Ca 2+ 10 -3 M K + Ca 2+ 10 -7 M Verapamil (cationic amphiphilic) Electro- mechanical coupling Impulse conduction Impulse generation Inhibition of coronary spasm Peripheral resistance Contraction Afterload O 2 -demand Blood pressure Vasodilation in arterial bed Selective inhibition of calcium influx Sinus node Ventricular muscle AV-node Contractility AV- conduction Heart rate Reflex tachy- cardia with nifedipine Heart muscle cell Ca 2+ Inhibition of cardiac functions Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of the RAA System Angiotensin-converting enzyme (ACE) is a component of the antihypotensive renin-angiotensin-aldosterone (RAA) system. Renin is produced by special- ized cells in the wall of the afferent ar- teriole of the renal glomerulus. These cells belong to the juxtaglomerular ap- paratus of the nephron, the site of con- tact between afferent arteriole and dis- tal tubule, and play an important part in controlling nephron function. Stimuli eliciting release of renin are: a drop in renal perfusion pressure, decreased rate of delivery of Na + or Cl – to the distal tu- bules, as well as β-adrenoceptor-medi- ated sympathoactivation. The glycopro- tein renin enzymatically cleaves the decapeptide angiotensin I from its cir- culating precursor substrate angiotensi- nogen. ACE, in turn, produces biologi- cally active angiotensin II (ANG II) from angiotensin I (ANG I). ACE is a rather nonspecific pepti- dase that can cleave C-terminal dipep- tides from various peptides (dipeptidyl carboxypeptidase). As “kininase II,” it contributes to the inactivation of kinins, such as bradykinin. ACE is also present in blood plasma; however, enzyme local- ized in the luminal side of vascular endo- thelium is primarily responsible for the formation of angiotensin II. The lung is rich in ACE, but kidneys, heart, and other organs also contain the enzyme. Angiotensin II can raise blood pres- sure in different ways, including (1) vasoconstriction in both the arterial and venous limbs of the circulation; (2) stimulation of aldosterone secretion, leading to increased renal reabsorption of NaCl and water, hence an increased blood volume; (3) a central increase in sympathotonus and, peripherally, en- hancement of the release and effects of norepinephrine. ACE inhibitors, such as captopril and enalaprilat, the active metabolite of enalapril, occupy the enzyme as false substrates. Affinity significantly influ- ences efficacy and rate of elimination. Enalaprilat has a stronger and longer- lasting effect than does captopril. Indi- cations are hypertension and cardiac failure. Lowering of an elevated blood pres- sure is predominantly brought about by diminished production of angiotensin II. Impaired degradation of kinins that ex- ert vasodilating actions may contribute to the effect. In heart failure, cardiac output rises again because ventricular afterload di- minishes due to a fall in peripheral re- sistance. Venous congestion abates as a result of (1) increased cardiac output and (2) reduction in venous return (de- creased aldosterone secretion, de- creased tonus of venous capacitance vessels). Undesired effects. The magnitude of the antihypertensive effect of ACE in- hibitors depends on the functional state of the RAA system. When the latter has been activated by loss of electrolytes and water (resulting from treatment with diuretic drugs), cardiac failure, or renal arterial stenosis, administration of ACE inhibitors may initially cause an ex- cessive fall in blood pressure. In renal arterial stenosis, the RAA system may be needed for maintaining renal function and ACE inhibitors may precipitate re- nal failure. Dry cough is a fairly frequent side effect, possibly caused by reduced inactivation of kinins in the bronchial mucosa. Rarely, disturbances of taste sensation, exanthema, neutropenia, proteinuria, and angioneurotic edema may occur. In most cases, ACE inhibitors are well tolerated and effective. Newer analogues include lisinopril, perindo- pril, ramipril, quinapril, fosinopril, be- nazepril, cilazapril, and trandolapril. Antagonists at angiotensin II re- ceptors. Two receptor subtypes can be distinguished: AT1, which mediates the above actions of AT II; and AT2, whose physiological role is still unclear. The sartans (candesartan, eprosartan, irbe- sartan, losartan, and valsartan) are AT1 antagonists that reliably lower high blood pressure. They do not inhibit degradation of kinins and cough is not a frequent side-effect. 124 Inhibitors of the RAA System Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of the RAA System 125 Renin A. Renin-angiotensin-aldosterone system and inhibitors Kidney Angiotensin I (Ang I) COOH ACE inhibitors Captopril Enalaprilat Enalapril Ang I Kinins Ang II Degradation products Vascular endothelium H 2 N Resistance vessels K + Angiotensinogen (α 2 -globulin) RR Vasoconstriction Cardiac output venous capacitance vessels Sympatho- activation H 2 O NaCl Arterial blood pressure Venous supply Peripheral resistance ACE Kininase II ACE Angiotensin I- converting- enzyme Dipeptidyl-Carboxypeptidase Losartan Receptors Aldosterone secretion AT 1 -receptor antagonists Angiotensin II NN Cl H NN NN H 3 C CH 2 OH O O O N HOOC CH 3 CH 3 HOOC N O SH CH 3 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Used to Influence Smooth Muscle Organs Bronchodilators. Narrowing of bron- chioles raises airway resistance, e.g., in bronchial or bronchitic asthma. Several substances that are employed as bron- chodilators are described elsewhere in more detail: β 2 -sympathomimetics (p. 84, given by pulmonary, parenteral, or oral route), the methylxanthine theo- phylline (p. 326, given parenterally or orally), as well as the parasympatholytic ipratropium (pp. 104, 107, given by in- halation). Spasmolytics. N-Butylscopolamine (p. 104) is used for the relief of painful spasms of the biliary or ureteral ducts. Its poor absorption (N.B. quaternary N; absorption rate <10%) necessitates par- enteral administration. Because the therapeutic effect is usually weak, a po- tent analgesic is given concurrently, e.g., the opioid meperidine. Note that some spasms of intestinal musculature can be effectively relieved by organic nitrates (in biliary colic) or by nifedipine (esoph- ageal hypertension and achalasia). Myometrial relaxants (Tocolyt- ics). β 2 -Sympathomimetics such as fe- noterol or ritodrine, given orally or par- enterally, can prevent premature labor or interrupt labor in progress when dan- gerous complications necessitate cesar- ean section. Tachycardia is a side effect produced reflexly because of β 2 -mediat- ed vasodilation or direct stimulation of cardiac β 1 -receptors. Magnesium sul- fate, given i.v., is a useful alternative when β-mimetics are contraindicated, but must be carefully titrated because its nonspecific calcium antagonism leads to blockade of cardiac impulse conduction and of neuromuscular transmission. Myometrial stimulants. The neu- rohypophyseal hormone oxytocin (p. 242) is given parenterally (or by the na- sal or buccal route) before, during, or af- ter labor in order to prompt uterine con- tractions or to enhance them. Certain prostaglandins or analogues of them (p. 196; F 2α : dinoprost; E 2 : dinoprostone, misoprostol, sulprostone) are capable of inducing rhythmic uterine contractions and cervical relaxation at any time. They are mostly employed as abortifacients (oral or vaginal application of misopros- tol in combination with mifepristone [p. 256]). Ergot alkaloids are obtained from Secale cornutum (ergot), the sclerotium of a fungus (Claviceps purpurea) parasi- tizing rye. Consumption of flour from contaminated grain was once the cause of epidemic poisonings (ergotism) char- acterized by gangrene of the extremities (St. Anthony’s fire) and CNS disturbanc- es (hallucinations). Ergot alkaloids contain lysergic acid (formula in A shows an amide). They act on uterine and vascular muscle. Ergo- metrine particularly stimulates the uter- us. It readily induces a tonic contraction of the myometrium (tetanus uteri). This jeopardizes placental blood flow and fe- tal O 2 supply. The semisynthetic deriva- tive methylergometrine is therefore used only after delivery for uterine con- tractions that are too weak. Ergotamine, as well as the ergotox- ine alkaloids (ergocristine, ergocryp- tine, ergocornine), have a predominant- ly vascular action. Depending on the in- itial caliber, constriction or dilation may be elicited. The mechanism of action is unclear; a mixed antagonism at α- adrenoceptors and agonism at 5-HT-re- ceptors may be important. Ergotamine is used in the treatment of migraine (p. 322). Its congener, dihydroergotamine, is furthermore employed in orthostatic complaints (p. 314). Other lysergic acid derivatives are the 5-HT antagonist methysergide, the dopamine agonists bromocriptine, per- golide, and cabergolide (pp. 114, 188), and the hallucinogen lysergic acid di- ethylamide (LSD, p. 240). 126 Drugs Acting on Smooth Muscle Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on Smooth Muscle 127 A. Drugs used to alter smooth muscle function Bronchial asthma Bronchodilation Spasmolysis Theophylline N-Butylscopolamine Scopolamine Biliary / renal colic Inhibition of labor Induction of labor Oxytocin Prostaglandins F 2α , E 2 Nitrates e.g., nitroglycerin β 2 -Sympathomimetics e.g., fenoterol Ipratropium Secale cornutum (ergot) Fungus: Claviceps purpurea e.g., ergometrine Contraindication: before delivery Indication: postpartum uterine atonia e.g., ergotamine O 2 O 2 Tonic contraction of uterus β 2 - Sympathomimetics Effect on vasomotor tone Secale alkaloids Spasm of smooth muscle Fixation of lumen at intemediate caliber Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Overview of Modes of Action (A) 1. The pumping capacity of the heart is regulated by sympathetic and parasym- pathetic nerves (pp. 84, 105). Drugs ca- pable of interfering with autonomic nervous function therefore provide a means of influencing cardiac perfor- mance. Thus, anxiolytics of the benzo- diazepine type (p. 226), such as diaze- pam, can be employed in myocardial in- farction to suppress sympathoactiva- tion due to life-threatening distress. Under the influence of antiadrenergic agents (p. 96), used to lower an elevated blood pressure, cardiac work is de- creased. Ganglionic blockers (p. 108) are used in managing hypertensive emergencies. Parasympatholytics (p. 104) and β-blockers (p. 92) prevent the transmission of autonomic nerve im- pulses to heart muscle cells by blocking the respective receptors. 2. An isolated mammalian heart whose extrinsic nervous connections have been severed will beat spontane- ously for hours if it is supplied with a nutrient medium via the aortic trunk and coronary arteries (Langendorff preparation). In such a preparation, only those drugs that act directly on cardio- myocytes will alter contractile force and beating rate. Parasympathomimetics and sym- pathomimetics act at membrane re- ceptors for visceromotor neurotrans- mitters. The plasmalemma also harbors the sites of action of cardiac glycosides (the Na/K-ATPases, p. 130), of Ca 2+ an- tagonists (Ca 2+ channels, p. 122), and of agents that block Na + channels (local anesthetics; p. 134, p. 204). An intracel- lular site is the target for phosphodies- terase inhibitors (e.g., amrinone, p. 132). 3. Mention should also be made of the possibility of affecting cardiac func- tion in angina pectoris (p. 306) or con- gestive heart failure (p. 132) by reduc- ing venous return, peripheral resis- tance, or both, with the aid of vasodila- tors; and by reducing sympathetic drive applying β-blockers. Events Underlying Contraction and Relaxation (B) The signal triggering contraction is a propagated action potential (AP) gener- ated in the sinoatrial node. Depolariza- tion of the plasmalemma leads to a rap- id rise in cytosolic Ca 2+ levels, which causes the contractile filaments to shorten (electromechanical coupling). The level of Ca 2+ concentration attained determines the degree of shortening, i.e., the force of contraction. Sources of Ca 2+ are: a) extracellular Ca 2+ entering the cell through voltage-gated Ca 2+ channels; b) Ca 2+ stored in membranous sacs of the sarcoplasmic reticulum (SR); c) Ca 2+ bound to the inside of the plas- malemma. The plasmalemma of cardio- myocytes extends into the cell interior in the form of tubular invaginations (transverse tubuli). The trigger signal for relaxation is the return of the membrane potential to its resting level. During repolarization, Ca 2+ levels fall below the threshold for activation of the myofilaments (3L115410 –7 M), as the plasmalemmal binding sites regain their binding capacity; the SR pumps Ca 2+ into its interior; and Ca 2+ that entered the cytosol during systole is again extruded by plasmalemmal Ca 2+ -ATPases with expenditure of ener- gy. In addition, a carrier (antiporter), utilizing the transmembrane Na + gradi- ent as energy source, transports Ca 2+ out of the cell in exchange for Na + moving down its transmembrane gradient (Na + /Ca 2+ exchange). 128 Cardiac Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Cardiac Drugs 129 Relaxation Ca 2 + 10 - 3 M B. Processes in myocardial contraction and relaxation A. Possible mechanisms for influencing heart function Drugs with indirect action Drugs with direct action Nutrient solution Force Rate β-Sympathomimetics Phosphodiesterase inhibitorsCardiac glycosides Parasympathomimetics Catamphiphilic Ca-antagonists Local anesthetics Na + Ca-ATPase 300 ms Para- sympathetic Sympathetic Epinephrine Psychotropic drugs Sympatholytics Ganglionic blockers Force Rate Contraction electrical excitation Ca-channel Sarcoplasmic reticulum Heart muscle cell Transverse tubule Ca 2 + 10 - 3 M Ca 2+ 10 -5 M Ca 2+ 10 -7 M Ca 2+ Na + Ca 2+ Na + Ca 2+ Na/Ca- exchange Plasma- lemmal binding sites 0 -80 Membrane potential [mV] t Force t Contraction Action potential Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Cardiac Glycosides Diverse plants (A) are sources of sugar- containing compounds (glycosides) that also contain a steroid ring (structural formulas, p. 133) and augment the con- tractile force of heart muscle (B): cardio- tonic glycosides. cardiosteroids, or “digi- talis.” If the inotropic, “therapeutic” dose is exceeded by a small increment, signs of poisoning appear: arrhythmia and contracture (B). The narrow therapeutic margin can be explained by the mecha- nism of action. Cardiac glycosides (CG) bind to the extracellular side of Na + /K + -ATPases of cardiomyocytes and inhibit enzyme ac- tivity. The Na + /K + -ATPases operate to pump out Na + leaked into the cell and to retrieve K + leaked from the cell. In this manner, they maintain the transmem- brane gradients for K + and Na + , the neg- ative resting membrane potential, and the normal electrical excitability of the cell membrane. When part of the en- zyme is occupied and inhibited by CG, the unoccupied remainder can increase its level of activity and maintain Na + and K + transport. The effective stimulus is a small elevation of intracellular Na + con- centration (normally approx. 7 mM). Concomitantly, the amount of Ca 2+ mo- bilized during systole and, thus, con- tractile force, increases. It is generally thought that the underlying cause is the decrease in the Na + transmembrane gradient, i.e., the driving force for the Na + /Ca 2+ exchange (p. 128), allowing the intracellular Ca 2+ level to rise. When too many ATPases are blocked, K + and Na + homeostasis is deranged; the mem- brane potential falls, arrhythmias occur. Flooding with Ca 2+ prevents relaxation during diastole, resulting in contracture. The CNS effects of CG (C) are also due to binding to Na + /K + -ATPases. En- hanced vagal nerve activity causes a de- crease in sinoatrial beating rate and ve- locity of atrioventricular conduction. In patients with heart failure, improved circulation also contributes to the re- duction in heart rate. Stimulation of the area postrema leads to nausea and vom- iting. Disturbances in color vision are evident. Indications for CG are: (1) chronic congestive heart failure; and (2) atrial fibrillation or flutter, where inhibition of AV conduction protects the ventricles from excessive atrial impulse activity and thereby improves cardiac perfor- mance (D). Occasionally, sinus rhythm is restored. Signs of intoxication are: (1) car- diac arrhythmias, which under certain circumstances are life-threatening, e.g., sinus bradycardia, AV-block, ventricular extrasystoles, ventricular fibrillation (ECG); (2) CNS disturbances — altered color vision (xanthopsia), agitation, confusion, nightmares, hallucinations; (3) gastrointestinal — anorexia, nausea, vomiting, diarrhea; (4) renal — loss of electrolytes and water, which must be differentiated from mobilization of ac- cumulated edema fluid that occurs with therapeutic dosage. Therapy of intoxication: adminis- tration of K + , which inter alia reduces binding of CG, but may impair AV-con- duction; administration of antiarrhyth- mics, such as phenytoin or lidocaine (p. 136); oral administration of colestyra- mine (p. 154, 156) for binding and pre- venting absorption of digitoxin present in the intestines (enterohepatic cycle); injection of antibody (Fab) fragments that bind and inactivate digitoxin and digoxin. Compared with full antibodies, fragments have superior tissue penet- rability, more rapid renal elimination, and lower antigenicity. 130 Cardiac Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Cardiac Drugs 131 C. Cardiac glycoside effects on the CNS A. Plants containing cardiac glycosides B. Therapeutic and toxic effects of cardiac glycosides (CG) Digitalis purpurea Red foxglove Convallaria majalis Lily of the valley Helleborus niger Christmas rose Contraction Time ′therapeutic′ ′toxic′ Dose of cardiac glycoside (CG) Na + Na + K + Heart muscle cell Ca 2+ K + K + Ca 2+ Na + K + Na + Disturbance of color vision Area postrema: nausea, vomiting "Re-entrant" excitation in atrial fibrillation Cardiac glycoside Decrease in ventricular rate D. Cardiac glycoside effects in atrial fibrillation Coupling Ca 2+ CG CG CG CG CG Na/K-ATPase Excitation of N. vagus: Heart rate Arrhythmia Contracture Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. The pharmacokinetics of cardiac glycosides (A) are dictated by their po- larity, i.e., the number of hydroxyl groups. Membrane penetrability is vir- tually nil in ouabain, high in digoxin, and very high in digitoxin. Ouabain (g- strophanthin) does not penetrate into cells, be they intestinal epithelium, re- nal tubular, or hepatic cells. At best, it is suitable for acute intravenous induction of glycoside therapy. The absorption of digoxin depends on the kind of galenical preparation used and on absorptive conditions in the intestine. Preparations are now of such quality that the derivatives methyl- digoxin and acetyldigoxin no longer offer any advantage. Renal reabsorption is in- complete; approx. 30% of the total amount present in the body (s.c. full “digitalizing” dose) is eliminated per day. When renal function is impaired, there is a risk of accumulation. Digi- toxin undergoes virtually complete re- absorption in gut and kidneys. There is active hepatic biotransformation: cleav- age of sugar moieties, hydroxylation at C12 (yielding digoxin), and conjugation to glucuronic acid. Conjugates secreted with bile are subject to enterohepatic cycling (p. 38); conjugates reaching the blood are renally eliminated. In renal in- sufficiency, there is no appreciable ac- cumulation. When digitoxin is with- drawn following overdosage, its effect decays more slowly than does that of di- goxin. Other positive inotropic drugs. The phosphodiesterase inhibitor am- rinone (cAMP elevation, p. 66) can be administered only parenterally for a maximum of 14 d because it is poorly tolerated. A closely related compound is milrinone. In terms of their positive in- otropic effect, β-sympathomimetics, unlike dopamine (p. 114), are of little therapeutic use; they are also arrhyth- mogenic and the sensitivity of the β-re- ceptor system declines during continu- ous stimulation. Treatment Principles in Chronic Heart Failure Myocardial insufficiency leads to a de- crease in stroke volume and venous congestion with formation of edema. Administration of (thiazide) diuretics (p. 62) offers a therapeutic approach of proven efficacy that is brought about by a decrease in circulating blood volume (decreased venous return) and periph- eral resistance, i.e., afterload. A similar approach is intended with ACE-inhibi- tors, which act by preventing the syn- thesis of angiotensin II (L50519 vasoconstric- tion) and reducing the secretion of al- dosterone (L50519 fluid retention). In severe cases of myocardial insufficiency, car- diac glycosides may be added to aug- ment cardiac force and to relieve the symptoms of insufficiency. In more recent times β-blocker on a long term were found to improve car- diac performance — particularly in idio- pathic dilating cardiomyopathy — pro- bably by preventing sympathetic over- drive. 132 Cardiac Drugs Substance Fraction Plasma concentr. Digitalizing Elimination Maintenance absorbed free total dose dose % (ng/mL) (mg) %/d (mg) Digitoxin 100 H116011 H1160120 H11601110 H116010.1 Digoxin 50–90 H116011 H116011.5 H11601130 H116010.3 Ouabain <1 H116011 H116011 0.5 no long-term use Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Cardiac Drugs 133 A. Pharmacokinetics of cardiac glycosides Plasma Albumin Liver- cell Intestinal epithelium Renal tubular epithelium Deconjugation 0% 35% 95% Cleavage of sugar Conjugation Digitoxin Digoxin Plasma t1 2 Ouabain Digoxin Digitoxin 9 h 2 – 3 days 5 – 7 days Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antiarrhythmic Drugs The electrical impulse for contraction (propagated action potential; p. 136) originates in pacemaker cells of the si- noatrial node and spreads through the atria, atrioventricular (AV) node, and adjoining parts of the His-Purkinje fiber system to the ventricles (A). Irregular- ities of heart rhythm can interfere dan- gerously with cardiac pumping func- tion. I. Drugs for selective control of si- noatrial and AV nodes. In some forms of arrhythmia, certain drugs can be used that are capable of selectively facilitat- ing and inhibiting (green and red ar- rows, respectively) the pacemaker func- tion of sinoatrial or atrioventricular cells. Sinus bradycardia. An abnormally low sinoatrial impulse rate (<60/min) can be raised by parasympatholytics. The quaternary ipratropium is prefer- able to atropine, because it lacks CNS penetrability (p. 107). Sympathomimet- ics also exert a positive chronotropic ac- tion; they have the disadvantage of in- creasing myocardial excitability (and automaticity) and, thus, promoting ec- topic impulse generation (tendency to extrasystolic beats). In cardiac arrest epinephrine can be used to reinitiate heart beat. Sinus tachycardia (resting rate >100 beats/min). β-Blockers eliminate sympathoexcitation and decrease car- diac rate. Atrial flutter or fibrillation. An ex- cessive ventricular rate can be de- creased by verapamil (p. 122) or cardiac glycosides (p. 130). These drugs inhibit impulse propagation through the AV node, so that fewer impulses reach the ventricles. II. Nonspecific drug actions on impulse generation and propagation. Impulses originating at loci outside the sinus node are seen in supraventricular or ventricular extrasystoles, tachycardia, atrial or ventricular flutter, and fibrilla- tion. In these forms of rhythm disorders, antiarrhythmics of the local anesthet- ic, Na + -channel blocking type (B) are used for both prophylaxis and therapy. Local anesthetics inhibit electrical exci- tation of nociceptive nerve fibers (p. 204); concomitant cardiac inhibition (cardiodepression) is an unwanted ef- fect. However, in certain types of ar- rhythmias (see above), this effect is use- ful. Local anesthetics are readily cleaved (arrows) and unsuitable for oral admin- istration (procaine, lidocaine). Given ju- diciously, intravenous lidocaine is an ef- fective antiarrhythmic. Procainamide and mexiletine, congeners endowed with greater metabolic stability, are ex- amples of orally effective antiarrhyth- mics. The desired and undesired effects are inseparable. Thus, these antiar- rhythmics not only depress electrical excitability of cardiomyocytes (negative bathmotropism, membrane stabiliza- tion), but also lower sinoatrial rate (neg. chronotropism), AV conduction (neg. dromotropism), and force of contraction (neg. inotropism). Interference with nor- mal electrical activity can, not too para- doxically, also induce cardiac arrhyth- mias–arrhythmogenic action. Inhibition of CNS neurons is the underlying cause of neurological effects such as vertigo, confusion, sensory dis- turbances, and motor disturbances (tremor, giddiness, ataxia, convulsions). 134 Cardiac Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Cardiac Drugs 135 B. Antiarrhythmics of the Na + -channel blocking type A. Cardiac impulse generation and conduction Main effect Antiarrhythmic effect Adverse effects CNS-disturbances Arrhythmia Cardiodepression Para- sympatholytics β-Sympatho- mimetics β-Blocker Verapamil Cardiac glycoside (Vagal stimulation) Antiarrhythmics of the local anesthetic (Na + -channel blocking) type: Inhibition of impulse generation and conduction Atrium Sinus node AV-node Bundle of His Ventricle Tawara′s node Purkinje fibers Esterases Procainamide Mexiletine Procaine Lidocaine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Electrophysiological Actions of Antiarrhythmics of the Na + -Channel Blocking Type Action potential and ionic currents. The transmembrane electrical potential of cardiomyocytes can be recorded through an intracellular microelectrode. Upon electrical excitation, a characteris- tic change occurs in membrane poten- tial—the action potential (AP). Its under- lying cause is a sequence of transient ionic currents. During rapid depolariza- tion (Phase 0), there is a short-lived in- flux of Na + through the membrane. A subsequent transient influx of Ca 2+ (as well as of Na + ) maintains the depola- rization (Phase 2, plateau of AP). A de- layed efflux of K + returns the membrane potential (Phase 3, repolarization) to its resting value (Phase 4). The velocity of depolarization determines the speed at which the AP propagates through the myocardial syncytium. Transmembrane ionic currents in- volve proteinaceous membrane pores: Na + , Ca 2+ , and K + channels. In A, the phasic change in the functional state of Na + channels during an action potential is illustrated. Effects of antiarrhythmics. Antiar- rhythmics of the Na + -channel blocking type reduce the probability that Na + channels will open upon membrane de- polarization (“membrane stabiliza- tion”). The potential consequences are (A, bottom): 1) a reduction in the veloc- ity of depolarization and a decrease in the speed of impulse propagation; aber- rant impulse propagation is impeded. 2) Depolarization is entirely absent; patho- logical impulse generation, e.g., in the marginal zone of an infarction, is sup- pressed. 3) The time required until a new depolarization can be elicited, i.e., the refractory period, is increased; pro- longation of the AP (see below) contrib- utes to the increase in refractory period. Consequently, premature excitation with risk of fibrillation is prevented. Mechanism of action. Na + -channel blocking antiarrhythmics resemble most local anesthetics in being cationic amphiphilic molecules (p. 208, excep- tion: phenytoin, p. 190). Possible molec- ular mechanisms of their inhibitory ef- fects are outlined on p. 204 in more de- tail. Their low structural specificity is reflected by a low selectivity towards different cation channels. Besides the Na + channel, Ca 2+ and K + channels are al- so likely to be blocked. Accordingly, cat- ionic amphiphilic antiarrhythmics af- fect both the depolarization and repola- rization phases. Depending on the sub- stance, AP duration can be increased (Class IA), decreased (Class IB), or re- main the same (Class IC). Antiarrhythmics representative of these categories include: Class IA— quinidine, procainamide, ajmaline, dis- opyramide, propafenone; Class IB—lido- caine, mexiletine, tocainide, as well as phenytoin; Class IC—flecainide. Note: With respect to classification, β-blockers have been assigned to Class II, and the Ca 2+ -channel blockers vera- pamil and diltiazem to Class IV. Commonly listed under a separate rubric (Class III) are amiodarone and the β-blocking agent sotalol, which both in- hibit K + -channels and which both cause marked prolongation of the AP with a lesser effect on Phase 0 rate of rise. Therapeutic uses. Because of their narrow therapeutic margin, these antiar- rhythmics are only employed when rhythm disturbances are of such sever- ity as to impair the pumping action of the heart, or when there is a threat of other complications. The choice of drug is empirical. If the desired effect is not achieved, another drug is tried. Combi- nations of antiarrhythmics are not cus- tomary. Amiodarone is reserved for spe- cial cases. 136 Cardiac Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Cardiac Drugs 137 A. Effects of antiarrhythmics of the Na + -channel blocking type Membrane potential Time [ms] Action potential (AP) Speed of AP propagation Heart muscle cell Na + Ca 2+ (+Na + ) Phase 0 Phase 3 Phase 4Phases 1,2 Fast Na + -entry” Slow Ca 2+ -entry Ionic currents during action potential Na + Na + -channels Open (active) Closed Opening impossible (inactivated) Closed Opening possible (resting, can be activated) States of Na + -channels during an action potential Suppression of AP generation Prolongation of refractory period = duration of inexcitability Stimulus 2500 1 2 3 4 Rate of depolarization K + Antiarrhythmics of the Na + -channel blocking type Inhibition of Na + -channel opening Inexcitability 0 Rate of depolarization 0 -80 [mV] Refractory period Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for the Treatment of Anemias Anemia denotes a reduction in red blood cell count, hemoglobin content, or both. Oxygen (O 2 ) transport capacity is decreased. Erythropoiesis (A). Blood corpus- cles develop from stem cells through several cell divisions. Hemoglobin is then synthesized and the cell nucleus is extruded. Erythropoiesis is stimulated by the hormone erythropoietin (a gly- coprotein), which is released from the kidneys when renal O 2 tension declines. Given an adequate production of erythropoietin, a disturbance of eryth- ropoiesis is due to two principal causes: 1. Cell multiplication is inhibited be- cause DNA synthesis is insufficient. This occurs in deficiencies of vitamin B 12 or folic acid (macrocytic hyperchromic anemia). 2. Hemoglobin synthesis is impaired. This situation arises in iron deficiency, since Fe 2+ is a constituent of hemoglobin (microcytic hypochromic anemia). Vitamin B 12 (B) Vitamin B 12 (cyanocobalamin) is pro- duced by bacteria; B 12 generated in the colon, however, is unavailable for ab- sorption (see below). Liver, meat, fish, and milk products are rich sources of the vitamin. The minimal requirement is about 1 μg/d. Enteral absorption of vi- tamin B 12 requires so-called “intrinsic factor” from parietal cells of the stom- ach. The complex formed with this gly- coprotein undergoes endocytosis in the ileum. Bound to its transport protein, transcobalamin, vitamin B 12 is destined for storage in the liver or uptake into tis- sues. A frequent cause of vitamin B 12 de- ficiency is atrophic gastritis leading to a lack of intrinsic factor. Besides megalo- blastic anemia, damage to mucosal lin- ings and degeneration of myelin sheaths with neurological sequelae will occur (pernicious anemia). Optimal therapy consists in paren- teral administration of cyanocobal- amin or hydroxycobalamin (Vitamin B 12a ; exchange of -CN for -OH group). Adverse effects, in the form of hyper- sensitivity reactions, are very rare. Folic Acid (B). Leafy vegetables and liver are rich in folic acid (FA). The min- imal requirement is approx. 50 μg/d. Polyglutamine-FA in food is hydrolyzed to monoglutamine-FA prior to being ab- sorbed. FA is heat labile. Causes of defi- ciency include: insufficient intake, mal- absorption in gastrointestinal diseases, increased requirements during preg- nancy. Antiepileptic drugs (phenytoin, primidone, phenobarbital) may de- crease FA absorption, presumably by in- hibiting the formation of monogluta- mine-FA. Inhibition of dihydro-FA re- ductase (e.g., by methotrexate, p. 298) depresses the formation of the active species, tetrahydro-FA. Symptoms of de- ficiency are megaloblastic anemia and mucosal damage. Therapy consists in oral administration of FA or in folinic acid (p. 298) when deficiency is caused by inhibitors of dihydro—FA—reductase. Administration of FA can mask a vitamin B 12 deficiency. Vitamin B 12 is re- quired for the conversion of methyltet- rahydro-FA to tetrahydro-FA, which is important for DNA synthesis (B). Inhibi- tion of this reaction due to B 12 deficien- cy can be compensated by increased FA intake. The anemia is readily corrected; however, nerve degeneration progress- es unchecked and its cause is made more difficult to diagnose by the ab- sence of hematological changes. Indis- criminate use of FA-containing multivi- tamin preparations can, therefore, be harmful. 138 Antianemics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antianemics 139 B. Vitamin B 12 and folate metabolism A. Erythropoiesis in bone marrow A very few large hemoglobin-rich erythrocytes A few small hemoglobin-poor erythrocytes H 3 C- Trans- cobalamin II HCl i.m. Parietal cell Streptomyces griseus Storage supply for 3 years Vit. B 12 deficiency Folate deficiency Inhibition of DNA synthesis (cell multiplication) Inhibition of hemoglobin synthesis Iron deficiency Vit. B 12 Intrinsic factor Folic acid H 4 DNA synthesis H 3 C- Folic acid H 4 H 3 C- Vit. B 12 Folic acidVit. B 12 Vit. B 12 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Iron Compounds Not all iron ingested in food is equally absorbable. Trivalent Fe 3+ is virtually not taken up from the neutral milieu of the small bowel, where the divalent Fe 2+ is markedly better absorbed. Uptake is particularly efficient in the form of heme (present in hemo- and myoglo- bin). Within the mucosal cells of the gut, iron is oxidized and either deposited as ferritin (see below) or passed on to the transport protein, transferrin, a β 1 -gly- coprotein. The amount absorbed does not exceed that needed to balance loss- es due to epithelial shedding from skin and mucosae or hemorrhage (so-called “mucosal block”). In men, this amount is approx. 1 mg/d; in women, it is ap- prox. 2 mg/d (menstrual blood loss), corresponding to about 10% of the die- tary intake. The transferrin-iron com- plex undergoes endocytotic uptake mainly into erythroblasts to be utilized for hemoglobin synthesis. About 70% of the total body store of iron (~5 g) is contained within erythro- cytes. When these are degraded by mac- rophages of the reticuloendothelial (mononuclear phagocyte) system, iron is liberated from hemoglobin. Fe 3+ can be stored as ferritin (= protein apoferri- tin + Fe 3+ ) or returned to erythropoiesis sites via transferrin. A frequent cause of iron deficiency is chronic blood loss due to gastric/in- testinal ulcers or tumors. One liter of blood contains 500 mg of iron. Despite a significant increase in absorption rate (up to 50%), absorption is unable to keep up with losses and the body store of iron falls. Iron deficiency results in impaired synthesis of hemoglobin and anemia (p. 138). The treatment of choice (after the cause of bleeding has been found and eliminated) consists of the oral admin- istration of Fe 2+ compounds, e.g., fer- rous sulfate (daily dose 100 mg of iron equivalent to 300 mg of FeSO 4 , divided into multiple doses). Replenishing of iron stores may take several months. Oral administration, however, is advan- tageous in that it is impossible to over- load the body with iron through an in- tact mucosa because of its demand-reg- ulated absorption (mucosal block). Adverse effects. The frequent gas- trointestinal complaints (epigastric pain, diarrhea, constipation) necessitate intake of iron preparations with or after meals, although absorption is higher from the empty stomach. Interactions. Antacids inhibit iron absorption. Combination with ascorbic acid (Vitamin C), for protecting Fe 2+ from oxidation to Fe 3+ , is theoretically sound, but practically is not needed. Parenteral administration of Fe 3+ salts is indicated only when adequate oral replacement is not possible. There is a risk of overdosage with iron deposi- tion in tissues (hemosiderosis). The binding capacity of transferrin is limited and free Fe 3+ is toxic. Therefore, Fe 3+ complexes are employed that can do- nate Fe 3+ directly to transferrin or can be phagocytosed by macrophages, ena- bling iron to be incorporated into ferri- tin stores. Possible adverse effects are, with i.m. injection: persistent pain at the injection site and skin discoloration; with i.v. injection: flushing, hypoten- sion, anaphylactic shock. 140 Antianemics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antianemics 141 Fe III A. Iron: possible routes of administration and fate in the organism Fe III-Salts Fe II-Salts Heme-Fe Fe III Ferritin Parenteral administration i.v. i.m. Uptake into macrophages spleen, liver, bone marrow Oral intake Fe III Absorption Duodenum upper jejunum Uptake into erythroblast bone marrow Loss through bleeding Erythrocyte blood Transport plasma Hemoglobin Hemosiderin = aggregated ferritin Ferritin Transferrin Fe III Fe III Fe III-complexes Fe III Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Prophylaxis and Therapy of Thromboses Upon vascular injury, the coagulation system is activated: thrombocytes and fibrin molecules coalesce into a “plug” (p. 148) that seals the defect and halts bleeding (hemostasis). Unnecessary formation of an intravascular clot – a thrombosis – can be life-threatening. If the clot forms on an atheromatous plaque in a coronary artery, myocardial infarction is imminent; a thrombus in a deep leg vein can be dislodged, carried into a lung artery, and cause complete or partial interruption of pulmonary blood flow (pulmonary embolism). Drugs that decrease the coagulabil- ity of blood, such as coumarins and hep- arin (A), are employed for the prophy- laxis of thromboses. In addition, at- tempts are directed at inhibiting the ag- gregation of blood platelets, which are prominently involved in intra-arterial thrombogenesis (p. 148). For the thera- py of thrombosis, drugs are used that dissolve the fibrin meshwork→fibrino- lytics (p. 146). An overview of the coagulation cascade and sites of action for coumar- ins and heparin is shown in A. There are two ways to initiate the cascade (B): 1) conversion of factor XII into its active form (XII a , intrinsic system) at intravas- cular sites denuded of endothelium; 2) conversion of factor VII into VII a (extrin- sic system) under the influence of a tis- sue-derived lipoprotein (tissue throm- boplastin). Both mechanisms converge via factor X into a common final path- way. The clotting factors are protein molecules. “Activation” mostly means proteolysis (cleavage of protein frag- ments) and, with the exception of fibrin, conversion into protein-hydrolyzing enzymes (proteases). Some activated factors require the presence of phos- pholipids (PL) and Ca 2+ for their proteo- lytic activity. Conceivably, Ca 2+ ions cause the adhesion of factor to a phos- pholipid surface, as depicted in C. Phos- pholipids are contained in platelet fac- tor 3 (PF3), which is released from ag- gregated platelets, and in tissue throm- boplastin (B). The sequential activation of several enzymes allows the afore- mentioned reactions to “snowball”, cul- minating in massive production of fibrin (p. 148). Progression of the coagulation cas- cade can be inhibited as follows: 1) coumarin derivatives decrease the blood concentrations of inactive fac- tors II, VII, IX, and X, by inhibiting their synthesis; 2) the complex consisting of heparin and antithrombin III neutraliz- es the protease activity of activated fac- tors; 3) Ca 2+ chelators prevent the en- zymatic activity of Ca 2+ -dependent fac- tors; they contain COO-groups that bind Ca 2+ ions (C): citrate and EDTA (ethy- lenediaminetetraacetic acid) form solu- ble complexes with Ca 2+ ; oxalate pre- cipitates Ca 2+ as insoluble calcium oxa- late. Chelation of Ca 2+ cannot be used for therapeutic purposes because Ca 2+ concentrations would have to be low- ered to a level incompatible with life (hypocalcemic tetany). These com- pounds (sodium salts) are, therefore, used only for rendering blood incoagu- lable outside the body. 142 Antithrombotics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antithrombotics 143 A. Inhibition of clotting cascade in vivo XII XIIa XI XIa IX IXa VIII + Ca 2+ + Pl VIIVIIa XXa Prothrombin II IIa Thrombin Fibrinogen a Fibrin B. Activation of clotting Platelets Endothelial defect Tissue thrombo- kinase Vessel rupture Clotting factor COO - Phospholipids e.g., PF 3 Ca 2+ -chelation Citrate EDTA Oxalate C. Inhibition of clotting by removal of Ca 2+ Synthesis susceptible to inhibition by coumarins Reaction susceptible to inhibition by heparin- antithrombin complex Fibrin XIIa VIIa VII XII PF 3 + Ca + – – – – – – COO – COO – V + Ca 2+ + Pl Ca 2+ + Pl (Phospholipids) Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Coumarin Derivatives (A) Vitamin K promotes the hepatic γ-car- boxylation of glutamate residues on the precursors of factors II, VII, IX, and X, as well as that of other proteins, e.g., pro- tein C, protein S, or osteocalcin. Carbox- yl groups are required for Ca 2+ -mediat- ed binding to phospholipid surfaces (p. 142). There are several vitamin K de- rivatives of different origins: K 1 (phy- tomenadione) from chlorophyllous plants; K 2 from gut bacteria; and K 3 (menadione) synthesized chemically. All are hydrophobic and require bile ac- ids for absorption. Oral anticoagulants. Structurally related to vitamin K, 4-hydroxycouma- rins act as “false” vitamin K and prevent regeneration of reduced (active) vita- min K from vitamin K epoxide, hence the synthesis of vitamin K-dependent clotting factors. Coumarins are well absorbed after oral administration. Their duration of action varies considerably. Synthesis of clotting factors depends on the intrahe- patocytic concentration ratio of cou- marins to vitamin K. The dose required for an adequate anticoagulant effect must be determined individually for each patient (one-stage prothrombin time). Subsequently, the patient must avoid changing dietary consumption of green vegetables (alteration in vitamin K levels), refrain from taking additional drugs likely to affect absorption or elim- ination of coumarins (alteration in cou- marin levels), and not risk inhibiting platelet function by ingesting acetylsali- cylic acid. The most important adverse ef- fect is bleeding. With coumarins, this can be counteracted by giving vitamin K 1 . Coagulability of blood returns to normal only after hours or days, when the liver has resumed synthesis and re- stored sufficient blood levels of clotting factors. In urgent cases, deficient factors must be replenished directly (e.g., by transfusion of whole blood or of pro- thrombin concentrate). Heparin (B) A clotting factor is activated when the factor that precedes it in the clotting cascade splits off a protein fragment and thereby exposes an enzymatic center. The latter can again be inactivated phys- iologically by complexing with anti- thrombin III (AT III), a circulating gly- coprotein. Heparin acts to inhibit clot- ting by accelerating formation of this complex more than 1000-fold. Heparin is present (together with histamine) in the vesicles of mast cells; its physiologi- cal role is unclear. Therapeutically used heparin is obtained from porcine gut or bovine lung. Heparin molecules are chains of amino sugars bearing -COO – and -SO 4 groups; they contain approx. 10 to 20 of the units depicted in (B); mean molecular weight, 20,000. Antico- agulant efficacy varies with chain length. The potency of a preparation is standardized in international units of activity (IU) by bioassay and compari- son with a reference preparation. The numerous negative charges are significant in several respects: (1) they contribute to the poor membrane pe- netrability—heparin is ineffective when applied by the oral route or topically on- to the skin and must be injected; (2) at- traction to positively charged lysine res- idues is involved in complex formation with ATIII; (3) they permit binding of heparin to its antidote, protamine (polycationic protein from salmon sperm). If protamine is given in heparin-in- duced bleeding, the effect of heparin is immediately reversed. For effective thromboprophylaxis, a low dose of 5000 IU is injected s.c. two to three times daily. With low dosage of heparin, the risk of bleeding is suffi- ciently small to allow the first injection to be given as early as 2 h prior to sur- gery. Higher daily i.v. doses are required to prevent growth of clots. Besides bleeding, other potential adverse effects are: allergic reactions (e.g., thrombocy- topenia) and with chronic administra- tion, reversible hair loss and osteoporo- sis. 144 Antithrombotics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antithrombotics 145 Heparin 3 x 5000 IU s.c. 30 000 IU i.v. B. Heparin: origin, structure, and mechanism of action A. Vitamin K-antagonists of the coumarin type and vitamin K Duration of action/days Carboxylation of glutamine residues Vit. K derivatives 4-Hydroxy- Coumarin derivatives Activated clotting factor Inacti- vation Inacti- vation Protamine Mast cell Vit. K 1 Vit. K 2 Vit. K 3 Menadione Phytomenadione Phenprocoumon Warfarin Acenocoumarol II, VII, IX, X ---- ---- + ++++ +++ + + + ---- I I a , IX a, Xa, XIa, XI Ia , X II I a AT III ++++ AT III ++++ Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Low-molecular-weight heparin (av- erage MW ~5000) has a longer duration of action and needs to be given only once daily (e.g., certoparin, dalteparin, enoxaparin, reviparin, tinzaparin). Frequent control of coagulability is not necessary with low molecular weight heparin and incidence of side ef- fects (bleeding, heparin-induced throm- bocytopenia) is less frequent than with unfractionated heparin. Fibrinolytic Therapy (A) Fibrin is formed from fibrinogen through thrombin (factor IIa)-catalyzed proteolytic removal of two oligopeptide fragments. Individual fibrin molecules polymerize into a fibrin mesh that can be split into fragments and dissolved by plasmin. Plasmin derives by proteolysis from an inactive precursor, plasmino- gen. Plasminogen activators can be infu- sed for the purpose of dissolving clots (e.g., in myocardial infarction). Throm- bolysis is not likely to be successful un- less the activators can be given very so- on after thrombus formation. Urokinase is an endogenous plasminogen activator obtained from cultured human kidney cells. Urokinase is better tolerated than is streptokinase. By itself, the latter is enzymatically inactive; only after bin- ding to a plasminogen molecule does the complex become effective in con- verting plasminogen to plasmin. Strep- tokinase is produced by streptococcal bacteria, which probably accounts for the frequent adverse reactions. Strepto- kinase antibodies may be present as a result of prior streptococcal infections. Binding to such antibodies would neu- tralize streptokinase molecules. With alteplase, another endoge- nous plasminogen activator (tissue plasminogen activator, tPA) is available. With physiological concentrations this activator preferentially acts on plasmin- ogen bound to fibrin. In concentrations needed for therapeutic fibrinolysis this preference is lost and the risk of bleed- ing does not differ with alteplase and streptokinase. Alteplase is rather short- lived (inactivation by complexing with plasminogen activator inhibitor, PAI) and has to be applied by infusion. Rete- plase, however, containing only the proteolytic active part of the alteplase molecule, allows more stabile plasma levels and can be applied in form of two injections at an interval of 30 min. Inactivation of the fibrinolytic system can be achieved by “plasmin in- hibitors,” such as ε-aminocaproic acid, p-aminomethylbenzoic acid (PAMBA), tranexamic acid, and aprotinin, which also inhibits other proteases. Lowering of blood fibrinogen concentration. Ancrod is a constituent of the venom from a Malaysian pit viper. It enzymatically cleaves a fragment from fibrinogen, resulting in the forma- tion of a degradation product that can- not undergo polymerization. Reduction in blood fibrinogen level decreases the coagulability of the blood. Since fibrino- gen (MW ~340 000) contributes to the viscosity of blood, an improved “fluid- ity” of the blood would be expected. Both effects are felt to be of benefit in the treatment of certain disorders of blood flow. 146 Antithrombotics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antithrombotics 147 A. Activators and inhibitors of fibrinolysis; ancrod Fibrinogen Fibrin Thrombin Ancrod Plasmin Plasmin-inhibitors e.g., Tranexamic acid Urokinase Human kidney cell culture Streptokinase StreptococciPlasminogen Antibody from prior infection Fever, chills, and inacti- vation Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Intra-arterial Thrombus Formation (A) Activation of platelets, e.g., upon con- tact with collagen of the extracellular matrix after injury to the vascular wall, constitutes the immediate and decisive step in initiating the process of primary hemostasis, i.e., cessation of bleeding. However, in the absence of vascular in- jury, platelets can be activated as a re- sult of damage to the endothelial cell lining of blood vessels. Among the mul- tiple functions of the endothelium, the production of NO˙ and prostacyclin plays an important role. Both substances in- hibit the tendency of platelets to adhere to the endothelial surface (platelet ad- hesiveness). Impairment of endothelial function, e.g., due to chronic hyperten- sion, cigarette smoking, chronic eleva- tion of plasma LDL levels or of blood glucose, increases the probability of contact between platelets and endothe- lium. The adhesion process involves GP IB/IX , a glycoprotein present in the platelet cell membrane and von Wille- brandt’s factor, an endothelial mem- brane protein. Upon endothelial con- tact, the platelet is activated with a re- sultant change in shape and affinity to fibrinogen. Platelets are linked to each other via fibrinogen bridges: they undergo aggregation. Platelet aggregation increases like an avalanche because, once activated, platelets can activate other platelets. On the injured endothelial cell, a platelet thrombus is formed, which obstructs blood flow. Ultimately, the vascular lu- men is occluded by the thrombus as the latter is solidified by a vasoconstriction produced by the release of serotonin and thromboxane A 2 from the aggregat- ed platelets. When these events occur in a larger coronary artery, the conse- quence is a myocardial infarction; in- volvement of a cerebral artery leads to stroke. The von Willebrandt’s factor plays a key role in thrombogenesis. Lack of this factor causes thrombasthenia, a patho- logically decreased platelet aggregation. Relative deficiency of the von Wille- brandt’s factor can be temporarily over- come by the vasopressin anlogue des- mopressin (p. 164), which increases the release of available factor from storage sites. Formation, Activation, and Aggregation of Platelets (B) Platelets originate by budding off from multinucleate precursor cells, the me- gakaryocytes. As the smallest formed element of blood (dia. 1–4 μm), they can be activated by various stimuli. Activa- tion entails an alteration in shape and secretion of a series of highly active sub- stances, including serotonin, platelet ac- tivating factor (PAF), ADP, and throm- boxane A 2 . In turn, all of these can acti- vate other platelets, which explains the explosive nature of the process. The primary consequence of activa- tion is a conformational change of an in- tegrin present in the platelet mem- brane, namely, GPIIB/IIIA. In its active conformation, GPIIB/IIIA shows high af- finity for fibrinogen; each platelet con- tains up to 50,000 copies. The high plas- ma concentration of fibrinogen and the high density of integrins in the platelet membrane permit rapid cross-linking of platelets and formation of a platelet plug. 148 Antithrombotics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antithrombotics 149 B. Aggregation of platelets by the integrin GPIIB/IIIA Megakaryocyte Glycoprotein IIB/IIIA Fibrinogen binding: possible impossible Platelet Adhesion Aggregation Platelet von Willebrandt’s factor FibrinogenActivated platelet Contact with collagen ADP Thrombin Thromboxane A 2 Serotonin A. Thrombogenesis Activation Fibrinogen dysfunctional endothelial cell Activated platelet Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of Platelet Aggregation (A) Platelets can be activated by mechanical and diverse chemical stimuli, some of which, e.g., thromboxane A 2 , thrombin, serotonin, and PAF, act via receptors on the platelet membrane. These receptors are coupled to G q proteins that mediate activation of phospholipase C and hence a rise in cytosolic Ca 2+ concentration. Among other responses, this rise in Ca 2+ triggers a conformational change in GPIIB/IIIA, which is thereby converted to its fbrinogen-binding form. In con- trast, ADP activates platelets by inhibit- ing adenylyl cyclase, thus causing inter- nal cAMP levels to decrease. High cAMP levels would stabilize the platelet in its inactive state. Formally, the two mes- senger substances, Ca 2+ and cAMP, can be considered functional antagonists. Platelet aggregation can be inhibit- ed by acetylsalicylic acid (ASA), which blocks thromboxane synthase, or by re- combinant hirudin (originally harvest- ed from leech salivary gland), which binds and inactivates thrombin. As yet, no drugs are available for blocking ag- gregation induced by serotonin or PAF. ADP-induced aggregation can be pre- vented by ticlopidine and clopidogrel; these agents are not classic receptor an- tagonists. ADP-induced aggregation is inhibited only in vivo but not in vitro in stored blood; moreover, once induced, inhibition is irreversible. A possible ex- planation is that both agents already interfere with elements of ADP receptor signal transduction at the megakaryo- cytic stage. The ensuing functional de- fect would then be transmitted to newly formed platelets, which would be inca- pable of reversing it. The intra-platelet levels of cAMP can be stabilized by prostacyclin or its analogues (e.g., iloprost) or by dipyrida- mole. The former activates adenyl cy- clase via a G-protein-coupled receptor; the latter inhibits a phosphodiesterase that breaks down cAMP. The integrin (GPIIB/IIIA)-antago- nists prevent cross-linking of platelets. Their action is independent of the ag- gregation-inducing stimulus. Abciximab is a chimeric human-murine monoclo- nal antibody directed against GPIIb/IIIa that blocks the fibrinogen-binding site and thus prevents attachment of fi- brinogen. The peptide derivatives, epti- fibatide and tirofiban block GPIIB/IIIA competitively, more selectively and ha- ve a shorter effect than does abciximab. Presystemic Effect of Acetylsalicylic Acid (B) Inhibition of platelet aggregation by ASA is due to a selective blockade of platelet cyclooxygenase (B). Selectivity of this action results from acetylation of this enzyme during the initial passage of the platelets through splanchnic blood vessels. Acetylation of the enzyme is ir- reversible. ASA present in the systemic circulation does not play a role in plate- let inhibition. Since ASA undergoes ex- tensive presystemic elimination, cyclo- oxygenases outside platelets, e.g., in en- dothelial cells, remain largely unaffect- ed. With regular intake, selectivity is en- hanced further because the anuclear platelets are unable to resynthesize new enzyme and the inhibitory effects of consecutive doses are added to each other. However, in the endothelial cells, de novo synthesis of the enzyme per- mits restoration of prostacyclin produc- tion. Adverse Effects of Antiplatelet Drugs All antiplatelet drugs increase the risk of bleeding. Even at the low ASA doses used to inhibit platelet function (100 mg/d), ulcerogenic and bronchocon- strictor (aspirin asthma) effects may oc- cur. Ticlopidine frequently causes diar- rhea and, more rarely, leukopenia, ne- cessitating cessation of treatment. Clo- pidogrel reportedly does not cause he- matological problems. As peptides, hirudin and abciximab need to be injected; therefore their use is restricted to intensive-care settings. 150 Antithrombotics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antithrombotics 151 Abciximab Tirofiban Eptifibatide Hirudin Argatroban A. Inhibitors of platelet aggregation Arachidonic acid B. Presystemic inactivation of platelet cyclooxygenase by acetylsalicylic acid Serotonin PAF GPIIB/IIIA [without affinity for fibrinogen] Thrombin ATP Phospho- diesterase Dipyridamole ASA Thromb- oxane A 2 Adenylate- cyclase Inactive Active ADP GPIIB/IIIA [Affinity for fibrinogen high] O COOH O CCH 3 Ticlopidine, Clopidogrel Low dose of acetyl- salicylic acid PlateletPlatelet with acetylated and blocked cyclooxygenase Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Plasma Volume Expanders Major blood loss entails the danger of life-threatening circulatory failure, i.e., hypovolemic shock. The immediate threat results not so much from the loss of erythrocytes, i.e., oxygen carriers, as from the reduction in volume of circu- lating blood. To eliminate the threat of shock, re- plenishment of the circulation is essen- tial. With moderate loss of blood, ad- ministration of a plasma volume ex- pander may be sufficient. Blood plasma consists basically of water, electrolytes, and plasma proteins. However, a plasma substitute need not contain plasma proteins. These can be suitably re- placed with macromolecules (“col- loids”) that, like plasma proteins, (1) do not readily leave the circulation and are poorly filtrable in the renal glomerulus; and (2) bind water along with its solutes due to their colloid osmotic properties. In this manner, they will maintain circula- tory filling pressure for many hours. On the other hand, volume substitution is only transiently needed and therefore complete elimination of these colloids from the body is clearly desirable. Compared with whole blood or plasma, plasma substitutes offer several advantages: they can be produced more easily and at lower cost, have a longer shelf life, and are free of pathogens such as hepatitis B or C or AIDS viruses. Three colloids are currently em- ployed as plasma volume expanders— the two polysaccharides, dextran and hydroxyethyl starch, as well as the poly- peptide, gelatin. Dextran is a glucose polymer formed by bacteria and linked by a 1→6 instead of the typical 1→4 bond. Com- mercial solutions contain dextran of a mean molecular weight of 70 kDa (dex- tran 70) or 40 kDa (lower-molecular- weight dextran, dextran 40). The chain length of single molecules, however, varies widely. Smaller dextran mole- cules can be filtered at the glomerulus and slowly excreted in urine; the larger ones are eventually taken up and de- graded by cells of the reticuloendothe- lial system. Apart from restoring blood volume, dextran solutions are used for hemodilution in the management of blood flow disorders. As for microcirculatory improve- ment, it is occasionally emphasized that low-molecular-weight dextran, unlike dextran 70, may directly reduce the ag- gregability of erythrocytes by altering their surface properties. With pro- longed use, larger molecules will accu- mulate due to the more rapid renal ex- cretion of the smaller ones. Consequent- ly, the molecular weight of dextran cir- culating in blood will tend towards a higher mean molecular weight with the passage of time. The most important adverse effect results from the antigenicity of dex- trans, which may lead to an anaphylac- tic reaction. Hydroxyethyl starch (hetastarch) is produced from starch. By virtue of its hydroxyethyl groups, it is metabolized more slowly and retained significantly longer in blood than would be the case with infused starch. Hydroxyethyl starch resembles dextrans in terms of its pharmacological properties and therapeutic applications. Gelatin colloids consist of cross- linked peptide chains obtained from collagen. They are employed for blood replacement, but not for hemodilution, in circulatory disturbances. 152 Plasma Volume Expanders Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Plasma Volume Expanders 153 Gelatin colloids = cross-linked peptide chains MW 35, 000 Circulation A. Plasma substitutes Peptides MW ~ 15, 000 Gelatin MW ~ 100, 000 Collagen MW ~ 300, 000 Plasma Plasma- proteins Erythrocytes Dextran MW 70, 000 MW 40, 000 Hydroxyethyl starch MW 450, 000 Sucrose Fructose Bacterium Leuconostoc mesenteroides Hydroxy- ethylation Starch Plasma- substitute with colloids Blood loss danger of shock Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Lipoprotein metabolism. Entero- cytes release absorbed lipids in the form of triglyceride-rich chylomicrons. By- passing the liver, these enter the circu- lation mainly via the lymph and are hy- drolyzed by extrahepatic endothelial lipoprotein lipases to liberate fatty ac- ids. The remnant particles move on into liver cells and supply these with choles- terol of dietary origin. The liver meets the larger part (60%) of its requirement for cholesterol by de novo synthesis from acetylcoen- zyme-A. Synthesis rate is regulated at the step leading from hydroxymethyl- glutaryl CoA (HMG CoA) to mevalonic acid (p. 157A), with HMG CoA reductase as the rate-limiting enzyme. The liver requires cholesterol for synthesizing VLDL particles and bile ac- ids. Triglyceride-rich VLDL particles are released into the blood and, like the chylomicrons, supply other tissues with fatty acids. Left behind are LDL particles that either return into the liver or sup- ply extrahepatic tissues with choleste- rol. LDL particles carry apolipoprotein B 100, by which they are bound to recep- tors that mediate uptake of LDL into the cells, including the hepatocytes (recep- tor-mediated endocytosis, p. 27). HDL particles are able to transfer cholesterol from tissue cells to LDL par- ticles. In this way, cholesterol is trans- ported from tissues to the liver. Hyperlipoproteinemias can be caused genetically (primary h.) or can occur in obesity and metabolic disor- ders (secondary h). Elevated LDL-cho- lesterol serum concentrations are asso- ciated with an increased risk of athero- sclerosis, especially when there is a con- comitant decline in HDL concentration (increase in LDL:HDL quotient). Treatment. Various drugs are avail- able that have different mechanisms of action and effects on LDL (cholesterol) and VLDL (triglycerides) (A). Their use is indicated in the therapy of primary hy- perlipoproteinemias. In secondary hy- perlipoproteinemias, the immediate goal should be to lower lipoprotein lev- els by dietary restriction, treatment of the primary disease, or both. Drugs (B). Colestyramine and coles- tipol are nonabsorbable anion-exchange resins. By virtue of binding bile acids, they promote consumption of choleste- rol for the synthesis of bile acids; the 154 li KT Lipid-Lowering Agents Triglycerides and cholesterol are essen- tial constituents of the organism. Among other things, triglycerides repre- sent a form of energy store and choles- terol is a basic building block of biologi- cal membranes. Both lipids are water insoluble and require appropriate trans- port vehicles in the aqueous media of lymph and blood. To this end, small amounts of lipid are coated with a layer of phospholipids, embedded in which are additional proteins—the apolipopro- teins (A). According to the amount and the composition of stored lipids, as well as the type of apolipoprotein, one dis- tinguishes 4 transport forms: Drugs used in Hyperlipoproteinemias Origin Density Mean sojourn Diameter in blood (nm) plasma (h) Chylomicron Gut epithelium <1.006 0.2 500 VLDL particle liver 0.95 –1.006 3 100–200 LDL particle (blood) 1.006–1.063 50 25 HDL particle liver 1.063–1.210 – 5–10 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs used in Hyperlipoproteinemias 155 Cell metabolism A. Lipoprotein metabolism LDL Dietary fats LDL Chylomicron Cholesterol Liver cell Lipoprotein synthesis Cholesterol Triglycerides Synthesis Cholesterol- ester Triglycerides B. Cholesterol metabolism in liver cell and cholesterol-lowering drugs Bile acids Lipoproteins HMG-CoA-Reductase inhibitors Liver cell Fat tissue Heart Skeletal muscle OH OH OH LDLHDL HDL VLDL Chylomicron remnant β-Sitosterol Gut: Cholesterol absorption Gut:: binding and excretion of bile acids (BA) Liver: BA synthesis Cholesterol consumption Cholesterol store Colestyramine Cholesterol Fatty acids Lipoprotein Lipase Cholesterol Apolipo- protein Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. liver meets its increased cholesterol de- mand by enhancing the expression of HMG CoA reductase and LDL receptors (negative feedback). At the required dosage, the resins cause diverse gastrointestinal distur- bances. In addition, they interfere with the absorption of fats and fat-soluble vi- tamins (A, D, E, K). They also adsorb and decrease the absorption of such drugs as digitoxin, vitamin K antagonists, and diuretics. Their gritty texture and bulk make ingestion an unpleasant experi- ence. The statins, lovastatin (L), simvasta- tin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) re- sembles that of the physiological sub- strate of the enzyme (A). L and S are lac- tones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metab- olites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also me- diates the selective hepatic uptake of the mycotoxin, amanitin (A). Atorvasta- tin has the longest duration of action. Normally viewed as presystemic elimi- nation, efficient hepatic extraction serves to confine the action of the sta- tins to the liver. Despite the inhibition of HMG CoA reductase, hepatic cholesterol content does not fall, because hepato- cytes compensate any drop in choleste- rol levels by increasing the synthesis of LDL receptor protein (along with the re- ductase). Because the newly formed re- ductase is inhibited, too, the hepatocyte must meet its cholesterol demand by uptake of LDL from the blood (B). Ac- cordingly, the concentration of circulat- ing LDL decreases, while its hepatic clearance from plasma increases. There is also a decreased likelihood of LDL be- ing oxidized into its proatheroslerotic degradation product. The combination of a statin with an ion-exchange resin intensifies the decrease in LDL levels. A rare, but dangerous, side effect of the statins is damage to skeletal muscula- ture. This risk is increased by combined use of fibric acid agents (see below). Nicotinic acid and its derivatives (pyridylcarbinol, xanthinol nicotinate, acipimox) activate endothelial lipopro- tein lipase and thereby lower triglyce- ride levels. At the start of therapy, a prostaglandin-mediated vasodilation occurs (flushing and hypotension) that can be prevented by low doses of acetyl- salicylic acid. Clofibrate and derivatives (bezafi- brate, etofibrate, gemfibrozil) lower plas- ma lipids by an unknown mechanism. They may damage the liver and skeletal muscle (myalgia, myopathy, rhabdo- myolysis). Probucol lowers HDL more than LDL; nonetheless, it appears effective in reducing atherogenesis, possibly by re- ducing LDL oxidation. H9275 3 -Polyunsaturated fatty acids (ei- cosapentaenoate, docosahexaenoate) are abundant in fish oils. Dietary sup- plementation results in lowered levels of triglycerides, decreased synthesis of VLDL and apolipoprotein B, and im- proved clearance of remnant particles, although total and LDL cholesterol are not decreased or are even increased. High dietary intake may correlate with a reduced incidence of coronary heart disease. 156 Drugs used in Hyperlipoproteinemias Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs used in Hyperlipoproteinemias 157 Low systemic availability Fluvastatin A. Accumulation and effect of HMG-CoA reductase inhibitors in liver Inhibition of HMG-CoA reductase LDL- Receptor Expression B. Regulation by cellular cholesterol concentration of HMG-CoA reductase and LDL-receptors LDL in blood Oral administration Extraction of lipophilic lactone Active uptake of anion HMG-CoA reductase Increased receptor- mediated uptake of LDL Cholesterol Cholesterol Lovastatin Mevalonate3-Hydroxy-3-methyl- glutaryl-CoA HMG-CoA Reductase Active form Expression Bio- activation O O CH 3 O O HO H 3 C N OH F COOH HO CH 3 CH 3 H 3 C H 3 C Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Diuretics – An Overview Diuretics (saluretics) elicit increased production of urine (diuresis). In the strict sense, the term is applied to drugs with a direct renal action. The predomi- nant action of such agents is to augment urine excretion by inhibiting the reab- sorption of NaCl and water. The most important indications for diuretics are: Mobilization of edemas (A): In ede- ma there is swelling of tissues due to ac- cumulation of fluid, chiefly in the extra- cellular (interstitial) space. When a diu- retic is given, increased renal excretion of Na + and H 2 O causes a reduction in plasma volume with hemoconcentra- tion. As a result, plasma protein concen- tration rises along with oncotic pres- sure. As the latter operates to attract water, fluid will shift from interstitium into the capillary bed. The fluid content of tissues thus falls and the edemas re- cede. The decrease in plasma volume and interstitial volume means a dimi- nution of the extracellular fluid volume (EFV). Depending on the condition, use is made of: thiazides, loop diuretics, al- dosterone antagonists, and osmotic diu- retics. Antihypertensive therapy. Diuretics have long been used as drugs of first choice for lowering elevated blood pres- sure (p. 312). Even at low dosage, they decrease peripheral resistance (without significantly reducing EFV) and thereby normalize blood pressure. Therapy of congestive heart failure. By lowering peripheral resistance, diu- retics aid the heart in ejecting blood (re- duction in afterload, pp. 132, 306); car- diac output and exercise tolerance are increased. Due to the increased excre- tion of fluid, EFV and venous return de- crease (reduction in preload, p. 306). Symptoms of venous congestion, such as ankle edema and hepatic enlarge- ment, subside. The drugs principally used are thiazides (possibly combined with K + -sparing diuretics) and loop diu- retics. Prophylaxis of renal failure. In circu- latory failure (shock), e.g., secondary to massive hemorrhage, renal production of urine may cease (anuria). By means of diuretics an attempt is made to main- tain urinary flow. Use of either osmotic or loop diuretics is indicated. Massive use of diuretics entails a hazard of adverse effects (A): (1) the decrease in blood volume can lead to hypotension and collapse; (2) blood vis- cosity rises due to the increase in eryth- ro- and thrombocyte concentration, bringing an increased risk of intravascu- lar coagulation or thrombosis. When depletion of NaCl and water (EFV reduction) occurs as a result of diu- retic therapy, the body can initiate counter-regulatory responses (B), namely, activation of the renin-angio- tensin-aldosterone system (p. 124). Be- cause of the diminished blood volume, renal blood flow is jeopardized. This leads to release from the kidneys of the hormone, renin, which enzymatically catalyzes the formation of angiotensin I. Angiotensin I is converted to angioten- sin II by the action of angiotensin-con- verting enzyme (ACE). Angiotensin II stimulates release of aldosterone. The mineralocorticoid promotes renal reab- sorption of NaCl and water and thus counteracts the effect of diuretics. ACE inhibitors (p. 124) augment the effec- tiveness of diuretics by preventing this counter-regulatory response. 158 Diuretics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Diuretics 159 B. Possible counter-regulatory responses during long-term diuretic therapy A. Mechanism of edema fluid mobilization by diuretics Edema Hemoconcentration Collapse, danger of thrombosis Salt and fluid retention Mobilization of edema fluid Protein molecules Colloid osmotic pressure Diuretic EFV: Na + , Cl - , H 2 O Diuretic Diuretic Angiotensinogen Renin Angiotensin I ACE Angiotensin II Aldosterone Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. NaCl Reabsorption in the Kidney (A) The smallest functional unit of the kid- ney is the nephron. In the glomerular capillary loops, ultrafiltration of plasma fluid into Bowman’s capsule (BC) yields primary urine. In the proximal tubules (pT), approx. 70% of the ultrafiltrate is retrieved by isoosmotic reabsorption of NaCl and water. In the thick portion of the ascending limb of Henle’s loop (HL), NaCl is absorbed unaccompanied by water. This is the prerequisite for the hairpin countercurrent mechanism that allows build-up of a very high NaCl con- centration in the renal medulla. In the distal tubules (dT), NaCl and water are again jointly reabsorbed. At the end of the nephron, this process involves an al- dosterone-controlled exchange of Na + against K + or H + . In the collecting tubule (C), vasopressin (antidiuretic hormone, ADH) increases the epithelial perme- ability for water, which is drawn into the hyperosmolar milieu of the renal medulla and thus retained in the body. As a result, a concentrated urine enters the renal pelvis. Na + transport through the tubular cells basically occurs in similar fashion in all segments of the nephron. The intracellular concentration of Na + is sig- nificantly below that in primary urine. This concentration gradient is the driv- ing force for entry of Na + into the cytosol of tubular cells. A carrier mechanism moves Na + across the membrane. Ener- gy liberated during this influx can be utilized for the coupled outward trans- port of another particle against a gradi- ent. From the cell interior, Na + is moved with expenditure of energy (ATP hy- drolysis) by Na + /K + -ATPase into the ex- tracellular space. The enzyme molecules are confined to the basolateral parts of the cell membrane, facing the interstiti- um; Na + can, therefore, not escape back into tubular fluid. All diuretics inhibit Na + reabsorp- tion. Basically, either the inward or the outward transport of Na + can be affect- ed. Osmotic Diuretics (B) Agents: mannitol, sorbitol. Site of action: mainly the proximal tubules. Mode of action: Since NaCl and H 2 O are reab- sorbed together in the proximal tubules, Na + concentration in the tubular fluid does not change despite the extensive reabsorption of Na + and H 2 O. Body cells lack transport mechanisms for polyhy- dric alcohols such as mannitol (struc- ture on p. 171) and sorbitol, which are thus prevented from penetrating cell membranes. Therefore, they need to be given by intravenous infusion. They also cannot be reabsorbed from the tubular fluid after glomerular filtration. These agents bind water osmotically and re- tain it in the tubular lumen. When Na ions are taken up into the tubule cell, water cannot follow in the usual amount. The fall in urine Na + concentra- tion reduces Na + reabsorption, in part because the reduced concentration gra- dient towards the interior of tubule cells means a reduced driving force for Na + influx. The result of osmotic diuresis is a large volume of dilute urine. Indications: prophylaxis of renal hypovolemic failure, mobilization of brain edema, and acute glaucoma. 160 Diuretics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Diuretics 161 A. Kidney: NaCl reabsorption in nephron and tubular cell dT BC C pT Cortex Medulla Thick portion of HL Lumen Inter- stitium Na/K- ATPaseNa + Na + "carrier" ADH HL Mannitol B. NaCl reabsorption in proximal tubule and effect of mannitol [Na + ] inside = [Na + ] outside [Na + ] inside < [Na + ] outside Na + Na + , Cl - Na + , Cl - + H 2 O H 2 O Aldosterone K + Diuretics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Diuretics of the Sulfonamide Type These drugs contain the sulfonamide group -SO 2 NH 2 . They are suitable for oral administration. In addition to being filtered at the glomerulus, they are sub- ject to tubular secretion. Their concen- tration in urine is higher than in blood. They act on the luminal membrane of the tubule cells. Loop diuretics have the highest efficacy. Thiazides are most fre- quently used. Their forerunners, the carbonic anhydrase inhibitors, are now restricted to special indications. Carbonic anhydrase (CAH) inhibi- tors, such as acetazolamide and sulthi- ame, act predominantly in the proximal tubules. CAH catalyzes CO 2 hydra- tion/dehydration reactions: H + + HCO 3 – ? H 2 CO 3 ? H 2 0 + CO 2 . The enzyme is used in tubule cells to generate H + , which is secreted into the tubular fluid in exchange for Na + . There, H + captures HCO 3 – , leading to for- mation of CO 2 via the unstable carbonic acid. Membrane-permeable CO 2 is taken up into the tubule cell and used to re- generate H + and HCO 3 – . When the en- zyme is inhibited, these reactions are slowed, so that less Na + , HCO 3 – and wa- ter are reabsorbed from the fast-flowing tubular fluid. Loss of HCO 3 – leads to aci- dosis. The diuretic effectiveness of CAH inhibitors decreases with prolonged use. CAH is also involved in the produc- tion of ocular aqueous humor. Present indications for drugs in this class in- clude: acute glaucoma, acute mountain sickness, and epilepsy. Dorzolamide can be applied topically to the eye to lower intraocular pressure in glaucoma. Loop diuretics include furosemide (frusemide), piretanide, and bumeta- nide. With oral administration, a strong diuresis occurs within 1 h but persists for only about 4 h. The effect is rapid, in- tense, and brief (high-ceiling diuresis). The site of action of these agents is the thick portion of the ascending limb of Henle’s loop, where they inhibit Na + /K + /2Cl – cotransport. As a result, these electrolytes, together with water, are excreted in larger amounts. Excre- tion of Ca 2+ and Mg 2+ also increases. Special toxic effects include: (reversible) hearing loss, enhanced sensitivity to renotoxic agents. Indications: pulmo- nary edema (added advantage of i.v. in- jection in left ventricular failure: imme- diate dilation of venous capacitance vessels L50478 preload reduction); refrac- toriness to thiazide diuretics, e.g., in re- nal hypovolemic failure with creatinine clearance reduction (<30 mL/min); pro- phylaxis of acute renal hypovolemic failure; hypercalcemia. Ethacrynic acid is classed in this group although it is not a sulfonamide. Thiazide diuretics (benzothiadia- zines) include hydrochlorothiazide, benzthiazide, trichlormethiazide, and cyclothiazide. A long-acting analogue is chlorthalidone. These drugs affect the intermediate segment of the distal tu- bules, where they inhibit a Na + /Cl – co- transport. Thus, reabsorption of NaCl and water is inhibited. Renal excretion of Ca 2+ decreases, that of Mg 2+ increases. Indications are hypertension, cardiac failure, and mobilization of edema. Unwanted effects of sulfonamide- type diuretics: (a) hypokalemia is a con- sequence of excessive K + loss in the ter- minal segments of the distal tubules where increased amounts of Na + are available for exchange with K + ; (b) hy- perglycemia and glycosuria; (c) hyper- uricemia—increase in serum urate lev- els may precipitate gout in predisposed patients. Sulfonamide diuretics com- pete with urate for the tubular organic anion secretory system. 162 Diuretics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Diuretics 163 e.g., furosemide Loop diuretics Na + K + 2 Cl - A. Diuretics of the sulfonamide type Anion secretory system e.g., acetazolamide Carbonic anhydrase inhibitors Na + H + HCO - 3 H 2 O CO 2 CAH HCO - 3 Na + HCO - 3 H + CO 2 H 2 O e.g., hydrochlorothiazide Thiazides Na + Cl - Sulfonamide diuretics Uric acid Gout Hypokalemia Normal state Loss of Na + , K + H 2 O Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Potassium-Sparing Diuretics (A) These agents act in the distal portion of the distal tubule and the proximal part of the collecting ducts where Na + is re- absorbed in exchange for K + or H + . Their diuretic effectiveness is relatively mi- nor. In contrast to sulfonamide diuretics (p. 162), there is no increase in K + secre- tion; rather, there is a risk of hyperkale- mia. These drugs are suitable for oral administration. a) Triamterene and amiloride, in ad- dition to glomerular filtration, undergo secretion in the proximal tubule. They act on the luminal membrane of tubule cells. Both inhibit the entry of Na + , hence its exchange for K + and H + . They are mostly used in combination with thiazide diuretics, e.g., hydrochlorothia- zide, because the opposing effects on K + excretion cancel each other, while the effects on secretion of NaCl complement each other. b) Aldosterone antagonists. The mineralocorticoid aldosterone pro- motes the reabsorption of Na + (Cl – and H 2 O follow) in exchange for K + . Its hor- monal effect on protein synthesis leads to augmentation of the reabsorptive ca- pacity of tubule cells. Spironolactone, as well as its metabolite canrenone, are an- tagonists at the aldosterone receptor and attenuate the effect of the hormone. The diuretic effect of spironolactone de- velops fully only with continuous ad- ministration for several days. Two pos- sible explanations are: (1) the conver- sion of spironolactone into and accumu- lation of the more slowly eliminated metabolite canrenone; (2) an inhibition of aldosterone-stimulated protein syn- thesis would become noticeable only if existing proteins had become nonfunc- tional and needed to be replaced by de novo synthesis. A particular adverse ef- fect results from interference with gon- adal hormones, as evidenced by the de- velopment of gynecomastia (enlarge- ment of male breast). Clinical uses in- clude conditions of increased aldoste- rone secretion, e.g., liver cirrhosis with ascites. Antidiuretic Hormone (ADH) and Derivatives (B) ADH, a nonapeptide, released from the posterior pituitary gland promotes re- absorption of water in the kidney. This response is mediated by vasopressin re- ceptors of the V 2 subtype. ADH enhanc- es the permeability of collecting duct epithelium for water (but not for elec- trolytes). As a result, water is drawn from urine into the hyperosmolar inter- stitium of the medulla. Nicotine aug- ments (p. 110) and ethanol decreases ADH release. At concentrations above those required for antidiuresis, ADH stimulates smooth musculature, includ- ing that of blood vessels (“vasopres- sin”). The latter response is mediated by receptors of the V 1 subtype. Blood pres- sure rises; coronary vasoconstriction can precipitate angina pectoris. Lypres- sin (8-L-lysine vasopressin) acts like ADH. Other derivatives may display on- ly one of the two actions. Desmopressin is used for the thera- py of diabetes insipidus (ADH deficien- cy), nocturnal enuresis, thrombasthe- mia (p. 148), and chronic hypotension (p. 314); it is given by injection or via the nasal mucosa (as “snuff”). Felypressin and ornipressin serve as adjunctive vasoconstrictors in infiltra- tion local anesthesia (p. 206). 164 Diuretics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Diuretics 165 B. Antidiuretic hormone (ADH) and derivatives A. Potassium-sparing diuretics Na + Canrenone Neuro- hypophysis H 2 O permeability of collecting duct Vasoconstriction Desmopressin Ornipressin Felypressin K + Aldosterone antagonists K + or H + Na + Protein synthesis Transport capacity Amiloride Triamterene Adiuretin = Vasopressin Ethanol Nicotine V 2 V 1 Spironolactone Aldosterone Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for Gastric and Duodenal Ulcers In the area of a gastric or duodenal pep- tic ulcer, the mucosa has been attacked by digestive juices to such an extent as to expose the subjacent connective tis- sue layer (submucosa). This self-diges- tion occurs when the equilibrium between the corrosive hydrochloric acid and acid-neutralizing mucus, which forms a protective cover on the mucosal surface, is shifted in favor of hydro- chloric acid. Mucosal damage can be promoted by Helicobacter pylori bacte- ria that colonize the gastric mucus. Drugs are employed with the fol- lowing therapeutic aims: (1) to relieve pain; (2) to accelerate healing; and (3) to prevent ulcer recurrence. Therapeu- tic approaches are threefold: (a) to re- duce aggressive forces by lowering H + output; (b) to increase protective forces by means of mucoprotectants; and (c) to eradicate Helicobacter pylori. I. Drugs for Lowering Acid Concentration Ia. Acid neutralization. H + -binding groups such as CO 3 2– , HCO 3 – or OH – , to- gether with their counter ions, are con- tained in antacid drugs. Neutralization reactions occurring after intake of CaCO 3 and NaHCO 3 , respectively, are shown in (A) at left. With nonabsorb- able antacids, the counter ion is dis- solved in the acidic gastric juice in the process of neutralization. Upon mixture with the alkaline pancreatic secretion in the duodenum, it is largely precipitated again by basic groups, e.g., as CaCO 3 or AlPO 4 , and excreted in feces. Therefore, systemic absorption of counter ions or basic residues is minor. In the presence of renal insufficiency, however, absorp- tion of even small amounts may cause an increase in plasma levels of counter ions (e.g., magnesium intoxication with paralysis and cardiac disturbances). Pre- cipitation in the gut lumen is respon- sible for other side effects, such as re- duced absorption of other drugs due to their adsorption to the surface of pre- cipitated antacid or, phosphate deple- tion of the body with excessive intake of Al(OH) 3 . Na + ions remain in solution even in the presence of HCO 3 – -rich pancreatic secretions and are subject to absorption, like HCO 3 – . Because of the uptake of Na + , use of NaHCO 3 must be avoided in con- ditions requiring restriction of NaCl in- take, such as hypertension, cardiac fail- ure, and edema. Since food has a buffering effect, antacids are taken between meals (e.g., 1 and 3 h after meals and at bedtime). Nonabsorbable antacids are preferred. Because Mg(OH) 2 produces a laxative effect (cause: osmotic action, p. 170, re- lease of cholecystokinin by Mg 2+ , or both) and Al(OH) 3 produces constipa- tion (cause: astringent action of Al 3+ , p. 178), these two antacids are frequently used in combination. Ib. Inhibitors of acid production. Acting on their respective receptors, the transmitter acetylcholine, the hormone gastrin, and histamine released intra- mucosally stimulate the parietal cells of the gastric mucosa to increase output of HCl. Histamine comes from entero- chromaffin-like (ECL) cells; its release is stimulated by the vagus nerve (via M 1 receptors) and hormonally by gastrin. The effects of acetylcholine and hista- mine can be abolished by orally applied antagonists that reach parietal cells via the blood. The cholinoceptor antagonist pi- renzepine, unlike atropine, prefers cho- linoceptors of the M 1 type, does not penetrate into the CNS, and thus pro- duces fewer atropine-like side effects (p. 104). The cholinoceptors on parietal cells probably belong to the M 3 subtype. Hence, pirenzepine may act by blocking M 1 receptors on ECL cells or submucosal neurons. Histamine receptors on parietal cells belong to the H 2 type (p. 114) and are blocked by H 2 -antihistamines. Be- cause histamine plays a pivotal role in the activation of parietal cells, H 2 -anti- histamines also diminish responsivity to other stimulants, e.g., gastrin (in gas- 166 Drugs for the Treatment of Peptic Ulcers Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for the Treatment of Peptic Ulcers 167 Inhibition of acid production N. vagus M 1 Pir enzepine Parietal cell ACh Histamine ECL- cell ATPase H 2 -Antihistamines Cimetidine Ranitidine Acid neutralization Antacids not absorbable absorbable CaCO 3 Mg(OH) 2 Al(OH) 3 NaHCO 3 A. Drugs used to lower gastric acid concentration or production Pancreas K + M 3 H 2 ACh H + H 2 CO 3 H 2 O CO 2 Ca 2+ Ca 2+ CO 3 2- H 2 O+CO 2 HCO 3 - H + Pancreas HCO 3 - Na + HCO 3 - Na + H + H + CaCO 3 CaCO 3 Absorption Omeprazole Proton pump- inhibitors Na + N N S O H N H 3 CO OCH 3 CH 3 H 3 C Gastrin CH 2 S (CH 2 ) 2 NH C NHCH 3 N NC N HN CH 3 OCH 2 CH 2 N H 3 C S (CH 2 ) 2 NH C NHCH 3 CH NO 2 H 3 C CaCO 3 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. trin-producing pancreatic tumors, Zol- linger-Ellison syndrome). Cimetidine, the first H 2 -antihistamine used thera- peutically, only rarely produces side ef- fects (CNS disturbances such as confu- sion; endocrine effects in the male, such as gynecomastia, decreased libido, im- potence). Unlike cimetidine, its newer and more potent congeners, ranitidine, nizatidine, and famotidine, do not inter- fere with the hepatic biotransformation of other drugs. Omeprazole (p. 167) can cause max- imal inhibition of HCl secretion. Given orally in gastric juice-resistant capsules, it reaches parietal cells via the blood. In the acidic milieu of the mucosa, an ac- tive metabolite is formed and binds co- valently to the ATP-driven proton pump (H + /K + ATPase) that transports H + in ex- change for K + into the gastric juice. Lan- soprazole and pantoprazole produce analogous effects. The proton pump in- hibitors are first-line drugs for the treat- ment of gastroesophageal reflux dis- ease. II. Protective Drugs Sucralfate (A) contains numerous alu- minum hydroxide residues. However, it is not an antacid because it fails to lower the overall acidity of gastric juice. After oral intake, sucralfate molecules under- go cross-linking in gastric juice, forming a paste that adheres to mucosal defects and exposed deeper layers. Here sucral- fate intercepts H + . Protected from acid, and also from pepsin, trypsin, and bile acids, the mucosal defect can heal more rapidly. Sucralfate is taken on an empty stomach (1 h before meals and at bed- time). It is well tolerated; however, re- leased Al 3+ ions can cause constipation. Misoprostol (B) is a semisynthetic prostaglandin derivative with greater stability than natural prostaglandin, permitting absorption after oral admin- istration. Like locally released prosta- glandins, it promotes mucus production and inhibits acid secretion. Additional systemic effects (frequent diarrhea; risk of precipitating contractions of the gravid uterus) significantly restrict its therapeutic utility. Carbenoxolone (B) is a derivative of glycyrrhetinic acid, which occurs in the sap of licorice root (succus liquiri- tiae). Carbenoxolone stimulates mucus production. At the same time, it has a mineralocorticoid-like action (due to in- hibition of 11-β-hydroxysteroid dehy- drogenase) that promotes renal reab- sorption of NaCl and water. It may, therefore, exacerbate hypertension, congestive heart failure, or edemas. It is obsolete. III. Eradication of Helicobacter py- lori C. This microorganism plays an im- portant role in the pathogenesis of chronic gastritis and peptic ulcer dis- ease. The combination of antibacterial drugs and omeprazole has proven effec- tive. In case of intolerance to amoxicillin (p. 270) or clarithromycin (p. 276), met- ronidazole (p. 274) can be used as a sub- stitute. Colloidal bismuth compounds are also effective; however, the problem of heavy-metal exposure compromises their long-term use. 168 Drugs for the Treatment of Peptic Ulcers Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for the Treatment of Peptic Ulcers 169 C. Helicobacter eradication Misoprostol B. Chemical structure and protective effect of misoprostol A. Chemical structure and protective effect of sucralfate R = – SO 3 [Al 2 (OH) 5 ] Sucralfate Conversion in acidic en- vironment pH < 4 Cross-linking and formation of paste Coating of mucosal defects R = – SO 3 [Al 2 (OH) 4 ] + – SO 3 - H + R R RR R R R R Helicobacter pylori Eradication e.g., short-term triple therapy Gastritis Peptic ulcer Amoxicillin Clarithromycin Omeprazole (2 x 1000 mg) (2 x 500 mg) (2 x 20 mg) 7 days 7 days 7 days Induction of labor Prostaglandin receptor K + H + HClMucus ATPase Parietal cell Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Laxatives Laxatives promote and facilitate bowel evacuation by acting locally to stimulate intestinal peristalsis, to soften bowel contents, or both. 1. Bulk laxatives. Distention of the intestinal wall by bowel contents stimu- lates propulsive movements of the gut musculature (peristalsis). Activation of intramural mechanoreceptors induces a neurally mediated ascending reflex con- traction (red in A) and descending re- laxation (blue) whereby the intralumi- nal bolus is moved in the anal direction. Hydrophilic colloids or bulk gels (B) comprise insoluble and nonabsorb- able carbohydrate substances that ex- pand on taking up water in the bowel. Vegetable fibers in the diet act in this manner. They consist of the indigestible plant cell walls containing homoglycans that are resistant to digestive enzymes, e.g., cellulose (1L504784β-linked glucose mo- lecules vs. 1L504784α glucoside bond in starch, p. 153). Bran, a grain milling waste product, and linseed (flaxseed) are both rich in cellulose. Other hydrophilic colloids de- rive from the seeds of Plantago species or karaya gum. Ingestion of hydrophilic gels for the prophylaxis of constipation usually entails a low risk of side effects. However, with low fluid intake in com- bination with a pathological bowel stenosis, mucilaginous viscous material could cause bowel occlusion (ileus). Osmotically active laxatives (C) are soluble but nonabsorbable particles that retain water in the bowel by virtue of their osmotic action. The osmotic pressure (particle concentration) of bowel contents always corresponds to that of the extracellular space. The in- testinal mucosa is unable to maintain a higher or lower osmotic pressure of the luminal contents. Therefore, absorption of molecules (e.g., glucose, NaCl) occurs isoosmotically, i.e., solute molecules are followed by a corresponding amount of water. Conversely, water remains in the bowel when molecules cannot be ab- sorbed. With Epsom and Glauber’s salts (MgSO 4 and Na 2 SO 4 , respectively), the SO 4 2– anion is nonabsorbable and re- tains cations to maintain electroneu- trality. Mg 2+ ions are also believed to promote release from the duodenal mu- cosa of cholecystokinin/pancreozymin, a polypeptide that also stimulates peris- talsis. These so-called saline cathartics elicit a watery bowel discharge 1–3 h af- ter administration (preferably in isoton- ic solution). They are used to purge the bowel (e.g., before bowel surgery) or to hasten the elimination of ingested poi- sons. Glauber’s salt (high Na + content) is contraindicated in hypertension, con- gestive heart failure, and edema. Epsom salt is contraindicated in renal failure (risk of Mg 2+ intoxication). Osmotic laxative effects are also produced by the polyhydric alcohols, mannitol and sorbitol, which unlike glu- cose cannot be transported through the intestinal mucosa, as well as by the non- hydrolyzable disaccharide, lactulose. Fermentation of lactulose by colon bac- teria results in acidification of bowel contents and microfloral damage. Lac- tulose is used in hepatic failure in order to prevent bacterial production of am- monia and its subsequent absorption (absorbable NH 3 L50478 nonabsorbable NH 4 + ), so as to forestall hepatic coma. 2. Irritant laxatives—purgatives cathartics. Laxatives in this group exert an irritant action on the enteric mucosa (A). Consequently, less fluid is absorbed than is secreted. The increased filling of the bowel promotes peristalsis; excita- tion of sensory nerve endings elicits en- teral hypermotility. According to the site of irritation, one distinguishes the small bowel irritant castor oil from the large bowel irritants anthraquinone and diphenolmethane derivatives (for de- tails see p. 174). Misuse of laxatives. It is a widely held belief that at least one bowel movement per day is essential for health; yet three bowel evacuations per week are quite normal. The desire for frequent bowel emptying probably stems from the time-honored, albeit 170 Laxatives Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Laxatives 171 C. Osmotically active laxatives B. Bulk laxatives A. Stimulation of peristalsis by an intraluminal bolus Stretch receptors Cellulose, agar-agar, bran, linseed H 2 O G = Glucose Contraction Relaxation H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O H 2 O Na + , Cl - H 2 O Isoosmotic absorption G H 2 O H 2 O G G H 2 O H 2 O H 2 O 2 Na + SO 4 2- H 2 OH 2 O Mannitol H 2 O G H 2 O G H 2 O G H 2 O Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. mistaken, notion that absorption of co- lon contents is harmful. Thus, purging has long been part of standard thera- peutic practice. Nowadays, it is known that intoxication from intestinal sub- stances is impossible as long as the liver functions normally. Nonetheless, purga- tives continue to be sold as remedies to “cleanse the blood” or to rid the body of “corrupt humors.” There can be no objection to the in- gestion of bulk substances for the pur- pose of supplementing low-residue “modern diets.” However, use of irritant purgatives or cathartics is not without hazards. Specifically, there is a risk of laxative dependence, i.e., the inability to do without them. Chronic intake of irri- tant purgatives disrupts the water and electrolyte balance of the body and can thus cause symptoms of illness (e.g., cardiac arrhythmias secondary to hypo- kalemia). Causes of purgative dependence (B). The defecation reflex is triggered when the sigmoid colon and rectum are filled. A natural defecation empties the large bowel up to and including the de- scending colon. The interval between natural stool evacuations depends on the speed with which these colon seg- ments are refilled. A large bowel irritant purgative clears out the entire colon. Accordingly, a longer period is needed until the next natural defecation can oc- cur. Fearing constipation, the user be- comes impatient and again resorts to the laxative, which then produces the desired effect as a result of emptying out the upper colonic segments. There- fore, a “compensatory pause” following cessation of laxative use must not give cause for concern (1). In the colon, semifluid material en- tering from the small bowel is thick- ened by absorption of water and salts (from about 1000 to 150 mL/d). If, due to the action of an irritant purgative, the colon empties prematurely, an enteral loss of NaCl, KCl and water will be in- curred. To forestall depletion of NaCl and water, the body responds with an increased release of aldosterone (p. 124), which stimulates their reabsorp- tion in the kidney. The action of aldoste- rone is, however, associated with in- creased renal excretion of KCl. The en- teral and renal K + loss add up to a K + de- pletion of the body, evidenced by a fall in serum K + concentration (hypokale- mia). This condition is accompanied by a reduction in intestinal peristalsis (bowel atonia). The affected individual infers “constipation,” again partakes of the purgative, and the vicious circle is closed (2). Chologenic diarrhea results when bile acids fail to be absorbed in the ile- um (e.g., after ileal resection) and enter the colon, where they cause enhanced secretion of electrolytes and water, leading to the discharge of fluid stools. 172 Laxatives Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Laxatives 173 B. Causes of laxative habituation A. Stimulation of peristalsis by mucosal irritation PeristalsisIrritation of mucosa Interval needed to refill colon Normal filling defecation reflex After normal evacuation of colon Laxative Longer interval needed to refill rectum Enteral loss of K + Na + , H 2 O Renal loss of K + Aldosterone Renal retention of Na + , H 2 O Reflex Filling Absorption Secretion of fluid Bowel inertia Hypokalemia “Constipation” Laxative 1 2 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 2.a Small Bowel Irritant Purgative, Ricinoleic Acid Castor oil comes from Ricinus commu- nis (castor plants; Fig: sprig, panicle, seed); it is obtained from the first cold- pressing of the seed (shown in natural size). Oral administration of 10–30 mL of castor oil is followed within 0.5 to 3 h by discharge of a watery stool. Ricinole- ic acid, but not the oil itself, is active. It arises as a result of the regular process- es involved in fat digestion: the duoden- al mucosa releases the enterohormone cholecystokinin/pancreozymin into the blood. The hormone elicits contraction of the gallbladder and discharge of bile acids via the bile duct, as well as release of lipase from the pancreas (intestinal peristalsis is also stimulated). Because of its massive effect, castor oil is hardly suitable for the treatment of ordinary constipation. It can be employed after oral ingestion of a toxin in order to has- ten elimination and to reduce absorp- tion of toxin from the gut. Castor oil is not indicated after the ingestion of lipo- philic toxins likely to depend on bile ac- ids for their absorption. 2.b Large Bowel Irritant Purgatives (p. 177 ff) Anthraquinone derivatives (p. 176) are of plant origin. They occur in the leaves (folia sennae) or fruits (fructus sennae) of the senna plant, the bark of Rhamnus frangulae and Rh. purshiana, (cortex frangulae, cascara sagrada), the roots of rhubarb (rhizoma rhei), or the leaf ex- tract from Aloe species (p. 176). The structural features of anthraquinone de- rivatives are illustrated by the proto- type structure depicted on p. 177. Among other substituents, the anthra- quinone nucleus contains hydroxyl groups, one of which is bound to a sugar (glucose, rhamnose). Following inges- tion of galenical preparations or of the anthraquinone glycosides, discharge of soft stool occurs after a latency of 6 to 8 h. The anthraquinone glycosides them- selves are inactive but are converted by colon bacteria to the active free agly- cones. Diphenolmethane derivatives (p. 177) were developed from phenolphthalein, an accidentally discovered laxative, use of which had been noted to result in rare but severe allergic reactions. Bisac- odyl and sodium picosulfate are convert- ed by gut bacteria into the active colon- irritant principle. Given by the enteral route, bisacodyl is subject to hydrolysis of acetyl residues, absorption, conjuga- tion in liver to glucuronic acid (or also to sulfate, p. 38), and biliary secretion into the duodenum. Oral administration is followed after approx. 6 to 8 h by dis- charge of soft formed stool. When given by suppository, bisacodyl produces its effect within 1 h. Indications for colon-irritant purga- tives are the prevention of straining at stool following surgery, myocardial in- farction, or stroke; and provision of re- lief in painful diseases of the anus, e.g., fissure, hemorrhoids. Purgatives must not be given in ab- dominal complaints of unclear origin. 3. Lubricant laxatives. Liquid paraffin (paraffinum subliquidum) is almost non- absorbable and makes feces softer and more easily passed. It interferes with the absorption of fat-soluble vitamins by trapping them. The few absorbed paraffin particles may induce formation of foreign-body granulomas in enteric lymph nodes (paraffinomas). Aspiration into the bronchial tract can result in li- poid pneumonia. Because of these ad- verse effects, its use is not advisable. 174 Laxatives and Purgatives Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Laxatives and Purgatives 175 A. Small-bowel irritant laxative: ricinoleic acid Ricinus communis Gall- bladder Pancreas Peristalsis CK/PZ = Cholecystokinin/pancreozymin CK/PZ Castor oil Glycerol + 3 Ricinoleic acids Bile acids Duodenum Ricinoleic acid – O – CH 2 Ricinoleic acid – O – CH Ricinoleic acid – O – CH 2 Lipase Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 176 Laxatives and Purgatives A. Plants containing anthraquinone glycosides Senna Frangula Rhubarb Aloe Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Laxatives and Purgatives 177 Sugar cleavage Reduction Anthraquinone glycoside Bacteria 1,8-Dihydroxy- anthrone -Anthranol e.g., 1,8-Dihydroxy- anthraquinone glycoside Glucur onide Esterase Diphenol B. Large-bowel irritant laxatives: diphenylmethane derivatives A. Large-bowel irritant laxatives: anthraquinone derivatives Glucuronidation Diphenol Bacteria Glucu- ronate Sulfate Bisacodyl Sodium picosulfate sugar Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antidiarrheal Agents Causes of diarrhea (in red): Many bacte- ria (e.g., Vibrio cholerae) secrete toxins that inhibit the ability of mucosal ente- rocytes to absorb NaCl and water and, at the same time, stimulate mucosal secre- tory activity. Bacteria or viruses that in- vade the gut wall cause inflammation characterized by increased fluid secre- tion into the lumen. The enteric muscu- lature reacts with increased peristalsis. The aims of antidiarrheal therapy are to prevent: (1) dehydration and electrolyte depletion; and (2) excessive- ly high stool frequency. Different ther- apeutic approaches (in green) listed are variously suited for these purposes. Adsorbent powders are nonab- sorbable materials with a large surface area. These bind diverse substances, in- cluding toxins, permitting them to be inactivated and eliminated. Medicinal charcoal possesses a particularly large surface because of the preserved cell structures. The recommended effective antidiarrheal dose is in the range of 4–8 g. Other adsorbents are kaolin (hy- drated aluminum silicate) and chalk. Oral rehydration solution (g/L of boiled water: NaCl 3.5, glucose 20, NaHCO 3 2.5, KCl 1.5). Oral administra- tion of glucose-containing salt solutions enables fluids to be absorbed because toxins do not impair the cotransport of Na + and glucose (as well as of H 2 O) through the mucosal epithelium. In this manner, although frequent discharge of stool is not prevented, dehydration is successfully corrected. Opioids. Activation of opioid recep- tors in the enteric nerve plexus results in inhibition of propulsive motor activ- ity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opi- um tincture (paregoric) containing mor- phine. Because of the CNS effects (seda- tion, respiratory depression, physical dependence), derivatives with periph- eral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not affect brain functions at normal dosage. Loperamide is, therefore, the opioid antidiarrheal of first choice. The pro- longed contact time of intestinal con- tents and mucosa may also improve ab- sorption of fluid. With overdosage, there is a hazard of ileus. It is contrain- dicated in infants below age 2 y. Antibacterial drugs. Use of these agents (e.g., cotrimoxazole, p. 272) is only rational when bacteria are the cause of diarrhea. This is rarely the case. It should be kept in mind that antibio- tics also damage the intestinal flora which, in turn, can give rise to diarrhea. Astringents such as tannic acid (home remedy: black tea) or metal salts precipitate surface proteins and are thought to help seal the mucosal epithe- lium. Protein denaturation must not in- clude cellular proteins, for this would mean cell death. Although astringents induce constipation (cf. Al 3+ salts, p. 166), a therapeutic effect in diarrhea is doubtful. Demulcents, e.g., pectin (home remedy: grated apples) are carbohy- drates that expand on absorbing water. They improve the consistency of bowel contents; beyond that they are devoid of any favorable effect. 178 Antidiarrheals Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antidiarrheals 179 A. Antidiarrheals and their sites of action Resident microflora Opioid- receptors Protein- containing mucus Precipitation of surface proteins, sealing of mucosa Astringents: e.g., tannic acid Viruses Pathogenic bacteria Fluid secretion Cl - Na + Toxins Glucose Na + Mucosal injury Antibacterial drugs: e.g., co-trimoxazole Adsorption e.g., to medicinal charcoal Toxins Inhibition of propulsive peristalsis Opium tincture with morphine Diphenoxylate Loperamide CNS Enhanced peristalsis Diarrhea Oral rehydration solution: salts and glucose Fluid loss Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for Dissolving Gallstones (A) Following its secretion from liver into bile, water-insoluble cholesterol is held in solution in the form of micellar com- plexes with bile acids and phospholip- ids. When more cholesterol is secreted than can be emulsified, it precipitates and forms gallstones (cholelithiasis). Precipitated cholesterol can be reincor- porated into micelles, provided the cho- lesterol concentration in bile is below saturation. Thus, cholesterol-contain- ing stones can be dissolved slowly. This effect can be achieved by long-term oral administration of chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA). Both are physiologically occur- ring, stereoisomeric bile acids (position of the 7-hydroxy group being β in UCDA and α in CDCA). Normally, they repre- sent a small proportion of the total amount of bile acid present in the body (circle diagram in A); however, this in- creases considerably with chronic ad- ministration because of enterohepatic cycling, p. 38). Bile acids undergo almost complete reabsorption in the ileum. Small losses via the feces are made up by de novo synthesis in the liver, keep- ing the total amount of bile acids con- stant (3–5 g). Exogenous supply re- moves the need for de novo synthesis of bile acids. The particular acid being sup- plied gains an increasingly larger share of the total store. The altered composition of bile in- creases the capacity for cholesterol up- take. Thus, gallstones can be dissolved in the course of a 1- to 2 y treatment, provided that cholesterol stones are pure and not too large (<15 mm), gall bladder function is normal, liver disease is absent, and patients are of normal body weight. UCDA is more effective (daily dose, 8–10 mg) and better toler- ated than is CDCA (15 mg/d; frequent diarrhea, elevation of liver enzymes in plasma). Stone formation may recur af- ter cessation of successful therapy. Compared with surgical treatment, drug therapy plays a subordinate role. UCDA may also be useful in primary bil- iary cirrhosis. Choleretics are supposed to stimu- late production and secretion of dilute bile fluid. This principle has little thera- peutic significance. Cholekinetics stimulate the gall- bladder to contract and empty, e.g., egg yolk, the osmotic laxative MgSO 4 , the cholecystokinin-related ceruletide (giv- en parenterally). Cholekinetics are em- ployed to test gallbladder function for diagnostic purposes. Pancreatic enzymes (B) from slaughtered animals are used to relieve excretory insufficiency of the pancreas (L50478 disrupted digestion of fats; steator- rhea, inter alia). Normally, secretion of pancreatic enzymes is activated by cholecystokinin/pancreozymin, the en- terohormone that is released into blood from the duodenal mucosa upon con- tact with chyme. With oral administra- tion of pancreatic enzymes, allowance must be made for their partial inactiva- tion by gastric acid (the lipases, particu- larly). Therefore, they are administered in acid-resistant dosage forms. Antiflatulents (carminatives) serve to alleviate meteorism (excessive accu- mulation of gas in the gastrointestinal tract). Aborad propulsion of intestinal contents is impeded when the latter are mixed with gas bubbles. Defoaming agents, such as dimethicone (dimethyl- polysiloxane) and simethicone, in com- bination with charcoal, are given orally to promote separation of gaseous and semisolid contents. 180 Other Gastrointestinal Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Other Gastrointestinal Drugs 181 CA : Cholic acid DCA : Desoxy-CA UDCA : Ursodesoxy-CA CDCA : Chenodesoxy-CA UDCA Gall-stone formed by cholesterol Ileum Excretion in feces Stomach Duodenum CK/PZ Fat- containing chymus Addition of dimethicone “Defoaming” C. Carminative effect of dimethicone Synthesis of bile acids to maintain store DAA CDCA CA UDCA DCA CDCA CA UDCA “Pancreatin” of slaughter animals: Protease, Amylase, Lipase Pancreatic enzyme B. Release of pancreatic enzymes and their replacement A. Gallstone dissolution Circulation Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Affecting Motor Function The smallest structural unit of skeletal musculature is the striated muscle fiber. It contracts in response to an impulse of its motor nerve. In executing motor pro- grams, the brain sends impulses to the spinal cord. These converge on α-moto- neurons in the anterior horn of the spi- nal medulla. Efferent axons course, bun- dled in motor nerves, to skeletal mus- cles. Simple reflex contractions to sen- sory stimuli, conveyed via the dorsal roots to the motoneurons, occur with- out participation of the brain. Neural circuits that propagate afferent impuls- es into the spinal cord contain inhibit- ory interneurons. These serve to pre- vent a possible overexcitation of moto- neurons (or excessive muscle contrac- tions) due to the constant barrage of sensory stimuli. Neuromuscular transmission (B) of motor nerve impulses to the striated muscle fiber takes place at the motor endplate. The nerve impulse liberates acetylcholine (ACh) from the axon ter- minal. ACh binds to nicotinic cholinocep- tors at the motor endplate. Activation of these receptors causes depolarization of the endplate, from which a propagated action potential (AP) is elicited in the surrounding sarcolemma. The AP trig- gers a release of Ca 2+ from its storage or- ganelles, the sarcoplasmic reticulum (SR), within the muscle fiber; the rise in Ca 2+ concentration induces a contrac- tion of the myofilaments (electrome- chanical coupling). Meanwhile, ACh is hydrolyzed by acetylcholinesterase (p. 100); excitation of the endplate sub- sides. If no AP follows, Ca 2+ is taken up again by the SR and the myofilaments relax. Clinically important drugs (with the exception of dantrolene) all inter- fere with neural control of the muscle cell (A, B, p. 183ff.) Centrally acting muscle relaxants (A) lower muscle tone by augmenting the activity of intraspinal inhibitory interneurons. They are used in the treat- ment of painful muscle spasms, e.g., in spinal disorders. Benzodiazepines en- hance the effectiveness of the inhibitory transmitter GABA (p. 226) at GABA A re- ceptors. Baclofen stimulates GABA B re- ceptors. α 2 -Adrenoceptor agonists such as clonidine and tizanidine probably act presynaptically to inhibit release of ex- citatory amino acid transmitters. The convulsant toxins, tetanus tox- in (cause of wound tetanus) and strych- nine diminish the efficacy of interneu- ronal synaptic inhibition mediated by the amino acid glycine (A). As a conse- quence of an unrestrained spread of nerve impulses in the spinal cord, motor convulsions develop. The involvement of respiratory muscle groups endangers life. Botulinum toxin from Clostridium botulinum is the most potent poison known. The lethal dose in an adult is ap- prox. 3 L1154 10 –6 mg. The toxin blocks exo- cytosis of ACh in motor (and also para- sympathetic) nerve endings. Death is caused by paralysis of respiratory mus- cles. Injected intramuscularly at minus- cule dosage, botulinum toxin type A is used to treat blepharospasm, strabis- mus, achalasia of the lower esophageal sphincter, and spastic aphonia. A pathological rise in serum Mg 2+ levels also causes inhibition of ACh re- lease, hence inhibition of neuromuscu- lar transmission. Dantrolene interferes with electro- mechanical coupling in the muscle cell by inhibiting Ca 2+ release from the SR. It is used to treat painful muscle spasms attending spinal diseases and skeletal muscle disorders involving excessive release of Ca 2+ (malignant hyperther- mia). 182 Drugs Acting on Motor Systems Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on Motor Systems 183 Depola- rization Attenuated inhibition Inhibitory interneuron Tetanus Toxin Inhibition of release Glycine Strychnine Receptor antagonist ConvulsantsMyotonolytics Increased inhibition Inhibitory neuron Benzodiazepines e.g., diazepam GABA Agonist Baclofen (GABA = γ-aminobutyric acid) B. Inhibition of neuromuscular transmission and electromechanical coupling A. Mechanisms for influencing skeletal muscle tone Antiepileptics Antiparkinsonian drugs Myotonolytics Dantrolene Muscle relaxants Mg 2+ Botulinum toxin inhibit ACh-release Muscle relaxants inhibit generation of action potential Sarcoplasmic reticulum Action potential Motor neuron Motor endplate ACh receptor (nicotinic) Myofilaments Contraction Ca 2+ Membrane potential Muscle tone ms 10 20 ACh t-Tubule Dantrolene inhibits Ca 2+ release Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Muscle Relaxants Muscle relaxants cause a flaccid paraly- sis of skeletal musculature by binding to motor endplate cholinoceptors, thus blocking neuromuscular transmission (p. 182). According to whether receptor oc- cupancy leads to a blockade or an exci- tation of the endplate, one distinguishes nondepolarizing from depolarizing muscle relaxants (p. 186). As adjuncts to general anesthetics, muscle relaxants help to ensure that surgical procedures are not disturbed by muscle contrac- tions of the patient (p. 216). Nondepolarizing muscle relaxants Curare is the term for plant-derived ar- row poisons of South American natives. When struck by a curare-tipped arrow, an animal suffers paralysis of skeletal musculature within a short time after the poison spreads through the body; death follows because respiratory mus- cles fail (respiratory paralysis). Killed game can be eaten without risk because absorption of the poison from the gas- trointestinal tract is virtually nil. The cu- rare ingredient of greatest medicinal importance is d-tubocurarine. This compound contains a quaternary nitro- gen atom (N) and, at the opposite end of the molecule, a tertiary N that is proto- nated at physiological pH. These two positively charged N atoms are common to all other muscle relaxants. The fixed positive charge of the quaternary N ac- counts for the poor enteral absorbabil- ity. d-Tubocurarine is given by i.v. in- jection (average dose approx. 10 mg). It binds to the endplate nicotinic cholino- ceptors without exciting them, acting as a competitive antagonist towards ACh. By preventing the binding of released ACh, it blocks neuromuscular transmis- sion. Muscular paralysis develops with- in about 4 min. d-Tubocurarine does not penetrate into the CNS. The patient would thus experience motor paralysis and inability to breathe, while remain- ing fully conscious but incapable of ex- pressing anything. For this reason, care must be taken to eliminate conscious- ness by administration of an appropri- ate drug (general anesthesia) before us- ing a muscle relaxant. The effect of a sin- gle dose lasts about 30 min. The duration of the effect of d-tubo- curarine can be shortened by adminis- tering an acetylcholinesterase inhibitor, such as neostigmine (p. 102). Inhibition of ACh breakdown causes the concen- tration of ACh released at the endplate to rise. Competitive “displacement” by ACh of d-tubocurarine from the recep- tor allows transmission to be restored. Unwanted effects produced by d-tu- bocurarine result from a nonimmune- mediated release of histamine from mast cells, leading to bronchospasm, ur- ticaria, and hypotension. More com- monly, a fall in blood pressure can be at- tributed to ganglionic blockade by d-tu- bocurarine. Pancuronium is a synthetic com- pound now frequently used and not likely to cause histamine release or gan- glionic blockade. It is approx. 5-fold more potent than d-tubocurarine, with a somewhat longer duration of action. Increased heart rate and blood pressure are attributed to blockade of cardiac M 2 - cholinoceptors, an effect not shared by newer pancuronium congeners such as vecuronium and pipecuronium. Other nondepolarizing muscle re- laxants include: alcuronium, derived from the alkaloid toxiferin; rocuroni- um, gallamine, mivacurium, and atra- curium. The latter undergoes spontane- ous cleavage and does not depend on hepatic or renal elimination. 184 Drugs Acting on Motor Systems Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on Motor Systems 185 ACh A. Non-depolarizing muscle relaxants Arrow poison of indigenous South Americans Blockade of ACh receptors No depolarization of endplate Relaxation of skeletal muscles (Respiratory paralysis) Artificial ventilation necessary (plus general anesthesia!) Antidote: cholinesterase inhibitors e.g., neostigmine (no enteral absorption) d-Tubocurarine Pancuronium Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Depolarizing Muscle Relaxants In this drug class, only succinylcholine (succinyldicholine, suxamethonium, A) is of clinical importance. Structurally, it can be described as a double ACh mole- cule. Like ACh, succinylcholine acts as agonist at endplate nicotinic cholino- ceptors, yet it produces muscle relaxa- tion. Unlike ACh, it is not hydrolyzed by acetylcholinesterase. However, it is a substrate of nonspecific plasma cholin- esterase (serum cholinesterase, p. 100). Succinylcholine is degraded more slow- ly than is ACh and therefore remains in the synaptic cleft for several minutes, causing an endplate depolarization of corresponding duration. This depola- rization initially triggers a propagated action potential (AP) in the surrounding muscle cell membrane, leading to con- traction of the muscle fiber. After its i.v. injection, fine muscle twitches (fascicu- lations) can be observed. A new AP can be elicited near the endplate only if the membrane has been allowed to repo- larize. The AP is due to opening of voltage- gated Na-channel proteins, allowing Na + ions to flow through the sarcolem- ma and to cause depolarization. After a few milliseconds, the Na channels close automatically (“inactivation”), the membrane potential returns to resting levels, and the AP is terminated. As long as the membrane potential remains in- completely repolarized, renewed open- ing of Na channels, hence a new AP, is impossible. In the case of released ACh, rapid breakdown by ACh esterase al- lows repolarization of the endplate and hence a return of Na channel excitabil- ity in the adjacent sarcolemma. With succinylcholine, however, there is a per- sistent depolarization of the endplate and adjoining membrane regions. Be- cause the Na channels remain inactivat- ed, an AP cannot be triggered in the ad- jacent membrane. Because most skeletal muscle fibers are innervated only by a single endplate, activation of such fibers, with lengths up to 30 cm, entails propagation of the AP through the entire cell. If the AP fails, the muscle fiber remains in a relaxed state. The effect of a standard dose of suc- cinylcholine lasts only about 10 min. It is often given at the start of anesthesia to facilitate intubation of the patient. As expected, cholinesterase inhibitors are unable to counteract the effect of succi- nylcholine. In the few patients with a genetic deficiency in pseudocholineste- rase (= nonspecific cholinesterase), the succinylcholine effect is significantly prolonged. Since persistent depolarization of endplates is associated with an efflux of K + ions, hyperkalemia can result (risk of cardiac arrhythmias). Only in a few muscle types (e.g., extraocular muscle) are muscle fibers supplied with multiple endplates. Here succinylcholine causes depolarization distributed over the entire fiber, which responds with a contracture. Intraocular pressure rises, which must be taken into account during eye surgery. In skeletal muscle fibers whose mo- tor nerve has been severed, ACh recep- tors spread in a few days over the entire cell membrane. In this case, succinyl- choline would evoke a persistent depo- larization with contracture and hyper- kalemia. These effects are likely to occur in polytraumatized patients undergoing follow-up surgery. 186 Drugs Acting on Motor Systems Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on Motor Systems 187 A. Action of the depolarizing muscle relaxant succinylcholine Depolarization Depolarization Acetylcholine Skeletal muscle cell Rapid ACh cleavage by acetylcholine esterases Propagation of action potential (AP) ACh 1 Repolarization of end plate2 ACh 3 New AP and contraction can be elicited Succinylcholine not degraded by acetylcholine esterases Succinylcholine Persistent depolarization of end plate New AP and contraction cannot be elicited Contraction Contraction Membrane potential Na + -channel Closed (opening not possible) Repolarization Closed (opening possible) Open Membrane potential Persistent depolarization No repolarization, renewed opening of Na + -channel impossible Membrane potential Succinylcholine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antiparkinsonian Drugs Parkinson’s disease (shaking palsy) and its syndromal forms are caused by a de- generation of nigrostriatal dopamine neurons. The resulting striatal dopa- mine deficiency leads to overactivity of cholinergic interneurons and imbalance of striopallidal output pathways, mani- fested by poverty of movement (akine- sia), muscle stiffness (rigidity), tremor at rest, postural instability, and gait dis- turbance. Pharmacotherapeutic measures are aimed at restoring dopaminergic func- tion or suppressing cholinergic hyper- activity. L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier; how- ever, its natural precursor, L-dihydroxy- phenylalanine (levodopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy- lated by DOPA-decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed, likely causing undesirable effects (tachycardia, ar- rhythmias resulting from activation of β 1 -adrenoceptors [p. 114], hypotension, and vomiting). Extracerebral produc- tion of dopamine can be prevented by inhibitors of DOPA-decarboxylase (car- bidopa, benserazide) that do not pene- trate the blood-brain barrier, leaving intracerebral decarboxylation unaffect- ed. Excessive elevation of brain dopa- mine levels may lead to undesirable re- actions, such as involuntary movements (dyskinesias) and mental disturbances. Dopamine receptor agonists. Defi- cient dopaminergic transmission in the striatum can be compensated by ergot derivatives (bromocriptine [p. 114], lisu- ride, cabergoline, and pergolide) and nonergot compounds (ropinirole, prami- pexole). These agonists stimulate dopa- mine receptors (D 2 , D 3 , and D 1 sub- types), have lower clinical efficacy than levodopa, and share its main adverse ef- fects. Inhibitors of monoamine oxi- dase-B (MAO B ). This isoenzyme breaks down dopamine in the corpus striatum and can be selectively inhibited by se- legiline. Inactivation of norepinephrine, epinephrine, and 5-HT via MAO A is un- affected. The antiparkinsonian effects of selegiline may result from decreased dopamine inactivation (enhanced levo- dopa response) or from neuroprotective mechanisms (decreased oxyradical for- mation or blocked bioactivation of an unknown neurotoxin). Inhibitors of catechol-O-methyl- transferase (COMT). L-Dopa and dopa- mine become inactivated by methyla- tion. The responsible enzyme can be blocked by entacapone, allowing higher levels of L-dopa and dopamine to be achieved in corpus striatum. Anticholinergics. Antagonists at muscarinic cholinoceptors, such as benzatropine and biperiden (p. 106), suppress striatal cholinergic overactiv- ity and thereby relieve rigidity and tremor; however, akinesia is not re- versed or is even exacerbated. Atropine- like peripheral side effects and impair- ment of cognitive function limit the tol- erable dosage. Amantadine. Early or mild parkin- sonian manifestations may be tempo- rarily relieved by amantadine. The underlying mechanism of action may involve, inter alia, blockade of ligand- gated ion channels of the glutamate/ NMDA subtype, ultimately leading to a diminished release of acetylcholine. Administration of levodopa plus carbidopa (or benserazide) remains the most effective treatment, but does not provide benefit beyond 3–5 y and is fol- lowed by gradual loss of symptom con- trol, on-off fluctuations, and develop- ment of orobuccofacial and limb dyski- nesias. These long-term drawbacks of levodopa therapy may be delayed by early monotherapy with dopamine re- ceptor agonists. Treatment of advanced disease requires the combined adminis- tration of antiparkinsonian agents. 188 Drugs Acting on Motor Systems Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on Motor Systems 189 A. Antiparkinsonian drugs Selegiline Inhibition of dopamine degradation by MAO-B in CNS Normal state Dopamine Acetylcholine Dopamine deficiency Predominance of acetylcholine Parkinson′s disease Amantadine NMDA receptor: Blockade of ionophore: attenuation of cholinergic neurons Blood-brain barrier Dopa- decarboxylase Carbidopa Inhibition of dopa- decarboxylase Dopamine substitution Stimulation of peripheral dop- amine receptors Adverse effects 2000 mg 200 mg Dopamine BenzatropineBromocriptine Acetylcholine antagonist Dopamine-receptor agonist Inhibition of catechol- O-methyltransferase L-Dopa Dopamine precursor COMT N HH CHN CH 3 CH 3 H N H 3 C COOH NH 2 C 2 H 5 N O CN C 2 H 5HO HO NO 2 Entacapone Br N H H N N H O O N N O O OH CH 3 H 3 C H 3 C CH3 CH 3 H O N H 3 C N HO H H HO COOH Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antiepileptics Epilepsy is a chronic brain disease of di- verse etiology; it is characterized by re- current paroxysmal episodes of uncon- trolled excitation of brain neurons. In- volving larger or smaller parts of the brain, the electrical discharge is evident in the electroencephalogram (EEG) as synchronized rhythmic activity and manifests itself in motor, sensory, psy- chic, and vegetative (visceral) phenom- ena. Because both the affected brain re- gion and the cause of abnormal excit- ability may differ, epileptic seizures can take many forms. From a pharmaco- therapeutic viewpoint, these may be classified as: – general vs. focal seizures; – seizures with or without loss of con- sciousness; – seizures with or without specific modes of precipitation. The brief duration of a single epi- leptic fit makes acute drug treatment unfeasible. Instead, antiepileptics are used to prevent seizures and therefore need to be given chronically. Only in the case of status epilepticus (a succession of several tonic-clonic seizures) is acute anticonvulsant therapy indicated — usually with benzodiazepines given i.v. or, if needed, rectally. The initiation of an epileptic attack involves “pacemaker” cells; these differ from other nerve cells in their unstable resting membrane potential, i.e., a de- polarizing membrane current persists after the action potential terminates. Therapeutic interventions aim to stabilize neuronal resting potential and, hence, to lower excitability. In specific forms of epilepsy, initially a single drug is tried to achieve control of seizures, valproate usually being the drug of first choice in generalized seizures, and car- bamazepine being preferred for partial (focal), especially partial complex, sei- zures. Dosage is increased until seizures are no longer present or adverse effects become unacceptable. Only when monotherapy with different agents proves inadequate can changeover to a second-line drug or combined use (“add on”) be recommended (B), provided that the possible risk of pharmacokinet- ic interactions is taken into account (see below). The precise mode of action of antiepileptic drugs remains unknown. Some agents appear to lower neuronal excitability by several mechanisms of action. In principle, responsivity can be decreased by inhibiting excitatory or ac- tivating inhibitory neurons. Most excit- atory nerve cells utilize glutamate and most inhibitory neurons utilize γ-ami- nobutyric acid (GABA) as their transmit- ter (p. 193A). Various drugs can lower seizure threshold, notably certain neu- roleptics, the tuberculostatic isoniazid, and β-lactam antibiotics in high doses; they are, therefore, contraindicated in seizure disorders. Glutamate receptors comprise three subtypes, of which the NMDA subtype has the greatest therapeutic importance. (N-methyl-D-aspartate is a synthetic selective agonist.) This recep- tor is a ligand-gated ion channel that, upon stimulation with glutamate, per- mits entry of both Na + and Ca 2+ ions into the cell. The antiepileptics lamotrigine, phenytoin, and phenobarbital inhibit, among other things, the release of glu- tamate. Felbamate is a glutamate antag- onist. Benzodiazepines and phenobarbital augment activation of the GABA A recep- tor by physiologically released amounts of GABA (B) (see p. 226). Chloride influx is increased, counteracting depolariza- tion. Progabide is a direct GABA-mimet- ic. Tiagabin blocks removal of GABA from the synaptic cleft by decreasing its re-uptake. Vigabatrin inhibits GABA ca- tabolism. Gabapentin may augment the availability of glutamate as a precursor in GABA synthesis (B) and can also act as a K + -channel opener. 190 Drugs Acting on Motor Systems Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on Motor Systems 191 Focal seizures EEG Epileptic attack μV 150 100 50 1 sec Valproic acid Carbamazepine Phenytoin TopiramateGabapentin Phenobarbital Ethosuximide FelbamateVigabatrin A. Epileptic attack, EEG, and antiepileptics Simple seizures Complex or secondarily generalized I. II. III. Tonic-clonic attack (grand mal) Tonic attack Clonic attack Myoclonic attack Absence seizure Generalized attacks Valproic acid Carbam- azepine, Phenytoin Ethosuximide Lamotrigine, Primidone, Phenobarbital B. Indications for antiepileptics Choice Drugs used in the treatment of status epilepticus: Benzodiazepines, e.g., diazepam Drugs used in the prophylaxis of epileptic seizures 0 Waking state μV 150 100 50 1 sec 0 Carbam- azepine Valproic acid, Phenytoin, Clobazam Primidone, Phenobar- bital Lamotrigine or Clonazepam Lamotrigine or Vigabatrin or Gabapentin alternative addition + + + COOH H 3 C H 3 C N NH 2 OC N N H O H O COOH H 2 N N N N Cl NH 2 H 2 N Cl NC 2 H 5 N O O H O H N H O O H 5 C 2 H 3 C CH CH 2 OCNH 2 O O CH 2 OCNH 2 COOHH 2 N H 2 C Lamotrigine or Vigabatrin or Gabapentin Lamotrigine O O O O O OSO 2 NH 2 CH 3 H 3 C H 3 C CH 3 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Carbamazepine, valproate, and phenytoin enhance inactivation of volt- age-gated sodium and calcium channels and limit the spread of electrical excita- tion by inhibiting sustained high-fre- quency firing of neurons. Ethosuximide blocks a neuronal T- type Ca 2+ channel (A) and represents a special class because it is effective only in absence seizures. All antiepileptics are likely, albeit to different degrees, to produce adverse effects. Sedation, difficulty in concentrat- ing, and slowing of psychomotor drive encumber practically all antiepileptic therapy. Moreover, cutaneous, hemato- logical, and hepatic changes may neces- sitate a change in medication. Pheno- barbital, primidone, and phenytoin may lead to osteomalacia (vitamin D prophy- laxis) or megaloblastic anemia (folate prophylaxis). During treatment with phenytoin, gingival hyperplasia may de- velop in ca. 20% of patients. Valproic acid (VPA) is gaining in- creasing acceptance as a first-line drug; it is less sedating than other anticonvul- sants. Tremor, gastrointestinal upset, and weight gain are frequently ob- served; reversible hair loss is a rarer oc- currence. Hepatotoxicity may be due to a toxic catabolite (4-en VPA). Adverse reactions to carbamaze- pine include: nystagmus, ataxia, diplo- pia, particularly if the dosage is raised too fast. Gastrointestinal problems and skin rashes are frequent. It exerts an antidiuretic effect (sensitization of col- lecting ducts to vasopressin L50478 water in- toxication). Carbamazepine is also used to treat trigeminal neuralgia and neuropathic pain. Valproate, carbamazepine, and oth- er anticonvulsants pose teratogenic risks. Despite this, treatment should continue during pregnancy, as the po- tential threat to the fetus by a seizure is greater. However, it is mandatory to ad- minister the lowest dose affording safe and effective prophylaxis. Concurrent high-dose administration of folate may prevent neural tube developmental de- fects. Carbamazepine, phenytoin, pheno- barbital, and other anticonvulsants (ex- cept for gabapentin) induce hepatic en- zymes responsible for drug biotransfor- mation. Combinations between anticon- vulsants or with other drugs may result in clinically important interactions (plasma level monitoring!). For the often intractable childhood epilepsies, various other agents are used, including ACTH and the glucocor- ticoid, dexamethasone. Multiple (mixed) seizures associated with the slow spike-wave (Lennox–Gastaut) syn- drome may respond to valproate, la- motrigine, and felbamate, the latter be- ing restricted to drug-resistant seizures owing to its potentially fatal liver and bone marrow toxicity. Benzodiazepines are the drugs of choice for status epilepticus (see above); however, development of toler- ance renders them less suitable for long-term therapy. Clonazepam is used for myoclonic and atonic seizures. Clobazam, a 1,5-benzodiazepine exhib- iting an increased anticonvulsant/seda- tive activity ratio, has a similar range of clinical uses. Personality changes and paradoxical excitement are potential side effects. Clomethiazole can also be effective for controlling status epilepticus, but is used mainly to treat agitated states, es- pecially alcoholic delirium tremens and associated seizures. Topiramate, derived from D-fruc- tose, has complex, long-lasting anticon- vulsant actions that cooperate to limit the spread of seizure activity; it is effec- tive in partial seizures and as an add-on in Lennox–Gastaut syndrome. 192 Drugs Acting on Motor Systems Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Acting on Motor Systems 193 A. Neuronal sites of action of antiepileptics B. Sites of action of antiepileptics in GABAergic synapse Chloride channel GABA Glutamic acid decarboxylase Glutamic acid Succinic semialdehyde Ending of inhibitory neuron Succinic acid α γ α β β Allosteric enhance- ment of GABA action α γ α β β Vigabatrin Inhibitor of GABA- transaminase Tiagabine Inhibition of GABA reuptake Gabapentin Improved utilization of GABA precursor: glutamate Progabide GABA- mimetic Barbiturates Benzodiazepine GABA- transaminase GABA A - receptor Excitatory neuron NMDA- receptor Voltage dependent Na + -channel Ca 2+ -channel GABA Inhibitory neuron Glutamate Na + Ca ++ CI – GABA A - receptor NMDA-receptor- antagonist felbamate, valproic acid Enhanced inactivation: carbamazepine valproic acid phenytoin Inhibition of glutamate release: phenytoin, lamotrigine phenobarbital Gabamimetics: benzodiazepine barbiturates vigabatrin tiagabine gabapentin T-Type- calcium channel blocker ethosuximide, (valproic acid) Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Pain Mechanisms and Pathways Pain is a designation for a spectrum of sensations of highly divergent character and intensity ranging from unpleasant to intolerable. Pain stimuli are detected by physiological receptors (sensors, nociceptors) least differentiated mor- phologically, viz., free nerve endings. The body of the bipolar afferent first-or- der neuron lies in a dorsal root ganglion. Nociceptive impulses are conducted via unmyelinated (C-fibers, conduction ve- locity 0.2–2.0 m/s) and myelinated ax- ons (Aδ-fibers, 5–30 m/s). The free end- ings of Aδ fibers respond to intense pressure or heat, those of C-fibers re- spond to chemical stimuli (H + , K + , hista- mine, bradykinin, etc.) arising from tis- sue trauma. Irrespective of whether chemical, mechanical, or thermal stim- uli are involved, they become signifi- cantly more effective in the presence of prostaglandins (p. 196). Chemical stimuli also underlie pain secondary to inflammation or ischemia (angina pectoris, myocardial infarction), or the intense pain that occurs during overdistention or spasmodic contrac- tion of smooth muscle abdominal or- gans, and that may be maintained by lo- cal anoxemia developing in the area of spasm (visceral pain). Aδ and C-fibers enter the spinal cord via the dorsal root, ascend in the dorsolateral funiculus, and then syn- apse on second-order neurons in the dorsal horn. The axons of the second-or- der neurons cross the midline and as- cend to the brain as the anterolateral pathway or spinothalamic tract. Based on phylogenetic age, neo- and paleospi- nothalamic tracts are distinguished. Thalamic nuclei receiving neospinotha- lamic input project to circumscribed ar- eas of the postcentral gyrus. Stimuli conveyed via this path are experienced as sharp, clearly localizable pain. The nuclear regions receiving paleospino- thalamic input project to the postcen- tral gyrus as well as the frontal, limbic cortex and most likely represent the pathway subserving pain of a dull, ach- ing, or burning character, i.e., pain that can be localized only poorly. Impulse traffic in the neo- and pa- leospinothalamic pathways is subject to modulation by descending projections that originate from the reticular forma- tion and terminate at second-order neu- rons, at their synapses with first-order neurons, or at spinal segmental inter- neurons (descending antinociceptive system). This system can inhibit im- pulse transmission from first- to sec- ond-order neurons via release of opio- peptides (enkephalins) or monoamines (norepinephrine, serotonin). Pain sensation can be influenced or modified as follows: L50188 elimination of the cause of pain L50188 lowering of the sensitivity of noci- ceptors (antipyretic analgesics, local anesthetics) L50188 interrupting nociceptive conduction in sensory nerves (local anesthetics) L50188 suppression of transmission of noci- ceptive impulses in the spinal me- dulla (opioids) L50188 inhibition of pain perception (opi- oids, general anesthetics) L50188 altering emotional responses to pain, i.e., pain behavior (antidepress- ants as “co-analgesics,” p. 230). 194 Drugs for the Suppression of Pain (Analgesics) Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for the Suppression of Pain (Analgesics) 195 A. Pain mechanisms and pathways Perception: sharp quick localizable Perception: dull delayed diffuse Descending antinociceptive pathway Paleospinothalamic tract Neospinothalamic tract Prostaglandins Local anesthetics Reticular formation Opioids Opioids Anti- depressants Anesthetics Gyrus postcentralis Nociceptors Cyclooxygenase inhibitors Inflammation Cause of pain Thalamus Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Eicosanoids Origin and metabolism. The eicosan- oids, prostaglandins, thromboxane, prostacyclin, and leukotrienes, are formed in the organism from arachi- donic acid, a C20 fatty acid with four double bonds (eicosatetraenoic acid). Arachidonic acid is a regular constituent of cell membrane phospholipids; it is released by phospholipase A 2 and forms the substrate of cyclooxygenases and lipoxygenases. Synthesis of prostaglandins (PG), prostacyclin, and thromboxane pro- ceeds via intermediary cyclic endoper- oxides. In the case of PG, a cyclopentane ring forms in the acyl chain. The letters following PG (D, E, F, G, H, or I) indicate differences in substitution with hydrox- yl or keto groups; the number sub- scripts refer to the number of double bonds, and the Greek letter designates the position of the hydroxyl group at C9 (the substance shown is PGF 2α ). PG are primarily inactivated by the enzyme 15- hydroxyprostaglandindehydrogenase. Inactivation in plasma is very rapid; during one passage through the lung, 90% of PG circulating in plasma are de- graded. PG are local mediators that at- tain biologically effective concentra- tions only at their site of formation. Biological effects. The individual PG (PGE, PGF, PGI = prostacyclin) pos- sess different biological effects. Nociceptors. PG increase sensitiv- ity of sensory nerve fibers towards ordi- nary pain stimuli (p. 194), i.e., at a given stimulus strength there is an increased rate of evoked action potentials. Thermoregulation. PG raise the set point of hypothalamic (preoptic) ther- moregulatory neurons; body tempera- ture increases (fever). Vascular smooth muscle. PGE 2 and PGI 2 produce arteriolar vasodila- tion; PGF 2α , venoconstriction. Gastric secretion. PG promote the production of gastric mucus and reduce the formation of gastric acid (p. 160). Menstruation. PGF 2α is believed to be responsible for the ischemic necrosis of the endometrium preceding men- struation. The relative proportions of in- dividual PG are said to be altered in dys- menorrhea and excessive menstrual bleeding. Uterine muscle. PG stimulate labor contractions. Bronchial muscle. PGE 2 and PGI 2 induce bronchodilation; PGF 2α causes constriction. Renal blood flow. When renal blood flow is lowered, vasodilating PG are released that act to restore blood flow. Thromboxane A 2 and prostacyclin play a role in regulating the aggregabil- ity of platelets and vascular diameter (p. 150). Leukotrienes increase capillary permeability and serve as chemotactic factors for neutrophil granulocytes. As “slow-reacting substances of anaphy- laxis,” they are involved in allergic reac- tions (p. 326); together with PG, they evoke the spectrum of characteristic in- flammatory symptoms: redness, heat, swelling, and pain. Therapeutic applications. PG de- rivatives are used to induce labor or to interrupt gestation (p. 126); in the ther- apy of peptic ulcer (p. 168), and in pe- ripheral arterial disease. PG are poorly tolerated if given systemically; in that case their effects cannot be confined to the intended site of action. 196 Antipyretic Analgesics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antipyretic Analgesics 197 A. Origin and effects of prostaglandins Kidney function Labor Fever Thromboxane Prostacyclin Cyclooxygenase Arachidonic acid Pain stimulus e.g., PGF 2α Prostaglandins e.g., leukotriene A 4 involved in allergic reactions Leukotrienes Vasodilation Phospholipase A 2 Lipoxygenase [ H + ] Mucus production Capillary permeability Nociceptor sensibility Impulse frequency in sensory fiber Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antipyretic Analgesics Acetaminophen, the amphiphilic acids acetylsalicylic acid (ASA), ibuprofen, and others, as well as some pyrazolone derivatives, such as aminopyrine and dipyrone, are grouped under the label antipyretic analgesics to distinguish them from opioid analgesics, because they share the ability to reduce fever. Acetaminophen (paracetamol) has good analgesic efficacy in toothaches and headaches, but is of little use in in- flammatory and visceral pain. Its mech- anism of action remains unclear. It can be administered orally or in the form of rectal suppositories (single dose, 0.5–1.0 g). The effect develops after about 30 min and lasts for approx. 3 h. Acetaminophen undergoes conjugation to glucuronic acid or sulfate at the phe- nolic hydroxyl group, with subsequent renal elimination of the conjugate. At therapeutic dosage, a small fraction is oxidized to the highly reactive N-acetyl- p-benzoquinonimine, which is detoxi- fied by coupling to glutathione. After in- gestion of high doses (approx. 10 g), the glutathione reserves of the liver are de- pleted and the quinonimine reacts with constituents of liver cells. As a result, the cells are destroyed: liver necrosis. Liver damage can be avoided if the thiol group donor, N-acetylcysteine, is given intravenously within 6–8 h after inges- tion of an excessive dose of acetamino- phen. Whether chronic regular intake of acetaminophen leads to impaired renal function remains a matter of debate. Acetylsalicylic acid (ASA) exerts an antiinflammatory effect, in addition to its analgesic and antipyretic actions. These can be attributed to inhibition of cyclooxygenase (p. 196). ASA can be giv- en in tablet form, as effervescent pow- der, or injected systemically as lysinate (analgesic or antipyretic single dose, O.5–1.0 g). ASA undergoes rapid ester hydrolysis, first in the gut and subse- quently in the blood. The effect outlasts the presence of ASA in plasma (t 1/2 ~ 20 min), because cyclooxygenases are irreversibly inhibited due to covalent binding of the acetyl residue. Hence, the duration of the effect depends on the rate of enzyme resynthesis. Further- more, salicylate may contribute to the effect. ASA irritates the gastric mucosa (direct acid effect and inhibition of cy- toprotective PG synthesis, p. 200) and can precipitate bronchoconstriction (“aspirin asthma,” pseudoallergy) due to inhibition of PGE 2 synthesis and over- production of leukotrienes. Because ASA inhibits platelet aggregation and pro- longs bleeding time (p. 150), it should not be used in patients with impaired blood coagulability. Caution is also needed in children and juveniles be- cause of Reye’s syndrome. The latter has been observed in association with feb- rile viral infections and ingestion of ASA; its prognosis is poor (liver and brain damage). Administration of ASA at the end of pregnancy may result in pro- longed labor, bleeding tendency in mother and infant, and premature clo- sure of the ductus arteriosus. Acidic nonsteroidal antiinflammatory drugs (NSAIDS; p. 200) are derived from ASA. Among antipyretic analgesics, di- pyrone (metamizole) displays the high- est efficacy. It is also effective in visceral pain. Its mode of action is unclear, but probably differs from that of acetamino- phen and ASA. It is rapidly absorbed when given via the oral or rectal route. Because of its water solubility, it is also available for injection. Its active metab- olite, 4-aminophenazone, is eliminated from plasma with a t 1/2 of approx. 5 h. Dipyrone is associated with a low inci- dence of fatal agranulocytosis. In sensi- tized subjects, cardiovascular collapse can occur, especially after intravenous injection. Therefore, the drug should be restricted to the management of pain refractory to other analgesics. Propy- phenazone presumably acts like meta- mizole both pharmacologically and tox- icologically. 198 Antipyretic Analgesics and Antiinflammatory Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antipyretic Analgesics and Antiinflammatory Drugs 199 A. Antipyretic analgesics Tooth- ache Head- ache Fever Inflammatory pain Pain of colic Acetaminophen Acetylsalicylic acid Dipyrone Acute massive over- dose Chronic abuse Hepato- toxicity Nephro- toxicity Impaired hemostasis with risk of bleeding Agranulo- cytosis Broncho- constriction Irritation of gastro- intestinal mucosa Risk of anaphylactoid shock >10g ? Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Nonsteroidal Antiinflammatory (Antirheumatic) Agents At relatively high dosage (> 4 g/d), ASA (p. 198) may exert antiinflammatory ef- fects in rheumatic diseases (e.g., rheu- matoid arthritis). In this dose range, central nervous signs of overdosage may occur, such as tinnitus, vertigo, drowsiness, etc. The search for better tolerated drugs led to the family of non- steroidal antiinflammatory drugs (NSAIDs). Today, more than 30 sub- stances are available, all of them sharing the organic acid nature of ASA. Structu- rally, they can be grouped into carbonic acids (e.g., diclofenac, ibuprofen, na- proxene, indomethacin [p. 320]) or enolic acids (e.g., azapropazone, piroxi- cam, as well as the long-known but poorly tolerated phenylbutazone). Like ASA, these substances have analgesic, antipyretic, and antiinflammatory ac- tivity. In contrast to ASA, they inhibit cy- clooxygenase in a reversible manner. Moreover, they are not suitable as in- hibitors of platelet aggregation. Since their desired effects are similar, the choice between NSAIDs is dictated by their pharmacokinetic behavior and their adverse effects. Salicylates additionally inhibit the transcription factor NF KB , hence the ex- pression of proinflammatory proteins. This effect is shared with glucocorti- coids (p. 248) and ibuprofen, but not with some other NSAIDs. Pharmacokinetics. NSAIDs are well absorbed enterally. They are highly bound to plasma proteins (A). They are eliminated at different speeds: diclofe- nac (t 1/2 = 1–2 h) and piroxicam (t 1/2 ~ 50 h); thus, dosing intervals and risk of ac- cumulation will vary. The elimination of salicylate, the rapidly formed metab- olite of ASA, is notable for its dose de- pendence. Salicylate is effectively reab- sorbed in the kidney, except at high uri- nary pH. A prerequisite for rapid renal elimination is a hepatic conjugation re- action (p. 38), mainly with glycine (→ salicyluric acid) and glucuronic acid. At high dosage, the conjugation may be- come rate limiting. Elimination now in- creasingly depends on unchanged sa- licylate, which is excreted only slowly. Group-specific adverse effects can be attributed to inhibition of cyclooxy- genase (B). The most frequent problem, gastric mucosal injury with risk of peptic ulceration, results from reduced synthe- sis of protective prostaglandins (PG), apart from a direct irritant effect. Gas- tropathy may be prevented by co-ad- ministration of the PG derivative, mis- oprostol (p. 168). In the intestinal tract, inhibition of PG synthesis would simi- larly be expected to lead to damage of the blood mucosa barrier and enteropa- thy. In predisposed patients, asthma at- tacks may occur, probably because of a lack of bronchodilating PG and in- creased production of leukotrienes. Be- cause this response is not immune me- diated, such “pseudoallergic” reactions are a potential hazard with all NSAIDs. PG also regulate renal blood flow as functional antagonists of angiotensin II and norepinephrine. If release of the lat- ter two is increased (e.g., in hypovole- mia), inhibition of PG production may result in reduced renal blood flow and re- nal impairment. Other unwanted effects are edema and a rise in blood pressure. Moreover, drug-specific side effects deserve attention. These concern the CNS (e.g., indomethacin: drowsiness, headache, disorientation), the skin (pi- roxicam: photosensitization), or the blood (phenylbutazone: agranulocyto- sis). Outlook: Cyclooxygenase (COX) has two isozymes: COX-1, a constitutive form present in stomach and kidney; and COX-2, which is induced in inflam- matory cells in response to appropriate stimuli. Presently available NSAIDs in- hibit both isozymes. The search for COX-2-selective agents (Celecoxib, Ro- fecoxib) is intensifying because, in theo- ry, these ought to be tolerated better. 200 Antipyretic Analgesics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antipyretic Analgesics 201 t 1/2 =13-30h Salicylic acid 50% 90% Acetyl- salicylic acid 99% Diclofenac Ibuprofen NaproxenPiroxicam Azapropazone t 1/2 =1-2h t 1/2 ~50h t 1/2 =9-12h t 1/2 ~14h t 1/2 ~2h t 1/2 ~3h Plasma protein binding A. Nonsteroidal antiinflammatory drugs (NSAIDs) B. NSAIDs: group-specific adverse effects 95% 99% 99% 99% Mucus production Acid secretion Mucosal blood flow NSAID-induced nephrotoxicity Arachidonic acid Prostaglandins Airway resistance t 1/2 =15min High dose Low dose NSAID-induced gastropathy Leukotrienes Renal blood flow NSAID-induced asthma Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Thermoregulation and Antipyretics Body core temperature in the human is about 37 °C and fluctuates within ± 1 °C during the 24 h cycle. In the resting state, the metabolic activity of vital or- gans contributes 60% (liver 25%, brain 20%, heart 8%, kidneys 7%) to total heat production. The absolute contribution to heat production from these organs changes little during physical activity, whereas muscle work, which contri- butes approx. 25% at rest, can generate up to 90% of heat production during strenuous exercise. The set point of the body temperature is programmed in the hypothalamic thermoregulatory center. The actual value is adjusted to the set point by means of various thermoregu- latory mechanisms. Blood vessels sup- plying the skin penetrate the heat-insu- lating layer of subcutaneous adipose tis- sue and therefore permit controlled heat exchange with the environment as a function of vascular caliber and rate of blood flow. Cutaneous blood flow can range from ~ 0 to 30% of cardiac output, depending on requirements. Heat con- duction via the blood from interior sites of production to the body surface pro- vides a controllable mechanism for heat loss. Heat dissipation can also be achieved by increased production of sweat, because evaporation of sweat on the skin surface consumes heat (evapo- rative heat loss). Shivering is a mecha- nism to generate heat. Autonomic neu- ral regulation of cutaneous blood flow and sweat production permit homeo- static control of body temperature (A). The sympathetic system can either re- duce heat loss via vasoconstriction or promote it by enhancing sweat produc- tion. When sweating is inhibited due to poisoning with anticholinergics (e.g., atropine), cutaneous blood flow in- creases. If insufficient heat is dissipated through this route, overheating occurs (hyperthermia). Thyroid hyperfunction poses a particular challenge to the thermoregu- latory system, because the excessive se- cretion of thyroid hormones causes metabolic heat production to increase. In order to maintain body temperature at its physiological level, excess heat must be dissipated—the patients have a hot skin and are sweating. The hypothalamic temperature controller (B1) can be inactivated by neuroleptics (p. 236), without impair- ment of other centers. Thus, it is pos- sible to lower a patient’s body tempera- ture without activating counter-regula- tory mechanisms (thermogenic shiver- ing). This can be exploited in the treat- ment of severe febrile states (hyperpy- rexia) or in open-chest surgery with cardiac by-pass, during which blood temperature is lowered to 10 °C by means of a heart-lung machine. In higher doses, ethanol and bar- biturates also depress the thermoregu- latory center (B1), thereby permitting cooling of the body to the point of death, given a sufficiently low ambient tem- perature (freezing to death in drunken- ness). Pyrogens (e.g., bacterial matter) el- evate—probably through mediation by prostaglandins (p. 196) and interleukin- 1—the set point of the hypothalamic temperature controller (B2). The body responds by restricting heat loss (cuta- neous vasoconstriction → chills) and by elevating heat production (shivering), in order to adjust to the new set point (fe- ver). Antipyretics such as acetamino- phen and ASA (p. 198) return the set point to its normal level (B2) and thus bring about a defervescence. 202 Antipyretic Analgesics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antipyretic Analgesics 203 Respiration Inhibition of sweat production Parasym- patholytics (Atropine) Hyperthermia Heat production Heat production B. Disturbances of thermoregulation A. Thermoregulation 37o 38o 39o 36o 35o 37o 38o 39o 36o 35o 37o 38o 39o 36o 35o 37o 38o 39o 36o 35o Hyper- thyroidism Increased heat production Thermoregulatory center (set point) Sympathetic system α-Adreno- ceptors Acetylcholine receptors Body temperature Temperature rise Fever e.g., paralysis Preferential inhibition Controlled hypothermia “Artificial hibernation” Uncontrolled heat loss Hypothermia, freezing to death 1 2 37o 38o 39o 36o 35o Metabolic activity Heat loss Heat conduction Heat radiation Evaporation of sweat Neuroleptics Ethanol Barbiturates Set point elevation AntipyreticsPyrogen Heat center Cutaneous blood flow Sweat production Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Local Anesthetics Local anesthetics reversibly inhibit im- pulse generation and propagation in nerves. In sensory nerves, such an effect is desired when painful procedures must be performed, e.g., surgical or den- tal operations. Mechanism of action. Nerve im- pulse conduction occurs in the form of an action potential, a sudden reversal in resting transmembrane potential last- ing less than 1 ms. The change in poten- tial is triggered by an appropriate stim- ulus and involves a rapid influx of Na + into the interior of the nerve axon (A). This inward flow proceeds through a channel, a membrane pore protein, that, upon being opened (activated), permits rapid movement of Na + down a chemi- cal gradient ([Na + ] ext ~ 150 mM, [Na + ] int ~ 7 mM). Local anesthetics are capable of inhibiting this rapid inward flux of Na + ; initiation and propagation of exci- tation are therefore blocked (A). Most local anesthetics exist in part in the cationic amphiphilic form (cf. p. 208). This physicochemical property fa- vors incorporation into membrane interphases, boundary regions between polar and apolar domains. These are found in phospholipid membranes and also in ion-channel proteins. Some evi- dence suggests that Na + -channel block- ade results from binding of local anes- thetics to the channel protein. It appears certain that the site of action is reached from the cytosol, implying that the drug must first penetrate the cell membrane (p. 206). Local anesthetic activity is also shown by uncharged substances, sug- gesting a binding site in apolar regions of the channel protein or the surround- ing lipid membrane. Mechanism-specific adverse ef- fects. Since local anesthetics block Na + influx not only in sensory nerves but al- so in other excitable tissues, they are applied locally and measures are taken (p. 206) to impede their distribution into the body. Too rapid entry into the circulation would lead to unwanted systemic reactions such as: L50188 blockade of inhibitory CNS neurons, manifested by restlessness and sei- zures (countermeasure: injection of a benzodiazepine, p. 226); general par- alysis with respiratory arrest after higher concentrations. L50188 blockade of cardiac impulse conduc- tion, as evidenced by impaired AV conduction or cardiac arrest (coun- termeasure: injection of epineph- rine). Depression of excitatory pro- cesses in the heart, while undesired during local anesthesia, can be put to therapeutic use in cardiac arrhythmi- as (p. 134). Forms of local anesthesia. Local anesthetics are applied via different routes, including infiltration of the tis- sue (infiltration anesthesia) or injec- tion next to the nerve branch carrying fibers from the region to be anesthe- tized (conduction anesthesia of the nerve, spinal anesthesia of segmental dorsal roots), or by application to the surface of the skin or mucosa (surface anesthesia). In each case, the local an- esthetic drug is required to diffuse to the nerves concerned from a depot placed in the tissue or on the skin. High sensitivity of sensory nerves, low sensitivity of motor nerves. Im- pulse conduction in sensory nerves is inhibited at a concentration lower than that needed for motor fibers. This differ- ence may be due to the higher impulse frequency and longer action potential duration in nociceptive, as opposed to motor, fibers. Alternatively, it may be related to the thickness of sensory and motor nerves, as well as to the distance between nodes of Ranvier. In saltatory impulse conduction, only the nodal membrane is depolarized. Because de- polarization can still occur after block- ade of three or four nodal rings, the area exposed to a drug concentration suffi- cient to cause blockade must be larger for motor fibers (p. 205B). This relationship explains why sen- sory stimuli that are conducted via 204 Local Anesthetics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Local Anesthetics 205 + A. Effects of local anesthetics B. Inhibition of impulse conduction in different types of nerve fibers Local anesthetic Na + -entry Propagated impulse Peripheral nerve Conduction block Local application CNS Restlessness, convulsions, respiratory paralysis Heart Impulse conduction cardiac arrest Na + Activated Na + -channel Na + Blocked Na + -channel apolar polar Cationic amphiphilic local anesthetic Local anesthetic Aα motor 0.8 – 1.4 mm 0.3 – 0.7 mm Aδ sensory C sensory and postganglionic Na + Blocked Na + -channel Uncharged local anesthetic Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. myelinated Aδ-fibers are affected later and to a lesser degree than are stimuli conducted via unmyelinated C-fibers. Since autonomic postganglionic fibers lack a myelin sheath, they are particu- larly susceptible to blockade by local anesthetics. As a result, vasodilation en- sues in the anesthetized region, because sympathetically driven vasomotor tone decreases. This local vasodilation is un- desirable (see below). Diffusion and Effect During diffusion from the injection site (i.e., the interstitial space of connective tissue) to the axon of a sensory nerve, the local anesthetic must traverse the perineurium. The multilayered peri- neurium is formed by connective tissue cells linked by zonulae occludentes (p. 22) and therefore constitutes a closed lipophilic barrier. Local anesthetics in clinical use are usually tertiary amines; at the pH of interstitial fluid, these exist partly as the neutral lipophilic base (symbolized by particles marked with two red dots) and partly as the protonated form, i.e., am- phiphilic cation (symbolized by parti- cles marked with one blue and one red dot). The uncharged form can penetrate the perineurium and enters the endo- neural space, where a fraction of the drug molecules regains a positive charge in keeping with the local pH. The same process is repeated when the drug penetrates the axonal membrane (axo- lemma) into the axoplasm, from which it exerts its action on the sodium chan- nel, and again when it diffuses out of the endoneural space through the unfenes- trated endothelium of capillaries into the blood. The concentration of local anes- thetic at the site of action is, therefore, determined by the speed of penetration into the endoneurium and the speed of diffusion into the capillary blood. In or- der to ensure a sufficiently fast build-up of drug concentration at the site of ac- tion, there must be a correspondingly large concentration gradient between drug depot in the connective tissue and the endoneural space. Injection of solu- tions of low concentration will fail to produce an effect; however, too high concentrations must also be avoided be- cause of the danger of intoxication re- sulting from too rapid systemic absorp- tion into the blood. To ensure a reasonably long-lasting local effect with minimal systemic ac- tion, a vasoconstrictor (epinephrine, less frequently norepinephrine (p. 84) or a vasopressin derivative; p. 164) is of- ten co-administered in an attempt to confine the drug to its site of action. As blood flow is diminished, diffusion from the endoneural space into the capillary blood decreases because the critical concentration gradient between endo- neural space and blood quickly becomes small when inflow of drug-free blood is reduced. Addition of a vasoconstrictor, moreover, helps to create a relative ischemia in the surgical field. Potential disadvantages of catecholamine-type vasoconstrictors include reactive hy- peremia following washout of the con- strictor agent (p. 90) and cardiostimula- tion when epinephrine enters the sys- temic circulation. In lieu of epinephrine, the vasopressin analogue felypressin (p. 164, 165) can be used as an adjunc- tive vasoconstrictor (less pronounced reactive hyperemia, no arrhythmogenic action, but danger of coronary constric- tion). Vasoconstrictors must not be ap- plied in local anesthesia involving the appendages (e.g., fingers, toes). 206 Local Anesthetics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Local Anesthetics 207 A. Disposition of local anesthetics in peripheral nerve tissue Vasoconstriction e.g., with epinephrine lipophilic amphiphilic Axolemma Axoplasm Axolemma Axoplasm Inter- stitium Cross section through peripheral nerve (light microscope) Peri- neurium Endoneural space Capillary wall Axon 0.1 mm Interstitium Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Characteristics of chemical struc- ture. Local anesthetics possess a uni- form structure. Generally they are sec- ondary or tertiary amines. The nitrogen is linked through an intermediary chain to a lipophilic moiety—most often an aromatic ring system. The amine function means that lo- cal anesthetics exist either as the neu- tral amine or positively charged ammo- nium cation, depending upon their dis- sociation constant (pK a value) and the actual pH value. The pK a of typical local anesthetics lies between 7.5 and 9.0. The pk a indicates the pH value at which 50% of molecules carry a proton. In its protonated form, the molecule possess- es both a polar hydrophilic moiety (pro- tonated nitrogen) and an apolar lipo- philic moiety (ring system)—it is amphi- philic. Graphic images of the procaine molecule reveal that the positive charge does not have a punctate localization at the N atom; rather it is distributed, as shown by the potential on the van der Waals’ surface. The non-protonated form (right) possesses a negative partial charge in the region of the ester bond and at the amino group at the aromatic ring and is neutral to slightly positively charged (blue) elsewhere. In the proto- nated form (left), the positive charge is prominent and concentrated at the ami- no group of the side chain (dark blue). Depending on the pK a , 50 to 5% of the drug may be present at physiologi- cal pH in the uncharged lipophilic form. This fraction is important because it represents the lipid membrane-perme- able form of the local anesthetic (p. 26), which must take on its cationic amphi- philic form in order to exert its action (p. 204). Clinically used local anesthetics are either esters or amides. This structural element is unimportant for efficacy; even drugs containing a methylene bridge, such as chlorpromazine (p. 236) or imipramine (p. 230), would exert a local anesthetic effect with appropriate application. Ester-type local anesthetics are subject to inactivation by tissue es- terases. This is advantageous because of the diminished danger of systemic in- toxication. On the other hand, the high rate of bioinactivation and, therefore, shortened duration of action is a disad- vantage. Procaine cannot be used as a surface anesthetic because it is inactivated fast- er than it can penetrate the dermis or mucosa. The amide type local anesthetic lidocaine is broken down primarily in the liver by oxidative N-dealkylation. This step can occur only to a restricted extent in prilocaine and articaine be- cause both carry a substituent on the C- atom adjacent to the nitrogen group. Ar- ticaine possesses a carboxymethyl group on its thiophen ring. At this posi- tion, ester cleavage can occur, resulting in the formation of a polar -COO – group, loss of the amphiphilic character, and conversion to an inactive metabolite. Benzocaine (ethoform) is a member of the group of local anesthetics lacking a nitrogen that can be protonated at physiological pH. It is used exclusively as a surface anesthetic. Other agents employed for surface anesthesia include the uncharged poli- docanol and the catamphiphilic cocaine, tetracaine, and lidocaine. 208 Local Anesthetics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Local Anesthetics 209 A. Local anesthetics and pH value 100 80 60 40 20 0 0 20 40 60 80 100 67 8 910 Procaine Lidocaine Prilocaine Articaine Mepivacaine Benzocaine [H + ] Proton concentration pH value Active form cationic- amphiphilic Poor Ability to penetrate lipophilic barriers and cell membranes Good Membrane- permeable form Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Opioid Analgesics—Morphine Type Source of opioids. Morphine is an opi- um alkaloid (p. 4). Besides morphine, opium contains alkaloids devoid of an- algesic activity, e.g., the spasmolytic pa- paverine, that are also classified as opi- um alkaloids. All semisynthetic deriva- tives (hydromorphone) and fully syn- thetic derivatives (pentazocine, pethi- dine = meperidine, l-methadone, and fentanyl) are collectively referred to as opioids. The high analgesic effectiveness of xenobiotic opioids derives from their affinity for receptors normally acted upon by endogenous opioids (enkepha- lins, β-endorphin, dynorphins; A). Opi- oid receptors occur in nerve cells. They are found in various brain regions and the spinal medulla, as well as in intra- mural nerve plexuses that regulate the motility of the alimentary and urogeni- tal tracts. There are several types of opi- oid receptors, designated μ, δ, κ, that mediate the various opioid effects; all belong to the superfamily of G-protein- coupled receptors (p. 66). Endogenous opioids are peptides that are cleaved from the precursors proenkephalin, pro-opiomelanocortin, and prodynorphin. All contain the ami- no acid sequence of the pentapeptides [Met]- or [Leu]-enkephalin (A). The ef- fects of the opioids can be abolished by antagonists (e.g., naloxone; A), with the exception of buprenorphine. Mode of action of opioids. Most neurons react to opioids with hyperpo- larization, reflecting an increase in K + conductance. Ca 2+ influx into nerve ter- minals during excitation is decreased, leading to a decreased release of excita- tory transmitters and decreased synap- tic activity (A). Depending on the cell population affected, this synaptic inhi- bition translates into a depressant or ex- citant effect (B). Effects of opioids (B). The analge- sic effect results from actions at the lev- el of the spinal cord (inhibition of noci- ceptive impulse transmission) and the brain (attenuation of impulse spread, inhibition of pain perception). Attention and ability to concentrate are impaired. There is a mood change, the direction of which depends on the initial condi- tion. Aside from the relief associated with the abatement of strong pain, there is a feeling of detachment (float- ing sensation) and sense of well-being (euphoria), particularly after intrave- nous injection and, hence, rapid build- up of drug levels in the brain. The desire to re-experience this state by renewed administration of drug may become overpowering: development of psycho- logical dependence. The atttempt to quit repeated use of the drug results in with- drawal signs of both a physical (cardio- vascular disturbances) and psychologi- cal (restlessness, anxiety, depression) nature. Opioids meet the criteria of “ad- dictive” agents, namely, psychological and physiological dependence as well as a compulsion to increase the dose. For these reasons, prescription of opioids is subject to special rules (Controlled Sub- stances Act, USA; Narcotic Control Act, Canada; etc). Regulations specify, among other things, maximum dosage (permissible single dose, daily maximal dose, maximal amount per single pre- scription). Prescriptions need to be is- sued on special forms the completion of which is rigorously monitored. Certain opioid analgesics, such as codeine and tramadol, may be prescribed in the usu- al manner, because of their lesser po- tential for abuse and development of dependence. 210 Opioids Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Opioids 211 A. Action of endogenous and exogenous opioids at opioid receptors β-Endorphin Ureter bladder bladder sphincter Vagal centers, Chemoreceptors of area postrema Oculomotor center (Edinger's nucleus) Dampening effects Pain sensation Mood alertness Respiratory center Cough center Emetic center Stimulant effects Mediated by opioid receptors MorphineProopiomelanocortin β-Lipotropin Proenkephalin Opioid receptors Naloxone K + -permeability Excitability Ca 2+ -influx Release of transmitters Antinociceptive system Analgesic Smooth musculature stomach bowel spastic constipation Antidiarrheal Analgesic Antitussive B. Effects of opioids O N CH 2 HO CH 2 CH HO O N O OHHO CH 3 Enkephalin 6 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Differences between opioids re- garding efficacy and potential for de- pendence probably reflect differing af- finity and intrinsic activity profiles for the individual receptor subtypes. A giv- en sustance does not necessarily behave as an agonist or antagonist at all recep- tor subtypes, but may act as an agonist at one subtype and as a partial ago- nist/antagonist or as a pure antagonist (p. 214) at another. The abuse potential is also determined by kinetic properties, because development of dependence is favored by rapid build-up of brain con- centrations. With any of the high-effica- cy opioid analgesics, overdosage is like- ly to result in respiratory paralysis (im- paired sensitivity of medullary chemo- receptors to CO 2 ). The maximally pos- sible extent of respiratory depression is thought to be less in partial agonist/ antagonists at opioid receptors (pentaz- ocine, nalbuphine). The cough-suppressant (antitussive) effect produced by inhibition of the cough reflex is independent of the ef- fects on nociception or respiration (antitussives: codeine. noscapine). Stimulation of chemoreceptors in the area postrema (p. 330) results in vomiting, particularly after first-time ad- ministration or in the ambulant patient. The emetic effect disappears with re- peated use because a direct inhibition of the emetic center then predominates, which overrides the stimulation of area postrema chemoreceptors. Opioids elicit pupillary narrowing (miosis) by stimulating the parasympa- thetic portion (Edinger-Westphal nu- cleus) of the oculomotor nucleus. Peripheral effects concern the mo- tility and tonus of gastrointestinal smooth muscle; segmentation is en- hanced, but propulsive peristalsis is in- hibited. The tonus of sphincter muscles is raised markedly. In this fashion, mor- phine elicits the picture of spastic con- stipation. The antidiarrheic effect is used therapeutically (loperamide, p. 178). Gastric emptying is delayed (py- loric spasm) and drainage of bile and pancreatic juice is impeded, because the sphincter of Oddi contracts. Likewise, bladder function is affected; specifically bladder emptying is impaired due to in- creased tone of the vesicular sphincter. Uses: The endogenous opioids (metenkephalin, leuenkephalin, β-en- dorphin) cannot be used therapeutically because, due to their peptide nature, they are either rapidly degraded or ex- cluded from passage through the blood- brain barrier, thus preventing access to their sites of action even after parenter- al administration (A). Morphine can be given orally or parenterally, as well as epidurally or intrathecally in the spinal cord. The opi- oids heroin and fentanyl are highly lipo- philic, allowing rapid entry into the CNS. Because of its high potency, fenta- nyl is suitable for transdermal delivery (A). In opiate abuse, “smack” (“junk,” “jazz,” “stuff,” “China white;” mostly heroin) is self administered by injection (“mainlining”) so as to avoid first-pass metabolism and to achieve a faster rise in brain concentration. Evidently, psy- chic effects (“kick,” “buzz,” “rush”) are especially intense with this route of ad- ministration. The user may also resort to other more unusual routes: opium can be smoked, and heroin can be taken as snuff (B). Metabolism (C). Like other opioids bearing a hydroxyl group, morphine is conjugated to glucuronic acid and elim- inated renally. Glucuronidation of the OH-group at position 6, unlike that at position 3, does not affect affinity. The extent to which the 6-glucuronide con- tributes to the analgesic action remains uncertain at present. At any rate, the ac- tivity of this polar metabolite needs to be taken into account in renal insuffi- ciency (lower dosage or longer dosing interval). 212 Opioids Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Opioids 213 A. Bioavailability of opioids with different routes of administration C. Metabolism of morphine Nasal mucosa, e.g., heroin sniffing Intravenous application "Mainlining" Oral application Bronchial mucosa e.g., opium smoking Met-Enkephalin Morphine Fentanyl Heroin Opioid Morphine N N CH 2 CH 2 C O CH 2 CH 3 Tyr Gly Gly Phe Met N CH 3 O OHHO Morphine-3- glucuronide Morphine-6- glucuronide B. Application and rate of disposition N CH 3 O H 3 C CH 3 OC O OC O Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Tolerance. With repeated adminis- tration of opioids, their CNS effects can lose intensity (increased tolerance). In the course of therapy, progressively larger doses are needed to achieve the same degree of pain relief. Development of tolerance does not involve the pe- ripheral effects, so that persistent con- stipation during prolonged use may force a discontinuation of analgesic therapy however urgently needed. Therefore, dietetic and pharmacological measures should be taken prophylacti- cally to prevent constipation, whenever prolonged administration of opioid drugs is indicated. Morphine antagonists and partial agonists. The effects of opioids can be abolished by the antagonists naloxone or naltrexone (A), irrespective of the re- ceptor type involved. Given by itself, neither has any effect in normal sub- jects; however, in opioid-dependent subjects, both precipitate acute with- drawal signs. Because of its rapid pre- systemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is giv- en orally. Naloxone is effective as anti- dote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrex- one may be used as an adjunct in with- drawal therapy. Buprenorphine behaves like a par- tial agonist/antagonist at μ-receptors. Pentazocine is an antagonist at μ-recep- tors and an agonist at κ-receptors (A). Both are classified as “low-ceiling” opi- oids (B), because neither is capable of eliciting the maximal analgesic effect obtained with morphine or meperidine. The antagonist action of partial agonists may result in an initial decrease in effect of a full agonist during changeover to the latter. Intoxication with buprenor- phine cannot be reversed with antago- nists, because the drug dissociates only very slowly from the opioid receptors and competitive occupancy of the re- ceptors cannot be achieved as fast as the clinical situation demands. Opioids in chronic pain: In the management of chronic pain, opioid plasma concentration must be kept con- tinuously in the effective range, because a fall below the critical level would cause the patient to experience pain. Fear of this situation would prompt in- take of higher doses than necessary. Strictly speaking, the aim is a prophy- lactic analgesia. Like other opioids (hydromor- phone, meperidine, pentazocine, co- deine), morphine is rapidly eliminated, limiting its duration of action to approx. 4 h. To maintain a steady analgesic ef- fect, these drugs need to be given every 4 h. Frequent dosing, including at night- time, is a major inconvenience for chronic pain patients. Raising the indi- vidual dose would permit the dosing interval to be lengthened; however, it would also lead to transient peaks above the therapeutically required plas- ma level with the attending risk of un- wanted toxic effects and tolerance de- velopment. Preferred alternatives in- clude the use of controlled-release preparations of morphine, a fentanyl adhesive patch, or a longer-acting opi- oid such as l-methadone. The kinetic properties of the latter, however, neces- sitate adjustment of dosage in the course of treatment, because low dos- age during the first days of treatment fails to provide pain relief, whereas high dosage of the drug, if continued, will lead to accumulation into a toxic con- centration range (C). When the oral route is unavailable opioids may be administered by contin- uous infusion (pump) and when appro- priate under control by the patient – ad- vantage: constant therapeutic plasma level; disadvantage: indwelling cathe- ter. When constipation becomes intol- erable morphin can be applied near the spinal cord permitting strong analgesic effect at much lower total dosage. 214 Opioids Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Opioids 215 Pentazocine A. Opioids: μ- and κ-receptor ligands B. Opioids: dose-response relationship C. Morphine and methadone dosage regimens Intoxication Analgesia Morphine t 1/2 = 2 h at low dose every 4 h Disadvantage: frequent dosing for sustained analgesia High dose Morphine in "high dose" every 12 h Disadvantages: transient hazard of intoxication, transient loss of analgesia Low Dose Methadone t 1/2 = 55 h Disadvantage: dose difficult to titrate Days 12 3 4 Drug concentration in plasma Morphine Meperidine Fentanyl Nalbuphine Naloxone μ κ μ κ μ κ μ κ μ κ μ κ Analgesic ef fect Dose (mg) 0,1 1 10 100 Fentanyl Bupr enorphine Morphine Meperidine Pentazocine 1234 H 3 C H 3 C CH CH 2 CH 3 CH 3 N C N O CH3 HO OH C O O N CH3 CH2 CH3 N N CH 2 C O CH 2 CH 3 CH 2 HO OH HO CH 2 N O HO HO H 2 C CH CH 2 O N O HO Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. General Anesthesia and General Anesthetic Drugs General anesthesia is a state of drug-in- duced reversible inhibition of central nervous function, during which surgical procedures can be carried out in the ab- sence of consciousness, responsiveness to pain, defensive or involuntary move- ments, and significant autonomic reflex responses (A). The required level of anesthesia de- pends on the intensity of the pain-pro- ducing stimuli, i.e., the degree of noci- ceptive stimulation. The skilful anesthe- tist, therefore, dynamically adapts the plane of anesthesia to the demands of the surgical situation. Originally, anes- thetization was achieved with a single anesthetic agent (e.g., diethylether— first successfully demonstrated in 1846 by W. T. G. Morton, Boston). To suppress defensive reflexes, such a “mono-anes- thesia” necessitates a dosage in excess of that needed to cause unconscious- ness, thereby increasing the risk of par- alyzing vital functions, such as cardio- vascular homeostasis (B). Modern anes- thesia employs a combination of differ- ent drugs to achieve the goals of surgical anesthesia (balanced anesthesia). This approach reduces the hazards of anes- thesia. In C are listed examples of drugs that are used concurrently or sequen- tially as anesthesia adjuncts. In the case of the inhalational anesthetics, the choice of adjuncts relates to the specific property to be exploited (see below). Muscle relaxants, opioid analgesics such as fentanyl, and the parasympatholytic atropine are discussed elsewhere in more detail. Neuroleptanalgesia can be consid- ered a special form of combination an- esthesia, in which the short-acting opi- oid analgesics fentanyl, alfentanil, remi- fentanil is combined with the strongly sedating and affect-blunting neurolep- tic droperidol. This procedure is used in high-risk patients (e.g., advanced age, liver damage). Neuroleptanesthesia refers to the combined use of a short-acting analge- sic, an injectable anesthetic, a short-act- ing muscle relaxant, and a low dose of a neuroleptic. In regional anesthesia (spinal an- esthesia) with a local anesthetic (p. 204), nociception is eliminated, while consciousness is preserved. This proce- dure, therefore, does not fall under the definition of general anesthesia. According to their mode of applica- tion, general anesthetics in the restrict- ed sense are divided into inhalational (gaseous, volatile) and injectable agents. Inhalational anesthetics are admin- istered in and, for the most part, elimi- nated via respired air. They serve to maintain anesthesia. Pertinent sub- stances are considered on p. 218. Injectable anesthetics (p. 220) are frequently employed for induction. Intravenous injection and rapid onset of action are clearly more agreeable to the patient than is breathing a stupefying gas. The effect of most injectable anes- thetics is limited to a few minutes. This allows brief procedures to be carried out or to prepare the patient for inhalation- al anesthesia (intubation). Administra- tion of the volatile anesthetic must then be titrated in such a manner as to coun- terbalance the waning effect of the in- jectable agent. Increasing use is now being made of injectable, instead of inhalational, an- esthetics during prolonged combined anesthesia (total intravenous anesthe- sia—TIVA). “TIVA” has become feasible thanks to the introduction of agents with a suit- ably short duration of action, including the injectable anesthetics propofol and etomidate, the analgesics alfentanil und remifentanil, and the muscle relaxant mivacurium. These drugs are eliminated within minutes after being adminster- ed, irrespective of the duration of anesthesia. 216 General Anesthetic Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. General Anesthetic Drugs 217 Pain stimulus C. Regimen for balanced anesthesia A. Goals of surgical anesthesia B. Traditional monoanesthesia vs. modern balanced anesthesia Muscle relaxation Loss of consciousness Autonomic stabilization Analgesia Motor reflexes Pain and suffering Autonomic reflexes Nociception Paralysis of vital centers Mono-anesthesia e.g., diethylether Reduced pain sensitivity Muscle relaxation Loss of consciousness Pancur onium N 2 O Halothaneautonom ic stabilization Atr opine Pentazocine analgesiaNeostigm ine r eversal of neurom uscular block M idazolam unconsciousness Pentazocine analgesia Diazepam anxiolysis Muscle relaxation Analgesia Unconsciousness m uscle r elaxation; intubation Succinycholine Pre- medication Induction Maintenance Recovery For unconsciousness: e.g., halothane or propofol For muscle relaxation e.g., pan- curonium For autonomic stabilization e.g., atropine For analgesia e.g., N 2 O or fentanyl Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhalational Anesthetics The mechanism of action of inhala- tional anesthetics is unknown. The di- versity of chemical structures (inert gas xenon; hydrocarbons; halogenated hy- drocarbons) possessing anesthetic ac- tivity appears to rule out involvement of specific receptors. According to one hy- pothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excit- ability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal al- veolar concentration (MAC) at which 50% of patients remain immobile fol- lowing a defined painful stimulus (skin incision). Whereas the poorly lipophilic N 2 O must be inhaled in high concentra- tions (>70% of inspired air has to be re- placed), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. The rates of onset and cessation of action vary widely between different in- halational anesthetics and also depend on the degree of lipophilicity. In the case of N 2 O, there is rapid elimination from the body when the patient is ventilated with normal air. Due to the high partial pressure in blood, the driving force for transfer of the drug into expired air is large and, since tissue uptake is minor, the body can be quickly cleared of N 2 O. In contrast, with halothane, partial pres- sure in blood is low and tissue uptake is high, resulting in a much slower elimi- nation. Given alone, N 2 O (nitrous oxide, “laughing gas”) is incapable of produc- ing anesthesia of sufficient depth for surgery. It has good analgesic efficacy that can be exploited when it is used in conjunction with other anesthetics. As a gas, N 2 O can be administered directly. Although it irreversibly oxidizes vita- min B 12 , N 2 O is not metabolized appre- ciably and is cleared entirely by exhala- tion (B). Halothane (boiling point [BP] 50 °C), enflurane (BP 56 °C), isoflurane (BP 48 °C), and the obsolete methoxyflu- rane (BP 104 °C) have to be vaporized by special devices. Part of the administered halothane is converted into hepatotoxic metabolites (B). Liver damage may re- sult from halothane anesthesia. With a single exposure, the risk involved is un- predictable; however, there is a correla- tion with the frequency of exposure and the shortness of the interval between successive exposures. Up to 70% of inhaled methoxyflu- rane is converted to metabolites that may cause nephrotoxicity, a problem that has led to the withdrawal of the drug. Degradation products of enflurane or isoflurane (fraction biotransformed <2%) are of no concern. Halothane exerts a pronounced hy- potensive effect, to which a negative in- otropic effect contributes. Enflurane and isoflurane cause less circulatory de- pression. Halothane sensitizes the myo- cardium to catecholamines (caution: se- rious tachyarrhythmias or ventricular fibrillation may accompany use of cate- cholamines as antihypotensives or toco- lytics). This effect is much less pro- nounced with enflurane and isoflurane. Unlike halothane, enflurane and isoflu- rane have a muscle-relaxant effect that is additive with that of nondepolarizing neuromuscular blockers. Desflurane is a close structural rela- tive of isoflurane, but has low lipophilic- ity that permits rapid induction and re- covery as well as good control of anes- thetic depth. 218 General Anesthetic Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. General Anesthetic Drugs 219 Low potency high partial pressure needed relatively little binding to tissue B. Elimination routes of different volatile anesthetics A. Lipophilicity, potency and elimination of N 2 O and halothane Anesthetic potency Lipophilicity Nitrous oxide N 2 O Xenon Cyclopropane Diethylether Enflurane Chloroform Halothane Partial pressure in tissue Time Termination of intake Partial pressure of anesthetic Binding Tissue Blood Alveolar air High potency low partial pressure sufficient relatively high binding in tissue Halothane N 2 O MetabolitesMetabolites Halothane Methoxy- fluraneEther Nitrous oxideN 2 O H 5 C 2 OC 2 H 5 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Injectable Anesthetics Substances from different chemical classes suspend consciousness when given intravenously and can be used as injectable anesthetics (B). Unlike inha- lational agents, most of these drugs af- fect consciousness only and are devoid of analgesic activity (exception: keta- mine). The effect cannot be ascribed to nonselective binding to neuronal cell membranes, although this may hold for propofol. Most injectable anesthetics are characterized by a short duration of ac- tion. The rapid cessation of action is largely due to redistribution: after intravenous injection, brain concentra- tion climbs rapidly to anesthetic levels because of the high cerebral blood flow; the drug then distributes evenly in the body, i.e., concentration rises in the pe- riphery, but falls in the brain—redistri- bution and cessation of anesthesia (A). Thus, the effect subsides before the drug has left the body. A second injection of the same dose, given immediately after recovery from the preceding dose, can therefore produce a more intense and longer effect. Usually, a single injection is administered. However, etomidate and propofol may be given by infusion over a longer time period to maintain unconsciousness. Thiopental and methohexital belong to the barbiturates which, depending on dose, produce sedation, sleepiness, or anesthesia. Barbiturates lower the pain threshold and thereby facilitate defen- sive reflex movements; they also de- press the respiratory center. Barbitu- rates are frequently used for induction of anesthesia. Ketamine has analgesic activity that persists beyond the period of uncon- sciousness up to 1 h after injection. On regaining consciousness, the patient may experience a disconnection between outside reality and inner men- tal state (dissociative anesthesia). Fre- quently there is memory loss for the du- ration of the recovery period; however, adults in particular complain about dis- tressing dream-like experiences. These can be counteracted by administration of a benzodiazepine (e.g., midazolam). The CNS effects of ketamine arise, in part, from an interference with excita- tory glutamatergic transmission via li- gand-gated cation channels of the NMDA subtype, at which ketamine acts as a channel blocker. The non-natural excitatory amino acid N-methyl-D- aspartate is a selective agonist at this re- ceptor. Release of catecholamines with a resultant increase in heart rate and blood pressure is another unrelated ac- tion of ketamine. Propofol has a remarkably simple structure. Its effect has a rapid onset and decays quickly, being experienced by the patient as fairly pleasant. The inten- sity of the effect can be well controlled during prolonged administration. Etomidate hardly affects the auto- nomic nervous system. Since it inhibits cortisol synthesis, it can be used in the treatment of adrenocortical overactivity (Cushing’s disease). Midazolam is a rapidly metabolized benzodiazepine (p. 228) that is used for induction of anesthesia. The longer-act- ing lorazepam is preferred as adjunct anesthetic in prolonged cardiac surgery with cardiopulmonary bypass; its am- nesiogenic effect is pronounced. 220 General Anesthetic Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. General Anesthetic Drugs 221 B. Intravenous anesthetics A. Termination of drug effect by redistribution CNS: relatively high blood flow Periphery: relatively low blood flow ml blood min x g tissue Initial situation i.v. injection High concentration in tissue Relatively large amount of drug Relatively small amount of drug mg drug min x g tissue Low concentration in tissue Preferential accumulation of drug in brain Decrease in tissue concentration Further increase in tissue concentration Redistribution Steady-state of distribution Sodium thiopental Ketamine Etomidate Sodium methohexital Propofol Midazolam Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Soporifics, Hypnotics During sleep, the brain generates a pat- terned rhythmic activity that can be monitored by means of the electroen- cephalogram (EEG). Internal sleep cy- cles recur 4 to 5 times per night, each cycle being interrupted by a Rapid Eye Movement (REM) sleep phase (A). The REM stage is characterized by EEG activ- ity similar to that seen in the waking state, rapid eye movements, vivid dreams, and occasional twitches of indi- vidual muscle groups against a back- ground of generalized atonia of skeletal musculature. Normally, the REM stage is entered only after a preceding non-REM cycle. Frequent interruption of sleep will, therefore, decrease the REM por- tion. Shortening of REM sleep (normally approx. 25% of total sleep duration) re- sults in increased irritability and rest- lessness during the daytime. With un- disturbed night rest, REM deficits are compensated by increased REM sleep on subsequent nights (B). Hypnotics fall into different catego- ries, including the benzodiazepines (e.g., triazolam, temazepam, clotiaze- pam, nitrazepam), barbiturates (e.g., hexobarbital, pentobarbital), chloral hy- drate, and H 1 -antihistamines with seda- tive activity (p. 114). Benzodiazepines act at specific receptors (p. 226). The site and mechanism of action of barbitu- rates, antihistamines, and chloral hy- drate are incompletely understood. All hypnotics shorten the time spent in the REM stages (B). With re- peated ingestion of a hypnotic on sever- al successive days, the proportion of time spent in REM vs. non-REM sleep returns to normal despite continued drug intake. Withdrawal of the hypnotic drug results in REM rebound, which ta- pers off only over many days (B). Since REM stages are associated with vivid dreaming, sleep with excessively long REM episodes is experienced as unre- freshing. Thus, the attempt to discon- tinue use of hypnotics may result in the impression that refreshing sleep calls for a hypnotic, probably promoting hypnotic drug dependence. Depending on their blood levels, both benzodiazepines and barbiturates produce calming and sedative effects, the former group also being anxiolytic. At higher dosage, both groups promote the onset of sleep or induce it (C). Unlike barbiturates, benzodiaze- pine derivatives administered orally lack a general anesthetic action; cere- bral activity is not globally inhibited (respiratory paralysis is virtually impos- sible) and autonomic functions, such as blood pressure, heart rate, or body tem- perature, are unimpaired. Thus, benzo- diazepines possess a therapeutic margin considerably wider than that of barbitu- rates. Zolpidem (an imidazopyridine) and zopiclone (a cyclopyrrolone) are hypnotics that, despite their different chemical structure, possess agonist ac- tivity at the benzodiazepine receptor (p. 226). Due to their narrower margin of safety (risk of misuse for suicide) and their potential to produce physical de- pendence, barbiturates are no longer or only rarely used as hypnotics. Depen- dence on them has all the characteris- tics of an addiction (p. 210). Because of rapidly developing tol- erance, choral hydrate is suitable only for short-term use. Antihistamines are popular as nonprescription (over-the-counter) sleep remedies (e.g., diphenhydramine, doxylamine, p. 114), in which case their sedative side effect is used as the princi- pal effect. 222 Hypnotics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hypnotics 223 C. Concentration dependence of barbiturate and benzodiazepine effects B. Effect of hypnotics on proportion of REM/NREM A. Succession of different sleep phases during night rest REM Waking state Sleep stage I Sleep stage IV Sleep stage III Sleep stage II REM-sleep= Rapid Eye Movement sleep NREM = No Rapid Eye Movement sleep Ratio NREM 5 1015202530 Nights without hypnotic Nights with hypnotic Nights after withdrawal of hypnotic Paralyzing Anesthetizing Hypnogenic Hypnagogic Calming, anxiolytic Triazolam Pentobarbital Effect Concentration in blood Pentobarbital Triazolam Barbiturates: Benzo- diazepines: REM Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Sleep–Wake Cycle and Hypnotics The physiological mechanisms regulat- ing the sleep-wake rhythm are not com- pletely known. There is evidence that histaminergic, cholinergic, glutamater- gic, and adrenergic neurons are more active during waking than during the NREM sleep stage. Via their ascending thalamopetal projections, these neu- rons excite thalamocortical pathways and inhibit GABA-ergic neurons. During sleep, input from the brain stem de- creases, giving rise to diminished tha- lamocortical activity and disinhibition of the GABA neurons (A). The shift in balance between excitatory (red) and inhibitory (green) neuron groups underlies a circadian change in sleep propensity, causing it to remain low in the morning, to increase towards early afternoon (midday siesta), then to de- cline again, and finally to reach its peak before midnight (B1). Treatment of sleep disturbances. Pharmacotherapeutic measures are in- dicated only when causal therapy has failed. Causes of insomnia include emo- tional problems (grief, anxiety, “stress”), physical complaints (cough, pain), or the ingestion of stimulant substances (caffeine-containing beverages, sympa- thomimetics, theophylline, or certain antidepressants). As illustrated for emo- tional stress (B2), these factors cause an imbalance in favor of excitatory influ- ences. As a result, the interval between going to bed and falling asleep becomes longer, total sleep duration decreases, and sleep may be interrupted by several waking periods. Depending on the type of insomnia, benzodiazepines (p. 226) with short or intermediate duration of action are in- dicated, e.g., triazolam and brotizolam (t 1/2 ~ 4–6 h); lormetazepam or temaze- pam (t 1/2 ~ 10–15 h). These drugs short- en the latency of falling asleep, lengthen total sleep duration, and reduce the fre- quency of nocturnal awakenings. They act by augmenting inhibitory activity. Even with the longer-acting benzodiaz- epines, the patient awakes after about 6–8 h of sleep, because in the morning excitatory activity exceeds the sum of physiological and pharmacological inhi- bition (B3). The drug effect may, howev- er, become unmasked at daytime when other sedating substances (e.g., ethanol) are ingested and the patient shows an unusually pronounced response due to a synergistic interaction (impaired abil- ity to concentrate or react). As the margin between excitatory and inhibitory activity decreases with age, there is an increasing tendency to- wards shortened daytime sleep periods and more frequent interruption of noc- turnal sleep (C). Use of a hypnotic drug should not be extended beyond 4 wk, because tol- erance may develop. The risk of a re- bound decrease in sleep propensity af- ter drug withdrawal may be avoided by tapering off the dose over 2 to 3 wk. With any hypnotic, the risk of sui- cidal overdosage cannot be ignored. Since benzodiazepine intoxication may become life-threatening only when other central nervous depressants (etha- nol) are taken simultaneously and can, moreover, be treated with specific ben- zodiazepine antagonists, the benzo- diazepines should be given preference as sleep remedies over the all but obso- lete barbiturates. 224 Hypnotics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hypnotics 225 B. Wake-sleep pattern, stress, and hypnotic drug action Waking state NREM-sleep Neurons with transmitters: Histamine Acetylcholine Glutamate Norepinephrine GABA A. Transmitters: waking state and sleep C. Changes of the arousal reaction in the elderly Hypnotic Hypnotic 1 2 3 1 2 Emotional stress Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Benzodiazepines Benzodiazepines modify affective re- sponses to sensory perceptions; specifi- cally, they render a subject indifferent towards anxiogenic stimuli, i.e., anxio- lytic action. Furthermore, benzodiaze- pines exert sedating, anticonvulsant, and muscle-relaxant (myotonolytic, p. 182) effects. All these actions result from augmenting the activity of inhibi- tory neurons and are mediated by spe- cific benzodiazepine receptors that form an integral part of the GABA A re- ceptor-chloride channel complex. The inhibitory transmitter GABA acts to open the membrane chloride channels. Increased chloride conductance of the neuronal membrane effectively short- circuits responses to depolarizing in- puts. Benzodiazepine receptor agonists increase the affinity of GABA to its re- ceptor. At a given concentration of GABA, binding to the receptors will, therefore, be increased, resulting in an augmented response. Excitability of the neurons is diminished. Therapeutic indications for benzo- diazepines include anxiety states asso- ciated with neurotic, phobic, and de- pressive disorders, or myocardial in- farction (decrease in cardiac stimula- tion due to anxiety); insomnia; prean- esthetic (preoperative) medication; epileptic seizures; and hypertonia of skeletal musculature (spasticity, rigid- ity). Since GABA-ergic synapses are con- fined to neural tissues, specific inhibi- tion of central nervous functions can be achieved; for instance, there is little change in blood pressure, heart rate, and body temperature. The therapeutic index of benzodiazepines, calculated with reference to the toxic dose produc- ing respiratory depression, is greater than 100 and thus exceeds that of bar- biturates and other sedative-hypnotics by more than tenfold. Benzodiazepine intoxication can be treated with a spe- cific antidote (see below). Since benzodiazepines depress re- sponsivity to external stimuli, automo- tive driving skills and other tasks re- quiring precise sensorimotor coordina- tion will be impaired. Triazolam (t 1/2 of elimination ~1.5–5.5 h) is especially likely to impair memory (anterograde amnesia) and to cause rebound anxiety or insomnia and daytime confusion. The severity of these and other adverse reactions (e.g., rage, violent hostility, hallucinations), and their increased frequency in the elderly, has led to curtailed or suspended use of triazolam in some countries (UK). Although benzodiazepines are well tolerated, the possibility of personality changes (nonchalance, paradoxical ex- citement) and the risk of physical de- pendence with chronic use must not be overlooked. Conceivably, benzodiaze- pine dependence results from a kind of habituation, the functional counterparts of which become manifest during absti- nence as restlessness and anxiety; even seizures may occur. These symptoms reinforce chronic ingestion of benzo- diazepines. Benzodiazepine antagonists, such as flumazenil, possess affinity for ben- zodiazepine receptors, but they lack in- trinsic activity. Flumazenil is an effec- tive antidote in the treatment of ben- zodiazepine overdosage or can be used postoperatively to arouse patients se- dated with a benzodiazepine. Whereas benzodiazepines possess- ing agonist activity indirectly augment chloride permeability, inverse agonists exert an opposite action. These sub- stances give rise to pronounced rest- lessness, excitement, anxiety, and con- vulsive seizures. There is, as yet, no therapeutic indication for their use. 226 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 227 A. Action of benzodiazepines Anxiolysis plus anticonvulsant effect, sedation, muscle relaxation Diazepam R 1 = Cl R 2 = CH 3 R 3 = R 4 = H Benzo diaz epine R 4 N N R 1 R 3 O R 2 Inhibition of excitation Hyper- polari- zation GABA GABA-gated Cl - -channel Cl - Benzodiazepines Unopposed excitation Normal GABA-ergic inhibition Enhanced GABA-ergic inhibition GABA-er gic neur on Benzodiazepine receptor GABA-receptor Chloride ionophore GABA= γ-amino- butryc acid Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Pharmacokinetics of Benzodiazepines All benzodiazepines exert their actions at specific receptors (p. 226). The choice between different agents is dictated by their speed, intensity, and duration of action. These, in turn, reflect physico- chemical and pharmacokinetic proper- ties. Individual benzodiazepines remain in the body for very different lengths of time and are chiefly eliminated through biotransformation. Inactivation may en- tail a single chemical reaction or several steps (e.g., diazepam) before an inactive metabolite suitable for renal elimina- tion is formed. Since the intermediary products may, in part, be pharmacologi- cally active and, in part, be excreted more slowly than the parent substance, metabolites will accumulate with con- tinued regular dosing and contribute significantly to the final effect. Biotransformation begins either at substituents on the diazepine ring (diaz- epam: N-dealkylation at position 1; midazolam: hydroxylation of the methyl group on the imidazole ring) or at the diazepine ring itself. Hydroxylated mid- azolam is quickly eliminated following glucuronidation (t 1/2 ~ 2 h). N-de- methyldiazepam (nordazepam) is bio- logically active and undergoes hydroxy- lation at position 3 on the diazepine ring. The hydroxylated product (oxaze- pam) again is pharmacologically active. By virtue of their long half-lives, diaze- pam (t 1/2 ~ 32 h) and, still more so, its metabolite, nordazepam (t 1/2 50–90 h), are eliminated slowly and accumulate during repeated intake. Oxazepam undergoes conjugation to glucuronic ac- id via its hydroxyl group (t 1/2 = 8 h) and renal excretion (A). The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B). Substances with a short half-life that are not converted to active metabolites can be used for in- duction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area) because they permit maintenance of steady plasma levels with single daily dosing. Midazolam enjoys use by the i.v. route in preanesthetic medication and anesthetic combination regimens. Benzodiazepine Dependence Prolonged regular use of benzodiaze- pines can lead to physical dependence. With the long-acting substances mar- keted initially, this problem was less ob- vious in comparison with other depen- dence-producing drugs because of the delayed appearance of withdrawal symptoms. The severity of the absti- nence syndrome is inversely related to the elimination t 1/2 , ranging from mild to moderate (restlessness, irritability, sensitivity to sound and light, insomnia, and tremulousness) to dramatic (de- pression, panic, delirium, grand mal sei- zures). Some of these symptoms pose diagnostic difficulties, being indistin- guishable from the ones originally treat- ed. Administration of a benzodiazepine antagonist would abruptly provoke ab- stinence signs. There are indications that substances with intermediate elim- ination half-lives are most frequently abused (violet area in B). 228 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 229 B. Rate of elimination of benzodiazepines A. Biotransformation of benzodiazepines Midazolam Diazepam as glucuronide Active metabolites Inactive Oxazepam Nordazepam Triazolam Brotizolam Oxazepam Lormetazepam Bromazepam Flunitrazepam Lorazepam Camazepam Nitrazepam Clonazepam Diazepam Temazepam Prazepam Applied drug Active metabolitePlasma elimination half-life Hypnagogic effect Abuse liability Anxiolytic effect 0203040506010 >60 h Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Manic-Depressive Illness Manic-depressive illness connotes a psychotic disorder of affect that occurs episodically without external cause. In endogenous depression (melancholia), mood is persistently low. Mania refers to the opposite condition (p. 234). Pa- tients may oscillate between these two extremes with interludes of normal mood. Depending on the type of disor- der, mood swings may alternate between the two directions (bipolar de- pression, cyclothymia) or occur in only one direction (unipolar depression). I. Endogenous Depression In this condition, the patient experienc- es profound misery (beyond the observer’s empathy) and feelings of se- vere guilt because of imaginary miscon- duct. The drive to act or move is inhibit- ed. In addition, there are disturbances mostly of a somatic nature (insomnia, loss of appetite, constipation, palpita- tions, loss of libido, impotence, etc.). Al- though the patient may have suicidal thoughts, psychomotor retardation pre- vents suicidal impulses from being car- ried out. In A, endogenous depression is illustrated by the layers of somber col- ors; psychomotor drive, symbolized by a sine oscillation, is strongly reduced. Therapeutic agents fall into two groups: L50188 Thymoleptics, possessing a pro- nounced ability to re-elevate de- pressed mood e.g., the tricyclic anti- depressants; L50188 Thymeretics, having a predominant activating effect on psychomotor drive, e g., monoamine oxidase inhib- itors. It would be wrong to administer drive-enhancing drugs, such as amphet- amines, to a patient with endogenous depression. Because this therapy fails to elevate mood but removes psychomo- tor inhibition (A), the danger of suicide increases. Tricyclic antidepressants (TCA; prototype: imipramine) have had the longest and most extensive therapeutic use; however, in the past decade, they have been increasingly superseded by the serotonin-selective reuptake inhibi- tors (SSRI; prototype: fluoxetine). The central seven-membered ring of the TCAs imposes a 120° angle between the two flanking aromatic rings, in contradistinction to the flat ring system present in phenothiazine type neuroleptics (p. 237). The side chain nitrogen is predominantly proto- nated at physiological pH. The TCAs have affinity for both re- ceptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal re- uptake of norepinephrine (p. 82) and se- rotonin (p. 116) is inhibited, with a re- sultant increase in activity. Muscarinic acetylcholine receptors, α-adrenocep- tors, and certain 5-HT and hista- mine(H 1 ) receptors are blocked. Inter- ference with the dopamine system is relatively minor. How interference with these trans- mitter/modulator substances translates into an antidepressant effect is still hy- pothetical. The clinical effect emerges only after prolonged intake, i.e., 2–3 wk, as evidenced by an elevation of mood and drive. However, the alteration in monoamine metabolism occurs as soon as therapy is started. Conceivably, adap- tive processes (such as downregulation of cortical serotonin and β-adrenocep- tors) are ultimately responsible. In healthy subjects, the TCAs do not im- prove mood (no euphoria). Apart from the antidepressant ef- fect, acute effects occur that are evident also in healthy individuals. These vary in degree among individual substances and thus provide a rationale for differ- entiated clinical use (p. 233), based upon the divergent patterns of interfer- ence with amine transmitters/modula- tors. Amitriptyline exerts anxiolytic, sedative and psychomotor dampening effects. These are useful in depressive patients who are anxious and agitated. In contrast, desipramine produces psychomotor activation. Imipramine 230 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 231 A. Effect of antidepressants Amphetamine Immediate W eek 9 W eek 7 W eek 5 W eek 3 Endogenous depr ession Imipramine 5HT or NA Inhibition of re-uptake Deficient drive Normal mood Normal drive M, H 1 , α 1 Blockade of receptors Ach NA Effects on synaptic transmission by inhibition of amine re-uptake and by receptor antagonism Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. occupies an intermediate position. It should be noted that, in the organism, biotransformation of imipramine leads to desipramine (N-desmethylimipra- mine). Likewise, the desmethyl deriva- tive of amitriptyline (nortriptyline) is less dampening. In nondepressive patients whose complaints are of predominantly psy- chogenic origin, the anxiolytic-sedative effect may be useful in efforts to bring about a temporary “psychosomatic un- coupling.” In this connection, clinical use as “co-analgesics” (p. 194) may be noted. The side effects of tricyclic antide- pressants are largely attributable to the ability of these compounds to bind to and block receptors for endogenous transmitter substances. These effects develop acutely. Antagonism at musca- rinic cholinoceptors leads to atropine- like effects such as tachycardia, inhibi- tion of exocrine glands, constipation, impaired micturition, and blurred vi- sion. Changes in adrenergic function are complex. Inhibition of neuronal cate- cholamine reuptake gives rise to super- imposed indirect sympathomimetic stimulation. Patients are supersensitive to catecholamines (e.g., epinephrine in local anesthetic injections must be avoided). On the other hand, blockade of α 1 -receptors may lead to orthostatic hypotension. Due to their cationic amphiphilic nature, the TCA exert membrane-stabi- lizing effects that can lead to distur- bances of cardiac impulse conduction with arrhythmias as well as decreases in myocardial contractility. All TCA lower the seizure threshold. Weight gain may result from a stimulant effect on appe- tite. Maprotiline, a tetracyclic com- pound, largely resembles tricyclic agents in terms of its pharmacological and clinical actions. Mianserine also possesses a tetracyclic structure, but differs insofar as it increases intrasyn- aptic concentrations of norepinephrine by blocking presynaptic α 2 -receptors, rather than reuptake. Moreover, it has less pronounced atropine-like activity. Fluoxetine, along with sertraline, fluvoxamine, and paroxetine, belongs to the more recently developed group of SSRI. The clinical efficacy of SSRI is con- sidered comparable to that of estab- lished antidepressants. Added advan- tages include: absence of cardiotoxicity, fewer autonomic nervous side effects, and relative safety with overdosage. Fluoxetine causes loss of appetite and weight reduction. Its main adverse ef- fects include: overarousal, insomnia, tremor, akathisia, anxiety, and distur- bances of sexual function. Moclobemide is a new representa- tive of the group of MAO inhibitors. In- hibition of intraneuronal degradation of serotonin and norepinephrine causes an increase in extracellular amine levels. A psychomotor stimulant thymeretic ac- tion is the predominant feature of MAO inhibitors. An older member of this group, tranylcypromine, causes irre- versible inhibition of the two isozymes MAO A and MAO B . Therefore, presystem- ic elimination in the liver of biogenic amines, such as tyramine, which are in- gested in food (e.g., aged cheese and Chianti), will be impaired. To avoid the danger of a hypertensive crisis, therapy with tranylcypromine or other nonse- lective MAO inhibitors calls for strin- gent dietary rules. With moclobemide, this hazard is much reduced because it inactivates only MAO A and does so in a reversible manner. 232 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 233 Serotonin Dopamine Anxiolysis α 1 -Blockade Parasympatho- lytic activity Indication Amitriptyline Patient: Depressive, anxious, agitated 50-200 mg/d t 1/2 = 9-20h Imipramine Depressive, normal drive 75-200 mg/d t 1/2 = 15-60h Desipramine Depressive, lack of drive and energy 20-40 mg/d t 1/2 = 48-96h Fluoxetine 300 mg/d t 1/2 = 1-2h Moclobemide A. Antidepressants: activity profiles 5-HT-Receptor M-Cholinoceptor α-Adrenoceptor D-Receptor Norepinephrine Acetylcholine 50-150 mg/d t 1/2 = 30-40h Patient: Patient: Patient: Patient: Drive, ener gy Depressive, lack of drive and energy Depressive, lack of drive and energy Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. II. Mania The manic phase is characterized by ex- aggerated elation, flight of ideas, and a pathologically increased psychomotor drive. This is symbolically illustrated in A by a disjointed structure and aggres- sive color tones. The patients are over- confident, continuously active, show progressive incoherence of thought and loosening of associations, and act irre- sponsibly (financially, sexually etc.). Lithium ions. Lithium salts (e.g., acetate, carbonate) are effective in con- trolling the manic phase. The effect be- comes evident approx. 10 d after the start of therapy. The small therapeutic index necessitates frequent monitoring of Li + serum levels. Therapeutic levels should be kept between 0.8–1.0 mM in fasting morning blood samples. At high- er values there is a risk of adverse effects. CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin (p. 164) leads to polyuria and thirst. Thyroid function is impaired (p. 244), with compensatory development of (euthyroid) goiter. The mechanism of action of Li ions remains to be fully elucidated. Chemi- cally, lithium is the lightest of the alkali metals, which include such biologically important elements as sodium and po- tassium. Apart from interference with transmembrane cation fluxes (via ion channels and pumps), a lithium effect of major significance appears to be mem- brane depletion of phosphatidylinositol bisphosphates, the principal lipid sub- strate used by various receptors in transmembrane signalling (p. 66). Blockade of this important signal trans- duction pathway leads to impaired abil- ity of neurons to respond to activation of membrane receptors for transmitters or other chemical signals. Another site of action of lithium may be GTP-binding proteins responsible for signal trans- duction initiated by formation of the ag- onist-receptor complex. Rapid control of an acute attack of mania may require the use of a neuro- leptic (see below). Alternate treatments. Mood-sta- bilization and control of manic or hy- pomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifed- ipine, nimodipine). Effects are delayed and apparently unrelated to the mecha- nisms responsible for anticonvulsant and cardiovascular actions, respective- ly. III. Prophylaxis With continued treatment for 6 to 12 months, lithium salts prevent the re- currence of either manic or depressive states, effectively stabilizing mood at a normal level. 234 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 235 A. Effect of lithium salts in mania Day 8 Day 6 Day 4 Day 2 Normal state Depression Mania H Na K Rb Cs Be Mg Ca Sr Ba Li + Normal state Mania Lithium Day 10 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Schizophrenia Schizophrenia is an endogenous psy- chosis of episodic character. Its chief symptoms reflect a thought disorder (i.e., distracted, incoherent, illogical thinking; impoverished intellectual content; blockage of ideation; abrupt breaking of a train of thought: claims of being subject to outside agencies that control the patient’s thoughts), and a disturbance of affect (mood inappropri- ate to the situation) and of psychomotor drive. In addition, patients exhibit delu- sional paranoia (persecution mania) or hallucinations (fearfulness hearing of voices). Contrasting these “positive” symptoms, the so-called “negative” symptoms, viz., poverty of thought, so- cial withdrawal, and anhedonia, assume added importance in determining the severity of the disease. The disruption and incoherence of ideation is symboli- cally represented at the top left (A) and the normal psychic state is illustrated as on p. 237 (bottom left). Neuroleptics After administration of a neuroleptic, there is at first only psychomotor damp- ening. Tormenting paranoid ideas and hallucinations lose their subjective im- portance (A, dimming of flashy colors); however, the psychotic processes still persist. In the course of weeks, psychic processes gradually normalize (A); the psychotic episode wanes, although complete normalization often cannot be achieved because of the persistence of negative symptoms. Nonetheless, these changes are significant because the pa- tient experiences relief from the tor- ment of psychotic personality changes; care of the patient is made easier and return to a familiar community environ- ment is accelerated. The conventional (or classical) neu- roleptics comprise two classes of com- pounds with distinctive chemical struc- tures: 1. the phenothiazines derived from the antihistamine promethazine (prototype: chlorpromazine), including their analogues (e.g., thioxanthenes); and 2. the butyrophenones (prototype: haloperidol). According to the chemical structure of the side chain, phenothia- zines and thioxanthenes can be subdi- vided into aliphatic (chlorpromazine, triflupromazine, p. 239 and piperazine congeners (trifluperazine, fluphenazine, flupentixol, p. 239). The antipsychotic effect is probably due to an antagonistic action at dop- amine receptors. Aside from their main antipsychotic action, neuroleptics dis- play additional actions owing to their antagonism at – muscarinic acetylcholine receptors L50478 atropine-like effects; – α-adrenoceptors for norepinephrine L50478 disturbances of blood pressure regulation; – dopamine receptors in the nigrostria- tal system L50478 extrapyramidal motor disturbances; in the area postrema L50478 antiemetic action (p. 330), and in the pituitary gland L50478 increased secretion of prolactin (p. 242); – histamine receptors in the cerebral cortex L50478 possible cause of sedation. These ancillary effects are also elicited in healthy subjects and vary in intensity among individual substances. Other indications. Acutely, there is sedation with anxiolysis after neurolep- tization has been started. This effect can be utilized for: “psychosomatic un- coupling” in disorders with a prominent psychogenic component; neurolepta- nalgesia (p. 216) by means of the buty- rophenone droperidol in combination with an opioid; tranquilization of over- excited, agitated patients; treatment of delirium tremens with haloperidol; as well as the control of mania (see p. 234). It should be pointed out that neuro- leptics do not exert an anticonvulsant action, on the contrary, they may lower seizure thershold. 236 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 237 W eek 9 W eek 7 W eek 5 W eek 3 after start of therapy Chlorpromazine Butyrophenone type: Haloperidol Sedation Autonomic disturbance due to atropine-like action Movement disorders due to dopamine antagonism Antiemetic effect A. Effects of neuroleptics in schizophrenia Phenothiazine type: Neuroleptics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Because they inhibit the thermoreg- ulatory center, neuroleptics can be em- ployed for controlled hypothermia (p. 202). Adverse Effects. Clinically most important and therapy-limiting are ex- trapyramidal disturbances; these result from dopamine receptor blockade. Acute dystonias occur immediately af- ter neuroleptization and are manifested by motor impairments, particularly in the head, neck, and shoulder region. Af- ter several days to months, a parkinso- nian syndrome (pseudoparkinsonism) or akathisia (motor restlessness) may develop. All these disturbances can be treated by administration of antiparkin- son drugs of the anticholinergic type, such as biperiden (i.e., in acute dysto- nia). As a rule, these disturbances disap- pear after withdrawal of neuroleptic medication. Tardive dyskinesia may be- come evident after chronic neurolep- tization for several years, particularly when the drug is discontinued. It is due to hypersensitivity of the dopamine re- ceptor system and can be exacerbated by administration of anticholinergics. Chronic use of neuroleptics can, on occasion, give rise to hepatic damage as- sociated with cholestasis. A very rare, but dramatic, adverse effect is the ma- lignant neuroleptic syndrome (skeletal muscle rigidity, hyperthermia, stupor) that can end fatally in the absence of in- tensive countermeasures (including treatment with dantrolene, p. 182). Neuroleptic activity profiles. The marked differences in action spectra of the phenothiazines, their derivatives and analogues, which may partially re- semble those of butyrophenones, are important in determining therapeutic uses of neuroleptics. Relevant parame- ters include: antipsychotic efficacy (symbolized by the arrow); the extent of sedation; and the ability to induce ex- trapyramidal adverse effects. The latter depends on relative differences in an- tagonism towards dopamine and ace- tylcholine, respectively (p. 188). Thus, the butyrophenones carry an increased risk of adverse motor reactions because they lack anticholinergic activity and, hence, are prone to upset the balance between striatal cholinergic and dop- aminergic activity. Derivatives bearing a piperazine moiety (e.g., trifluperazine, fluphena- zine) have greater antipsychotic poten- cy than do drugs containing an aliphatic side chain (e.g., chlorpromazine, triflu- promazine). However, their antipsy- chotic effects are qualitatively indistin- guishable. As structural analogues of the phenothiazines, thioxanthenes (e.g., chlorprothixene, flupentixol) possess a central nucleus in which the N atom is replaced by a carbon linked via a double bond to the side chain. Unlike the phe- nothiazines, they display an added thy- moleptic activity. Clozapine is the prototype of the so-called atypical neuroleptics, a group that combines a relative lack of extrapy- ramidal adverse effects with superior efficacy in alleviating negative symp- toms. Newer members of this class in- clude risperidone, olanzapine, and ser- tindole. Two distinguishing features of these atypical agents are a higher affin- ity for 5-HT 2 (or 5-HT 6 ) receptors than for dopamine D 2 receptors and relative selectivity for mesolimbic, as opposed to nigrostriatal, dopamine neurons. Clozapine also exhibits high affinity for dopamine receptors of the D 4 subtype, in addition to H 1 histamine and musca- rinic acetylcholine receptors. Clozapine may cause dose–dependent seizures and agranulocytosis, necessitating close hematological monitoring. It is strongly sedating. When esterified with a fatty acid, both fluphenazine and haloperidol can be applied intramuscularly as depot preparations. 238 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 239 40% 40% 20% less sedating strongly Dopamine- ≈ ACh effect Triflupromazine 30 – 150 mg/d 1 10 50 Clozapine FlupentixolTrifluoperazine R=H Fluphenazine 2.5 – 10 mg/d Haloperidol 2 – 6 mg/d R=H Long-acting or “depot” neuroleptics i.m. 50–150 mg every 2 weeks i.m. 50–150 mg every 4 weeks R = O C C 9 H 19 R = O C C 9 H 19 25 – 200 mg/d 15 – 20 mg/d -decanoate -decanoate Dopamine- < ACh effect extrapyramidal disturbancesDopamine A. Neuroleptics: Antipsychotic potency, sedative, and extrapyramidal motor effects R R ACh 2 – 10 mg/d Relative potency Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychotomimetics (Psychedelics, Hallucinogens) Psychotomimetics are able to elicit psy- chic changes like those manifested in the course of a psychosis, such as illu- sionary distortion of perception and hallucinations. This experience may be of dreamlike character; its emotional or intellectual transposition appears inad- equate to the outsider. A psychotomimetic effect is pictori- ally recorded in the series of portraits drawn by an artist under the influence of lysergic acid diethylamide (LSD). As the intoxicated state waxes and wanes like waves, he reports seeing the face of the portrayed subject turn into a gri- mace, phosphoresce bluish-purple, and fluctuate in size as if viewed through a moving zoom lens, creating the illusion of abstruse changes in proportion and grotesque motion sequences. The dia- bolic caricature is perceived as threat- ening. Illusions also affect the senses of hearing and smell; sounds (tones) are “experienced” as floating beams and visual impressions as odors (“synesthe- sia”). Intoxicated individuals see them- selves temporarily from the outside and pass judgement on themselves and their condition. The boundary between self and the environment becomes blurred. An elating sense of being one with the other and the cosmos sets in. The sense of time is suspended; there is neither present nor past. Objects are seen that do not exist, and experiences felt that transcend explanation, hence the term “psychedelic” (Greek delosis = revelation) implying expansion of con- sciousness. The contents of such illusions and hallucinations can occasionally become extremely threatening (“bad” or “bum trip”); the individual may feel provoked to turn violent or to commit suicide. In- toxication is followed by a phase of in- tense fatigue, feelings of shame, and hu- miliating emptiness. The mechanism of the psychoto- genic effect remains unclear. Some hal- lucinogens such as LSD, psilocin, psilocy- bin (from fungi), bufotenin (the cutane- ous gland secretion of a toad), mescaline (from the Mexican cactuses Lophophora williamsii and L. diffusa; peyote) bear a structural resemblance to 5-HT (p. 116), and chemically synthesized ampheta- mine-derived hallucinogens (4-methyl- 2,5-dimethoxyamphetamine; 3,4-di- methoxyamphetamine; 2,5-dimethoxy- 4-ethyl amphetamine) are thought to interact with the agonist recognition site of the 5-HT 2A receptor. Conversely, most of the psychotomimetic effects are annulled by neuroleptics having 5-HT 2A antagonist activity (e.g. clozapine, ris- peridone). The structures of other agents such as tetrahydrocannabinol (from the hemp plant, Cannabis sativa— hashish, marihuana), muscimol (from the fly agaric, Amanita muscaria), or phencyclidine (formerly used as an in- jectable general anesthetic) do not re- veal a similar connection. Hallucina- tions may also occur as adverse effects after intake of other substances, e.g., scopolamine and other centrally active parasympatholytics. The popular psychostimulant, me- thylenedioxy-methamphetamine (MD- MA, “ecstasy”) acutely increases neuro- nal dopamine and norepinephrine re- lease and causes a delayed and selective degeneration of forebrain 5-HT nerve terminals. Although development of psycho- logical dependence and permanent psy- chic damage cannot be considered es- tablished sequelae of chronic use of psy- chotomimetics, the manufacture and commercial distribution of these drugs are prohibited (Schedule I, Controlled Drugs). 240 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 241 A. Psychotomimetic effect of LSD in a portrait artist Lysergic acid diethylamide 0.0001 g/70 kg HN N CH 3 C 2 H 5 C O N C 2 H 5 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hypothalamic and Hypophyseal Hormones The endocrine system is controlled by the brain. Nerve cells of the hypothala- mus synthesize and release messenger substances that regulate adenohy- pophyseal (AH) hormone release or are themselves secreted into the body as hormones. The latter comprise the so- called neurohypophyseal (NH) hor- mones. The axonal processes of hypotha- lamic neurons project to the neurohy- pophysis, where they store the nona- peptides vasopressin (= antidiuretic hor- mone, ADH) and oxytocin and release them on demand into the blood. Thera- peutically (ADH, p. 64, oxytocin, p. 126), these peptide hormones are given pa- renterally or via the nasal mucosa. The hypothalamic releasing hor- mones are peptides. They reach their target cells in the AH lobe by way of a portal vascular route consisting of two serially connected capillary beds. The first of these lies in the hypophyseal stalk, the second corresponds to the capillary bed of the AH lobe. Here, the hypothalamic hormones diffuse from the blood to their target cells, whose ac- tivity they control. Hormones released from the AH cells enter the blood, in which they are distributed to peripheral organs (1). Nomenclature of releasing hor- mones: RH–releasing hormone; RIH—re- lease inhibiting hormone. GnRH: gonadotropin-RH = gona- dorelin stimulates the release of FSH (follicle-stimulating hormone) and LH (luteinizing hormone). TRH: thyrotropin-RH (protirelin) stimulates the release of TSH (thyroid stimulating hormone = thyrotropin). CRH: corticotropin-RH stimulates the release of ACTH (adrenocorticotrop- ic hormone = corticotropin). GRH: growth hormone-RH (soma- tocrinin) stimulates the release of GH (growth hormone = STH, somatotropic hormone). GRIH somatostatin inhibits release of STH (and also other peptide hormones including insulin, glucagon, and gastrin). PRH: prolactin-RH remains to be characterized or established. Both TRH and vasoactive intestinal peptide (VIP) are implicated. PRIH inhibits the release of prolac- tin and could be identical with dop- amine. Hypothalamic releasing hormones are mostly administered (parenterally) for diagnostic reasons to test AH func- tion. Therapeutic control of AH cells. GnRH is used in hypothalamic infertility in women to stimulate FSH and LH se- cretion and to induce ovulation. For this purpose, it is necessary to mimic the physiologic intermittent “pulsatile” re- lease (approx. every 90 min) by means of a programmed infusion pump. Gonadorelin superagonists are GnRH analogues that bind with very high avidity to GnRH receptors of AH cells. As a result of the nonphysiologic uninterrupted receptor stimulation, in- itial augmentation of FSH and LH output is followed by a prolonged decrease. Bu- serelin, leuprorelin, goserelin, and trip- torelin are used in patients with prostat- ic carcinoma to reduce production of testosterone, which promotes tumor growth. Testosterone levels fall as much as after extirpation of the testes (2). The dopamine D 2 agonists bromo- criptine and cabergoline (pp. 114, 188) inhibit prolactin-releasing AH cells (in- dications: suppression of lactation, pro- lactin-producing tumors). Excessive, but not normal, growth hormone re- lease can also be inhibited (indication: acromegaly) (3). Octreotide is a somatostatin ana- logue; it is used in the treatment of somatostatin-secreting pituitary tu- mors. 242 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 243 PRH PRIH A. Hypothalamic and hypophyseal hormones GnRH TRH CRH GRH GRIH ADH Oxytocin STH(GH) ProlactinACTH ADHTSH OxytocinFSH, LH Ovum maturation; Estradiol, Progesterone Spermatogenesis; Testosterone Thyroxine Cortisol Growth Somatomedins Lactation Milk ejection Labor H 2 O Hypothalamic releasing hormones Synthesis and release of AH hormones AH-cells Synthesis Synthesis Release into blood Release into blood Neur ohypophysis Adenohypophysis (AH) Application parenteral nasal 1 90 min Released amount Pulsatile r e lease Rhythmic stimulation AH- cell FSH LH Persistent stimulation D 2 -Receptors GnRH Leuprorelin Dopamine agonist Bromocriptine 23. Cessation of hormone secretion, "chemical castration" Inhibition of prolactin Buserelin Hypothalamus secretion of STH Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Thyroid Hormone Therapy Thyroid hormones accelerate metab- olism. Their release (A) is regulated by the hypophyseal glycoprotein TSH, whose release, in turn, is controlled by the hypothalamic tripeptide TRH. Secre- tion of TSH declines as the blood level of thyroid hormones rises; by means of this negative feedback mechanism, hor- mone production is “automatically” ad- justed to demand. The thyroid releases predominantly thyroxine (T 4 ). However, the active form appears to be triiodothyronine (T 3 ); T 4 is converted in part to T 3 , receptor affinity in target organs being 10-fold higher for T 3 . The effect of T 3 develops more rapid- ly and has a shorter duration than does that of T 4 . Plasma elimination t 1/2 for T 4 is about 7 d; that for T 3 , however, is only 1.5 d. Conversion of T 4 to T 3 releases io- dide; 150 μg T 4 contains 100 μg of io- dine. For therapeutic purposes, T 4 is cho- sen, although T 3 is the active form and better absorbed from the gut. However, with T 4 administration, more constant blood levels can be achieved because degradation of T 4 is so slow. Since ab- sorption of T 4 is maximal from an empty stomach, T 4 is taken about 1 / 2 h before breakfast. Replacement therapy of hypothy- roidism. Whether primary, i.e., caused by thyroid disease, or secondary, i.e., re- sulting from TSH deficiency, hypothy- roidism is treated by oral administra- tion of T 4 . Since too rapid activation of metabolism entails the hazard of car- diac overload (angina pectoris, myocar- dial infarction), therapy is usually start- ed with low doses and gradually in- creased. The final maintenance dose re- quired to restore a euthyroid state de- pends on individual needs (approx. 150 μg/d). Thyroid suppression therapy of euthyroid goiter (B). The cause of goi- ter (struma) is usually a dietary defi- ciency of iodine. Due to an increased TSH action, the thyroid is activated to raise utilization of the little iodine avail- able to a level at which hypothyroidism is averted. Therefore, the thyroid in- creases in size. In addition, intrathyroid depletion of iodine stimulates growth. Because of the negative feedback regulation of thyroid function, thyroid activation can be inhibited by adminis- tration of T 4 doses equivalent to the en- dogenous daily output (approx. 150 μg/d). Deprived of stimulation, the inactive thyroid regresses in size. If a euthyroid goiter has not persist- ed for too long, increasing iodine supply (potassium iodide tablets) can also be effective in reversing overgrowth of the gland. In older patients with goiter due to iodine deficiency there is a risk of pro- voking hyperthyroidism by increasing iodine intake (p. 247): During chronic maximal stimulation, thyroid follicles can become independent of TSH stimu- lation (“autonomic tissue”). If the iodine supply is increased, thyroid hormone production increases while TSH secre- tion decreases due to feedback inhibi- tion. The activity of autonomic tissue, however, persists at a high level; thy- roxine is released in excess, resulting in iodine-induced hyperthyroidism. Iodized salt prophylaxis. Goiter is endemic in regions where soils are defi- cient in iodine. Use of iodized table salt allows iodine requirements (150– 300 μg/d) to be met and effectively pre- vents goiter. 244 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 245 B. Endemic goiter and its treatment with thyroxine A. Thyroid hormones - release, effects, degradation Thyroid Effector cell: receptor affinity L-Thyroxine, Levothyroxine, 3,5,3′,5′-Tetraiodothyronine, T 4 Liothyronine 3,5,3′-Triiodothyronine, T 3 T 3 T 4 10 1 = ~ 90 μg/Day ~ 9 μg/Day ~ 25 μg/Day I - I - I - I - Hypothalamus TRH TSH Decrease in sensivity to TRH Hypophysis "reverse T 3 " 3,3′,5′-Triiodothyronine Urine Feces Deiodinase Thyroxine Triiodothyronine Deiodination coupling Duration T 3 T 4 Day 2. 9. 10 Days30 4020 TSH Hypophysis Normal state I - T 4 , T 3 T 4 , T 3 TSH T 4 Therap. admini- stration Inhibition Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hyperthyroidism and Antithyroid Drugs Thyroid overactivity in Graves’ disease (A) results from formation of IgG anti- bodies that bind to and activate TSH re- ceptors. Consequently, there is overpro- duction of hormone with cessation of TSH secretion. Graves’ disease can abate spontaneously after 1–2 y. Therefore, initial therapy consists of reversible suppression of thyroid activity by means of antithyroid drugs. In other forms of hyperthyroidism, such as hor- mone-producing (morphologically be- nign) thyroid adenoma, the preferred therapeutic method is removal of tissue, either by surgery or administration of 131 iodine in sufficient dosage. Radioio- dine is taken up into thyroid cells and destroys tissue within a sphere of a few millimeters by emitting β-(electron) particles during its radioactive decay. Concerning iodine-induced hyper- thyroidism, see p. 244 (B). Antithyroid drugs inhibit thyroid function. Release of thyroid hormone (C) is preceded by a chain of events. A membrane transporter actively accu- mulates iodide in thyroid cells; this is followed by oxidation to iodine, iodina- tion of tyrosine residues in thyroglobu- lin, conjugation of two diiodotyrosine groups, and formation of T 4 and T 3 moieties. These reactions are catalyzed by thyroid peroxidase, which is local- ized in the apical border of the follicular cell membrane. T 4 -containing thyro- globulin is stored inside the thyroid fol- licles in the form of thyrocolloid. Upon endocytotic uptake, colloid undergoes lysosomal enzymatic hydrolysis, ena- bling thyroid hormone to be released as required. A “thyrostatic” effect can re- sult from inhibition of synthesis or re- lease. When synthesis is arrested, the antithyroid effect develops after a delay, as stored colloid continues to be uti- lized. Antithyroid drugs for long-term therapy (C). Thiourea derivatives (thioureylenes, thioamides) inhibit peroxidase and, hence, hormone syn- thesis. In order to restore a euthyroid state, two therapeutic principles can be applied in Graves’ disease: a) monother- apy with a thioamide with gradual dose reduction as the disease abates; b) ad- ministration of high doses of a thio- amide with concurrent administration of thyroxine to offset diminished hor- mone synthesis. Adverse effects of thi- oamides are rare; however, the possibil- ity of agranulocytosis has to be kept in mind. Perchlorate, given orally as the so- dium salt, inhibits the iodide pump. Ad- verse reactions include aplastic anemia. Compared with thioamides, its thera- peutic importance is low but it is used as an adjunct in scintigraphic imaging of bone by means of technetate when accumulation in the thyroid gland has to be blocked. Short-term thyroid suppression (C). Iodine in high dosage (>6000 μg/d) exerts a transient “thyrostatic” effect in hyperthyroid, but usually not in euthyr- oid, individuals. Since release is also blocked, the effect develops more rapid- ly than does that of thioamides. Clinical applications include: preop- erative suppression of thyroid secretion according to Plummer with Lugol’s solu- tion (5% iodine + 10% potassium iodide, 50–100 mg iodine/d for a maximum of 10 d). In thyrotoxic crisis, Lugol’s solu- tion is given together with thioamides and β-blockers. Adverse effects: aller- gies; contraindications: iodine-induced thyrotoxicosis. Lithium ions inhibit thyroxine re- lease. Lithium salts can be used instead of iodine for rapid thyroid suppression in iodine-induced thyrotoxicosis. Re- garding administration of lithium in manic-depressive illness, see p. 234. 246 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 247 C. Antithyroid drugs and their modes of action A. Graves’ disease B. Iodine hyperthyroidosis in endemic goiter I - Hypophysis T 4 , T 3 TSH I - TSH- like anti- bodies T 4 , T 3 Autonomous tissue T 4 , T 3 Lysosome Storage in colloid I - T 4 - ClO 4 - Perchlorate Iodine in high dose Lithium ions I - e T 4 - Tyrosine Tyrosine I I I TG Synthesis T 4 - T 4 Peroxidase Thioamides Propylthiouracil Conversion during absorption Carbimazole Thiamazole Methimazole Release Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Glucocorticoid Therapy I. Replacement therapy. The adrenal cortex (AC) produces the glucocorticoid cortisol (hydrocortisone) and the mine- ralocorticoid aldosterone. Both steroid hormones are vitally important in adap- tation responses to stress situations, such as disease, trauma, or surgery. Cor- tisol secretion is stimulated by hypo- physeal ACTH, aldosterone secretion by angiotensin II in particular (p. 124). In AC failure (primary AC insuffiency: Addison’s disease), both cortisol and al- dosterone must be replaced; when ACTH production is deficient (secondary AC in- sufficiency), cortisol alone needs to be re- placed. Cortisol is effective when given orally (30 mg/d, 2/3 a.m., 1/3 p.m.). In stress situations, the dose is raised by 5- to 10-fold. Aldosterone is poorly effective via the oral route; instead, the mineralocorticoid fludrocortisone (0.1 mg/d) is given. II. Pharmacodynamic therapy with glucocorticoids (A). In unphysio- logically high concentrations, cortisol or other glucocorticoids suppress all phas- es (exudation, proliferation, scar forma- tion) of the inflammatory reaction, i.e., the organism’s defensive measures against foreign or noxious matter. This effect is mediated by multiple compo- nents, all of which involve alterations in gene transcription (p. 64). Glucocorti- coids inhibit the expression of genes en- coding for proinflammatory proteins (phospholipase-A2, cyclooxygenase 2, IL-2-receptor). The expression of these genes is stimulated by the transcription factor NF ΚB . Binding to the glucocorti- coid receptor complex prevents translo- cation af NF ΚB to the nucleus. Converse- ly, glucocorticoids augment the expres- sion of some anti-inflammatory pro- teins, e.g., lipocortin, which in turn in- hibits phospholipase A2. Consequently, release of arachidonic acid is dimin- ished, as is the formation of inflamma- tory mediators of the prostaglandin and leukotriene series (p. 196). At very high dosage, nongenomic effects may also contribute. Desired effects. As anti-allergics, immunosuppressants, or anti-inflamma- tory drugs, glucocorticoids display ex- cellent efficacy against “undesired” in- flammatory reactions. Unwanted effects. With short-term use, glucocorticoids are practically free of adverse effects, even at the highest dosage. Long-term use is likely to cause changes mimicking the signs of Cushing’s syndrome (endogenous overproduction of cortisol). Sequelae of the anti-inflammatory action: lowered resistance to infection, delayed wound healing, impaired healing of peptic ul- cers. Sequelae of exaggerated glucocor- ticoid action: a) increased gluconeogen- esis and release of glucose; insulin-de- pendent conversion of glucose to trigly- cerides (adiposity mainly noticeable in the face, neck, and trunk); “steroid-dia- betes” if insulin release is insufficient; b) increased protein catabolism with atrophy of skeletal musculature (thin extremities), osteoporosis, growth re- tardation in infants, skin atrophy. Se- quelae of the intrinsically weak, but now manifest, mineralocorticoid action of cortisol: salt and fluid retention, hy- pertension, edema; KCl loss with danger of hypokalemia. Measures for Attenuating or Preventing Drug-Induced Cushing’s Syndrome a) Use of cortisol derivatives with less (e.g., prednisolone) or negligible miner- alocorticoid activity (e.g., triamcinolone, dexamethasone). Glucocorticoid activ- ity of these congeners is more pro- nounced. Glucorticoid, anti-inflamma- tory and feedback inhibitory (p. 250) ac- tions on the hypophysis are correlated. An exclusively anti-inflammatory con- gener does not exist. The “glucocorti- coid” related Cushingoid symptoms cannot be avoided. The table lists rela- tive activity (potency) with reference to cortisol, whose mineralo- and glucocor- ticoid activities are assigned a value of 1.0. All listed glucocorticoids are effec- tive orally. 248 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 249 Unwanted Wanted A. Glucocorticoids: principal and adverse effects Inflammation redness, swelling heat, pain; scar Glucocorticoid action Mineralocorticoid action Hypertension Diabetes mellitus Cortisol unphysiologically high concentration Muscle weakness Osteo- porosis Growth inhibition Skin atrophy Tissue atrophy Triamcinolone Aldosterone Prednisolone Dexamethasone Glucose Gluconeogenesis Amino acids Protein catabolism K + Na + H 2 O e.g., allergy autoimmune disease, transplant rejection Healing of tissue injury due to bacteria, viruses, fungi, trauma 1 4 7,5 30 0,3 1 0,8 0 0 3000 Cortisol Prednisolone Triamcinolone Dexamethasone Potency Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. b) Local application. Typical adverse effects, however, also occur locally, e.g., skin atrophy or mucosal colonization with candidal fungi. To minimize systemic absorption after inhalation, derivatives should be used that have a high rate of presystemic elimination, such as beclomethasone dipropionate, flunisolide, budesonide, or fluticasone propionate (p. 14). b) Lowest dosage possible. For long- term medication, a just sufficient dose should be given. However, in attempt- ing to lower the dose to the minimal ef- fective level, it is necessary to take into account that administration of exoge- nous glucocorticoids will suppress pro- duction of endogenous cortisol due to activation of an inhibitory feedback mechanism. In this manner, a very low dose could be “buffered,” so that un- physiologically high glucocorticoid ac- tivity and the anti-inflammatory effect are both prevented. Effect of glucocorticoid adminis- tration on adrenocortical cortisol pro- duction (A). Release of cortisol depends on stimulation by hypophyseal ACTH, which in turn is controlled by hypotha- lamic corticotropin-releasing hormone (CRH). In both the hypophysis and hy- pothalamus there are cortisol receptors through which cortisol can exert a feed- back inhibition of ACTH or CRH release. By means of these cortisol “sensors,” the regulatory centers can monitor whether the actual blood level of the hormone corresponds to the “set-point.” If the blood level exceeds the set-point, ACTH output is decreased and, thus, also the cortisol production. In this way cortisol level is maintained within the required range. The regulatory centers respond to synthetic glucocorticoids as they do to cortisol. Administration of exogenous cortisol or any other glucocorticoid re- duces the amount of endogenous corti- sol needed to maintain homeostasis. Re- lease of CRH and ACTH declines ("inhi- bition of higher centers by exogenous glucocorticoid”) and, thus, cortisol se- cretion (“adrenocortical suppression”). After weeks of exposure to unphysio- logically high glucocorticoid doses, the cortisol-producing portions of the ad- renal cortex shrink (“adrenocortical atrophy”). Aldosterone-synthesizing ca- pacity, however, remains unaffected. When glucocorticoid medication is sud- denly withheld, the atrophic cortex is unable to produce sufficient cortisol and a potentially life-threatening cortisol deficiency may develop. Therefore, glu- cocorticoid therapy should always be tapered off by gradual reduction of the dosage. Regimens for prevention of adrenocortical atrophy. Cortisol secre- tion is high in the early morning and low in the late evening (circadian rhythm). This fact implies that the regu- latory centers continue to release CRH or ACTH in the face of high morning blood levels of cortisol; accordingly, sensitivity to feedback inhibition must be low in the morning, whereas the op- posite holds true in the late evening. a) Circadian administration: The daily dose of glucocorticoid is given in the morning. Endogenous cortisol pro- duction will have already begun, the regulatory centers being relatively in- sensitive to inhibition. In the early morning hours of the next day, CRF/- ACTH release and adrenocortical stimu- lation will resume. b) Alternate-day therapy: Twice the daily dose is given on alternate morn- ings. On the “off” day, endogenous corti- sol production is allowed to occur. The disadvantage of either regimen is a recrudescence of disease symptoms during the glucocorticoid-free interval. 250 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 251 Hypo- physis Adrenal cortex Cortisol 30 mg/day Cortisol production under normal conditions Exogenous administration Adreno- cortical atrophy Decrease in cortisol production with cortisol dose < daily production Cortisol deficiency after abrupt cessation of administration Cortisol concentration normal circadian time-course Morning dose Inhibition of endogenous cortisol production Elimination of exogenous glucocorticoid during daytime Start of early morning cortisol production A. Cortisol release and its modification by glucocorticoids CRH ACTH Hypothalamus Cessation of cortisol production with cortisol dose > daily production h04 8121620244 8 Glucocorticoid-induced inhibition of cortisol production Glucocorticoid concentration h04 8121620244 8 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Androgens, Anabolic Steroids, Antiandrogens Androgens are masculinizing substanc- es. The endogenous male gonadal hor- mone is the steroid testosterone from the interstitial Leydig cells of the testis. Testosterone secretion is stimulated by hypophyseal luteinizing hormone (LH), whose release is controlled by hypotha- lamic GnRH (gonadorelin, p. 242). Re- lease of both hormones is subject to feedback inhibition by circulating tes- tosterone. Reduction of testosterone to dihydrotestosterone occurs in most tar- get organs; the latter possesses higher affinity for androgen receptors. Rapid intrahepatic degradation (plasma t 1/2 ~ 15 min) yields androsterone among other metabolites (17-ketosteroids) that are eliminated as conjugates in the urine. Because of rapid hepatic metab- olism, testosterone is unsuitable for oral use. Although it is well absorbed, it undergoes virtually complete pre- systemic elimination. Testosterone (T.) derivatives for clinical use. T. esters for i.m. depot injec- tion are T. propionate and T. heptanoate (or enanthate). These are given in oily solution by deep intramuscular injec- tion. Upon diffusion of the ester from the depot, esterases quickly split off the acyl residue, to yield free T. With in- creasing lipophilicity, esters will tend to remain in the depot, and the duration of action therefore lengthens. A T. ester for oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this ester is absorbed into the lymph, ena- bling it to bypass the liver and enter, via the thoracic duct, the general circula- tion. 17-a Methyltestosterone is effective by the oral route due to its increased metabolic stability, but because of the hepatotoxicity of C17-alkylated andro- gens (cholestasis, tumors) its use should be avoided. Orally active mesterolone is 1α-methyl-dihydrotestosterone. Trans- dermal delivery systems for T. are also available. Indications. For hormone replace- ment in deficiency of endogenous T. production and palliative treatment of breast cancer, T. esters for depot injec- tion are optimally suited. Secondary sex characteristics and libido are main- tained; however, fertility is not promot- ed. On the contrary, spermatogenesis may be suppressed because of feedback inhibition of hypothalamohypophyseal gonadotropin secretion. Stimulation of spermatogenesis in gonadotropin (FSH, LH) deficiency can be achieved by injection of HMG and HCG. HMG or human menopausal gonadotropin is obtained from the urine of postmenopausal women and is rich in FSH activity. HCG, human chorionic gonadotropin, from the urine of preg- nant women, acts like LH. Anabolics are testosterone deriva- tives (e.g., clostebol, metenolone, nan- drolone, stanozolol) that are used in de- bilitated patients, and misused by ath- letes, because of their protein anabolic effect. They act via stimulation of andro- gen receptors and, thus, also display an- drogenic actions (e.g., virilization in fe- males, suppression of spermatogene- sis). The antiandrogen cyproterone acts as a competitive antagonist of T. In addition, it has progestin activity whereby it inhibits gonadotropin secre- tion (p. 254). Indications: in men, inhi- bition of sex drive in hypersexuality; prostatic cancer. In women: treatment of virilization, with potential utilization of the gestagenic contraceptive effect. Flutamide, an androgen receptor antagonist possessing a different chem- ical structure, lacks progestin activity. Finasteride inhibits 5α-reductase, the enzyme converting T. into dihydro- testosterone (DHT). Thus, the androgen- ic stimulus is reduced in those tissues in which DHT is the active species (e.g., prostate). T.-dependent tissues or func- tions are not or hardly affected (e.g., skeletal muscle, negative feedback inhi- bition of gonadotropin secretion, and li- bido). Finasteride can be used in benign prostate hyperplasia to shrink the gland and, possibly, to improve micturition. 252 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 253 Target cell Dihydro- testosterone A. Testosterone and derivatives Testes Inhibition Ester cleavage R Testosterone ester in oily solution Skeletal muscle i. m. Depot injection Ester cleavage Oral intake Ductus thoracicus Androsterone Testosterone Methyl- testosterone Testosterone undecanoate 17-Ketosteroid Lymph vessels GnRH Hypothalamus Hypophysis LH R = -propionate -heptanoate Duration of effect 2 weeks C – C – C – C – C – C C – C 1 2 Conjugation with sulfate, glucuronate Testosterone Inactivation Antagonist Cyproterone Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Follicular Growth and Ovulation, Estrogen and Progestin Production Follicular maturation and ovulation, as well as the associated production of fe- male gonadal hormones, are controlled by the hypophyseal gonadotropins FSH (follicle-stimulating hormone) and LH (luteinizing hormone). In the first half of the menstrual cycle, FSH promotes growth and maturation of ovarian folli- cles that respond with accelerating syn- thesis of estradiol. Estradiol stimulates endometrial growth and increases the permeability of cervical mucus for sperm cells. When the estradiol blood level approaches a predetermined set- point, FSH release is inhibited due to feedback action on the anterior hypoph- ysis. Since follicle growth and estrogen production are correlated, hypophysis and hypothalamus can “monitor” the follicular phase of the ovarian cycle through their estrogen receptors. With- in hours after ovulation, the tertiary fol- licle develops into the corpus luteum, which then also releases progesterone in response to LH. The former initiates the secretory phase of the endometrial cycle and lowers the permeability of cervical mucus. Nonruptured follicles continue to release estradiol under the influence of FSH. After 2 wk, production of progesterone and estradiol subsides, causing the secretory endometrial layer to be shed (menstruation). The natural hormones are unsuit- able for oral application because they are subject to presystemic hepatic elim- ination. Estradiol is converted via es- trone to estriol; by conjugation, all three can be rendered water soluble and amenable to renal excretion. The major metabolite of progesterone is pregnan- diol, which is also conjugated and elimi- nated renally. Estrogen preparations. Depot preparations for i.m. injection are oily solutions of esters of estradiol (3- or 17- OH group). The hydrophobicity of the acyl moiety determines the rate of ab- sorption, hence the duration of effect (p. 252). Released ester is hydrolyzed to yield free estradiol. Orally used preparations. Ethinyl- estradiol (EE) is more stable metaboli- cally, passes largely unchanged through the liver after oral intake and mimics es- tradiol at estrogen receptors. Mestranol itself is inactive; however, cleavage of the C-3 methoxy group again yields EE. In oral contraceptives, one of the two agents forms the estrogen component (p. 256). (Sulfate-)conjugated estrogens can be extracted from equine urine and are used for the prevention of post- menopausal osteoporosis and in the therapy of climacteric complaints. Be- cause of their high polarity (sulfate, glu- curonide), they would hardly appear suitable for this route of administration. For transdermal delivery, an adhesive patch is available that releases estradiol transcutaneously into the body. Progestin preparations. Depot formulations for i.m. injection are 17- α-hydroxyprogesterone caproate and medroxyprogesterone acetate. Prepara- tions for oral use are derivatives of 17α- ethinyltestosterone = ethisterone (e.g., norethisterone, dimethisterone, lynes- trenol, desogestrel, gestoden), or of 17α-hydroxyprogesterone acetate (e.g., chlormadinone acetate or cyproterone acetate). These agents are mainly used as the progestin component in oral con- traceptives. Indications for estrogens and pro- gestins include: hormonal contracep- tion (p. 256), hormone replacement, as in postmenopausal women for prophy- laxis of osteoporosis; bleeding anoma- lies, menstrual complaints. Concerning adverse effects, see p. 256. Estrogens with partial agonist ac- tivity (raloxifene, tamoxifene) are be- ing investigated as agents used to re- place estrogen in postmenopausal os- teoporosis treatment, to lower plasma lipids, and as estrogen antagonists in the prevention of breast cancer. Raloxi- fen—in contrast to tamoxifen—is an an- tagonist at uterine estrogen receptors. 254 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 255 A. Estradiol, progesterone, and derivatives Conjugation with sulfate, glucuronate GnRH Hypothalamus Hypophysis FSH LH Conjugation Pregnanediol Estradiol Ethinylestradiol (EE) Progesterone Ethinyltestosterone, a gestagen Mestranol = 3-Methylether of EE Conjugated estrogens Estriol Estrone Estradiol Estradiol Inactivation Ovary Inactivation Progesterone Estradiol Duration of effect 1 week Medroxyprogesterone acetate Hydroxyprogesterone caproate 8 - 12 weeks Duration of effect 1 2 week 3 weeks -valerate -benzoate Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Oral Contraceptives Inhibitors of ovulation. Negative feed- back control of gonadotropin release can be utilized to inhibit the ovarian cy- cle. Administration of exogenous es- trogens (ethinylestradiol or mestranol) during the first half of the cycle permits FSH production to be suppressed (as it is by administration of progestins alone). Due to the reduced FSH stimula- tion of tertiary follicles, maturation of follicles and, hence, ovulation are pre- vented. In effect, the regulatory brain centers are deceived, as it were, by the elevated estrogen blood level, which signals normal follicular growth and a decreased requirement for FSH stimula- tion. If estrogens alone are given during the first half of the cycle, endometrial and cervical responses, as well as other functional changes, would occur in the normal fashion. By adding a progestin (p. 254) during the second half of the cy- cle, the secretory phase of the endome- trium and associated effects can be elic- ited. Discontinuance of hormone ad- ministration would be followed by menstruation. The physiological time course of es- trogen-progesterone release is simulat- ed in the so-called biphasic (sequen- tial) preparations (A). In monophasic preparations, estrogen and progestin are taken concurrently. Early adminis- tration of progestin reinforces the inhi- bition of CNS regulatory mechanisms, prevents both normal endometrial growth and conditions for ovum im- plantation, and decreases penetrability of cervical mucus for sperm cells. The two latter effects also act to prevent conception. According to the staging of progestin administration, one distin- guishes (A): one-, two-, and three-stage preparations. In all cases, “withdrawal- bleeding” occurs when hormone intake is discontinued (if necessary, by substi- tuting dummy tablets). Unwanted effects: An increased in- cidence of thrombosis and embolism is attributed to the estrogen component in particular. Hypertension, fluid reten- tion, cholestasis, benign liver tumors, nausea, chest pain, etc. may occur. Ap- parently there is no increased overall risk of malignant tumors. Minipill. Continuous low-dose ad- ministration of progestin alone can pre- vent conception. Ovulations are not suppressed regularly; the effect is then due to progestin-induced alterations in cervical and endometrial function. Be- cause of the need for constant intake at the same time of day, a lower success rate, and relatively frequent bleeding anomalies, these preparations are now rarely employed. “Morning-after” pill. This refers to administration of a high dose of estro- gen and progestin, preferably within 12 to 24 h, but no later than 72 h after coi- tus. Menstrual bleeding ensues, which prevents implantation of the fertilized ovum (normally on the 7th day after fer- tilization, p. 74). Similarly, implantation can be inhibited by mifepristone, which is an antagonist at both progesterone and glucocorticoid receptors and which also offers a noninvasive means of in- ducing therapeutic abortion in early pregnancy. Stimulation of ovulation. Gona- dotropin secretion can be increased by pulsatile delivery of GnRH (p. 242). The estrogen antagonists clomiphene and cy- clofenil block receptors mediating feed- back inhibition of central neuroendo- crine circuits and thereby disinhibit gonadotropin release. Gonadotropins can be given in the form of HMG and HCG (p. 252). 256 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 257 A. Oral contraceptives Hypophysis FSH LH Ovary Hypophysis 7. 14. 21. 28.1. Ovulation Ovulation Ovary Penetrability by sperm cells Day of cycle Readiness for nidation No ovulation Inhibition Estradiol Progesterone Estradiol Progesterone 7. 14. 21. 28.1. Intake of estradiol derivative Intake of progestin Minipill 7. 14. 21. 28.Days of cycle Biphasic preparation One-stage regimen Monophasic preparations Two-stage regimen Three-stage regimen Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Insulin Therapy Insulin is synthesized in the B- (or β-) cells of the pancreatic islets of Langer- hans. It is a protein (MW 5800) consist- ing of two peptide chains linked by two disulfide bridges; the A chain has 21 and the B chain 30 amino acids. Insulin is the “blood-sugar lowering” hormone. Upon ingestion of dietary carbohydrates, it is released into the blood and acts to pre- vent a significant rise in blood glucose concentration by promoting uptake of glucose in specific organs, viz., the heart, adipose tissue, and skeletal mus- cle, or its conversion to glycogen in the liver. It also increases lipogenesis and protein synthesis, while inhibiting lipo- lysis and release of free fatty acids. Insulin is used in the replacement therapy of diabetes mellitus to supple- ment a deficient secretion of endoge- nous hormone. Sources of therapeutic insulin preparations (A). Insulin can be ob- tained from pancreatic tissue of slaugh- tered animals. Porcine insulin differs from human insulin merely by one B chain amino acid, bovine insulin by two amino acids in the A chain and one in the B chain. With these slight differenc- es, animal and human hormone display similar biological activity. Compared with human hormone, porcine insulin is barely antigenic and bovine insulin has a little higher antigenicity. Human insu- lin is produced by two methods: biosyn- thetically, by substituting threonine for the C-terminal alanine in the B chain of porcine insulin; or by gene technology involving insertion of the appropriate human DNA into E. coli bacteria. Types of preparations (B). As a peptide, insulin is unsuitable for oral administration (destruction by gas- trointestinal proteases) and thus needs to be given parenterally. Usually, insulin preparations are injected subcutane- ously. The duration of action depends on the rate of absorption from the injec- tion site. Short-acting insulin is dispensed as a clear neutral solution known as regular insulin. In emergencies, such as hyperglycemic coma, it can be given intravenously (mostly by infusion be- cause i.v. injections have too brief an ac- tion; plasma t 1/2 ~ 9 min). With the usu- al subcutaneous application, the effect is evident within 15 to 20 min, reaches a peak after approx. 3 h, and lasts for ap- prox. 6 h. Lispro insulin has a faster on- set and slightly shorter duration of ac- tion. Insulin suspensions. When the hormone is injected as a suspension of insulin-containing particles, its dissolu- tion and release in subcutaneous tissue are retarded (rapid, intermediate, and slow insulins). Suitable particles can be obtained by precipitation of apolar, poorly water-soluble complexes con- sisting of anionic insulin and cationic partners, e.g., the polycationic protein protamine or the compound aminoqui- nuride (Surfen). In the presence of zinc and acetate ions, insulin crystallizes; crystal size determines the rate of disso- lution. Intermediate insulin prepara- tions (NPH or isophane, lente or zinc in- sulin) act for 18 to 26 h, slow prepara- tions (protamine zinc insulin, ultralente or extended zinc insulin) for up to 36 h. Combination preparations con- tain insulin mixtures in solution and in suspension (e.g., ultralente); the plasma concentration-time curve represents the sum of the two components. Unwanted effects. Hypoglycemia results from absolute or relative over- dosage (see p. 260). Allergic reactions are rare—locally: redness at injection site, atrophy of adipose tissue (lipodystro- phy); systemically: urticaria, skin rash, anaphylaxis. Insulin resistance can re- sult from binding to inactivating anti- bodies. A possible local lipohypertrophy can be avoided by alternating injection sites. 258 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 259 B. Insulin: preparations and blood level-time curves A. Insulin production S - S S - S Ala Thr30Porcine insulin Human insulinInsulin B-chain A-chain Production: DNA E. coli Hours after injection 6121824 Intermediate Slow Insulin mixtur es Insulin suspension = pr otamine zinc insulin Insulin solution = r egular insulin Insulin concentration in blood Rapid Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Treatment of Insulin-Dependent Diabetes Mellitus “Juvenile onset” (type I) diabetes mellit- us is caused by the destruction of insu- lin-producing B cells in the pancreas, necessitating replacement of insulin (daily dose approx. 40 U, equivalent to approx. 1.6 mg). Therapeutic objectives are: (1) prevention of life-threatening hypergly- cemic (diabetic) coma; (2) prevention of diabetic sequelae (angiopathy with blindness, myocardial infarction, renal failure), with precise “titration” of the patient being essential to avoid even short-term spells of pathological hyper- glycemia; (3) prevention of insulin overdosage leading to life-threatening hypoglycemic shock (CNS disturbance due to lack of glucose). Therapeutic principles. In healthy subjects, the amount of insulin is “auto- matically” matched to carbohydrate in- take, hence to blood glucose concentra- tion. The critical secretory stimulus is the rise in plasma glucose level. Food in- take and physical activity (increased glucose uptake into musculature, de- creased insulin demand) are accompa- nied by corresponding changes in insu- lin secretion (A, left track). In the diabetic, insulin could be ad- ministered as it is normally secreted; that is, injection of short-acting insulin before each main meal plus bedtime ad- ministration of a Lente preparation to avoid a nocturnal shortfall of insulin. This regimen requires a well-educated, cooperative, and competent patient. In other cases, a fixed-dosage schedule will be needed, e.g., morning and eve- ning injections of a combination insulin in constant respective dosage (A). To avoid hypo- or hyperglycemias with this regimen, dietary carbohydrate (CH) intake must be synchronized with the time course of insulin absorption from the s.c. depot. Caloric intake is to be dis- tributed (50% CH, 30% fat, 20% protein) in small meals over the day so as to achieve a steady CH supply—snacks, late night meal. Rapidly absorbable CH (sweets, cakes) must be avoided (hyper- glycemic—peaks) and replaced with slowly digestible ones. Acarbose (an α-glucosidase inhibi- tor) delays intestinal formation of glu- cose from disaccharides. Any change in eating and living habits can upset control of blood sugar: skipping a meal or unusual physical stress leads to hypoglycemia; increased CH intake provokes hyperglycemia. Hypoglycemia is heralded by warning signs: tachycardia, unrest, tremor, pallor, profuse sweating. Some of these are due to the release of glu- cose-mobilizing epinephrine. Counter- measures: glucose administration, rap- idly absorbed CH orally or 10–20 g glu- cose i.v. in case of unconsciousness; if necessary, injection of glucagon, the pancreatic hyperglycemic hormone. Even with optimal control of blood sugar, s.c. administration of insulin can- not fully replicate the physiological sit- uation. In healthy subjects, absorbed glucose and insulin released from the pancreas simultaneously reach the liver in high concentration, whereby effec- tive presystemic elimination of both substances is achieved. In the diabetic, s.c. injected insulin is uniformly distrib- uted in the body. Since insulin concen- tration in blood supplying the liver can- not rise, less glucose is extracted from portal blood. A significant amount of glucose enters extrahepatic tissues, where it has to be utilized. 260 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 261 A. Control of blood sugar in healthy and diabetic subjects 10 12 14 16 18 20 22 24 2 4 6 8 10 12 16 18 22 24 2 4 6 8 10 12 14 16 20 22 24 Time B S L N D S B L S S S L B B L D B B L D no lunch Feast Feast Carbohydrate absorption Blood sugar Insulin r elease fr om pancr eas Carbohydrate absorption Blood sugar Insulin r elease fr om depot Glucose Diabetic Healthy subject B = Breakfast S = Snack L = Lunch D = Dinner N = Supper L Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Treatment of Maturity-Onset (Type II) Diabetes Mellitus In overweight adults, a diabetic meta- bolic condition may develop (type II or non-insulin-dependent diabetes) when there is a relative insulin deficiency— enhanced demand cannot be met by a diminishing insulin secretion. The cause of increased insulin require- ment is a loss of insulin receptors or an impairment of the signal cascade acti- vated by the insulin receptor. Accord- ingly, insulin sensitivity of cells de- clines. This can be illustrated by com- paring concentration-binding curves in cells from normal and obese individuals (A). In the obese, the maximum binding possible (plateau of curve) is displaced downward, indicative of the reduction in receptor numbers. Also, at low insulin concentrations, there is less binding of insulin, compared with the control con- dition. For a given metabolic effect a certain number of receptors must be oc- cupied. As shown by the binding curves (dashed lines), this can still be achieved with a reduced receptor number, al- though only at a higher concentration of insulin. Development of adult diabetes (B). Compared with a normal subject, the obese subject requires a continually elevated output of insulin (orange curves) to avoid an excessive rise of blood glucose levels (green curves) dur- ing a glucose load. When the secretory capacity of the pancreas decreases, this is first noted as a rise in blood glucose during glucose loading (latent diabetes). Subsequently, not even the fasting blood level can be maintained (mani- fest, overt diabetes). A diabetic condi- tion has developed, although insulin re- lease is not lower than that in a healthy person (relative insulin deficiency). Treatment. Caloric restriction to restore body weight to normal is asso- ciated with an increase in insulin recep- tor number or cellular responsiveness. The releasable amount of insulin is again adequate to maintain a normal metabolic rate. Therapy of first choice is weight reduction, not administration of drugs! Should the diabetic condition fail to resolve, consideration should first be given to insulin replacement (p. 260). Oral antidiabetics of the sulfonylurea type increase the sensitivity of B-cells towards glucose, enabling them to in- crease release of insulin. These drugs probably promote depolarization of the β-cell membrane by closing off ATP-gat- ed K + channels. Normally, these chan- nels are closed when intracellular levels of glucose, hence of ATP, increase. This drug class includes tolbutamide (500– 2000 mg/d) and glyburide (glibencla- mide) (1.75–10.5 mg/d). In some pa- tients, it is not possible to stimulate in- sulin secretion from the outset; in oth- ers, therapy fails later on. Matching dos- age of the oral antidiabetic and caloric intake follows the same principles as apply to insulin. Hypoglycemia is the most important unwanted effect. En- hancement of the hypoglycemic effect can result from drug interactions: dis- placement of antidiabetic drug from plasma protein-binding sites by sulfon- amides or acetylsalicylic acid. Metformin, a biguanide deriva- tive, can lower excessive blood glucose levels, provided that insulin is present. Metformin does not stimulate insulin re- lease. Glucose release from the liver is decreased, while peripheral uptake is enhanced. The danger of hypoglycemia apparently is not increased. Frequent adverse effects include: anorexia, nau- sea, and diarrhea. Overproduction of lac- tic acid (lactate acidosis, lethality 50%) is a rare, potentially fatal reaction. Metfor- min is used in combination with sulfony- lureas or by itself. It is contraindicated in renal insufficiency and should therefore be avoided in elderly patients. Thiazolidinediones (Glitazones: ro- siglitazone, pioglitazone) are insulin- sensitizing agents that augment tissue responsiveness by promoting the syn- thesis or the availability of plasmalem- mal glucose transporters via activation of a transcription factor (peroxisome proliferator-activated receptor-γ). 262 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 263 Diagnosis: latent overt Diabetes mellitus C. Action of oral antidiabetic drugs A. Insulin concentration and binding in normal and overweight subjects B. Development of maturity-onset diabetes Insulin receptor binding needed for euglycemia Insulin binding Normal receptor number Decreased receptor number Normal diet Obesity Insulin concentration Glucose in blood Insulin r elease Time Oral anti- diabetic Therapy of 1st choice Therapy of 2nd choice Membrane depolarization ATP Insulin B cell Glucose Blockade Sulfonylurea derivatives Tolbutamide K + Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for Maintaining Calcium Homeostasis At rest, the intracellular concentration of free calcium ions (Ca 2+ ) is kept at 0.1 μM (see p. 128 for mechanisms in- volved). During excitation, a transient rise of up to 10 μM elicits contraction in muscle cells (electromechanical coup- ling) and secretion in glandular cells (electrosecretory coupling). The cellular content of Ca 2+ is in equilibrium with the extracellular Ca 2+ concentration (approx. 1000 μM), as is the plasma pro- tein-bound fraction of calcium in blood. Ca 2+ may crystallize with phosphate to form hydroxyapatite, the mineral of bone. Osteoclasts are phagocytes that mobilize Ca 2+ by resorption of bone. Slight changes in extracellular Ca 2+ con- centration can alter organ function: thus, excitability of skeletal muscle in- creases markedly as Ca 2+ is lowered (e.g., in hyperventilation tetany). Three hormones are available to the body for maintaining a constant extracellular Ca 2+ concentration. Vitamin D hormone is derived from vitamin D (cholecalciferol). Vitamin D can also be produced in the body; it is formed in the skin from dehydrocholes- terol during irradiation with UV light. When there is lack of solar radiation, dietary intake becomes essential, cod liver oil being a rich source. Metaboli- cally active vitamin D hormone results from two successive hydroxylations: in the liver at position 25 (L50478 calcifediol) and in the kidney at position 1 (L50478 calci- triol = vit. D hormone). 1-Hydroxylation depends on the level of calcium homeo- stasis and is stimulated by parathor- mone and a fall in plasma levels of Ca 2+ or phosphate. Vit. D hormone promotes enteral absorption and renal reabsorp- tion of Ca 2+ and phosphate. As a result of the increased Ca 2+ and phosphate con- centration in blood, there is an in- creased tendency for these ions to be deposited in bone in the form of hy- droxyapatite crystals. In vit. D deficien- cy, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic use aims at replacement. Mostly, vit. D is given; in liver disease calcifediol may be indicated, in renal disease calcitriol. Ef- fectiveness, as well as rate of onset and cessation of action, increase in the order vit. D. < 25-OH-vit. D < 1,25-di-OH-vit. D. Overdosage may induce hypercal- cemia with deposits of calcium salts in tissues (particularly in kidney and blood vessels): calcinosis. The polypeptide parathormone is released from the parathyroid glands when plasma Ca 2+ level falls. It stimu- lates osteoclasts to increase bone resorp- tion; in the kidneys, it promotes calcium reabsorption, while phosphate excre- tion is enhanced. As blood phosphate concentration diminishes, the tendency of calcium to precipitate as bone miner- al decreases. By stimulating the forma- tion of vit. D hormone, parathormone has an indirect effect on the enteral up- take of Ca 2+ and phosphate. In parathor- mone deficiency, vitamin D can be used as a substitute that, unlike parathor- mone, is effective orally. The polypeptide calcitonin is se- creted by thyroid C-cells during immi- nent hypercalcemia. It lowers plasma Ca 2+ levels by inhibiting osteoclast activ- ity. Its uses include hypercalcemia and osteoporosis. Remarkably, calcitonin in- jection may produce a sustained analge- sic effect that is not restricted to bone pain. Hypercalcemia can be treated by (1) administering 0.9% NaCl solution plus furosemide (if necessary) L50478 renal excretion L50518; (2) the osteoclast inhibi- tors calcitonin, plicamycin, or clodro- nate (a bisphosphonate) L50478 bone cal- cium mobilization L50519; (3) the Ca 2+ chela- tors EDTA sodium or sodium citrate; as well as (4) glucocorticoids. 264 Hormones Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 265 A. Calcium homeostasis of the body Ef fect on cell function Skin 7-Dehydrocholesterol Cod liver oil Cholecalciferol (vitamin D 3 ) 50-5000μg/day 1,25-Dihydroxychole- calciferol (calcitriol) 0,5-2μg/day 25-Hydroxychole- calciferol (calcifediol) Parafollicular cells of thyroid Ca 2+ + PO 4 3- Parathyroid hormone, Ca 2+ , PO 4 3- Parathyroid glands Electrical excitability Muscle cell Gland cell Ca 2+ ~1 x 10 -7 M Contraction Secretion ~10 -5 M Ca 2+ Albumin Globulin ~1 x 10 -3 M Ca Ca 1 x 10 -3 M Ca 2+ + PO 4 3- Parathyroid hormone Calcitonin Vit. D-Hormone Ca 2+ Ca 10 (PO 4 ) 6 (OH) 2 Bone trabeculae Hydroxyapatite crystals Osteoclast 1 1 25 25 7 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs Drugs for Treating Bacterial Infections When bacteria overcome the cutaneous or mucosal barriers and penetrate body tissues, a bacterial infection is present. Frequently the body succeeds in remov- ing the invaders, without outward signs of disease, by mounting an immune re- sponse. If bacteria multiply faster than the body’s defenses can destroy them, infectious disease develops with inflam- matory signs, e.g., purulent wound in- fection or urinary tract infection. Appro- priate treatment employs substances that injure bacteria and thereby prevent their further multiplication, without harming cells of the host organism (1). Apropos nomenclature: antibiotics are produced by microorganisms (fungi, bacteria) and are directed “against life” at any phylogenetic level (prokaryotes, eukaryotes). Chemotherapeutic agents originate from chemical synthesis. This distinction has been lost in current us- age. Specific damage to bacteria is partic- ularly practicable when a substance interferes with a metabolic process that occurs in bacterial but not in host cells. Clearly this applies to inhibitors of cell wall synthesis, because human and ani- mal cells lack a cell wall. The points of attack of antibacterial agents are sche- matically illustrated in a grossly simpli- fied bacterial cell, as depicted in (2). In the following sections, polymyx- ins and tyrothricin are not considered further. These polypeptide antibiotics enhance cell membrane permeability. Due to their poor tolerability, they are prescribed in humans only for topical use. The effect of antibacterial drugs can be observed in vitro (3). Bacteria multi- ply in a growth medium under control conditions. If the medium contains an antibacterial drug, two results can be discerned: 1. bacteria are killed—bacte- ricidal effect; 2. bacteria survive, but do not multiply—bacteriostatic effect. Al- though variations may occur under therapeutic conditions, different drugs can be classified according to their re- spective primary mode of action (color tone in 2 and 3). When bacterial growth remains un- affected by an antibacterial drug, bacte- rial resistance is present. This may oc- cur because of certain metabolic charac- teristics that confer a natural insensitiv- ity to the drug on a particular strain of bacteria (natural resistance). Depending on whether a drug affects only a few or numerous types of bacteria, the terms narrow-spectrum (e.g., penicillin G) or broad-spectrum (e.g., tetracyclines) antibiotic are applied. Naturally sus- ceptible bacterial strains can be trans- formed under the influence of antibac- terial drugs into resistant ones (acquired resistance), when a random genetic al- teration (mutation) gives rise to a resist- ant bacterium. Under the influence of the drug, the susceptible bacteria die off, whereas the mutant multiplies un- impeded. The more frequently a given drug is applied, the more probable the emergence of resistant strains (e.g., hos- pital strains with multiple resistance)! Resistance can also be acquired when DNA responsible for nonsuscepti- bility (so-called resistance plasmid) is passed on from other resistant bacteria by conjugation or transduction. 266 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 267 A. Principles of antibacterial therapy Selective antibacterial toxicity BacteriaBody cells Cell membrane Cell wall Bacterium DNA RNA Protein 1 day Antibiotic Insensitive strain Sensitive strain with resistant mutant Selection 3. 2. 1. Immune defenses Anti- bacterial drugs Bacterial invasion: infection Penicillins Cephalosporins "Gyrase-inhibitors" Nitroimidazoles Bacitracin Vancomycin Polymyxins Tyrothricin Rifampin Tetracyclines Chloramphenicol Erythromycin Clindamycin Aminoglycosides Sulfonamides Trimethoprim Tetrahydro- folate synthesis Resistance Bacteriostatic Bactericidal Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of Cell Wall Synthesis In most bacteria, a cell wall surrounds the cell like a rigid shell that protects against noxious outside influences and prevents rupture of the plasma mem- brane from a high internal osmotic pressure. The structural stability of the cell wall is due mainly to the murein (peptidoglycan) lattice. This consists of basic building blocks linked together to form a large macromolecule. Each basic unit contains the two linked aminosug- ars N-acetylglucosamine and N-acetyl- muramyl acid; the latter bears a peptide chain. The building blocks are synthe- sized in the bacterium, transported out- ward through the cell membrane, and assembled as illustrated schematically. The enzyme transpeptidase cross-links the peptide chains of adjacent amino- sugar chains. Inhibitors of cell wall synthesis are suitable antibacterial agents, be- cause animal and human cells lack a cell wall. They exert a bactericidal action on growing or multiplying germs. Mem- bers of this class include β-lactam anti- biotics such as the penicillins and cepha- losporins, in addition to bacitracin and vancomycin. Penicillins (A). The parent sub- stance of this group is penicillin G (ben- zylpenicillin). It is obtained from cul- tures of mold fungi, originally from Pen- icillium notatum. Penicillin G contains the basic structure common to all peni- cillins, 6-amino-penicillanic acid (p. 271, 6-APA), comprised of a thiazolidine and a 4-membered β-lactam ring. 6- APA itself lacks antibacterial activity. Penicillins disrupt cell wall synthesis by inhibiting transpeptidase. When bacte- ria are in their growth and replication phase, penicillins are bactericidal; due to cell wall defects, the bacteria swell and burst. Penicillins are generally well toler- ated; with penicillin G, the daily dose can range from approx. 0.6 g i.m. (= 10 6 international units, 1 Mega I.U.) to 60 g by infusion. The most important ad- verse effects are due to hypersensitivity (incidence up to 5%), with manifesta- tions ranging from skin eruptions to anaphylactic shock (in less than 0.05% of patients). Known penicillin allergy is a contraindication for these drugs. Be- cause of an increased risk of sensitiza- tion, penicillins must not be used local- ly. Neurotoxic effects, mostly convul- sions due to GABA antagonism, may oc- cur if the brain is exposed to extremely high concentrations, e.g., after rapid i.v. injection of a large dose or intrathecal injection. Penicillin G undergoes rapid renal elimination mainly in unchanged form (plasma t 1/2 ~ 0.5 h). The duration of the effect can be prolonged by: 1. Use of higher doses, enabling plas- ma levels to remain above the minimal- ly effective antibacterial concentration; 2. Combination with probenecid. Re- nal elimination of penicillin occurs chiefly via the anion (acid)-secretory system of the proximal tubule (-COOH of 6-APA). The acid probenecid (p. 316) competes for this route and thus retards penicillin elimination; 3. Intramuscular administration in depot form. In its anionic form (-COO - ) penicillin G forms poorly water-soluble salts with substances containing a posi- tively charged amino group (procaine, p. 208; clemizole, an antihistamine; benzathine, dicationic). Depending on the substance, release of penicillin from the depot occurs over a variable inter- val. 268 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 269 A. Penicillin G: structure and origin; mode of action of penicillins; methods for prolonging duration of action Bacterium Cell wall Cell membrane Cell wall building block Amino acid chain Cross-linked by transpeptidase Sugar Penicillin G Fungus Penicillium notatum Human Penicillin allergy Neurotoxicity at very high dosage Plasma concentration 3 x Dose Minimal bactericidal concentration Time Increasing the dose Anion secretory system Combination with probenecid Depot preparations ~1 ~7-28 ~2 Inhibition of cell wall synthesis Probenecid Penicillin Pr ocaine Penicillin + - Clemizole Penicillin + - Benzathine 2 Penicillins + - + Duration of action (d) Antibody Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Although very well tolerated, peni- cillin G has disadvantages (A) that limit its therapeutic usefulness: (1) It is inac- tivated by gastric acid, which cleaves the β-lactam ring, necessitating paren- teral administration. (2) The β-lactam ring can also be opened by bacterial en- zymes (β-lactamases); in particular, penicillinase, which can be produced by staphylococcal strains, renders them re- sistant to penicillin G. (3) The antibacte- rial spectrum is narrow; although it en- compasses many gram-positive bacte- ria, gram-negative cocci, and spiro- chetes, many gram-negative pathogens are unaffected. Derivatives with a different sub- stituent on 6-APA possess advantages (B): (1) Acid resistance permits oral ad- ministration, provided that enteral ab- sorption is possible. All derivatives shown in (B) can be given orally. Penicil- lin V (phenoxymethylpenicillin) exhib- its antibacterial properties similar to those of penicillin G. (2) Due to their penicillinase resistance, isoxazolylpen- icillins (oxacillin dicloxacillin, flucloxacil- lin) are suitable for the (oral) treatment of infections caused by penicillinase- producing staphylococci. (3) Extended activity spectrum: The aminopenicillin amoxicillin is active against many gram- negative organisms, e.g., coli bacteria or Salmonella typhi. It can be protected from destruction by penicillinase by combination with inhibitors of penicilli- nase (clavulanic acid, sulbactam, tazo- bactam). The structurally close congener am- picillin (no 4-hydroxy group) has a simi- lar activity spectrum. However, because it is poorly absorbed (<50%) and there- fore causes more extensive damage to the gut microbial flora (side effect: diar- rhea), it should be given only by injec- tion. A still broader spectrum (including Pseudomonas bacteria) is shown by car- boxypenicillins (carbenicillin, ticarcillin) and acylaminopenicillins (mezclocillin, azlocillin, piperacillin). These substanc- es are neither acid stable nor penicilli- nase resistant. Cephalosporins (C). These β-lac- tam antibiotics are also fungal products and have bactericidal activity due to in- hibition of transpeptidase. Their shared basic structure is 7-aminocepha- losporanic acid, as exemplified by cephalexin (gray rectangle). Cephalo- sporins are acid stable, but many are poorly absorbed. Because they must be given parenterally, most—including those with high activity—are used only in clinical settings. A few, e.g., cepha- lexin, are suitable for oral use. Cephalo- sporins are penicillinase-resistant, but cephalosporinase-forming organisms do exist. Some derivatives are, however, also resistant to this β-lactamase. Cephalosporins are broad-spectrum antibacterials. Newer derivatives (e.g., cefotaxime, cefmenoxin, cefoperazone, ceftriaxone, ceftazidime, moxalactam) are also effective against pathogens re- sistant to various other antibacterials. Cephalosporins are mostly well tolerat- ed. All can cause allergic reactions, some also renal injury, alcohol intolerance, and bleeding (vitamin K antagonism). Other inhibitors of cell wall syn- thesis. Bacitracin and vancomycin interfere with the transport of pepti- doglycans through the cytoplasmic membrane and are active only against gram-positive bacteria. Bacitracin is a polypeptide mixture, markedly nephro- toxic and used only topically. Vancomy- cin is a glycopeptide and the drug of choice for the (oral) treatment of bowel inflammations occurring as a complica- tion of antibiotic therapy (pseudomem- branous enterocolitis caused by Clos- tridium difficile). It is not absorbed. 270 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 271 C. Cephalosporin A. Disadvantages of penicillin G B. Derivatives of penicillin G 6-Aminopenicillanic acid Penicillin G Penicillinase Staphylococci E. coli Salmonella typhi Gonococci Pneumococci Streptococci Narr ow-action spectrum Active Not active H + Cl - Resis- tant Resistant, but sensitive to cephalosporinase Broad Cefalexin Penicillin V Oxacillin Amoxicillin Resis- tant Resis- tant Resis- tant Sensitive Resistant Resistant Narrow Narrow Broad PenicillinaseAcid Spectrum Concentration needed to inhibit penicillin G- sensitive bacteria Gram-positive Gram-negative Acid sensitivity Penicillinase sensitivity Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of Tetrahydrofolate Synthesis Tetrahydrofolic acid (THF) is a co-en- zyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and required for cell growth and replication. Lack of THF leads to inhibition of cell proliferation. Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihy- drofolate reductase. DHF is made from folic acid, a vitamin that cannot be syn- thesized in the body, but must be taken up from exogenous sources. Most bacte- ria do not have a requirement for folate, because they are capable of synthesiz- ing folate, more precisely DHF, from precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and tri- methoprim. Sulfonamides structurally resem- ble p-aminobenzoic acid (PABA), a pre- cursor in bacterial DHF synthesis. As false substrates, sulfonamides competi- tively inhibit utilization of PABA, hence DHF synthesis. Because most bacteria cannot take up exogenous folate, they are depleted of DHF. Sulfonamides thus possess bacteriostatic activity against a broad spectrum of pathogens. Sulfon- amides are produced by chemical syn- thesis. The basic structure is shown in (A). Residue R determines the pharma- cokinetic properties of a given sulfon- amide. Most sulfonamides are well ab- sorbed via the enteral route. They are metabolized to varying degrees and eliminated through the kidney. Rates of elimination, hence duration of effect, may vary widely. Some members are poorly absorbed from the gut and are thus suitable for the treatment of bacte- rial bowel infections. Adverse effects may include, among others, allergic re- actions, sometimes with severe skin damage, displacement of other plasma protein-bound drugs or bilirubin in neo- nates (danger of kernicterus, hence con- traindication for the last weeks of gesta- tion and in the neonate). Because of the frequent emergence of resistant bacte- ria, sulfonamides are now rarely used. Introduced in 1935, they were the first broad-spectrum chemotherapeutics. Trimethoprim inhibits bacterial DHF reductase, the human enzyme be- ing significantly less sensitive than the bacterial one (rarely bone marrow de- pression). A 2,4-diaminopyrimidine, tri- methoprim, has bacteriostatic activity against a broad spectrum of pathogens. It is used mostly as a component of co- trimoxazole. Co-trimoxazole is a combination of trimethoprim and the sulfonamide sul- famethoxazole. Since THF synthesis is inhibited at two successive steps, the antibacterial effect of co-trimoxazole is better than that of the individual com- ponents. Resistant pathogens are infre- quent; a bactericidal effect may occur. Adverse effects correspond to those of the components. Although initially developed as an antirheumatic agent (p. 320), sulfasala- zine (salazosulfapyridine) is used main- ly in the treatment of inflammatory bowel disease (ulcerative colitis and terminal ileitis or Crohn’s disease). Gut bacteria split this compound into the sulfonamide sulfapyridine and mesala- mine (5-aminosalicylic acid). The latter is probably the anti-inflammatory agent (inhibition of synthesis of chemotactic signals for granulocytes, and of H 2 O 2 formation in mucosa), but must be present on the gut mucosa in high con- centrations. Coupling to the sulfon- amide prevents premature absorption in upper small bowel segments. The cleaved-off sulfonamide can be ab- sorbed and may produce typical adverse effects (see above). Dapsone (p. 280) has several thera- peutic uses: besides treatment of lepro- sy, it is used for prevention/prophylaxis of malaria, toxoplasmosis, and actino- mycosis. 272 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 273 A. Inhibitors of tetrahydrofolate synthesis (Vitamin) DHF-Reductase R determines pharmacokinetics Duration of effect Dosing interval Sulfasalazine (not absorbable) Cleavage by intestinal bacteria Mesalamine Sulfapyridine (absorbable) Bacterium Human cell Synthesis of purines Thymidine Sulfonamidesp-Aminobenzoic acid Combination of Trimethoprim and Sulfamethoxazole Co-trimoxazole = Dihydro- folic acid (DHF) Tetrahydro- folic acid Folic acid Trimethoprim Sulfisoxazole 6 hours Sulfamethoxazole 12 hours Sulfalene 7 days Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of DNA Function Deoxyribonucleic acid (DNA) serves as a template for the synthesis of nucleic ac- ids. Ribonucleic acid (RNA) executes protein synthesis and thus permits cell growth. Synthesis of new DNA is a pre- requisite for cell division. Substances that inhibit reading of genetic informa- tion at the DNA template damage the regulatory center of cell metabolism. The substances listed below are useful as antibacterial drugs because they do not affect human cells. Gyrase inhibitors. The enzyme gy- rase (topoisomerase II) permits the or- derly accommodation of a ~1000 μm- long bacterial chromosome in a bacteri- al cell of ~1 μm. Within the chromoso- mal strand, double-stranded DNA has a double helical configuration. The for- mer, in turn, is arranged in loops that are shortened by supercoiling. The gy- rase catalyzes this operation, as illus- trated, by opening, underwinding, and closing the DNA double strand such that the full loop need not be rotated. Derivatives of 4-quinolone-3-car- boxylic acid (green portion of ofloxacin formula) are inhibitors of bacterial gy- rases. They appear to prevent specifical- ly the resealing of opened strands and thereby act bactericidally. These agents are absorbed after oral ingestion. The older drug, nalidixic acid, affects exclu- sively gram-negative bacteria and at- tains effective concentrations only in urine; it is used as a urinary tract anti- septic. Norfloxacin has a broader spec- trum. Ofloxacin, ciprofloxacin, and enoxacin, and others, also yield system- ically effective concentrations and are used for infections of internal organs. Besides gastrointestinal problems and allergy, adverse effects particularly involve the CNS (confusion, hallucina- tions, seizures). Since they can damage epiphyseal chondrocytes and joint car- tilages in laboratory animals, gyrase in- hibitors should not be used during preg- nancy, lactation, and periods of growth. Azomycin (nitroimidazole) deriv- atives, such as metronidazole, damage DNA by complex formation or strand breakage. This occurs in obligate an- aerobes, i.e., bacteria growing under O 2 exclusion. Under these conditions, con- version to reactive metabolites that at- tack DNA takes place (e.g., the hydroxyl- amine shown). The effect is bactericidal. A similar mechanism is involved in the antiprotozoal action on Trichomonas va- ginalis (causative agent of vaginitis and urethritis) and Entamoeba histolytica (causative agent of large bowel inflam- mation, amebic dysentery, and hepatic abscesses). Metronidazole is well ab- sorbed via the enteral route; it is also given i.v. or topically (vaginal insert). Because metronidazole is considered potentially mutagenic, carcinogenic, and teratogenic in the human, it should not be used longer than 10 d, if possible, and be avoided during pregnancy and lactation. Timidazole may be considered equivalent to metronidazole. Rifampin inhibits the bacterial en- zyme that catalyzes DNA template-di- rected RNA transcription, i.e., DNA-de- pendent RNA polymerase. Rifampin acts bactericidally against mycobacteria (M. tuberculosis, M. leprae), as well as many gram-positive and gram-negative bac- teria. It is well absorbed after oral inges- tion. Because resistance may develop with frequent usage, it is restricted to the treatment of tuberculosis and lepro- sy (p. 280). Rifampin is contraindicated in the first trimester of gestation and during lactation. Rifabutin resembles rifampin but may be effective in infections resistant to the latter. 274 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 275 Indication: TB Streptomyces species A. Antibacterial drugs acting on DNA RNA Twisting by opening, underwinding, and closure of DNA strand 1 2 3 4 Gyrase Gyrase inhibitors 4-Quinolone- 3-carboxylate- derivates, e. g. DNA-double helix Damage to DNA DNA-dependent RNA polymerase Anaerobic bacteria Nitroimidazole e. g., metronidazole Trichomonas infection Amebic infection Rifampicin Bacterial chromosome ofloxacin Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibitors of Protein Synthesis Protein synthesis means translation into a peptide chain of a genetic mes- sage first copied (transcribed) into m- RNA (p. 274). Amino acid (AA) assembly occurs at the ribosome. Delivery of ami- no acids to m-RNA involves different transfer RNA molecules (t-RNA), each of which binds a specific AA. Each t-RNA bears an “anticodon” nucleobase triplet that is complementary to a particular m-RNA coding unit (codon, consisting of 3 nucleobases. Incorporation of an AA normally in- volves the following steps (A): 1. The ribosome “focuses” two co- dons on m-RNA; one (at the left) has bound its t-RNA-AA complex, the AA having already been added to the pep- tide chain; the other (at the right) is ready to receive the next t-RNA-AA complex. 2. After the latter attaches, the AAs of the two adjacent complexes are linked by the action of the enzyme pep- tide synthetase (peptidyltransferase). Concurrently, AA and t-RNA of the left complex disengage. 3. The left t-RNA dissociates from m-RNA. The ribosome can advance along the m-RNA strand and focus on the next codon. 4. Consequently, the right t-RNA- AA complex shifts to the left, allowing the next complex to be bound at the right. These individual steps are suscepti- ble to inhibition by antibiotics of differ- ent groups. The examples shown origi- nate primarily from Streptomyces bac- teria, some of the aminoglycosides also being derived from Micromonospora bacteria. 1a. Tetracyclines inhibit the bind- ing of t-RNA-AA complexes. Their action is bacteriostatic and affects a broad spectrum of pathogens. 1b. Aminoglycosides induce the binding of “wrong” t-RNA-AA complex- es, resulting in synthesis of false pro- teins. Aminoglycosides are bactericidal. Their activity spectrum encompasses mainly gram-negative organisms. Streptomycin and kanamycin are used predominantly in the treatment of tu- berculosis. Note on spelling: -mycin designates origin from Streptomyces species; -mi- cin (e.g., gentamicin) from Micromono- spora species. 2. Chloramphenicol inhibits pep- tide synthetase. It has bacteriostatic ac- tivity against a broad spectrum of pathogens. The chemically simple mole- cule is now produced synthetically. 3. Erythromycin suppresses ad- vancement of the ribosome. Its action is predominantly bacteriostatic and di- rected against gram-positve organisms. For oral administration, the acid-labile base (E) is dispensed as a salt (E. stear- ate) or an ester (e.g., E. succinate). Erythromycin is well tolerated. It is a suitable substitute in penicillin allergy or resistance. Azithromycin, clarithromy- cin, and roxithromycin are derivatives with greater acid stability and better bioavailability. The compounds men- tioned are the most important members of the macrolide antibiotic group, which includes josamycin and spiramycin. An unrelated action of erythromycin is its mimicry of the gastrointestinal hor- mone motiline (L50518 interprandial bowel motility). Clindamycin has antibacterial ac- tivity similar to that of erythromycin. It exerts a bacteriostatic effect mainly on gram-positive aerobic, as well as on an- aerobic pathogens. Clindamycin is a semisynthetic chloro analogue of lin- comycin, which derives from a Strepto- myces species. Taken orally, clindamy- cin is better absorbed than lincomycin, has greater antibacterial efficacy and is thus preferred. Both penetrate well into bone tissue. 276 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 277 A. Protein synthesis and modes of action of antibacterial drugs Ribosome Peptide chain mRNA tRNA Insertion of incorrect amino acid Amino acid Streptomyces species Tetracyclines Aminoglycosides Erythromycin Chloramphenicol Peptide synthetase Doxycycline Tobramycin Chloramphenicol Erythromycin Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Tetracyclines are absorbed from the gastrointestinal tract to differing de- grees, depending on the substance, ab- sorption being nearly complete for doxycycline and minocycline. Intrave- nous injection is rarely needed (rolite- tracycline is available only for i.v. ad- ministration). The most common un- wanted effect is gastrointestinal upset (nausea, vomiting, diarrhea, etc.) due to (1) a direct mucosal irritant action of these substances and (2) damage to the natural bacterial gut flora (broad-spec- trum antibiotics) allowing colonization by pathogenic organisms, including Candida fungi. Concurrent ingestion of antacids or milk would, however, be in- appropriate because tetracyclines form insoluble complexes with plurivalent cations (e.g., Ca 2+ , Mg 2+ , Al 3+ , Fe 2+/3+ ) re- sulting in their inactivation; that is, ab- sorbability, antibacterial activity, and local irritant action are abolished. The ability to chelate Ca 2+ accounts for the propensity of tetracyclines to accumu- late in growing teeth and bones. As a re- sult, there occurs an irreversible yellow- brown discoloration of teeth and a rever- sible inhibition of bone growth. Because of these adverse effects, tetracycline should not be given after the second month of pregnancy and not prescribed to children aged 8 y and under. Other adverse effects are increased photosen- sitivity of the skin and hepatic damage, mainly after i.v. administration. The broad-spectrum antibiotic chloramphenicol is completely ab- sorbed after oral ingestion. It undergoes even distribution in the body and readi- ly crosses diffusion barriers such as the blood-brain barrier. Despite these ad- vantageous properties, use of chloram- phenicol is rarely indicated (e.g., in CNS infections) because of the danger of bone marrow damage. Two types of bone marrow depression can occur: (1) a dose-dependent, toxic, reversible form manifested during therapy and, (2) a frequently fatal form that may occur af- ter a latency of weeks and is not dose dependent. Due to high tissue penet- rability, the danger of bone marrow de- pression must also be taken into ac- count after local use (e.g., eye drops). Aminoglycoside antibiotics con- sist of glycoside-linked amino-sugars (cf. gentamicin C 1α , a constituent of the gentamicin mixture). They contain nu- merous hydroxyl groups and amino groups that can bind protons. Hence, these compounds are highly polar, poorly membrane permeable, and not absorbed enterally. Neomycin and paro- momycin are given orally to eradicate intestinal bacteria (prior to bowel sur- gery or for reducing NH 3 formation by gut bacteria in hepatic coma). Amino- glycosides for the treatment of serious infections must be injected (e.g., gen- tamicin, tobramycin, amikacin, netilmi- cin, sisomycin). In addition, local inlays of a gentamicin-releasing carrier can be used in infections of bone or soft tissues. Aminoglycosides gain access to the bac- terial interior by the use of bacterial transport systems. In the kidney, they enter the cells of the proximal tubules via an uptake system for oligopeptides. Tubular cells are susceptible to damage (nephrotoxicity, mostly reversible). In the inner ear, sensory cells of the vestib- ular apparatus and Corti’s organ may be injured (ototoxicity, in part irreversible). 278 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 279 A. Aspects of the therapeutic use of tetracyclines, chloramphenicol, and aminoglycosides Irritation of mucous membranes Absorption Antibacterial effect on gut flora Disadvantage: bone marrow toxicity Advantage: good penetration through barriers Gentamicin C 1a Basic oligopeptides Transport system No absorption "bowel sterilization" Bacterium H + Inactivation by chelation of Ca 2+ , Al 3+ etc. Chelation Chloramphenicol Cochlear and vestibular ototoxicity H + H + Nephro- toxicity High hydrophilicity no passive diffusion through membranes e.g., neomycin Tetracyclines Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for Treating Mycobacterial Infections Mycobacteria are responsible for two diseases: tuberculosis, mostly caused by M. tuberculosis, and leprosy due to M. le- prae. The therapeutic principle appli- cable to both is combined treatment with two or more drugs. Combination therapy prevents the emergence of re- sistant mycobacteria. Because the anti- bacterial effects of the individual sub- stances are additive, correspondingly smaller doses are sufficient. Therefore, the risk of individual adverse effects is lowered. Most drugs are active against only one of the two diseases. Antitubercular Drugs (1) Drugs of choice are: isoniazid, rifampin, ethambutol, along with streptomycin and pyrazinamide. Less well tolerated, second-line agents include: p-aminosal- icylic acid, cycloserine, viomycin, ka- namycin, amikacin, capreomycin, ethi- onamide. Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. (In the bacte- rium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellu- larly.) Isoniazid is rapidly absorbed after oral administration. In the liver, it is in- activated by acetylation, the rate of which is genetically controlled and shows a characteristic distribution in different ethnic groups (fast vs. slow acetylators). Notable adverse effects are: peripheral neuropathy, optic neu- ritis preventable by administration of vitamin B 6 (pyridoxine); hepatitis, jaun- dice. Rifampin. Source, antibacterial ac- tivity, and routes of administration are described on p. 274. Albeit mostly well tolerated, this drug may cause several adverse effects including hepatic dam- age, hypersensitivity with flu-like symptoms, disconcerting but harmless red/orange discoloration of body fluids, and enzyme induction (failure of oral contraceptives). Concerning rifabutin see p. 274. Ethambutol. The cause of its specific antitubercular action is unknown. Ethambutol is given orally. It is general- ly well tolerated, but may cause dose- dependent damage to the optic nerve with disturbances of vision (red/green blindness, visual field defects). Pyrazinamide exerts a bactericidal action by an unknown mechanism. It is given orally. Pyrazinamide may impair liver function; hyperuricemia results from inhibition of renal urate elimina- tion. Streptomycin must be given i.v. (pp. 278ff) like other aminoglycoside antibi- otics. It damages the inner ear and the labyrinth. Its nephrotoxicity is compar- atively minor. Antileprotic Drugs (2) Rifampin is frequently given in combi- nation with one or both of the following agents: Dapsone is a sulfone that, like sul- fonamides, inhibits dihydrofolate syn- thesis (p. 272). It is bactericidal against susceptible strains of M. leprae. Dapsone is given orally. The most frequent ad- verse effect is methemoglobinemia with accelerated erythrocyte degradation (hemolysis). Clofazimine is a dye with bacterici- dal activity against M. leprae and anti- inflammatory properties. It is given orally, but is incompletely absorbed. Be- cause of its high lipophilicity, it accu- mulates in adipose and other tissues and leaves the body only rather slowly (t 1/2 ~ 70 d). Red-brown skin pigmenta- tion is an unwanted effect, particularly in fair-skinned patients. 280 Antibacterial Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antibacterial Drugs 281 an aminoglycoside antibiotic Streptomycin Vestibular and cochlear ototoxicity A. Drugs used to treat infections with mycobacteria (1. tuberculosis, 2. leprosy) Isonicotinic acid Nicotinic acid Folate synthesis p-Aminobenzoic acid Clofazimine Skin discoloration Pyrazinamide Liver damage Combination therapy Reduced risk of bacterial resistance Reduction of dose and of risk of adverse reactions Mycobacterium leprae Mycobacterium tuberculosis 1 2 Rifampin Liver damage and enzyme induction Ethambutol Optic nerve damage Isoniazid CNS damage and peripheral neuropathy (Vit. B 6 -administration) Liver damage Dapsone Hemolysis Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs Used in the Treatment of Fungal Infections Infections due to fungi are usually con- fined to the skin or mucous membranes: local or superficial mycosis. However, in immune deficiency states, internal or- gans may also be affected: systemic or deep mycosis. Mycoses are most commonly due to dermatophytes, which affect the skin, hair, and nails following external infec- tion. Candida albicans, a yeast organism normally found on body surfaces, may cause infections of mucous membranes, less frequently of the skin or internal or- gans when natural defenses are im- paired (immunosuppression, or damage of microflora by broad-spectrum antibi- otics). Imidazole derivatives inhibit er- gosterol synthesis. This steroid forms an integral constituent of cytoplasmic membranes of fungal cells, analogous to cholesterol in animal plasma mem- branes. Fungi exposed to imidazole de- rivatives stop growing (fungistatic ef- fect) or die (fungicidal effect). The spec- trum of affected fungi is very broad. Be- cause they are poorly absorbed and poorly tolerated systemically, most imidazoles are suitable only for topical use (clotrimazole, econazole oxiconazole, isoconazole, bifonazole, etc.). Rarely, this use may result in contact dermatitis. Mi- conazole is given locally, or systemically by short-term infusion (despite its poor tolerability). Because it is well absorbed, ketoconazole is available for oral admin- istration. Adverse effects are rare; how- ever, the possibility of fatal liver dam- age should be noted. Remarkably, keto- conazole may inhibit steroidogenesis (gonadal and adrenocortical hormones). Fluconazole and itraconazole are newer, orally effective triazole derivatives. The topically active allylamine naftidine and the morpholine amorolfine also in- hibit ergosterol synthesis, albeit at an- other step. The polyene antibiotics, ampho- tericin B and nystatin, are of bacterial origin. They insert themselves into fun- gal cell membranes (probably next to ergosterol molecules) and cause forma- tion of hydrophilic channels. The resul- tant increase in membrane permeabil- ity, e.g., to K + ions, accounts for the fun- gicidal effect. Amphotericin B is active against most organisms responsible for systemic mycoses. Because of its poor absorbability, it must be given by infu- sion, which is, however, poorly tolerat- ed (chills, fever, CNS disturbances, im- paired renal function, phlebitis at the infusion site). Applied topically to skin or mucous membranes, amphotericin B is useful in the treatment of candidal mycosis. Because of the low rate of en- teral absorption, oral administration in intestinal candidiasis can be considered a topical treatment. Nystatin is used on- ly for topical therapy. Flucytosine is converted in candida fungi to 5-fluorouracil by the action of a specific cytosine deaminase. As an anti- metabolite, this compound disrupts DNA and RNA synthesis (p. 298), result- ing in a fungicidal effect. Given orally, flucytosine is rapidly absorbed. It is well tolerated and often combined with am- photericin B to allow dose reduction of the latter. Griseofulvin originates from molds and has activity only against derma- tophytes. Presumably, it acts as a spin- dle poison to inhibit fungal mitosis. Al- though targeted against local mycoses, griseofulvin must be used systemically. It is incorporated into newly formed keratin. “Impregnated” in this manner, keratin becomes unsuitable as a fungal nutrient. The time required for the erad- ication of dermatophytes corresponds to the renewal period of skin, hair, or nails. Griseofulvin may cause uncharac- teristic adverse effects. The need for prolonged administration (several months), the incidence of side effects, and the availability of effective and safe alternatives have rendered griseofulvin therapeutically obsolete. 282 Antifungal Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antifungal Drugs 283 Streptomyces bacteria NystatinAmphotericin B A. Antifungal drugs Mitotic spindle DNA/RNA metabolism Uracil Cytosine Deaminase Fungal cell 5-Fluoruracil Ergosterol Polyene Antibiotics Mold fungi Incorporation into growing skin, hair, nails "Impregnation effect" 25-50 weeks 2-4 weeks Griseofulvin Synthesis Cell wall Cytoplasmic membrane Imidazole derivatives e.g., clotrimazole Flucytosine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Chemotherapy of Viral Infections Viruses essentially consist of genetic material (nucleic acids, green strands in (A) and a capsular envelope made up of proteins (blue hexagons), often with a coat (gray ring) of a phospholipid (PL) bilayer with embedded proteins (small blue bars). They lack a metabolic system but depend on the infected cell for their growth and replication. Targeted thera- peutic suppression of viral replication requires selective inhibition of those metabolic processes that specifically serve viral replication in infected cells. To date, this can be achieved only to a limited extent. Viral replication as exemplified by Herpes simplex viruses (A): (1) The viral particle attaches to the host cell membrane (adsorption) by linking its capsular glycoproteins to specific struc- tures of the cell membrane. (2) The viral coat fuses with the plasmalemma of the host cell and the nucleocapsid (nucleic acid plus capsule) enters the cell interi- or (penetration). (3) The capsule opens (“uncoating”) near the nuclear pores and viral DNA moves into the cell nucle- us. The genetic material of the virus can now direct the cell’s metabolic system. (4a) Nucleic acid synthesis: The genetic material (DNA in this instance) is repli- cated and RNA is produced for the pur- pose of protein synthesis. (4b) The pro- teins are used as “viral enzymes” cata- lyzing viral multiplication (e.g., DNA polymerase and thymidine kinase), as capsomers, or as coat components, or are incorporated into the host cell membrane. (5) Individual components are assembled into new virus particles (maturation). (6) Release of daughter vi- ruses results in spread of virus inside and outside the organism. With herpes viruses, replication entails host cell de- struction and development of disease symptoms. Antiviral mechanisms (A). The or- ganism can disrupt viral replication with the aid of cytotoxic T-lymphocytes that recognize and destroy virus-pro- ducing cells (viral surface proteins) or by means of antibodies that bind to and inactivate extracellular virus particles. Vaccinations are designed to activate specific immune defenses. Interferons (IFN) are glycoproteins that, among other products, are re- leased from virus-infected cells. In neighboring cells, interferon stimulates the production of “antiviral proteins.” These inhibit the synthesis of viral pro- teins by (preferential) destruction of vi- ral DNA or by suppressing its transla- tion. Interferons are not directed against a specific virus, but have a broad spec- trum of antiviral action that is, however, species-specific. Thus, interferon for use in humans must be obtained from cells of human origin, such as leukocytes (IFN-α), fibroblasts (IFN-β), or lympho- cytes (IFN-γ). Interferons are also used to treat certain malignancies and auto- immune disorders (e.g., IFN-α for chron- ic hepatitis C and hairy cell leukemia; IFN-β for severe herpes virus infections and multiple sclerosis). Virustatic antimetabolites are “false” DNA building blocks (B) or nucle- osides. A nucleoside (e.g., thymidine) consists of a nucleobase (e.g., thymine) and the sugar deoxyribose. In antime- tabolites, one of the components is de- fective. In the body, the abnormal nucle- osides undergo bioactivation by attach- ment of three phosphate residues (p. 287). Idoxuridine and congeners are in- corporated into DNA with deleterious results. This also applies to the synthesis of human DNA. Therefore, idoxuridine and analogues are suitable only for topi- cal use (e.g., in herpes simplex keratitis). Vidarabine inhibits virally induced DNA polymerase more strongly than it does the endogenous enzyme. Its use is now limited to topical treatment of se- vere herpes simplex infection. Before the introduction of the better tolerated acyclovir, vidarabine played a major part in the treatment of herpes simplex encephalitis. Among virustatic antimetabolites, acyclovir (A) has both specificity of the highest degree and optimal tolerability, 284 Antiviral Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antiviral Drugs 285 1. Adsorption Virus- infected Proteins with antigenic properties Specific immune defense e.g., cytotoxic T-lymphocytes DNA Capsule Envelope 4a. Nucleic acid synthesis 5. RNA DNA Incorrect: R: - I Idoxuridine - CF 3 Trifluridine - C 2 H 2 Edoxudine Insertion into DNA instead of thymidine Correct: Thymidine Thymine Desoxyribose Incorrect: Vidarabine Acyclovir Ganciclovir Adenine Guanine Arabinose Inhibition of viral DNA polymerase B. Chemical structure of virustatic antimetabolites Glycoprotein Interferon Antiviral proteins 2. Penetration Viral DNA polymerase 6. Release 4b. Pr otein 3.Uncoating A. Virus multiplication and modes of action of antiviral agents Antimetabolites = incorrect DNA building blocks Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. because it undergoes bioactivation only in infected cells, where it preferentially inhibits viral DNA synthesis. (1) A virally coded thymidine kinase (specific to H. simplex and varicella-zoster virus) per- forms the initial phosphorylation step; the remaining two phosphate residues are attached by cellular kinases. (2) The polar phosphate residues render acyclo- vir triphosphate membrane imperme- able and cause it to accumulate in in- fected cells. (3) Acyclovir triphosphate is a preferred substrate of viral DNA polymerase; it inhibits enzyme activity and, following its incorporation into vi- ral DNA, induces strand breakage be- cause it lacks the 3’-OH group of deoxy- ribose that is required for the attach- ment of additional nucleotides. The high therapeutic value of acyclovir is evident in severe infections with H. simplex vi- ruses (e.g., encephalitis, generalized in- fection) and varicella-zoster viruses (e.g., severe herpes zoster). In these cas- es, it can be given by i.v. infusion. Acy- clovir may also be given orally despite its incomplete (15%–30%) enteral ab- sorption. In addition, it has topical uses. Because host DNA synthesis remains unaffected, adverse effects do not in- clude bone marrow depression. Acyclo- vir is eliminated unchanged in urine (t 1/2 ~ 2.5 h). Valacyclovir, the L-valyl ester of acyclovir, is a prodrug that can be ad- ministered orally in herpes zoster infec- tions. Its absorption rate is approx. twice that of acyclovir. During passage through the intestinal wall and liver, the valine residue is cleaved by esterases, generating acyclovir. Famcyclovir is an antiherpetic pro- drug with good bioavailability when given orally. It is used in genital herpes and herpes zoster. Cleavage of two ace- tate groups from the “false sugar” and oxidation of the purine ring to guanine yields penciclovir, the active form. The latter differs from acyclovir with respect to its “false sugar” moiety, but mimics it pharmacologically. Bioactivation of penciclovir, like that of acyclovir, in- volves formation of the triphosphory- lated antimetabolite via virally induced thymidine kinase. Ganciclovir (structure on p. 285) is given by infusion in the treatment of se- vere infections with cytomegaloviruses (also belonging to the herpes group); these do not induce thymidine kinase, phosphorylation being initiated by a different viral enzyme. Ganciclovir is less well tolerated and, not infrequent- ly, produces leukopenia and thrombo- penia. Foscarnet represents a diphos- phate analogue. As shown in (A), incorporation of nucleotide into a DNA strand entails cleavage of a diphosphate residue. Fos- carnet (B) inhibits DNA polymerase by interacting with its binding site for the diphosphate group. Indications: system- ic therapy of severe cytomegaly infec- tion in AIDS patients; local therapy of herpes simplex infections. Amantadine (C) specifically affects the replication of influenza A (RNA) vi- ruses, the causative agent of true in- fluenza. These viruses are endocytosed into the cell. Release of viral DNA re- quires protons from the acidic content of endosomes to penetrate the virus. Presumably, amantadine blocks a chan- nel protein in the viral coat that permits influx of protons; thus, “uncoating” is prevented. Moreover, amantadine in- hibits viral maturation. The drug is also used prophylactically and, if possible, must be taken before the outbreak of symptoms. It also is an antiparkinsonian (p. 188). 286 Antiviral Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antiviral Drugs 287 Viral DNA polymerase Infected cell: herpes simplex or varicella-zoster Viral thymidine kinase Cellular kinases Acyclovir A. Activation of acyclovir and inhibition of viral DNA synthesis B. Inhibitor of DNA polymerase: B. Foscarnet Influenza A-virus Endosome Viral channel protein H + Inhibition of uncoating C. Prophylaxis for viral flu DNA synthesis DNA-chain termination Inhibition Base Base Base Viral DNA template Active metabolite Amantadine Base Foscarnet C O O PO O O P OO O PO O P O O Viral DNA polymerase Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for the Treatment of AIDS Replication of the human immuno- deficiency virus (HIV), the causative agent of AIDS, is susceptible to targeted interventions, because several virus- specific metabolic steps occur in infect- ed cells (A). Viral RNA must first be tran- scribed into DNA, a step catalyzed by vi- ral “reverse transcriptase.” Double- stranded DNA is incorporated into the host genome with the help of viral inte- grase. Under control by viral DNA, viral replication can then be initiated, with synthesis of viral RNA and proteins (in- cluding enzymes such as reverse tran- scriptase and integrase, and structural proteins such as the matrix protein lin- ing the inside of the viral envelope). These proteins are assembled not indi- vidually but in the form of polyproteins. These precursor proteins carry an N-ter- minal fatty acid (myristoyl) residue that promotes their attachment to the inter- ior face of the plasmalemma. As the vi- rus particle buds off the host cell, it car- ries with it the affected membrane area as its envelope. During this process, a protease contained within the polypro- tein cleaves the latter into individual, functionally active proteins. I. Inhibitors of Reverse Transcriptase IA. Nucleoside agents These substances are analogues of thy- mine (azidothymidine, stavudine), adenine (didanosine), cytosine (lami- vudine, zalcitabine), and guanine (car- bovir, a metabolite of abacavir). They have in common an abnormal sugar moiety. Like the natural nucleosides, they undergo triphosphorylation, giving rise to nucleotides that both inhibit re- verse transcriptase and cause strand breakage following incorporation into viral DNA. The nucleoside inhibitors differ in terms of l) their ability to decrease cir- culating HIV load; 2) their pharmacoki- netic properties (half life L50478 dosing interval L50478 compliance; organ distribu- tion L50478 passage through blood-brainbar- rier); 3) the type of resistance-inducing mutations of the viral genome and the rate at which resistance develops; and 4) their adverse effects (bone marrow depression, neuropathy, pancreatitis). IB. Non-nucleoside inhibitors The non-nucleoside inhibitors of re- verse transcriptase (nevirapine, dela- virdine, efavirenz) are not phosphory- lated. They bind to the enzyme with high selectivity and thus prevent it from adopting the active conformation. Inhi- bition is noncompetitive. II. HIV protease inhibitors Viral protease cleaves precursor pro- teins into proteins required for viral replication. The inhibitors of this pro- tease (saquinavir, ritonavir, indinavir, and nelfinavir) represent abnormal proteins that possess high antiviral effi- cacy and are generally well tolerated in the short term. However, prolonged ad- ministration is associated with occa- sionally severe disturbances of lipid and carbohydrate metabolism. Biotransfor- mation of these drugs involves cyto- chrome P 450 (CYP 3A4) and is therefore subject to interaction with various other drugs inactivated via this route. For the dual purpose of increasing the effectiveness of antiviral therapy and preventing the development of a therapy-limiting viral resistance, inhibi- tors of reverse transcriptase are com- bined with each other and/or with pro- tease inhibitors. Combination regimens are de- signed in accordance with substance- specific development of resistance and pharmacokinetic parameters (CNS penetrability, “neuroprotection,” dosing frequency). 288 Antiviral Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antiviral Drugs 289 A. Antiretroviral drugs Viral RNA DNA e.g., zidovudine Inhibitors of reverse transcriptase Envelope Matrix protein Reverse transcriptase Integrase Viral RNA Polyproteins Protease Mature virus Cleavage of polypeptide precursor Inhibitors of HIV protease CH3 N H O N H NH O N N O O H2N H3C CH3 HO e.g., saquinavir O N=N=N HOCH 2 N O N H O H 3 C RNA + - Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Disinfectants and Antiseptics Disinfection denotes the inactivation or killing of pathogens (protozoa, bacteria, fungi, viruses) in the human environ- ment. This can be achieved by chemical or physical means; the latter will not be discussed here. Sterilization refers to the killing of all germs, whether patho- genic, dormant, or nonpathogenic. Anti- sepsis refers to the reduction by chemi- cal agents of germ numbers on skin and mucosal surfaces. Agents for chemical disinfection ideally should cause rapid, complete, and persistent inactivation of all germs, but at the same time exhibit low toxic- ity (systemic toxicity, tissue irritancy, antigenicity) and be non-deleterious to inanimate materials. These require- ments call for chemical properties that may exclude each other; therefore, compromises guided by the intended use have to be made. Disinfectants come from various chemical classes, including oxidants, halogens or halogen-releasing agents, alcohols, aldehydes, organic acids, phe- nols, cationic surfactants (detergents) and formerly also heavy metals. The ba- sic mechanisms of action involve de- naturation of proteins, inhibition of en- zymes, or a dehydration. Effects are de- pendent on concentration and contact time. Activity spectrum. Disinfectants inactivate bacteria (gram-positive > gram-negative > mycobacteria), less ef- fectively their sporal forms, and a few (e.g., formaldehyde) are virucidal. Applications Skin “disinfection.” Reduction of germ counts prior to punctures or surgical procedures is desirable if the risk of wound infection is to be minimized. Useful agents include: alcohols (1- and 2-propanol; ethanol 60–90%; iodine-re- leasing agents like polyvinylpyrrolidone [povidone, PVP]-iodine as a depot form of the active principle iodine, instead of iodine tincture), cationic surfactants, and mixtures of these. Minimal contact times should be at least 15 s on skin are- as with few sebaceous glands and at least 10 min on sebaceous gland-rich ones. Mucosal disinfection: Germ counts can be reduced by PVP iodine or chlor- hexidine (contact time 2 min), although not as effectively as on skin. Wound disinfection can be achieved with hydrogen peroxide (0.3%–1% solu- tion; short, foaming action on contact with blood and thus wound cleansing) or with potassium permanganate (0.0015% solution, slightly astringent), as well as PVP iodine, chlorhexidine, and biguanidines. Hygienic and surgical hand disinfec- tion: The former is required after a sus- pected contamination, the latter before surgical procedures. Alcohols, mixtures of alcohols and phenols, cationic surfac- tants, or acids are available for this pur- pose. Admixture of other agents pro- longs duration of action and reduces flammability. Disinfection of instruments: Instru- ments that cannot be heat- or steam- sterilized can be precleaned and then disinfected with aldehydes and deter- gents. Surface (floor) disinfection employs aldehydes combined with cationic sur- factants and oxidants or, more rarely, acidic or alkalizing agents. Room disinfection: room air and surfaces can be disinfected by spraying or vaporizing of aldehydes, provided that germs are freely accessible. 290 Disinfectants Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Disinfectants 291 Tissue A. Disinfectants Application sites Examples Active principles 1. Oxidants 2. Halogens chlorine sodium hypochlorite iodine tincture Skin 3. Alcohols R-OH (R=C 2 -C 6 ) e. g., ethanol isopropanol Regular e.g., hands Acute, e.g., before local procedures 4. Aldehydes e. g., formaldehyde glutaraldehyde 5. Organic acids e. g., lactic acid Mucous membranes 6. Phenols Nonhalogenated: e. g., phenylphenol eugenol thymol halogenated: chlormethylphenol 7. Cationic surfactants Cationic soaps e. g., benzalkonium chlorhexidine 8. Heavy metal salts Inanimate material: durable against chemical + physical measures Inanimate matter: sensitive to heat, acids, oxidation etc. Disinfection of instruments Skin disinfection Disinfection of floors or excrement Disinfection of mucous membranes Wound disinfection Phenols NaOCl Cationic surfactants Phenols Cationic surfactants Alcohols Iodine tincture Chlor- hexidine Chlor- hexidine Chlor- hexidine KMnO 4 H 2 O 2 STOP Cationic surfactants Aldehydes Disinfectants do not afford selective inhibition of bacteria viruses, or fungi e. g., hydrogen peroxide, potassium permanganate, peroxycarbonic acids e. g., phenylmercury borate Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drugs for Treating Endo- and Ectoparasitic Infestations Adverse hygienic conditions favor hu- man infestation with multicellular or- ganisms (referred to here as parasites). Skin and hair are colonization sites for arthropod ectoparasites, such as insects (lice, fleas) and arachnids (mites). Against these, insecticidal or arachnici- dal agents, respectively, can be used. Endoparasites invade the intestines or even internal organs, and are mostly members of the phyla of flatworms and roundworms. They are combated with anthelmintics. Anthelmintics. As shown in the ta- ble, the newer agents praziquantel and mebendazole are adequate for the treat- ment of diverse worm diseases. They are generally well tolerated, as are the other agents listed. Insecticides. Whereas fleas can be effectively dealt with by disinfection of clothes and living quarters, lice and mites require the topical application of insecticides to the infested subject. Chlorphenothane (DDT) kills in- sects after absorption of a very small amount, e.g., via foot contact with sprayed surfaces (contact insecticide). The cause of death is nervous system damage and seizures. In humans DDT causes acute neurotoxicity only after absorption of very large amounts. DDT is chemically stable and degraded in the environment and body at extremely slow rates. As a highly lipophilic sub- stance, it accumulates in fat tissues. Widespread use of DDT in pest control has led to its accumulation in food chains to alarming levels. For this rea- son its use has now been banned in many countries. Lindane is the active γ-isomer of hexachlorocyclohexane. It also exerts a neurotoxic action on insects (as well as humans). Irritation of skin or mucous membranes may occur after topical use. Lindane is active also against intrader- mal mites (Sarcoptes scabiei, causative agent of scabies), besides lice and fleas. It is more readily degraded than DDT. Permethrin, a synthetic pyreth- roid, exhibits similar anti-ectoparasitic activity and may be the drug of choice due to its slower cutaneous absorption, fast hydrolytic inactivation, and rapid renal elimination. 292 Antiparasitic Agents Worms (helminths) Anthelmintic drug of choice Flatworms (platyhelminths) tape worms (cestodes) praziquantel* flukes (trematodes) e.g., Schistosoma praziquantel species (bilharziasis) Roundworms (nematodes) pinworm (Enterobius vermicularis) mebendazole or pyrantel pamoate whipworm (Trichuris trichiura) mebendazole Ascaris lumbricoides mebendazole or pyrantel pamoate Trichinella spiralis** mebendazole and thiabendazole Strongyloides stercoralis thiabendazole Hookworm (Necator americanus, and mebendazole or pyrantel pamoate Ancylostoma duodenale) mebendazole or pyrantel pamoate * not for ocular or spinal cord cysticercosis ** [thiabendazole: intestinal phase; mebendazole: tissue phase] Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antiparasitic Agents 293 Flea Damage to nervous system: convulsions, death A. Endo- and ectoparasites: therapeutic agents Tapeworms e.g., beef tapeworm Louse Round- worms, e.g., ascaris Pinworm Trichinella larvae Scabies mite Spasm, injury of integument Praziquantel Mebendazole Hexachlorocyclo- hexane (Lindane) Chlor- phenothane (DDT) Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antimalarials The causative agents of malaria are plas- modia, unicellular organisms belonging to the order hemosporidia (class proto- zoa). The infective form, the sporozoite, is inoculated into skin capillaries when infected female Anopheles mosquitoes (A) suck blood from humans. The sporo- zoites invade liver parenchymal cells where they develop into primary tissue schizonts. After multiple fission, these schizonts produce numerous mero- zoites that enter the blood. The pre- erythrocytic stage is symptom free. In blood, the parasite enters erythrocytes (erythrocytic stage) where it again mul- tiplies by schizogony, resulting in the formation of more merozoites. Rupture of the infected erythrocytes releases the merozoites and pyrogens. A fever attack ensues and more erythrocytes are in- fected. The generation period for the next crop of merozoites determines the interval between fever attacks. With Plasmodium vivax and P. ovale, there can be a parallel multiplication in the liver (paraerythrocytic stage). Moreover, some sporozoites may become dormant in the liver as “hypnozoites” before en- tering schizogony. When the sexual forms (gametocytes) are ingested by a feeding mosquito, they can initiate the sexual reproductive stage of the cycle that results in a new generation of transmittable sporozoites. Different antimalarials selectively kill the parasite’s different developmen- tal forms. The mechanism of action is known for some of them: pyrimetha- mine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits syn- thesis of dihydrofolic acid (p. 272). Chlo- roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts. Antimalarial drug choice takes into account tolerability and plasmodial re- sistance. Tolerability. The first available antimalarial, quinine, has the smallest therapeutic margin. All newer agents are rather well tolerated. Plasmodium (P.) falciparum, re- sponsible for the most dangerous form of malaria, is particularly prone to de- velop drug resistance. The incidence of resistant strains rises with increasing frequency of drug use. Resistance has been reported for chloroquine and also for the combination pyrimethamine/ sulfadoxine. Drug choice for antimalarial chemoprophylaxis. In areas with a risk of malaria, continuous intake of antima- larials affords the best protection against the disease, although not against infection. The drug of choice is chloroquine. Because of its slow excre- tion (plasma t 1/2 = 3d and longer), a sin- gle weekly dose is sufficient. In areas with resistant P. falciparum, alternative regimens are chloroquine plus pyri- methamine/sulfadoxine (or proguanil, or doxycycline), the chloroquine ana- logue amodiaquine, as well as quinine or the better tolerated derivative meflo- quine (blood-schizonticidal). Agents ac- tive against blood schizonts do not pre- vent the (symptom-free) hepatic infec- tion, only the disease-causing infection of erythrocytes (“suppression therapy”). On return from an endemic malaria re- gion, a 2 wk course of primaquine is ad- equate for eradication of the late hepat- ic stages (P. vivax and P. ovale). Protection from mosquito bites (net, skin-covering clothes, etc.) is a very important prophylactic measure. Antimalarial therapy employs the same agents and is based on the same principles. The blood-schizonticidal halofantrine is reserved for therapy on- ly. The pyrimethamine-sulfadoxine combination may be used for initial self- treatment. Drug resistance is accelerating in many endemic areas; malaria vaccines may hold the greatest hope for control of infection. 294 Antiparasitic Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antiparasitic Drugs 295 A. Malaria: stages of the plasmodial life cycle in the human; hi h Fever Fever Primaquine Primaquine Chloroquine Quinine Proguanil Pyrimethamine Fever 2 days : Tertian malaria Pl. vivax, Pl. ovale 3 days: Quartan malaria Pl. malariae No fever periodicity: Pernicious malaria: Pl. falciparum not P. falcip. Pl. falcip. Hepatocyte Primary tissue schizont Sulfadoxine Chloroquine Mefloquine Halofantrine Quinine Proguanil Pyrimethamine Merozoites Hypnozoite Pr eerythr ocytic cycle 1-4 weeks Erythr ocytic cycle Blood schizont Erythrocyte Only Pl. vivax Pl. ovale Gametocytes Sporozoites Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Chemotherapy of Malignant Tumors A tumor (neoplasm) consists of cells that proliferate independently of the body’s inherent “building plan.” A ma- lignant tumor (cancer) is present when the tumor tissue destructively invades healthy surrounding tissue or when dis- lodged tumor cells form secondary tu- mors (metastases) in other organs. A cure requires the elimination of all ma- lignant cells (curative therapy). When this is not possible, attempts can be made to slow tumor growth and there- by prolong the patient’s life or improve quality of life (palliative therapy). Chemotherapy is faced with the prob- lem that the malignant cells are endoge- nous and are not endowed with special metabolic properties. Cytostatics (A) are cytotoxic sub- stances that particularly affect prolife- rating or dividing cells. Rapidly dividing malignant cells are preferentially in- jured. Damage to mitotic processes not only retards tumor growth but may also initiate apoptosis (programmed cell death). Tissues with a low mitotic rate are largely unaffected; likewise, most healthy tissues. This, however, also ap- plies to malignant tumors consisting of slowly dividing differentiated cells. Tis- sues that have a physiologically high mitotic rate are bound to be affected by cytostatic therapy. Thus, typical ad- verse effects occur: Loss of hair results from injury to hair follicles; gastrointestinal distur- bances, such as diarrhea, from inad- equate replacement of enterocytes whose life span is limited to a few days; nausea and vomiting from stimulation of area postrema chemoreceptors (p. 330); and lowered resistance to infection from weakening of the immune system (p. 300). In addition, cytostatics cause bone marrow depression. Resupply of blood cells depends on the mitotic activity of bone marrow stem and daughter cells. When myeloid proliferation is arrested, the short-lived granulocytes are the first to be affected (neutropenia), then blood platelets (thrombopenia) and, finally, the more long-lived erythrocytes (ane- mia). Infertility is caused by suppression of spermatogenesis or follicle matura- tion. Most cytostatics disrupt DNA me- tabolism. This entails the risk of a po- tential genomic alteration in healthy cells (mutagenic effect). Conceivably, the latter accounts for the occurrence of leukemias several years after cytostatic therapy (carcinogenic effect). Further- more, congenital malformations are to be expected when cytostatics must be used during pregnancy (teratogenic ef- fect). Cytostatics possess different mech- anisms of action. Damage to the mitotic spindle (B). The contractile proteins of the spindle apparatus must draw apart the replicat- ed chromosomes before the cell can di- vide. This process is prevented by the so-called spindle poisons (see also col- chicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vin- blastine (from the periwinkle plant, Vin- ca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. Paclitaxel, from the bark of the pa- cific yew (Taxus brevifolia), inhibits dis- assembly of microtubules and induces atypical ones. Docetaxel is a semisyn- thetic derivative. 296 Anticancer Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Anticancer Drugs 297 A. Chemotherapy of tumors: principal and adverse effects B. Cytostatics: inhibition of mitosis Malignant tissue with numerous mitoses Wanted effect: inhibition of tumor growth Healthy tissue with few mitoses Little effect Healthy tissue with numerous mitoses Lymph node Inhibition of lymphocyte multiplication: immune weakness Unwanted effects Diarrhea Germinal cell damage Lowered resistance to infection Bone marrow Inhibition of granulo-, thrombocyto-, and erythropoiesis Vinca alkaloids Vinca rosea Paclitaxel Western yew tree Damage to hair follicle Hair loss Inhibition of ephithelial renewal Cytostatics inhibit cell division Inhibition of formation Microtubules of mitotic spindle Inhibition of degradation Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibition of DNA and RNA syn- thesis (A). Mitosis is preceded by repli- cation of chromosomes (DNA synthesis) and increased protein synthesis (RNA synthesis). Existing DNA (gray) serves as a template for the synthesis of new (blue) DNA or RNA. De novo synthesis may be inhibited by: Damage to the template (1). Alky- lating cytostatics are reactive com- pounds that transfer alkyl residues into a covalent bond with DNA. For instance, mechlorethamine (nitrogen mustard) is able to cross-link double-stranded DNA on giving off its chlorine atoms. Correct reading of genetic information is there- by rendered impossible. Other alkylat- ing agents are chlorambucil, melphalan, thio-TEPA, cyclophosphamide (p. 300, 320), ifosfamide, lomustine, and busul- fan. Specific adverse reactions include irreversible pulmonary fibrosis due to busulfan and hemorrhagic cystitis caused by the cyclophosphamide me- tabolite acrolein (preventable by the uroprotectant mesna). Cisplatin binds to (but does not alkylate) DNA strands. Cystostatic antibiotics insert them- selves into the DNA double strand; this may lead to strand breakage (e.g., with bleomycin). The anthracycline antibiotics daunorubicin and adriamycin (doxorubi- cin) may induce cardiomyopathy. Ble- omycin can also cause pulmonary fibro- sis. The epipodophyllotoxins, etopo- side and teniposide, interact with topo- isomerase II, which functions to split, transpose, and reseal DNA strands (p. 274); these agents cause strand breakage by inhibiting resealing. Inhibition of nucleobase synthe- sis (2). Tetrahydrofolic acid (THF) is re- quired for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 272). The folate analogues aminopterin and methotrexate (ame- thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed by administration of folinic acid (5-for- myl-THF, leucovorin, citrovorum fac- tor). Incorporation of false building blocks (3). Unnatural nucleobases (6- mercaptopurine; 5-fluorouracil) or nu- cleosides with incorrect sugars (cytara- bine) act as antimetabolites. They inhib- it DNA/RNA synthesis or lead to synthe- sis of missense nucleic acids. 6-Mercaptopurine results from bio- transformation of the inactive precursor azathioprine (p. 37). The uricostatic allo- purinol inhibits the degradation of 6- mercaptopurine such that co-adminis- tration of the two drugs permits dose reduction of the latter. Frequently, the combination of cy- tostatics permits an improved thera- peutic effect with fewer adverse reac- tions. Initial success can be followed by loss of effect because of the emergence of resistant tumor cells. Mechanisms of resistance are multifactorial: Diminished cellular uptake may re- sult from reduced synthesis of a trans- port protein that may be needed for membrane penetration (e.g., metho- trexate). Augmented drug extrusion: in- creased synthesis of the P-glycoprotein that extrudes drugs from the cell (e.g., anthracyclines, vinca alkaloids, epipo- dophyllotoxins, and paclitaxel) is re- ponsible for multi-drug resistance (mdr-1 gene amplification). Diminished bioactivation of a pro- drug, e.g., cytarabine, which requires intracellular phosphorylation to be- come cytotoxic. Change in site of action: e.g., in- creased synthesis of dihydrofolate re- ductase may occur as a compensatory response to methotrexate. Damage repair: DNA repair en- zymes may become more efficient in re- pairing defects caused by cisplatin. 298 Anticancer Drugs Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Anticancer Drugs 299 A. Cytostatics: alkylating agents and cytostatic antibiotics (1), inhibitors of tetrahydrofolate synthesis (2), antimetabolites (3) instead of instead of Damage to template Alkylation e. g., by mechlor- ethamine Insertion of daunorubicin, doxorubicin, bleomycin, actinomycin D, etc. Streptomyces bacteria Inhibition of nucleotide synthesis Purines Thymine Nucleotide Tetrahydro- folate Dihydrofolate Reductase Folic acid Inhibition by Purine antimetabolite Insertion of incorrect building blocks Pyrimidine antimetabolite 6-Mercaptopurine from Azathioprine Adenine Uracil Cytarabine Cytosine Cytosine Desoxyribose instead of 5-Fluorouracil Arabinose Aminopterin Methotrexate DNA DNA DNA 3 2 1 RNA Building blocks Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Inhibition of Immune Responses Both the prevention of transplant rejec- tion and the treatment of autoimmune disorders call for a suppression of im- mune responses. However, immune suppression also entails weakened de- fenses against infectious pathogens and a long-term increase in the risk of neo- plasms. A specific immune response be- gins with the binding of antigen by lym- phocytes carrying specific receptors with the appropriate antigen-binding site. B-lymphocytes “recognize” antigen surface structures by means of mem- brane receptors that resemble the anti- bodies formed subsequently. T-lympho- cytes (and naive B-cells) require the antigen to be presented on the surface of macrophages or other cells in con- junction with the major histocompat- ibility complex (MHC); the latter per- mits recognition of antigenic structures by means of the T-cell receptor. T-help- er cells carry adjacent CD-3 and CD-4 complexes, cytotoxic T-cells a CD-8 complex. The CD proteins assist in dock- ing to the MHC. In addition to recogni- tion of antigen, activation of lympho- cytes requires stimulation by cytokines. Interleukin-1 is formed by macrophag- es, and various interleukins (IL), includ- ing IL-2, are made by T-helper cells. As antigen-specific lymphocytes prolife- rate, immune defenses are set into mo- tion. I. Interference with antigen re- cognition. Muromonab CD3 is a mono- clonal antibody directed against mouse CD-3 that blocks antigen recognition by T-lymphocytes (use in graft rejection). II. Inhibition of cytokine produc- tion or action. Glucocorticoids mod- ulate the expression of numerous genes; thus, the production of IL-1 and IL-2 is inhibited, which explains the suppression of T-cell-dependent im- mune responses. Glucocorticoids are used in organ transplantations, autoim- mune diseases, and allergic disorders. Systemic use carries the risk of iatro- genic Cushing’s syndrome (p. 248). Cyclosporin A is an antibiotic poly- peptide from fungi and consists of 11, in part atypical, amino acids. Given orally, it is absorbed, albeit incompletely. In lymphocytes, it is bound by cyclophilin, a cytosolic receptor that inhibits the phosphatase calcineurin. The latter plays a key role in T-cell signal trans- duction. It contributes to the induction of cytokine production, including that of IL-2. The breakthroughs of modern transplantation medicine are largely at- tributable to the introduction of cyclo- sporin A. Prominent among its adverse effects are renal damage, hypertension, and hyperkalemia. Tacrolimus, a macrolide, derives from a streptomyces species; pharma- cologically it resembles cyclosporin A, but is more potent and efficacious. The monoclonal antibodies daclizu- mab and basiliximab bind to the α- chain of the II-2 receptor of T-lympho- cytes and thus prevent their activation, e.g., during transplant rejection. III. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclo- phosphamide (p. 298). The antipro- liferative effect is not specific for lym- phocytes and involves both T- and B- cells. Mycophenolate mofetil has a more specific effect on lymphocytes than on other cells. It inhibits inosine mono- phosphate dehydrogenase, which cata- lyzes purine synthesis in lymphocytes. It is used in acute tissue rejection re- sponses. IV. Anti-T-cell immune serum is obtained from animals immunized with human T-lymphocytes. The antibodies bind to and damage T-cells and can thus be used to attenuate tissue rejection. 300 Immune Modulators Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Immune Modulators 301 Antigen Macrophage MHC II MHC I Glucocorticoids Inhibition of transcription of cytokines, e. g., IL-1 IL-2 CD4 CD3 CD8 CD3 Muromonab- CD3 Monoclonal antibody B-Lymphocyte T-Helper- cell T-Lymphocyte Cyclophilin Inhibition Calcineurin, a phosphatase Transcription of cytokines e. g., IL-2 Cytotoxic, antiproliferative drugs Azathioprine, Methotrexate, Cyclo- phosphamide, Mycophenolate mofetil Proliferation differentiation into plasma cells Cytotoxic T-lymphocytes Cytokines: chemotaxis Antibody-mediated immune reaction Immune reaction: delayed hypersensitivity Elimination of “foreign” cells A. Immune reaction and immunosuppressives Uptake Degradation Presentation MHC II Interleukins Virus-infected cell, transplanted cell. tumor cell Synthesis of "foreign" proteins Presentation Phagocytosis Degradation Presentation IL-1 IL-2 T-cell receptor and Cyclosporin A IL-2 receptor blockade Daclizumab Basiliximab Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antidotes and treatment of poisonings Drugs used to counteract drug overdos- age are considered under the appropri- ate headings, e.g., physostigmine with atropine; naloxone with opioids; flu- mazenil with benzodiazepines; anti- body (Fab fragments) with digitalis; and N-acetyl-cysteine with acetaminophen intoxication. Chelating agents (A) serve as anti- dotes in poisoning with heavy metals. They act to complex and, thus, “inactiv- ate” heavy metal ions. Chelates (from Greek: chele = claw [of crayfish]) repre- sent complexes between a metal ion and molecules that carry several bind- ing sites for the metal ion. Because of their high affinity, chelating agents “at- tract” metal ions present in the organ- ism. The chelates are non-toxic, are ex- creted predominantly via the kidney, maintain a tight organometallic bond also in the concentrated, usually acidic, milieu of tubular urine and thus pro- mote the elimination of metal ions. Na 2 Ca-EDTA is used to treat lead poisoning. This antidote cannot pene- trate cell membranes and must be given parenterally. Because of its high binding affinity, the lead ion displaces Ca 2+ from its bond. The lead-containing chelate is eliminated renally. Nephrotoxicity pre- dominates among the unwanted effects. Na 3 Ca-Pentetate is a complex of dieth- ylenetriaminopentaacetic acid (DPTA) and serves as antidote in lead and other metal intoxications. Dimercaprol (BAL, British Anti-Le- wisite) was developed in World War II as an antidote against vesicant organic arsenicals (B). It is able to chelate vari- ous metal ions. Dimercaprol forms a li- quid, rapidly decomposing substance that is given intramuscularly in an oily vehicle. A related compound, both in terms of structure and activity, is di- mercaptopropanesulfonic acid, whose sodium salt is suitable for oral adminis- tration. Shivering, fever, and skin reac- tions are potential adverse effects. Deferoxamine derives from the bacterium Streptomyces pilosus. The substance possesses a very high iron- binding capacity, but does not withdraw iron from hemoglobin or cytochromes. It is poorly absorbed enterally and must be given parenterally to cause increased excretion of iron. Oral administration is indicated only if enteral absorption of iron is to be curtailed. Unwanted effects include allergic reactions. It should be noted that blood letting is the most ef- fective means of removing iron from the body; however, this method is unsuit- able for treating conditions of iron over- load associated with anemia. D-penicillamine can promote the elimination of copper (e.g., in Wilson’s disease) and of lead ions. It can be given orally. Two additional uses are cystinu- ria and rheumatoid arthritis. In the for- mer, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In the latter, pen- icillamine can be used as a basal regi- men (p. 320). The therapeutic effect may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibit- ed. Unwanted effects are: cutaneous damage (diminished resistance to me- chanical stress with a tendency to form blisters), nephrotoxicity, bone marrow depression, and taste disturbances. 302 Antidotes Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antidotes 303 EDTA: Ethylenediaminetetra-acetate A. Chelation of lead ions by EDTA Dimercaprol (i.m.) DMPS Deferoxamine D-Penicillamine B. Chelators Na 2 Ca- EDTA Dissolution of cystine stones: Cysteine-S-S-Cysteine Inhibition of collagen polymerization Arsenic, mercury, gold ions Dimercaptopropane sulfonate β,β-Dimethylcysteine chelation with Cu 2+ and Pb 2+ 2Na + Ca 2+ Fe 3 + CH 2 CH 2 N N CH 2 CH 2 CH 2 CH 2 C C C C O - O - O - O - O O O O Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antidotes for cyanide poisoning (A). Cyanide ions (CN - ) enter the organ- ism in the form of hydrocyanic acid (HCN); the latter can be inhaled, re- leased from cyanide salts in the acidic stomach juice, or enzymatically liberat- ed from bitter almonds in the gastroin- testinal tract. The lethal dose of HCN can be as low as 50 mg. CN - binds with high affinity to trivalent iron and thereby ar- rests utilization of oxygen via mito- chondrial cytochrome oxidases of the respiratory chain. An internal asphyxia- tion (histotoxic hypoxia) ensues while erythrocytes remain charged with O 2 (venous blood colored bright red). In small amounts, cyanide can be converted to the relatively nontoxic thiocyanate (SCN - ) by hepatic “rhoda- nese” or sulfur transferase. As a thera- peutic measure, thiosulfate can be given i.v. to promote formation of thiocya- nate, which is eliminated in urine. How- ever, this reaction is slow in onset. A more effective emergency treatment is the i.v. administration of the methe- moglobin-forming agent 4-dimethyl- aminophenol, which rapidly generates trivalent from divalent iron in hemoglo- bin. Competition between methemoglo- bin and cytochrome oxidase for CN - ions favors the formation of cyanmethemo- globin. Hydroxocobalamin is an alterna- tive, very effective antidote because its central cobalt atom binds CN - with high affinity to generate cyanocobalamin. Tolonium chloride (Toluidin Blue). Brown-colored methemoglobin, containing tri- instead of divalent iron, is incapable of carrying O 2 . Under nor- mal conditions, methemoglobin is pro- duced continuously, but reduced again with the help of glucose-6-phosphate dehydrogenase. Substances that pro- mote formation of methemoglobin (B) may cause a lethal deficiency of O 2 . To- lonium chloride is a redox dye that can be given i.v. to reduce methemoglobin. Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type (p. 102). Phos- phorylation of acetylcholinesterase causes an irreversible inhibition of ace- tylcholine breakdown and hence flood- ing of the organism with the transmit- ter. Possible sequelae are exaggerated parasympathomimetic activity, block- ade of ganglionic and neuromuscular transmission, and respiratory paralysis. Therapeutic measures include: 1. administration of atropine in high dos- age to shield muscarinic acetylcholine receptors; and 2. reactivation of acetyl- cholinesterase by obidoxime, which successively binds to the enzyme, cap- tures the phosphate residue by a nu- cleophilic attack, and then dissociates from the active center to release the en- zyme from inhibition. Ferric Ferrocyanide (“Berlin Blue,” B) is used to treat poisoning with thallium salts (e.g., in rat poison), the initial symptoms of which are gastroin- testinal disturbances, followed by nerve and brain damage, as well as hair loss. Thallium ions present in the organism are secreted into the gut but undergo reabsorption. The insoluble, nonabsorb- able colloidal Berlin Blue binds thallium ions. It is given orally to prevent absorp- tion of acutely ingested thallium or to promote clearance from the organism by intercepting thallium that is secreted into the intestines. 304 Antidotes Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antidotes 305 Nitrite Potassium cyanide KCN Hydrogen cyanide HCN Rhodanese Sulfur donors Na 2 S 2 O 3 Sodium thiosulfate SCN - H + + CN - Fe III -Hb Methemoglobin formation DMAP Complex formation Hydroxocobalamin Vit.B 12a Cyanocobalamin Vit.B 12 Fe 3+ Mitochondrial cytochrome oxidase A. Cyanide poisoning and antidotes Substances forming methemoglobin H 2 N Aniline O 2 N Fe II -Hb Tolonium chloride (toluidin blue) Organophosphates e.g., Paraoxon Reactivated Acetylcholine esterase Phosphorylated, inactivated Reactivator: obidoxime Ferric ferrocyanide Thallium ion B. Poisons and antidotes H + K + Fe III -Hb Nitrobenzene = Tl excretion “Prussian Blue” Fe III [Fe II (CN) 6 ] 34 Tl + Tl + Tl + 2 Cl - 2 Cl - Inhibition of cellular respiration e.g., NO 2 - Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Angina Pectoris An anginal pain attack signals a tran- sient hypoxia of the myocardium. As a rule, the oxygen deficit results from in- adequate myocardial blood flow due to narrowing of larger coronary arteries. The underlying causes are: most com- monly, an atherosclerotic change of the vascular wall (coronary sclerosis with exertional angina); very infrequently, a spasmodic constriction of a morpholog- ically healthy coronary artery (coronary spasm with angina at rest; variant angi- na); or more often, a coronary spasm oc- curring in an atherosclerotic vascular segment. The goal of treatment is to prevent myocardial hypoxia either by raising blood flow (oxygen supply) or by lower- ing myocardial blood demand (oxygen demand) (A). Factors determining oxygen sup- ply. The force driving myocardial blood flow is the pressure difference between the coronary ostia (aortic pressure) and the opening of the coronary sinus (right atrial pressure). Blood flow is opposed by coronary flow resistance, which in- cludes three components. (1) Due to their large caliber, the proximal coro- nary segments do not normally contrib- ute significantly to flow resistance. However, in coronary sclerosis or spasm, pathological obstruction of flow occurs here. Whereas the more com- mon coronary sclerosis cannot be over- come pharmacologically, the less com- mon coronary spasm can be relieved by appropriate vasodilators (nitrates, ni- fedipine). (2) The caliber of arteriolar re- sistance vessels controls blood flow through the coronary bed. Arteriolar caliber is determined by myocardial O 2 tension and local concentrations of metabolic products, and is “automati- cally” adjusted to the required blood flow (B, healthy subject). This metabolic autoregulation explains why anginal at- tacks in coronary sclerosis occur only during exercise (B, patient). At rest, the pathologically elevated flow resistance is compensated by a corresponding de- crease in arteriolar resistance, ensuring adequate myocardial perfusion. During exercise, further dilation of arterioles is impossible. As a result, there is ischemia associated with pain. Pharmacological agents that act to dilate arterioles would thus be inappropriate because at rest they may divert blood from underper- fused into healthy vascular regions on account of redundant arteriolar dilation. The resulting “steal effect” could pro- voke an anginal attack. (3) The intra- myocardial pressure, i.e., systolic squeeze, compresses the capillary bed. Myocardial blood flow is halted during systole and occurs almost entirely dur- ing diastole. Diastolic wall tension (“pre- load”) depends on ventricular volume and filling pressure. The organic nitrates reduce preload by decreasing venous return to the heart. Factors determining oxygen de- mand. The heart muscle cell consumes the most energy to generate contractile force. O 2 demand rises with an increase in (1) heart rate, (2) contraction velocity, (3) systolic wall tension (“afterload”). The latter depends on ventricular vol- ume and the systolic pressure needed to empty the ventricle. As peripheral resis- tance increases, aortic pressure rises, hence the resistance against which ven- tricular blood is ejected. O 2 demand is lowered by β-blockers and Ca-antago- nists, as well as by nitrates (p. 308). 306 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 307 B. Pathogenesis of exertion angina in coronary sclerosis O 2 -supply during diastole O 2 -demand during systole Flow resistance: 1. Coronary arterial caliber 2. Arteriolar caliber 3. Systolic wall tension = Afterload 1. Heart rate 2. Contraction velocity Peripheral resistance Venous supply Healthy subject Patient with coronary sclerosis Rest Exercise A. O 2 supply and demand of the myocardium Narrow Wide Compensa- tory dilation of arterioles Rate Contraction velocity Afterload Wide Wide Additional dilation not possible Angina pectoris Left atrium Coronary artery Left ventricle Pressure p Vol.Vol. Pressure p Right atrium p-for ce Time Aorta 3. Diastolic wall tension = Preload Venous reservoir Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Antianginal Drugs Antianginal agents derive from three drug groups, the pharmacological prop- erties of which have already been pre- sented in more detail, viz., the organic nitrates (p. 120), the Ca 2+ antagonists (p. 122), and the β-blockers (pp. 92ff). Organic nitrates (A) increase blood flow, hence O 2 supply, because diastolic wall tension (preload) declines as ve- nous return to the heart is diminished. Thus, the nitrates enable myocardial flow resistance to be reduced even in the presence of coronary sclerosis with angina pectoris. In angina due to coro- nary spasm, arterial dilation overcomes the vasospasm and restores myocardial perfusion to normal. O 2 demand falls because of the ensuing decrease in the two variables that determine systolic wall tension (afterload): ventricular fill- ing volume and aortic blood pressure. Calcium antagonists (B) decrease O 2 demand by lowering aortic pressure, one of the components contributing to afterload. The dihydropyridine nifedi- pine is devoid of a cardiodepressant ef- fect, but may give rise to reflex tachy- cardia and an associated increase in O 2 demand. The catamphiphilic drugs ve- rapamil and diltiazem are cardiode- pressant. Reduced beat frequency and contractility contribute to a reduction in O 2 demand; however, AV-block and me- chanical insufficiency can dangerously jeopardize heart function. In coronary spasm, calcium antagonists can induce spasmolysis and improve blood flow (p. 122). β-Blockers (C) protect the heart against the O 2 -wasting effect of sympa- thetic drive by inhibiting β-receptor- mediated increases in cardiac rate and speed of contraction. Uses of antianginal drugs (D). For relief of the acute anginal attack, rap- idly absorbed drugs devoid of cardiode- pressant activity are preferred. The drug of choice is nitroglycerin (NTG, 0.8–2.4 mg sublingually; onset of action within 1 to 2 min; duration of effect ~30 min). Isosorbide dinitrate (ISDN) can also be used (5–10 mg sublingual- ly); compared with NTG, its action is somewhat delayed in onset but of long- er duration. Finally, nifedipine may be useful in chronic stable, or in variant an- gina (5–20 mg, capsule to be bitten and the contents swallowed). For sustained daytime angina pro- phylaxis, nitrates are of limited value because “nitrate pauses” of about 12 h are appropriate if nitrate tolerance is to be avoided. If attacks occur during the day, ISDN, or its metabolite isosorbide mononitrate, may be given in the morn- ing and at noon (e.g., ISDN 40 mg in ex- tended-release capsules). Because of hepatic presystemic elimination, NTG is not suitable for oral administration. Continuous delivery via a transdermal patch would also not seem advisable because of the potential development of tolerance. With molsidomine, there is less risk of a nitrate tolerance; however, due to its potential carcinogenicity, its clinical use is restricted. The choice between calcium antag- onists must take into account the diffe- rential effect of nifedipine versus verap- amil or diltiazem on cardiac perfor- mance (see above). When β-blockers are given, the potential consequences of re- ducing cardiac contractility (withdraw- al of sympathetic drive) must be kept in mind. Since vasodilating β 2 -receptors are blocked, an increased risk of va- sospasm cannot be ruled out. Therefore, monotherapy with β-blockers is recom- mended only in angina due to coronary sclerosis, but not in variant angina. 308 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 309 D. Clinical uses of antianginal drugs B. Effects of Ca-antagonists O 2 -supply O 2 -demand Afterload Rate Contraction velocity A. Effects of nitrates C. Effects of β-blockers Exercise Rest Sympathetic system β-blocker Relaxation of resistance vessels Relaxation of coronary spasm Ca- antagonists Afterload O 2 -demand p Preload Nitrates e.g., Nitroglycerin (GTN), Isosorbide dinitrate (ISDN) Nitrate tolerance Relaxation of coronary spasm Venous capacitance vessels Resistance vessels Vasorelaxation Angina pectoris Coronary sclerosis Coronary spasm GTN, ISDN Nifedipine Long-acting nitrates Ca-antagonistsβ-blocker Therapy of attack Anginal prophylaxis p Diastole pSystole Vol Vol Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Acute Myocardial Infarction Myocardial infarction is caused by acute thrombotic occlusion of a coronary artery (A). Therapeutic interventions aim to restore blood flow in the occlud- ed vessel in order to reduce infarct size or to rescue ischemic myocardial tissue. In the area perfused by the affected ves- sel, inadequate supply of oxygen and glucose impairs the function of heart muscle: contractile force declines. In the great majority of cases, the left ventricle (anterior or posterior wall) is involved. The decreased work capacity of the in- farcted myocardium leads to a reduc- tion in stroke volume (SV) and hence cardiac output (CO). The fall in blood pressure (RR) triggers reflex activation of the sympathetic system. The resul- tant stimulation of cardiac β-adreno- ceptors elicits an increase in both heart rate and force of systolic contraction, which, in conjunction with an α-adren- oceptor-mediated increase in peripher- al resistance, leads to a compensatory rise in blood pressure. In ATP-depleted cells in the infarct border zone, resting membrane potential declines with a concomitant increase in excitability that may be further exacerbated by acti- vation of β-adrenoceptors. Together, both processes promote the risk of fatal ventricular arrhythmias. As a conse- quence of local ischemia, extracellular concentrations of H + and K + rise in the affected region, leading to excitation of nociceptive nerve fibers. The resultant sensation of pain, typically experienced by the patient as annihilating, reinforces sympathetic activation. The success of infarct therapy criti- cally depends on the length of time between the onset of the attack and the start of treatment. Whereas some thera- peutic measures are indicated only after the diagnosis is confirmed, others ne- cessitate prior exclusion of contraindi- cations or can be instituted only in spe- cially equipped facilities. Without ex- ception, however, prompt action is im- perative. Thus, a staggered treatment schedule has proven useful. The antiplatelet agent, ASA, is ad- ministered at the first suspected signs of infarction. Pain due to ischemia is treat- ed predominantly with antianginal drugs (e.g., nitrates). In case this treat- ment fails (no effect within 30 min, ad- ministration of morphine, if needed in combination with an antiemetic to pre- vent morphine-induced vomiting, is in- dicated. If ECG signs of myocardial in- farction are absent, the patient is stabi- lized by antianginal therapy (nitrates, β- blockers) and given ASA and heparin. When the diagnosis has been con- firmed by electrocardiography, at- tempts are started to dissolve the thrombus pharmacologically (thrombo- lytic therapy: alteplase or streptoki- nase) or to remove the obstruction by mechanical means (balloon dilation or angioplasty). Heparin is given to pre- vent a possible vascular reocclusion, i.e., to safeguard the patency of the affected vessel. Regardless of the outcome of thrombolytic therapy or balloon dila- tion, a β-blocker is administered to sup- press imminent arrhythmias, unless it is contraindicated. Treatment of life- threatening ventricular arrhythmias calls for an antiarrhythmic of the class of Na + -channel blockers, e.g., lidocaine. To improve long-term prognosis, use is made of a β-blocker (L50519 incidence of re- infarction and acute cardiac mortality) and an ACE inhibitor (prevention of ventricular enlargement after myocar- dial infarction) (A). 310 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 311 no A. Drugs for the treatment of acute myocardial infarction A. Algorithm for the treatment of acute myocardial infarction noyes yes Suspected myocardial infarct Acetylsalicylic acid Ischemic pain ECG Thrombolysis contraindicated yes Angioplasty contraindicated Glycerol trinitrate Force SV RR SV x HR = CO SV x HR = CO H + K + Pain Preload reduction: nitrate Afterload reduction: ACE-inhibitor Antiplatelet drugs, thrombolytic agent, heparin If needed: antiarrhythmic: e.g., lidocaine Persistent pain: opioids and if needed: antiemetics β-blocker Analgesic: opioids Infarct α βββ Excitability Arrhythmia Sympathetic nervous system Peripheral resistance no Standard therapy β-blocker, ACE-inhibitor, optional heparin ST-segment elevation left bundle block Thrombolysis successful no Angioplasty opt. GPIIb/IIIA- blocker yes yes no Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hypertension Arterial hypertension (high blood pres- sure) generally does not impair the well-being of the affected individual; however, in the long term it leads to vascular damage and secondary compli- cations (A). The aim of antihypertensive therapy is to prevent the latter and, thus, to prolong life expectancy. Hypertension infrequently results from another disease, such as a cate- cholamine-secreting tumor (pheochro- mocytoma); in most cases the cause cannot be determined: essential (pri- mary) hypertension. Antihypertensive drugs are indicated when blood pres- sure cannot be sufficiently controlled by means of weight reduction or a low- salt diet. In principle, lowering of either cardiac output or peripheral resistance may decrease blood pressure (cf. p. 306, 314, blood pressure determinants). The available drugs influence one or both of these determinants. The therapeutic utility of antihypertensives is deter- mined by their efficacy and tolerability. The choice of a specific drug is deter- mined on the basis of a benefit:risk as- sessment of the relevant drugs, in keep- ing with the patient’s individual needs. In instituting single-drug therapy (monotherapy), the following consider- ations apply: β-blockers (p. 92) are of value in the treatment of juvenile hy- pertension with tachycardia and high cardiac output; however, in patients disposed to bronchospasm, even β 1 -se- lective blockers are contraindicated. Thiazide diuretics (p. 162) are potential- ly well suited in hypertension associat- ed with congestive heart failure; how- ever, they would be unsuitable in hypo- kalemic states. When hypertension is accompanied by angina pectoris, the preferred choice would be a β-blocker or calcium antagonist (p. 122) rather than a diuretic. As for the calcium an- tagonists, it should be noted that verap- amil, unlike nifedipine, possesses car- diodepressant activity. α-Blockers may be of particular benefit in patients with benign prostatic hyperplasia and im- paired micturition. At present, only β- blockers and diuretics have undergone large-scale clinical trials, which have shown that reduction in blood pressure is associated with decreased morbidity and mortality due to stroke and conges- tive heart failure. In multidrug therapy, it is neces- sary to consider which agents rationally complement each other. A β-blocker (bradycardia, cardiodepression due to sympathetic blockade) can be effective- ly combined with nifedipine (reflex tachycardia), but obviously not with ve- rapamil (bradycardia, cardiodepres- sion). Monotherapy with ACE inhibitors (p. 124) produces an adequate reduc- tion of blood pressure in 50% of pa- tients; the response rate is increased to 90% by combination with a (thiazide) diuretic. When vasodilators such as di- hydralazine or minoxidil (p. 118) are given, β-blockers would serve to pre- vent reflex tachycardia, and diuretics to counteract fluid retention. Abrupt termination of continuous treatment can be followed by rebound hypertension (particularly with short t 1/2 β-blockers). Drugs for the control of hyperten- sive crises include nifedipine (capsule, to be chewed and swallowed), nitrogly- cerin (sublingually), clonidine (p.o. or i.v., p. 96), dihydralazine (i.v.), diazoxide (i.v.), fenoldopam (by infusion, p. 114) and sodium nitroprusside (p. 120, by in- fusion). The nonselective α-blocker phentolamine (p. 90) is indicated only in pheochromocytoma. Antihypertensives for hyperten- sion in pregnancy are β 1 -selective adrenoceptor-blockers, methyldopa (p. 96), and dihydralazine (i.v. infusion) for eclampsia (massive rise in blood pressure with CNS symptoms). 312 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 313 In severe cases further combination with A. Arterial hypertension and pharmacotherapeutic approaches Diur etics β -blockers Ca- antagonists α 1 -blockers ACE inhibitors AT 1 -antagonists If therapeutic result inadequate change to drug from another group or combine with drug from another group Drug selection according to conditions and needs of the individual patient Initial monotherapy with one of the five drug groups Antihypertensive therapy Hypertension Systolic: blood pressure > 160 mmHg Diastolic: blood pressure > 96 mmHg Secondary diseases: Heart failure Coronary atherosclerosis angina pectoris, myocardial infarction, arrhythmia Atherosclerosis of cerebral vessels cerebral infarction stroke Cerebral hemorrhage Atherosclerosis of renal vessels renal failure Decreased life expectancy [mm Hg] α-blocker e.g., prazosine Central α 2 -agonist e.g., clonidine Vasodilation e.g., dihydralazine minoxidil Reserpine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hypotension The venous side of the circulation, ex- cluding the pulmonary circulation, ac- commodates ~ 60% of the total blood volume; because of the low venous pressure (mean ~ 15 mmHg) it is part of the low-pressure system. The arterial vascular beds, representing the high- pressure system (mean pressure, ~ 100 mmHg), contain ~ 15%. The arteri- al pressure generates the driving force for perfusion of tissues and organs. Blood draining from the latter collects in the low-pressure system and is pumped back by the heart into the high-pressure system. The arterial blood pressure (ABP) depends on: (1) the volume of blood per unit of time that is forced by the heart into the high-pressure system—cardiac output corresponding to the product of stroke volume and heart rate (beats/ min), stroke volume being determined inter alia by venous filling pressure; (2) the counterforce opposing the flow of blood, i.e., peripheral resistance, which is a function of arteriolar caliber. Chronic hypotension (systolic BP < 105 mmHg). Primary idiopathic hypo- tension generally has no clinical impor- tance. If symptoms such as lassitude and dizziness occur, a program of physi- cal exercise instead of drugs is advis- able. Secondary hypotension is a sign of an underlying disease that should be treated first. If stroke volume is too low, as in heart failure, a cardiac glycoside can be given to increase myocardial contractility and stroke volume. When stroke volume is decreased due to insuf- ficient blood volume, plasma substi- tutes will be helpful in treating blood loss, whereas aldosterone deficiency re- quires administration of a mineralocor- ticoid (e.g., fludrocortisone). The latter is the drug of choice for orthostatic hy- potension due to autonomic failure. A parasympatholytic (or electrical pace- maker) can restore cardiac rate in bradycardia. Acute hypotension. Failure of or- thostatic regulation. A change from the recumbent to the erect position (ortho- stasis) will cause blood within the low- pressure system to sink towards the feet because the veins in body parts below the heart will be distended, despite a re- flex venoconstriction, by the weight of the column of blood in the blood ves- sels. The fall in stroke volume is partly compensated by a rise in heart rate. The remaining reduction of cardiac output can be countered by elevating the pe- ripheral resistance, enabling blood pres- sure and organ perfusion to be main- tained. An orthostatic malfunction is present when counter-regulation fails and cerebral blood flow falls, with resul- tant symptoms, such as dizziness, “black-out,” or even loss of conscious- ness. In the sympathotonic form, sympa- thetically mediated circulatory reflexes are intensified (more pronounced tachycardia and rise in peripheral resis- tance, i.e., diastolic pressure); however, there is failure to compensate for the re- duction in venous return. Prophylactic treatment with sympathomimetics therefore would hold little promise. In- stead, cardiovascular fitness training would appear more important. An in- crease in venous return may be achieved in two ways. Increasing NaCl intake augments salt and fluid reserves and, hence, blood volume (contraindi- cations: hypertension, heart failure). Constriction of venous capacitance ves- sels might be produced by dihydroer- gotamine. Whether this effect could al- so be achieved by an α-sympathomi- metic remains debatable. In the very rare asympathotonic form, use of sympa- thomimetics would certainly be reason- able. In patients with hypotension due to high thoracic spinal cord transections (resulting in an essentially complete sympathetic denervation), loss of sym- pathetic vasomotor control can be com- pensated by administration of sympa- thomimetics. 314 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 315 A. Treatment of hypotension Heart Kidney Intestines Skeletal muscle Lung Brain Low-pressure system High-pressure system Venous return Stroke vol. x rate = cardiac output Blood pressure (BP) Peripheral resistance α-Sympatho- mimetics Arteriolar caliber β-Sympathomimetics Cardiac glycosides Parasym- patholytics Redistribution of blood volume Initial condition Constriction of venous capacitance vessels, e.g., dihydroergotamine if appropriate, α-sympathomimetics Increase of blood volume BP Sa lt NaCl + H 2 O 0,9% NaCl NaCl + H 2 O Mineralo- corticoid BP BP Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Gout Gout is an inherited metabolic disease that results from hyperuricemia, an el- evation in the blood of uric acid, the end-product of purine degradation. The typical gout attack consists of a highly painful inflammation of the first meta- tarsophalangeal joint (“podagra”). Gout attacks are triggered by precipitation of sodium urate crystals in the synovial fluid of joints. During the early stage of inflamma- tion, urate crystals are phagocytosed by polymorphonuclear leukocytes (1) that engulf the crystals by their ameboid cy- toplasmic movements (2). The phago- cytic vacuole fuses with a lysosome (3). The lysosomal enzymes are, however, unable to degrade the sodium urate. Further ameboid movement dislodges the crystals and causes rupture of the phagolysosome. Lysosomal enzymes are liberated into the granulocyte, re- sulting in its destruction by self-diges- tion and damage to the adjacent tissue. Inflammatory mediators, such as pros- taglandins and chemotactic factors, are released (4). More granulocytes are at- tracted and suffer similar destruction; the inflammation intensifies—the gout attack flares up. Treatment of the gout attack aims to interrupt the inflammatory response. The drug of choice is colchicine, an alka- loid from the autumn crocus (Colchicum autumnale). It is known as a “spindle poison” because it arrests mitosis at metaphase by inhibiting contractile spindle proteins. Its antigout activity is due to inhibition of contractile proteins in the neutrophils, whereby ameboid mobility and phagocytotic activity are prevented. The most common adverse effects of colchicine are abdominal pain, vomiting, and diarrhea, probably due to inhibition of mitoses in the rapidly di- viding gastrointestinal epithelial cells. Colchicine is usually given orally (e.g., 0.5 mg hourly until pain subsides or gas- trointestinal disturbances occur; maxi- mal daily dose, 10 mg). Nonsteroidal anti-inflammatory drugs, such as indomethacin and phe- nylbutazone, are also effective. In se- vere cases, glucocorticoids may be in- dicated. Effective prophylaxis of gout at- tacks requires urate blood levels to be lowered to less than 6 mg/100 mL. Diet. Purine (cell nuclei)-rich foods should be avoided, e.g., organ meats. Milk, dairy products, and eggs are low in purines and are recommended. Coffee and tea are permitted since the meth- ylxanthine caffeine does not enter pu- rine metabolism. Uricostatics decrease urate pro- duction. Allopurinol, as well as its accu- mulating metabolite alloxanthine (oxy- purinol), inhibit xanthine oxidase, which catalyzes urate formation from hypoxanthine via xanthine. These pre- cursors are readily eliminated via the urine. Allopurinol is given orally (300–800 mg/d). Except for infrequent allergic reactions, it is well tolerated and is the drug of choice for gout pro- phylaxis. At the start of therapy, gout at- tacks may occur, but they can be pre- vented by concurrent administration of colchicine (0.5–1.5 mg/d). Uricosurics, such as probenecid, benzbromarone (100 mg/d), or sulfinpyrazone, pro- mote renal excretion of uric acid. They saturate the organic acid transport system in the proximal renal tubules, making it unavailable for urate reab- sorption. When underdosed, they inhib- it only the acid secretory system, which has a smaller transport capacity. Urate elimination is then inhibited and a gout attack is possible. In patients with urate stones in the urinary tract, uricosurics are contraindicated. 316 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 317 A. Gout and its therapy Alloxanthine Xanthine Hypoxanthine Uric acid Nucleus Lysosome Phagocyte Chemotactic factors 1 2 3 Gout attack Colchicine 4 Anion (urate) reabsorption Anion secretion Uricostatic Uricosuric Probenecid Xanthine Oxidase Allopurinol Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Osteoporosis Osteoporosis is defined as a generalized decrease in bone mass (osteopenia) that affects bone matrix and mineral content equally, giving rise to fractures of verte- bral bodies with bone pain, kyphosis, and shortening of the torso. Fractures of the hip and the distal radius are also common. The underlying process is a disequilibrium between bone formation by osteoblasts and bone resorption by osteoclasts. Classification: Idiopathic osteopor- osis type I, occurring in postmenopausal females; type II, occurring in senescent males and females (>70 y). Secondary osteoporosis: associated with primary disorders such as Cushing’s disease, or induced by drugs, e.g., chronic therapy with glucocorticoids or heparin. In these forms, the cause can be eliminated. Postmenopausal osteoporosis represents a period of accelerated loss of bone mass. The lower the preexisting bone mass, the earlier the clinical signs become manifest. Risk factors are: premature meno- pause, physical inactivity, cigarette smoking, alcohol abuse, low body weight, and calcium-poor diet. Prophylaxis: Administration of es- trogen can protect against postmeno- pausal loss of bone mass. Frequently, conjugated estrogens are used (p. 254). Because estrogen monotherapy increas- es the risk of uterine cancer, a gestagen needs to be given concurrently (except after hysterectomy), as e.g., in an oral contraceptive preparation (p. 256). Under this therapy, menses will contin- ue. The risk of thromboembolic disor- ders is increased and that of myocardial infarction probably lowered. Hormone treatment can be extended for 10 y or longer. Before menopause, daily cal- cium intake should be kept at 1 g (con- tained in 1 L of milk), and 1.5 g thereaf- ter. Therapy. Formation of new bone matrix is induced by fluoride. Adminis- tered as sodium fluoride, it stimulates osteoblasts. Fluoride is substituted for hydroxyl residues in hydroxyapatite to form fluorapatite, the latter being more resistant to resorption by osteoclasts. To safeguard adequate mineralization of new bone, calcium must be supplied in sufficient amounts. However, simulta- neous administration would result in precipitation of nonabsorbable calcium fluoride in the intestines. With sodium monofluorophosphate this problem is circumvented. The new bone formed may have increased resistance to com- pressive, but not torsional, strain and paradoxically bone fragility may in- crease. Because the conditions under which bone fragility is decreased re- main unclear, fluoride therapy is not in routine use. Calcitonin (p. 264) inhibits osteo- clast activity, hence bone resorption. As a peptide it needs to be given by injec- tion (or, alternatively, as a nasal spray). Salmonid is more potent than human calcitonin because of its slower elimina- tion. Bisphosphonates structurally mimic endogenous pyrophosphate, which inhibits precipitation and disso- lution of bone minerals. They retard bone resorption by osteoclasts and, in part, also decrease bone mineralization. Indications include: tumor osteolysis, hypercalcemia, and Paget’s disease. Clinical trials with etidronate, adminis- tered as an intermittent regimen, have yielded favorable results in osteoporo- sis. With the newer drugs clodronate, pamidronate, and alendronate, inhibi- tion of osteoclasts predominates; a con- tinuous regimen would thus appear to be feasible. Bisphosphonates irritate esophage- al and gastric mucus membranes; tab- lets should be swallowed with a reason- able amount of water (250 mL) and the patient should keep in an upright posi- tion for 30 min following drug intake. 318 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 319 Normal state Osteoporosis Organic bone matrix, Osteoid Bone mineral: hydroxyapatite A. Bone: normal state and osteoporosis In postmenopause Estrogen (+ Gestagen) Calcium-salts 1 – 1.5g Ca 2+ per day Physiological constituent: Pyrophosphoric acid B. Osteoporosis: drugs for prophylaxis and treatment OsteoclastsOsteoblasts Formation Resorption Promotion of bone formation Inhibition of bone resorption Fluoride ions NaF: Activation of osteoblasts, Formation of Fluorapatite Calcitonin Peptide consisting of 32 amino acids Bisphosphonates e. g., alendronic acid HO P O C P OOH (CH 2 ) 3 NH 2 OH OHOH HO P O O P O OH OHOH Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Rheumatoid Arthritis Rheumatoid arthritis or chronic poly- arthritis is a progressive inflammatory joint disease that intermittently attacks more and more joints, predominantly those of the fingers and toes. The prob- able cause of rheumatoid arthritis is a pathological reaction of the immune system. This malfunction can be pro- moted or triggered by various condi- tions, including genetic disposition, age–related wear and tear, hypother- mia, and infection. An initial noxious stimulus elicits an inflammation of synovial membranes that, in turn, leads to release of antigens through which the inflammatory process is maintained. Inflammation of the syn- ovial membrane is associated with lib- eration of inflammatory mediator sub- stances that, among other actions, chemotactically stimulate migration (diapedesis) of phagocytic blood cells (granulocytes, macrophages) into the synovial tissue. The phagocytes produce destructive enzymes that promote tis- sue damage. Due to the production of prostaglandins and leukotrienes (p. 196) and other factors, the inflamma- tion spreads to the entire joint. As a re- sult, joint cartilage is damaged and the joint is ultimately immobilized or fused. Pharmacotherapy. Acute relief of inflammatory symptoms can be achieved by prostaglandin synthase inhibitors; nonsteroidal anti-inflam- matory drugs, or NSAIDs, such as diclof- enac, indomethacin, piroxicam, p. 200), and glucocorticoids (p. 248). The inevi- tably chronic use of NSAIDs is likely to cause adverse effects. Neither NSAIDs nor glucocorticoids can halt the pro- gressive destruction of joints. The use of disease-modifying agents may reduce the requirement for NSAIDs. The use of such agents does not mean that intervention in the basic pa- thogenetic mechanisms (albeit hoped for) is achievable. Rather, disease-modi- fying therapy permits acutely acting agents to be used as add-ons or as re- quired. The common feature of disease- modifiers is their delayed effect, which develops only after treatment for several weeks. Among possible mechanisms of action, inhibition of macrophage activ- ity and inhibition of release or activity of lysosomal enzymes are being dis- cussed. Included in this category are: sulfasalazine (an inhibitor of lipoxyge- nase and cyclooxygenase, p. 272), chlo- roquine (lysosomal binding), gold com- pounds (lysosomal binding; i.m.: au- rothioglucose, aurothiomalate; p.o.: au- ranofin, less effective), as well as D-pen- icillamine (chelation of metal ions need- ed for enzyme activity, p. 302). Frequent adverse reactions are: damage to skin and mucous membranes, renal toxicity, and blood dyscrasias. In addition, use is made of cytostatics and immune sup- pressants such as methotrexate (low dose, once weekly) and leflumomid as well as of cytokin antibodies (inflixi- mab) and soluble cytokin receptors (etanercept). Methotrexate exerts an anti-inflammatory effect, apart from its anti-autoimmune action and, next to sulfasalazine, is considered to have the most favorable risk:benefit ratio. In most severe cases cytostatics such as azathioprin and cyclophosphamide will have to be used. Surgical removal of the inflamed synovial membrane (synovectomy) fre- quently provides long-term relief. If fea- sible, this approach is preferred because all pharmacotherapeutic measures en- tail significant adverse effects. 320 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 321 A. Rheumatoid arthritis and its treatment Genetic disposition Environmental factors Acute trigger Synovitis Immune system: reaction against articular tissue Infection trauma Chemo- tactic factors Inflammation Pain Inflammation Cartilage destruction Prostaglandins Permeability Collagenases Phospholipases Peptidases Bone destruction IL-1 TNF α Non-steroidal anti-inflammatory drugs (NSAIDs) Glucocorticoids Methotrexate, p.o. /s.c. weekly dosing Sulfasalazine p.o. Gold parenteral Pneumonitis, nausea, vomiting, myelosuppression allergic reaction, nephrotoxicity, gastrointestinal disturbances Lesions of mucous membranes, kidney, skin, blood dyscrasias Months Years 123456 Relief of symptoms “Remission” Discontinuation because of: side effects or insufficient efficacy Side effects: Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Migraine Migraine is a syndrome characterized by recurrent attacks of intense head- ache and nausea that occur at irregular intervals and last for several hours. In classic migraine, the attack is typically heralded by an “aura” accompanied by spreading homonymous visual field de- fects with colored sharp edges (“fortifi- cation” spectra). In addition, the patient cannot focus on certain objects, has a ravenous appetite for particular foods, and is hypersensitive to odors (hyperos- mia) or light (photophobia). The exact cause of these complaints is unknown; however, a disturbance in cranial blood flow is the likely underlying pathoge- netic mechanism. In addition to an often inherited predisposition, precipitating factors are required to provoke an at- tack, e.g., psychic stress, lack of sleep, certain foods. Pharmacotherapy of mi- graine has two aims: stopping the acute attack and preventing subsequent ones. Treatment of the attack. For symptomatic relief, headaches are treated with analgesics (acetamino- phen, acetylsalicylic acid), and nausea is treated with metoclopramide (p. 330) or domperidone. Since there is delayed gastric emptying during the attack, drug absorption can be markedly retarded, hence effective plasma levels are not obtained. Because metoclopramide stimulates gastric emptying, it pro- motes absorption of ingested analgesic drugs and thus facilitates pain relief. If acetylsalicylic acid is adminis- tered i.v. as the lysine salt, its bioavail- ability is complete. Therefore, i.v. injec- tion may be advisable in acute attacks. Should analgesics prove insuffi- ciently effective, ergotamine or one of the 5-HT 1 , agonists may help control the acute attack in most cases or prevent an imminent attack. The probable common mechanism of action is a stimulation of serotonin receptors of the 5-HT 1D (or perhaps also the 1B and 1F) subtype. Moreover, ergotamine has affinity for dopamine receptors (L50478 nausea, eme- sis), as well as α-adrenoceptors and 5- HT 2 receptors (L50518 vascular tone, L50518 platelet aggregation). With frequent use, the vascular side effects may give rise to severe peripheral ischemia (er- gotism). Overuse (>once per week) of ergotamine may provoke “rebound” headaches, thought to result from per- sistent vasodilation. Though different in character (tension-type headache), these prompt further consumption of ergotamine. Thus, a vicious circle devel- ops with chronic abuse of ergotamine or other analgesics that may end with irre- versible disturbances of peripheral blood flow and impairment of renal function. Administered orally, ergotamine and sumatriptan, eletriptan, naratrip- tan, rizatriptan, and zolmitriptan have only limited bioavailability. Dihydroer- gotamine may be given by i.m. or slow i.v. injection, sumatriptan subcutane- ously or by nasal spray. Prophylaxis. Taken regularly over a longer period, a heterogeneous group of drugs comprising propranolol, nadolol, atenolol, and metoprolol (β-blockers), flunarizine (H 1 -histamine, dopamine, and calcium antagonist), pizotifen (pi- zotyline, 5-HT-antagonist), methyser- gide (partial 5-HT ID -agonist and nonse- lective 5-HT-antagonist, p. 126), NSAIDs (p. 200), and calcitonin (p. 264) may de- crease the frequency, intensity, and du- ration of migraine attacks. Among the β- blockers (p. 90), only those lacking in- trinsic sympathomimetic activity are ef- fective. 322 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 323 Migraine attack: Headache Hypersensitivity of olfaction, gustation, audition, vision Nausea, vomiting Acetylsalicylic acid 1000 mg or acetaminophen 1000 mg (Dihydro)- Ergotamine Sumatriptan and other triptans Meto- clopramide inhibited accelerated delayed improved Relief of migraine Psychosis Nausea, vomiting Platelet aggregation α 1 + α 2 Vaso- constriction Er gotamine α 1 + α 2 Sumatriptan and other triptans A. Migraine and its treatment Gastric emptying Drug absorption Migraine or 6 mg 100 mg 1 mg 1-2 mg 5-HT 1D 5-HT 1A D 2 5-HT 2 5-HT 1D 5-HT 1A D 2 5-HT 2 When therapeutic effect inadequate Neurogenic inflammation, local edema, vasodilation Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Common Cold The common cold—colloquially the flu, catarrh, or grippe (strictly speaking, the rarer infection with influenza viruses)— is an acute infectious inflammation of the upper respiratory tract. Its sym- ptoms, sneezing, running nose (due to rhinitis), hoarseness (laryngitis), diffi- culty in swallowing and sore throat (pharyngitis and tonsillitis), cough asso- ciated with first serous then mucous sputum (tracheitis, bronchitis), sore muscles, and general malaise can be present individually or concurrently in varying combination or sequence. The term stems from an old popular belief that these complaints are caused by ex- posure to chilling or dampness. The causative pathogens are different virus- es (rhino-, adeno-, parainfluenza v.) that may be transmitted by aerosol droplets produced by coughing and sneezing. Therapeutic measures. First at- tempts of a causal treatment consist of zanamavir, an inhibitor of viral neura- minidase, an enzyme necessary for virus adsorption and infection of cells. How- ever, since symptoms of common cold abate spontaneously, there is no com- pelling need to use drugs. Conventional remedies are intended for symptomatic relief. Rhinitis. Nasal discharge could be prevented by parasympatholytics; how- ever, other atropine–like effects (pp. 104ff) would have to be accepted. Therefore, parasympatholytics are hardly ever used, although a corre- sponding action is probably exploited in the case of H 1 antihistamines, an ingre- dient of many cold remedies. Locally ap- plied (nasal drops) vasoconstricting α- sympathomimetics (p. 90) decongest the nasal mucosa and dry up secretions, clearing the nasal passage. Long-term use may cause damage to nasal mucous membranes (p. 90). Sore throat, swallowing prob- lems. Demulcent lozenges containing surface anesthetics such as ethylamino- benzoate (benzocaine) or tetracaine (p. 208) may provide relief; however, the risk of allergic reactions should be borne in mind. Cough. Since coughing serves to expel excess tracheobronchial secre- tions, suppression of this physiological reflex is justified only when coughing is dangerous (after surgery) or unproduc- tive because of absent secretions. Co- deine and noscapine (p. 212) suppress cough by a central action. Mucous airway obstruction. Mu- colytics, such as acetylcysteine, split di- sulfide bonds in mucus, hence reduce its viscosity and promote clearing of bron- chial mucus. Other expectorants (e.g., hot beverages, potassium iodide, and ipecac) stimulate production of watery mucus. Acetylcysteine is indicated in cystic fibrosis patients and inhaled as an aerosol. Whether mucolytics are indi- cated in the common cold and whether expectorants like bromohexine or am- broxole effectively lower viscosity of bronchial secretions may be questioned. Fever. Antipyretic analgesics (ace- tylsalicylic acid, acetaminophen, p. 198) are indicated only when there is high fe- ver. Fever is a natural response and use- ful in monitoring the clinical course of an infection. Muscle aches and pains, head- ache. Antipyretic analgesics are effective in relieving these symptoms. 324 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 325 A. Drugs used in common cold Local use of α-sympathomimetics (nasal drops or spray) H 1 -Antihistamines Caution: sedation Viral infection Causal therapy impossible Accumulation in airways of mucus, inadequate expulsion by cough Acetylsalicylic acid Acetaminophen Decongestion of mucous membranes Soreness Headache Fever Sniffles, runny nose Common cold Flu Sore throat Cough Airway congestion Surface anesthetics Caution: risk of sensitization Antitussive: Mucolytics Acetylcysteine Give warm fluids Bromhexine Codeine Potassium iodide solution Expectorants: Stimulation of bronchial secretion Dextrometorphan Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Allergic Disorders IgE-mediated allergic reactions (p. 72) involve mast cell release of histamine (p. 114) and production of other media- tors (such as leukotrienes, p. 196). Re- sultant responses include: relaxation of vascular smooth muscle, as evidenced lo- cally by vasodilation (e.g., conjunctival congestion) or systemically by hypoten- sion (as in anaphylactic shock); en- hanced capillary permeability with transudation of fluid into tissues— swelling of conjunctiva and mucous membranes of the upper airways (“hay fever”), cutaneous wheal formation; contraction of bronchial smooth muscle— bronchial asthma; stimulation of intesti- nal smooth muscle—diarrhea. 1. Stabilization of mast cells. Cromolyn prevents IgE-mediated re- lease of mediators, although only after chronic treatment. Moreover, by inter- fering with the actions of mediator sub- stances on inflammatory cells, it causes a more general inhibition of allergic in- flammation. It is applied locally to: con- junctiva, nasal mucosa, bronchial tree (inhalation), intestinal mucosa (absorp- tion almost nil with oral intake). Indica- tions: prophylaxis of hay fever, allergic asthma, and food allergies. 2. Blockade of histamine recep- tors. Allergic reactions are predomi- nantly mediated by H 1 receptors. H 1 antihistamines (p. 114) are mostly used orally. Their therapeutic effect is often disappointing. Indications: allergic rhinitis (hay fever). 3. Functional antagonists of me- diators of allergy. a) α-Sympathomi- metics, such as naphazoline, oxymeta- zoline, and tetrahydrozoline, are ap- plied topically to the conjunctival and nasal mucosa to produce local vasocon- striction, and decongestion and to dry up secretions (p. 90), e.g., in hay fever. Since they may cause mucosal damage, their use should be short-term. b) Epinephrine, given i.v., is the most important drug in the management of anaphylactic shock: it constricts blood vessels, reduces capillary permeability, and dilates bronchi. c) β 2 -Sympathomimetics, such as terbutaline, fenoterol, and albuterol, are employed in bronchial asthma, mostly by inhalation, and parenterally in emer- gencies. Even after inhalation, effective amounts can reach the systemic circula- tion and cause side effects (e.g., palpita- tions, tremulousness, restlessness, hy- pokalemia). During chronic administra- tion, the sensitivity of bronchial muscu- lature is likely to decline. d) Theophylline belongs to the methylxanthines. Whereas caffeine (1,3,7-trimethylxanthine) predomi- nantly stimulates the CNS and constricts cerebral blood vessels, theophylline (1,3-dimethylxanthine) possesses addi- tional marked bronchodilator, cardio- stimulant, vasorelaxant, and diuretic ac- tions. These effects are attributed to both inhibition of phosphodiesterase (→ c AMP elevation, p. 66) and antago- nism at adenosine receptors. In bronchi- al asthma, theophylline can be given orally for prophylaxis or parenterally to control the attack. Manifestations of overdosage include tonic-clonic sei- zures and cardiac arrhythmias as early signs. e) Ipratropium (p. 104) can be in- haled to induce bronchodilation; how- ever, it often lacks sufficient effective- ness in allergic bronchospasm. f) Glucocorticoids (p. 248) have significant anti-allergic activity and probably interfere with different stages of the allergic response. Indications: hay fever, bronchial asthma (preferably local application of analogues with high pre- systemic elimination, e.g., beclometha- sone, budesonide); anaphylactic shock (i.v. in high dosage)—a probably nonge- nomic action of immediate onset. 326 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 327 A. Anti-allergic therapy Antigen (e.g., pollen, penicillin G) IgE Antibodies Inhibitors of leukotriene synthesis: e. g., zileuton Release of histamine Histamine receptor Reaction of target cells Vascular smooth muscle, permeability Mucous membranes of nose and eye: redness swelling, secretion Skin: wheal formation Circulation: anaphyl. shock Bronchial musculature Glucocorticoids Vasodilation Edema α-Sympatho- mimetics: e. g., naphazoline Epinephrine Contraction Bronchial asthma Theophylline β2-Sympathomimetics: e. g., terbutaline H 1 -Antihistamines Leukotrienes Leukotriene receptor antagonist: e. g., zafirlukast COOHS CH3 OH NCl CH3 Leukotriene receptor O O N H N CH 3 H 3 C N N H N H OH OH HO CH 3 CH 3 CH 3 CHO OOO COOOOC O O OH CH 2 CH 2 Mast cell stabilization by cromolyn Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Bronchial Asthma Definition: a recurrent, episodic short- ness of breath caused by bronchocon- striction arising from airway inflamma- tion and hyperreactivity. Asthma patients tend to underesti- mate the true severity of their disease. Therefore, self-monitoring by the use of home peak expiratory flow meters is an essential part of the therapeutic pro- gram. With proper education, the pa- tient can detect early signs of deteriora- tion and can adjust medication within the framework of a physician-directed therapeutic regimen. Pathophysiology. One of the main pathogenetic factors is an allergic in- flammation of the bronchial mucosa. For instance, leukotrienes that are formed during an IgE-mediated im- mune response (p. 326) exert a chemo- tactic effect on inflammatory cells. As the inflammation develops, bronchi be- come hypersensitive to spasmogenic stimuli. Thus, stimuli other than the original antigen(s) can act as triggers (A); e.g., breathing of cold air is an im- portant trigger in exercise-induced asthma. Cyclooxygenase inhibitors (p. 196) exemplify drugs acting as asth- ma triggers. Management. Avoidance of asthma triggers is an important prophylactic measure, though not always feasible. Drugs that inhibit allergic inflammma- tory mechanisms or reduce bronchial hyperreactivity, viz., glucocorticoids, “mast-cell stabilizers,” and leukotriene antagonists, attack crucial pathogenetic links. Bronchodilators, such as β 2 -sym- pathomimetics, theophylline, and ipra- tropium, provide symptomatic relief. The step scheme (B) illustrates suc- cessive levels of pharmacotherapeutic management at increasing degrees of disease severity. First treatment of choice for the acute attack are short-acting, aerosolized β 2 -sympathomimetics, e.g., salbutamol, albuterol, terbutaline, fenoterol, and others. Their action occurs within min- utes and lasts for 4 to 6 h. If β 2 -mimetics have to be used more frequently than three times a week, more severe disease is present. At this stage, management includes anti- inflammatory drugs, such as “mast-cell stabilizers” (in children or juvenile pa- tients) or else glucocorticoids. Inhala- tional treatment must be administered regularly, improvement being evident only after several weeks. With proper use of glucocorticoids undergoing high presystemic elimination, concern about systemic adverse effects is unwarrant- ed. Possible local adverse effects are: oropharyngeal candidiasis and dyspho- nia. To minimize the risk of candidiasis, drug administration should occur be- fore morning or evening meals, or be followed by rinsing of the oropharynx. Anti-inflammatory therapy is the more successful the less use is made of as- needed β 2 -mimetic medication. Severe cases may, however, require an intensified bronchodilator treatment with systemic β 2 -mimetics or theophyl- line (systemic use only; low therapeutic index; monitoring of plasma levels needed). Salmeterol is a long-acting in- halative β 2 -mimetic (duration: 12 h; on- set ~20 min) that offers the advantage of a lower systemic exposure. It is used prophylactically at bedtime for noctur- nal asthma. Zafirlukast is a long-acting, selec- tive, and potent leukotriene receptor (LTD 4 , LTE 4 ) antagonist with anti-in- flammatory/antiallergic activity and ef- ficacy in the maintenance therapy of chronic asthma. It is given both orally and by inhalation. The onset of action is slow (3 to 14 d). Protective effects against inhaled LTD 4 last up to 12 to 24 h. Ipratropium may be effective in some patients as an adjunct anti-asth- matic, but has greater utility in prevent- ing bronchospastic episodes in chronic bronchitis. 328 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 329 Antigens, infections, ozone, SO 2 , NO 2 Bronchial spasm Dust, cold air, drugs A. Bronchial asthma, pathophysiology and therapeutic approach Mild asthma Severe asthmaModerate asthma Modified after INTERNATIONAL CONSENSUS REPORT 1992 Glucocorticoids systemic Glucocorticoids B. Bronchial asthma treatment algorithm Noxious stimuli "or" "or/and" Glucocorticoids Parasympatholytics Allergens Avoid exposure Treat inflammation Dilate bronchi Mast cell- stabilizer” or glucocorticoids “ Antiinflammatory treatment, inhalative, chronically Bronchodilation as needed: short-acting inhalative β 2 -mimetics Maintained bronchodilation 4 x/day4 x/day4 x/day3 x /week< – Theophylline p.o./? 2 -mimetics p.o. or long-acting ? 2 -mimetics inhalative Inflammation Bronchial hyperreactivity < – < – < – or leukotriene antagonists Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Emesis In emesis the stomach empties in a ret- rograde manner. The pyloric sphincter is closed while the cardia and esopha- gus relax to allow the gastric contents to be propelled orad by a forceful, synchro- nous contraction of abdominal wall muscles and diaphragm. Closure of the glottis and elevation of the soft palate prevent entry of vomitus into the tra- chea and nasopharynx. As a rule, there is prodromal salivation or yawning. Co- ordination between these different stages depends on the medullary cen- ter for emesis, which can be activated by diverse stimuli. These are conveyed via the vestibular apparatus, visual, ol- factory, and gustatory inputs, as well as viscerosensory afferents from the upper alimentary tract. Furthermore, psychic experiences may also activate the emetic center. The mechanisms underlying motion sickness (kinetosis, sea sickness) and vomiting during preg- nancy are still unclear. Polar substances cannot reach the emetic center itself because it is pro- tected by the blood-brain barrier. How- ever, they can indirectly excite the cen- ter by activating chemoreceptors in the area postrema or receptors on periph- eral vagal nerve endings. Antiemetic therapy. Vomiting can be a useful reaction enabling the body to eliminate an orally ingested poison. Antiemetic drugs are used to prevent ki- netosis, pregnancy vomiting, cytotoxic drug-induced or postoperative vomit- ing, as well as vomiting due to radiation therapy. Motion sickness. Effective prophy- laxis can be achieved with the parasym- patholytic scopolamine (p. 106) and H 1 antihistamines (p. 114) of the diphenyl- methane type (e.g., diphenhydramine, meclizine). Antiemetic activity is not a property shared by all parasympatho- lytics or antihistamines. The efficacy of the drugs mentioned depends on the ac- tual situation of the individual (gastric filling, ethanol consumption), environ- mental conditions (e.g., the behavior of fellow travellers), and the type of mo- tion experienced. The drugs should be taken 30 min before the start of travel and repeated every 4 to 6 h. Scopola- mine applied transdermally through an adhesive patch can provide effective protection for up to 3 d. Pregnancy vomiting is prone to occur in the first trimester; thus phar- macotherapy would coincide with the period of maximal fetal vulnerability to chemical injury. Accordingly, antiemet- ics (antihistamines, or neuroleptics if required) should be used only when continuous vomiting threatens to dis- turb electrolyte and water balance to a degree that places the fetus at risk. Drug-induced vomiting. To pre- vent vomiting during anticancer chemotherapy (especially with cispla- tin), effective use can be made of 5-HT 3 - receptor antagonists (e.g., ondansetron, granisetron, and tropisetron), alone or in combination with glucocorticoids (methylprednisolone, dexamethasone). Anticipatory nausea and vomiting, re- sulting from inadequately controlled nausea and emesis in patients undergo- ing cytotoxic chemotherapy, can be at- tenuated by a benzodiazepine such as lorazepam. Dopamine agonist-induced nausea in parkinsonian patients (p. 188) can be counteracted with D 2 -receptor antagonists that penetrate poorly into the CNS (e.g., domperidone, sulpiride). Metoclopramide is effective in nausea and vomiting of gastrointestinal origin (5-HT 4 -receptor agonism) and at high dosage also in chemotherapy- and radi- ation-induced sickness (low potency antagonism at 5-HT 3 - and D 2 -recep- tors). Phenothiazines (e.g., levomeprom- azine, trimeprazine, perphenazine) may suppress nausea/emesis that follows certain types of surgery or is due to opi- oid analgesics, gastrointestinal irrita- tion, uremia, and diseases accompanied by elevated intracranial pressure. The synthetic cannabinoids dronab- inol and nabilone have antinau- seant/antiemetic effects that may bene- fit AIDS and cancer patients. 330 Therapy of Selected Diseases Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Selected Diseases 331 A. Emetic stimuli and antiemetic drugs Pregnancy vomiting Kinetoses e.g., sea sickness Psychogenic vomiting Sight Olfaction Taste Intramucosal sensory nerve endings in mouth, pharynx, and stomach Vestibular system Chemoreceptors (drug-induced vomiting) Area postrema Emetic center Chemo- receptors Scopolamine H 1 -Antihistamines Diphenhydramine Meclozine Dopamine antagonists Domperidone Metoclopramide Ondansetron 5-HT 3 -antagonist N NN O N H O N H Cl Parasympatholytics Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. A. Foundations and basic principles of pharmacology Hardman JG, Limbird LE. Goodman & Gilman’s. The pharmacological basis of therapeutics. 9 th ed. New York: McGraw-Hill; 1996. Levine RR. Pharmacology: drug actions and reactions. 5 th ed. New York: Parthe- non Publishing Group; 1996. Munson PL, Mueller RA, Breese GR. Prin- ciples of pharmacology. London: Chap- man & Hall; 1995. Mutschler E, Derendorf H. Drug ac- tions—basic principles and therapeutic aspects. Stuttgart: Medpharm Scientific Pub.; Boca Raton: CRC Press; 1995. Page CR, Curtis MJ, Sutter MC, Walker MJA, Hoffman BB. Integrated pharma- cology. London: Mosby; 1997. Pratt WB, Taylor P. Principles of drug ac- tion—the basis of pharmacology. 3 rd ed. New York: Churchill Livingstone; 1990. Rang HP, Dale MM, Ritter JM, Gardiner P. Pharmacology. 4 th ed. New York: Churchill Livingstone; 1999. B. Clinical pharmacology Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacothera- py–a pathophysiological approach. 3 rd ed. Norwalk, Conn: Appleton & Lange; 1997. Kuemmerle H, Shibuya T, Tillement JP. Human pharmacology: the basis of clin- ical pharmacology. Amsterdam: Elsevi- er; 1991. Laurence DR, Bennett PN. Clinical phar- macology. 8 th ed. Edinburgh: Churchill Livingstone; 1998. Melmon KL, Morelli HF, Hoffman BB, Nierenberg DW. Clinical Pharmacolo- gy—basic principles in therapeutics. 3 rd ed. New York: McGraw-Hill; 1992. The Medical Letter on Drugs and Thera- peutics. New Rochelle NY: The Medical Letter Inc.; published bi-weekly. Clinical Pharmacology—Electronic drug reference. Tampa, Florida: Gold Stan- dard Multimedia Inc.; updated every 4 months. C. Drug interactions and adverse effects D’Arcey PF, Griffin JP. Iatrogenic diseas- es. Oxford: Oxford University Press; 1986. Davies DM. Textbook of adverse drug reactions. 4 th ed. Oxford: Oxford Univer- sity Press; 1992. Hansten PD, Horn JR. Drug interactions, analysis and management. Vancouver, WA: Applied Therapeutics Inc.; 1999; updated every 4 months. D. Drugs in pregnancy and lactation Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 5 th ed. Baltimore: Williams & Wilkins; 1998. Rubin PC. Prescribing in pregnancy. Lon- don: British Medical Journal; 1987 E. Pharmacokinetics Rowland M, Tozer TN. Clinical pharma- cokinetics: concepts and applications. 3 rd ed. Baltimore: Williams & Wilkins; 1995. F. Toxicology Amdur MO, Doull J, Klaassen CD. Casa- rett and Doull’s toxicology: the basic science of poisons. 5 th ed. New York: McGraw-Hill; 1995. 332 Further Reading Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 333 Drug Indexes Nomenclature. The terms active agent and pharmacon designate substances that are capable of modifying life pro- cesses irrespective of whether the ef- fects elicited may benefit or harm the organisms concerned. By this definition, a toxin is also a pharmacon. Taken in a narrower sense, a pharmacon means a substance that is used for therapeutic purposes. An unequivocal term for such a substance is medicinal drug. A drug can be identified by different designations: – the chemical name – the generic (nonproprietary) name – a trade or brand name The drug diazepam may serve as an illustrative example. Chemically, this compound is called 7-chloro-1,3-dihy- dro-1-methyl-5-phenyl-2H-1,4-benzo- diazepin-2-one, a term too unwieldy for everyday use. A simpler name is diaze- pam. This is not a legally protected name but a generic (nonproprietary) name. An INN (= international nonpro- prietary name) is a generic name that has been agreed upon by an interna- tional commission. Preparations containing diazepam were first marketed under the trade name Valium by its manufacturer, Hoff- mann–La Roche, Inc. This name is a reg- istered trademark. After patent protec- tion for the manufacture of diazepam- containing drug preparations expired, other companies were free to produce preparations containing this drug. Each invented a proprietary name for its “own” preparation. As a result, there now exists a plethora of proprietary la- bels for diazepam preparations (as of 1991, more than 50). Some of these eas- ily reveal the active ingredient, because the company name is simply added to the generic name, e.g., Diazepam- (com- pany’s name). Other designations are new creations, as for example, Vivol. Similarly, some other commercially successful drugs are sold under more than 20 different brand labels. The num- ber of proprietary names, therefore, greatly exceeds the number of available drugs. For the sake of clarity, only INNs or generic (nonproprietary) names are used in this atlas to designate drugs, such as the name “diazepam” in the above example. Use of Indexes The indexes are meant to help the read- er: 1. identify a commercial preparation for a given drug. This information is found in the index “Generic Name → Popri- etary Name.” 2. obtain information about the phar- macological properties of the active in- gredient in a commercial preparation. In order to find the generic (nonproprie- tary) name, the second index “Proprie- tary Name → Generic Name” can be consulted. Page references pertaining to the drug can then be looked up in the In- dex. The list of proprietary names given below will necessarily be incomplete due to their multitude. For drugs that are marketed under several brand names, the trade name of the original manufacturer will be listed; in the case of some frequently prescribed generics, some proprietary names of other manu- facturers will also be listed. Brand names that clearly reveal the drug’s identity have been omitted. Combina- tion preparations have not been includ- ed, barring a few exceptions. Many a brand name is not listed in the index “Proprietary Name → Generic Name.” In these cases, it will be useful to consult the packaging information, which should list the generic (nonpro- prietary) name or INN. Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 334 Drug Index Drug Name Trade Name (* denotes investigational drug status in USA) A Abacavir Ziagen Abciximab ReoPro Acarbose Precose Acebutolol Monitan, Sectral Acenocoumarin (= Nicoumalone) Sintrom Acetaminophen see Paracetamol Acetazolamide Diamox, Glaupax Acetylcysteine Airbron, Fabrol, Mucomyst, Parvolex Acetyldigoxin Acylanid Acetylsalicylic acid Aspirin, Arthrisin, Asadrine, Ecotrin, Entrophen, Pyronoval, Supasa Aciclovir Zovirax ACTH Acthar, Cortrophin Actinomycin D Cosmegen Acyclovir Zovirax ADH (= Vasopressin) Pitressin, Presyn Adrenalin see epinephrine Adriamycin See doxorubicin Ajmaline Cardiorhythmino; Gilurytmal Albuterol See Salbutamol Alcuronium Alloferin Aldosterone Aldocorten Alendronate Fosamax Alfentanil Alfenta Alfuzosin Alfoten, Xatral Allopurinol Alloprin, Novopurol, Urosin, Zyloprim, Zyloric Alprazolam Xanax Alprenolol Aprobal, Aptine, Gubernal Alprostadil (= PGE1) Prostin VR, Minprog Alteplase Activase Aluminium hydroxide Aldrox, Alu-Tab, Amphojel, Fluagel Amantadine Solu-Contenton, Virofral, Symmetrel Ambroxol Ambril, Bronchopront, Mucosolvan, Surfactal Amikacin Amikin, Briclin, Novamin Amiloride Arumil, Colectril, Midamor, Nilurid Amiloride + Hydrochlorothiazide Moduret ε-Aminocaproic acid Amicar, Afibrin, Capramol ε-Aminocaproic acid + Thromboplastin Epsilon-Tachostyptan Aminomethylbenzoic acid Gumbix, Pamba 5-Aminosalicylic acid Propasa, Rezipas Amiodarone Cordarex, Cordarone Amitriptyline Amitril, Elavil, Endep, Enovil, Levate, Mevaril Amodiaquine Camoquin, Flavoquine Amoxicillin Amoxil, Clamoxyl, Moxacin, Novamoxin Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 335 d-Amphetamine Dexedrine, Synatan Amphotericin B Amphozone, Fungilin, Fungizone, Moronal Ampicillin Amcill, Omnipen, Penbritin, Polycillin, Principen, Tota- cillin Amrinone Inocor, Wincoram Ancrod* Arvin, Arwin, Viprinex Angiotensin II Hypertensin Aprindine Amidonal, Aspenon, Fibocil Ardeparin Normiflo Articaine Ultracain, Ubistesin Astemizole Hismanal Atenolol Prenormine, Tenormin Atorvastatin Lipitor Atracurium Tracrium Atropine Atropisol, Borotropin Auranofin Ridaura Aurothioglucose Aureotan, Auromyose, Solganal Azapropazone Prolixan Azathioprine Azanin, Imuran, Imurek Azidothymidine Retrovir Azithromycin Zithromax Azlocillin Azlin, Securopen Aztreonam Azactam B Bacitracin Altracin, Baciguent, Topitracin Baclofen Lioresal Basiliximab Simulect Beclomethasone Aldecin, Beclovent, Beconase, Becotide, Propaderm, Vanceril Benazepril Lotensin Benserazide Madopar (plus Levodopa) Benzathine-Penicillin G Bicillin, Megacillin, Tardocillin Benztropine Cogentin Benzbromarone Desuric, Narcaricin, Normurat, Uricovac Benzocaine Anaesthesin, Americaine, Anacaine Betaxolol Betoptic, Kerlone Bezafibrate Befizal, Bezalip, Bezatol, Cedur Bifonazole Amycor, Bedriol, Mycospor, Mycosporan Biperiden Akineton, Akinophyl Bisacodyl Bicol, Broxalax, Durolax, Dulcolax, Laxanin, Laxbene, Nigalax, Pyrilax, Telemin, Ulcolax Bismuth subsalicylate Pepto-Bismol Bisoprolol Concor, Detensiel, Emcor, Isoten, Soprol, Zebeta Bitolterol Effectin, Tornalate Bleomycin Blenoxane Botulinum Toxin Type A Oculinum Bromazepam Durazanil, Lectopam, Lexotan Bromhexine Auxit, Bisolvon, Ophthosol Bromocriptine Parlodel, Pravidel, Serono-Bagren Brotizolam Lendorm (A), Lendormin Bucindolol* Bextra Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Budesonide Pulmicort, Spirocort Bumetanide Bumex, Burinex, Fontego, Fordiuran Bunitrolol Betriol, Stresson Bupranolol Betadran, Betadrenol, Looser, Panimit Buprenorphine Buprene, Temgesic Bupropion Wellbatrin, Wellbutrin Buserelin Sprecur, Suprefact Buspirone Buspar Busulfan Mielucin, Mitosan, Myleran, Sulfabutin Butizid Saltucin N-Butyl-scopolamine Buscopan, Hyoscin-N-Butylbromid C Calcifediol Calderol, Dedrogyl, Hidroferol Calcitonin Calcimer, Calsynar, Cibacalcin, Karil Calcitriol Rocaltrol Calcium carbonate Calsan, Caltrate, Nu-Cal Camazepam Albego Canrenone Kanrenol, Soldactone, Venactone Candesartan Atacand Capreomycin Capastat, Caprolin Captopril Acediur, Acepril, Alopresin, Capoten, Cesplon, Hypertil, Lopirin, Tensobon Carazolol Conducton, Suacron Carbachol Doryl, Miostat, Lentin Carbamazepine Epitol, Mazepine, Sirtal, Tegretol, Timonil Carbenicillin Anabactyl (A), Carindapen, Geopen, Pyopen Carbenoxolone Biogastrone, Bioplex, Neogel, Sanodin Carbidopa + Levodopa Isicom, Nacom, Sinemet Carbimazole Neo-Mercazole, Neo-Thyreostat Carboplatin Paraplatin Carteolol Arteoptic, Caltidren, Carteol, Endak, Ocupress, Tenalin Carvedilol Coreg Cefalexin Keflex, Keftab Cefazolin Ancef, Ketzol Cefixime Suprax Cefmenoxime Bestcall, Cefmax, Cemix, Tacef Cefoperazone Cefobid, Cefobis, Tomabef Cefotaxime Claforan Cefoxitin Mefoxin Ceftazidime Fortaz, Fortum, Tacicef Ceftriaxone Acantex, Rocephin Cefuroxime axetil Ceftin Cellulose Avicel Cephalexin Cepexin (A), Ceporex, Keflex, Losporal Cerivastatin Baycol Chenodeoxycholic acid Chenix Chloralhydrate Lorinal, Noctec, Somnos Chlorambucil Chloraminophene, Leukeran Chloramphenicol Chloromycetin, Chloroptic, Leukomycin, Paraxin, Sopa- mycetin, Spersanicol Chlorhexidine Baxedin, Chlor-hex, Hibidil, Hibitane, Plak-out 336 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 337 Chlormadinone acetate Gestafortin Chloroquine Aralen, Avloclor, Quinachlor Chlorpromazine Largactil, Hibanil, Megaphen, Thorazine Chlorpropamide Diabinese Chlorprothixene Taractan, Tarasan, Truxal Chlorthalidone Hygroton Cholecalciferol D-Tabs, Vigantol, Vigorsan Clorazepate Novoclopate, Tranxene Cilazapril Inhibace Cimetidine Peptol, Tagamet Ciprofloxacin Ciprobay, Cipro Cisapride Propulsid Cisplatin Platinex, Platinol Citalopram Celexa Clarithromycin Biaxin Clavulanic Acid + Amoxicillin Augmentin Clemastine Tavist Clindamycin Cleocin, Dalacin, Sobelin Clobazam Frisium Clodronate* Clasteon, Ossiten, Ostac Clofazimine Lampren Clofibrate Atromid-S, Claripex, Skleromexe Clomethiazole Distraneurin, Hemineurin Clomiphene Clomid, Dyneric, Omifin, Pergotime, Serophene Clonazepam Clonopin, Iktorivil, Rivotril Clonidine Catapres, Dixarit Clopidogrel Plavix Clostebol Macrobin, Steranabol Clotiazepam Clozan, Rize, Tienor, Trecalmo, Veratran Clotrimazole Canesten, Clotrimaderm, Gyne-Lotrimin, Mycelex, Trimysten Cloxacillin Clovapen, Tegopen Clozapine Clozaril Codeine Codicept, Paveral Colestipol Cholestabyl, Cholestid Colestyramine Questran, Cuemid Corticotropin Acthar, Cortigel, Cortrophin Cortisol (Hydrocortisone) Alocort, Cortate, Cortef, Cortenema, Hyderm, Hyocort, Rectocort, Unicort Cortisone Cortelan, Cortogen, Cortone Cotrimoxazole Bactrim, Novotrimel, Protrin Septra Cromoglycate (Cromolyn) Intal, Nalcrom, Opticrom, Rynacrom, Vistacrom Cyanocobalamin Anacobin, Bedoz, Rubion, Rubramin Cyclofenil Fertodur, Ondogyne, Ondonid, Sanocrisin, Sexovid Cyclopenthiazide Navidrix, Salimid Cyclophosphamide Cytoxan, Endoxan, Procytox Cyclosporine Neoral, Sandimmune, Sang-35 Cyproheptadine Anarexol, Nuran, Periactin, Peritol, Vimicon Cyproterone-acetate Androcur Cytarabine Udicil, Cytosar Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. D Daclizumab Zenapax Dactinomycin See Actinomycin D Dalteparin Fragmin Danaparoid Orgaran Dantrolene Dantrium Dapsone Avlosulfone, Eporal, Diphenasone, Udolac Daunorubicin Cerubidine, Daunoblastin, Ondena Deferoxamine Desferal Delavirdine Rescriptor Desipramine Pertofran, Norpramin Desmopressin DDAVP, Minirin, Stimate Desogestrel + Ethinylestradiol Marvelon Dexamethasone Decadron, Deronil, Hexadrol, Spersadex Dexetimide Tremblex Dextran Hyskon Diazepam Apaurin, Atensine, Diastat, Dizac, Eridan, Lembrol, Meval, Noan, Tensium, Valium, Vatran, Vivol Diazoxide Eudemine, Hyperstat, Mutabase, Proglicem Diclofenac Allvoran, Diclophlogont, Rhumalgan, Voltaren, Voltarol Dicloxacillin Diclocil, Dynapen, Pathocil Didanosine (ddI) Videx Diethylstilbestrol Honvol Digitoxin Crystodigin, Digicor, Digimerck, Digacin, Lanicor, Lanoxin, Lenoxin, Novodigoxin Digoxin immune FAB Digibind Dihydralazine Dihyzin, Nepresol, Pressunic Dihydroergotamine Angionorm, D.E.H.45, Dihydergot, Divegal, Endophle- ban Diltiazem Cardizem Dimenhydrinate Dimetab, Dramamine, Dymenate, Marmine Dinoprost Minprostin F2α, Prostarmon, Prostin F2 Alpha Dinoprostone Prepidil, Prostin E2 Diphenhydramine Allerdryl, Benadryl, Insommal, Nautamine Diphenoxylate Diarsed, Lomotil, Retardin Disopyramide Norpace, Rythmodan Dobutamine Dobutrex Docetaxel Taxotere Dolasetron Anzemet Domperidone* Euciton, Evoxin, Motilium, Nauzelin, Peridon Dopamine Dopastat, Intropin Dorzolamide Trusopt Doxacurium Nuromax Doxazosin Cardura, Carduran Doxepin Adapin, Sinequan, Triadapin Doxorubicin Adriblastin, Adriamycin Doxycycline C-Pak, Doxicin, Vibramycin Doxylamine Decapryn Dronabinol Marinol Droperidol Inapsine, Droleptan 338 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 339 E Econazole Ecostatin, Gyno-Pevaryl Ecothiopate Phospholine Iodide Enalapril Vasotec, Xanef Enflurane Ethrane Enoxacin Bactidan, Comprecin, Enoram Enoxaparin Lovenox Entacapone* Comtan Epinephrine Adrenalin, Bronchaid, Epifin, Epinal, EpiPen, Epitrate, Lyophrin, Simplene, Suprarenin, Vaponefrine Ephedrine Bofedrol, Efedron, Va-tro-nol Eprosartan Teveten Eptifibatide Integriline Ergocalciferol Drisdol Ergometrine (= Ergonovine) Ergotrate Maleate, Ermalate Ergonovine Ergotrate Ergotamine Ergomar, Gynergen, Migril Erythomcyin E-mycin, Eryc, Erythromid Erythromycin-estolate Dowmycin, Ilosone, Novorythro Erythromycin-ethylsuccinate EES, Erythrocin, Wyamycin Erythromycin-propionate Cimetrin Erythromycin-stearate Erymycin, Erythrocin Erythromycin-succinate Monomycin Erythropoietin (= epoetin alfa) Epogen Esmolol Brevibloc Estradiol Estrace Estradiol-benzoate Progynon B Estradiol-valerate Delestrogen, Dioval, Femogex, Progynova Estratriol = Estriol Theelol Etanercept Enbrel Ethacrynic acid Edecrin, Hydromedin, Reomax Ethambutol Etibi, Myambutol Ethinylestradiol Estinyl, Feminone, Lynoral Ethionamide Trecator Ethopropazine Parsitan, Parsitol Ethosuximide Petinimid, Suxinutin, Zarontin Etidocaine Duranest Etidronate Calcimux, Diodronel, Diphos Etilefrine Apocretin, Effontil, Effortil, Ethyl Adrianol, Circupon, Kertasin, Pulsamin, Etodolac Lodine Etomidate Amidate Etoposide Toposar, VePesid Etretinate Tegison, Tigason F Famotidine Pepcid, Pepdul Felbamate Felbatol Felodipine Plendil Felypressin Octapressin Fenfluramine Ganal, Ponderal, Pondimin Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Fenofibrate Lipidyl, Tricor Fenoldopam Corlopam Fenoprofen Nalfon, Nalgesic Fenoterol Berotec, Partusisten Fentanyl Sublimaze Fentanyl + Droperidol Innovar Finasteride Propecia, Proscar Flecainide Tambocor Flucloxacillin Fluclox Fluconazole Diflucan Flucytosine Alcoban, Ancotil Fludrocortisone Alflorone, F-Cortef, Florinef Flumazenil Anexate, Romazicon Flunarizine Dinaplex, Flugeral, Sibelium Flunisolide Aerobid, Bronalide, Nasalide, Rhinalar Flunitrazepam* Hypnosedon, Narcozep, Rohypnol Fluoxetine Prozac 5-Fluorouracil Adrucil, Effudex, Effurix Flupentixol Depixol, Fluanxol Fluphenazine Moditen, Prolixin Flurazepam* Dalmane Flutamide Drogenil, Eulexin Fluticasone Cutivate, Flixonase, Flonase, Flovent Fluvastatin Lescol Fluvoxamine Floxifral, Faverin, Luvox Folic acid Foldine, Folvite, Leucovorin Foscarnet Foscavir Fosinopril Monopril Furosemide Fusid, Lasix, Seguril, Uritol G Gabapentin Neurontin Gallamine Flaxedil Gallopamil Algocor, Corgal, Procorum, Wingom Ganciclovir Cytovene, Vitrasert Gelatin-colloids Gelafundin, Haemaccel Gemfibrozil Lopid Gentamicin Cidomycin, Garamycin, Refobacin, Sulmycin Glibenclamide (= glyburide) Daonil, DiaBeta, Euglucon, Glynase, Micronase Glimepiride Amaryl Glipizide Glucotrol Glyceryltrinitrate (= nitroglycerin) Ang-O-Span, Nitrocap, Nitrogard, Nitroglyn, Nitrolingual, Nitrong, Nitrostat Glycopyrrolate Robinul Gonadorelin Factrel, Kryptocur, Relefact Goserelin Zoladex Gramicidin Gramoderm Granisetron Kytril Griseofulvin Fulvicin, Grisovin, Likuden Guanabenz Wytensin Guanethidine Ismelin, Visutensil Guanfacine Tenex 340 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 341 H Halofantrine Halfan Haloperidol Haldol, Serenace Halothane Fluothane, Narkotan HCG (= chorionic gonadotropin) Chorex, Choron, Entromone, Follutein, Gonic, Pregnesin, Pregnyl, Profasi Heparin Calciparin, Hepalean, Liquemin Heparin, low molecular Fragmin, Fraxiparin Hetastarch (HES) Hespan Hexachlorophane see Lindane Hexobarbital Evipal Hydralazine Alazine, Apresoline Hydrochlorothiazide Aprozide, Diaqua, Diuchlor, Esidrex, Hydromal, Neo- Codema, Oretic Hydromorphone Dilaudid, Hymorphan Hydroxocobalamin Acti-B12, Alpha-redisol, Sytobex Hydroxychloroquine Plaquenil Hydroxyethyl starch Hespan Hydroxyprogesterone caproate Duralutin, Gesterol L.A., Hylutin, Hyroxon, Pro-Depo Hyoscyamine sulfate Cystospaz-M, Levbid, Levsin I Ibuprofen Actiprophen, Advil, Motrin, Nuprin, Trendar Idoxuridine Dendrid, Herplex, Kerecid, Stoxil Ifosfamide Ifex Iloprost Latanaprost Imipramine Dynaprin, Impril, Janimine, Melipramin, Tofranil, Typramine Indapamide Lozide, Lozol, Natrilix Indinavir Crixivan Indomethacin Ammuno, Indocid, Indocin, Indome, Metacen Infliximab Remicade Insulin Humalog, Humulin, Iletin, Novolin, Velosulin Interferon-α2 Berofor alpha 2 Interferon-α2b Intron A Interferon-α2a Roferon A3 Interferon-β Fiblaferon 3 Interferon-β-1a Avonex Interferon-β-1b Betaseron Interferon-γ Actimmune Ipratropium Atrovent, Itrop Irbesartan Avapro Isoconazole Gyno-Travogen, Travogen Isoetharine Arm-a-Med, Bisorine, Bronkosol, Dey-Lute Isoflurane Forane Isoniazid Armazid, Isotamine, Lamiazid, Nydrazid, Rimifon, Tee- baconin Isoprenaline (= Isoproterenol) Aludrin, Isuprel, Neo Epinin, Saventrine Isosorbide dinitrate Cedocard, Coradus, Coronex, Isordil, Sorbitrate 5-Isosorbide mononitrate Coleb, Elantan, Ismo Isotretinoin Acutane Roche, Roaccutan Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 342 Drug Name → Trade Name Isoxsuprine Rolisox, Vasodilan, Vasoprine Isradipine DynaCirc Itroconazole Sporanox K Kanamycin Anamid, Kantrex, Klebcil Kaolin + Pectin (= attapulgite) Kaopectate, Donnagel-MB, Pectokay Ketamine Ketalar Ketoconazol Nizoral Ketorolac Acular, Toradol Ketotifen Zaditen L Labetalol Normodyne, Trandate Lactulose Cephulac, Chronulac, Duphalac Lamivudine (3TC) Epivir Lamotrigine Lamictal Lansoprazole Prevacid Leflunomide Arava Lepirudin Refludan Leuprorelide Lupron Levodopa Larodopa, Dopar, Dopaidan Levodopa + Benserazide Madopar, Prolopa Levodopa + Carbidopa Sinemet Levomepromazine Levoprome, Nozinan Lidocaine Dalcaine, Lidopen, Nulicaine, Xylocain, Xylocard Lincomycin Albiotic, Cillimycin, Lincocin Lindane Hexit, Kwell, Kildane, Scabene Liothyronine Cytomel, Triostat Lisinopril Prinivil, Zestril Lispro insulin Humalog Lisuride Cuvalit, Dopergin, Eunal, Lysenyl Lithium carbonate Carbolite, Duoralith, Eskalith Lithium carbonate Lithane, Lithobid, Lithotabs Lomustine CeeNu Loperamide Imodium, Kaopectate II Loratidine Claritin Lorazepam Alzapam, Ativan, Loraz Lorcainide Lopantrol, Lorivox, Remivox Lormetazepam Ergocalm, Loramet, Noctamid Losartan Cozaar Lovastatin Mevacor, Mevinacor Lypressin Diapid, Vasopressin Sandoz M Mannitol Isotol, Osmitrol Maprotiline Ludiomil Mazindol Mazonor, Sanorex Mebendazole Vermox Mechlorethamine Mustargen Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 343 Meclizine (meclozine) Antivert, Antrizine, Bonamine, Whevert Meclofenamate Meclomen Medroxyprogesterone-acetate Amen, Depo-Provera, Oragest Mefloquine Lariam Melphalan Alkeran Menadione Synkayvit Meperidine Demerol Mepindolol Betagon, Caridian, Corindolan Mepivacaine Carbocaine, Isocaine 6-Mercaptopurine Purinethol Mesalamine (Mesalazine) Asacol, Pentasa, Rowasa Mesna Mesnex, Uromitexan Mesterolone Androviron, Proviron Mestranol Menophase, Norquen, Ovastol Metamizol (= Dipyrone) Algocalmin, Bonpyrin, Divarine, Feverall, Metilon, No- valgin, Paralgin, Sulpyrin Metaproterenol Alupent, Metaprel Metformin Diabex, Glucophage Methadone Dolophine, Methadose, Physoseptone Methamphetamine Desoxyn, Methampex Methimazole Tapazole Methohexital Brevital Methotrexate Folex, Mexate Methoxyflurane Penthrane, Methofane Methyl-Dopa Aldomet, Amodopa, Dopamet, Novomedopa, Presinol, Sembrina Methylcellulose Celevac, Cellothyl, Citrucel, Cologel, Lacril, Murocel Methylergometrine (Methylergonovine) Methergine, Metenarin, Methylergobrevin, Ryegono- vin, Partergin, Spametrin-M Methylphenidate Ritalin Methylprylon Noludar Methyltestosterone Android, Metandren, Testred, Virilon Methysergide Sansert Metipranolol Optipranolol Metoclopramide Clopra, Emex, Maxeran, Maxolan, Reclomide, Reglan Metoprolol Betaloc, Lopressor Metronidazole Clont, Femazole, Flagyl, Metronid, Protostat, Satric Mexiletin Mexitil Mezlocillin Mezlin Mianserin Bolvidon, Norval Mibefradil Posicor Miconazole Micatin, Monistat Midazolam Versed Mifepristone RU 486 Milrinone Primacor Minocycline Minocin, Vectrin Minoxidil Loniten, Rogaine Misoprostol Cytotec Mithramycin Mithracin Mitoxantrone Novantrone Mivacurium Miracron Moclobemide Aurorix Molsidomine Corvaton, Duracoron, Molsidolat Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Montelukast Singulair Morphine hydrochloride Morphitec Morphine sulfate Astramorph, Duramorph, Epimorph, Roxanol, Statex Muromonab-CD3 Orthoclone OKT3 Mycophenolate Mofetil CellCept N Nabilone Cesamet Nadolol Corgard Naftifin Naftin Nalbuphine Nubain Nalidixic acid Negram, Nogram Naloxone Narcan Naltrexone Nalorex, Revia, Trexan Nandrolone Anabolin, Androlone, Deca-Durabolin, Hybolin Decano- ate, Kabolin Naphazoline Albalon, Degest-2, Privine, Vasocon Naproxen Aleve, Naprosyn, Naxen Narcotine (= Noscapine) Coscopin, Coscotab Nadroparin* Fraxiparine Nedocromil Tilade Nelfinavir Viracept Neomycin Mycifradin, Myciguent Neostigmine Prostigmin Netilmicin Netromycin Nevirapine Viramune Nicardipine Cardene Niclosamide Niclocide, Yomesan Nifedipine Adalat, Procardia Nimodipine Nimotop Nisoldipine Sular Nitrazepam Atempol, Mogadon Nitrendipine Bayotensin, Baypress Nitroglycerin See Glyceryl trinitrate Nitroprusside sodium Nipride, Nitropress Nizatidine Axid Nor-Diazepam Tranxilium N, Vegesan Noradrenalin (= Norepinephrine) Arterenol, Levophed Norethisterone Micronor = Norethindrone Norlutin, Nor-Q D Norfloxacin Noroxin Noscapine (= Narcotine) Coscopin, Coscotab Nortriptyline Pamelor Nystatin Korostatin, Mycostatin, Mykinac, Nilstat, Nystex, O-V Statin O Octreotide Sandostatin Ofloxacin Tarivid Olanzapine Zyprexa Omeprazole Losec, Prilosec 344 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 345 Ondansetron Zofran Opium Tincture (laudanum) Paregoric Orciprenaline (= Metaproterenol) Alupent Ornipressin POR 8 Oxacillin Bactocill, Prostaphlin Oxatomide Tinset Oxazepam Oxpam, Serax, Zapex Oxiconazole Oxistat Oxprenolol Trasicor Oxymetazoline Afrin, Allerest, Coricidin, Dristan, Neo-Synephrine, Sinarest Oxytocin Pitocin, Syntocinon P Paclitaxel Taxol Pamidronate Aminomux Pancuronium Pavulon Pantoprazole* Pantolac Papaverine Cerebid, Cerespan, Delapav, Myobid, Papacon, Pavabid, Pavadur, Vasal Paracetamol = acetaminophen Acephen, Anacin-3, Bromo-Seltzer, Datril, Tempra, Tylenol, Valadol, Valorin Paromomycin Humatin Paroxetine Paxil Penbutolol Levatol Penciclovir Denavir D-Penicillamine Cuprimine, Depen Penicillin G Bicillin, Cryspen, Deltapen, Lanacillin, Megacillin, Par- cillin, Pensorb, Pentids, Permapen, Pfizerpin Pencillin V Betapen-VK, Bopen-VK, Cocillin-VK, Lanacillin-VK, Le- dercillin VK, Nadopen-V, Novopen-VK, Penapar VK, Penbec-V, Pen-Vee K, Pfizerpen VK, Robicillin-VK, Uti- cillin-VK, V-Cillin K, Veetids Pentazocine Fortral, Talwin Pentobarbital Butylone, Nembutal, Novarectal, Pentanca Pentoxifylline Trental Pergolide Permax Perindopril Coversum Permethrin Elimite, Nix, Permanone Pethidine = Meperidine Demerol, Dolantin Phencyclidine Sernyl Pheniramine Daneral, Inhiston Phenobarbital Barbita, Gardenal, Solfoton Phenolphthalein Alophen, Correctol, Espotabs, Evac-U-gen, Evac-U-Lax, Ex-Lax, Modane, Prulet Phenoxybenzamine Dibenzyline Phenprocoumon Liquamar, Marcumar Phentolamine Regitin, Rogitin Phenylbutazone Algoverine, Azolid, Butagen, Butazolidin, Malgesic Phenytoin Dilantin Physostigmine Antilirium Phytomenadione Konakion Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Pilocarpine Akarpine, Almocarpine, I-Pilopine, Miocarpine, Isopto- Carpine, Pilokair Pindolol Visken Piperacillin Pipracil Pipecuronium Arduan Pirenzepine Gastrozepin Piroxicam Felden Pizotifen = Pizotyline Litec, Mosegor, Sandomigran Plicamycin Mithracin Polidocanol Thesit Pranlukast* Ultair Pravastatin Pravachol Prazepam Centrax Praziquantel Biltricide Prazosin Minipress Prednisolone Articulose, Codelsol, Cortalone, Delta-Cortef, Deltastab, Econopred, Hydeltrasol, Inflamase, Key-Pred, Metalone, Metreton, Pediapred, Predate, Predcor, Prelone Prednisone Meticorten, Orasone, Panasol, Winpred Prilocaine Citanest, Xylonest Primaquine Primaquine Primidone Myidone, Mysoline, Sertan Probenecid Benemid, Probalan Probucol Lovelco Procaine Novocaine Procainamide Procan SR, Promine, Pronestyl, Rhythmin Procarbazine Natulan Procyclidine Kemadrin Progabide Gabren(e) Progesterone Femotrone, Progestasert Promethazine Anergan, Ganphen, Mallergan, Pentazine, Phenazine, Phenergan, Prometh, Prorex, Provigan, Remsed Propafenone Rhythmol Propofol Diprivan Propranolol Detensol, Inderal Propylthiouracil Propyl-Thyracil Pyrantel Pamoate Antiminth Pyrazinamide Aldinamide, Tebrazid Pyridostigmine Mestinon, Regonol Pyridoxine Bee-six, Hexa-Betalin, Pyroxine Pyrimethamine Daraprim Pyrimethamine + Sulfadoxine Fansidar Q Quazepam Doral Quinacrine Atabrine Quinapril Accupril Quinidine Cardioqin, Cin-Quin, Quinalan, Quinidex, Quinora Quinine Quinaminoph, Quinamm, Quine, Quinite 346 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 347 R Raloxifene Evista Ramipril Altace Ranitidine Zantac Remifentanil Ultiva Repaglinide Actulin, NovoNorm, Prandin Reserpine Sandril, Serpalan, Serpasil, Zepine Ribavirin Virazole, Rebetol Rifabutin Mycobutin Rifampin Rifadin, Rimactan Ritodrine Yutopar Ritonavir Norvir Rocuronium Zemuron Rolitetracyclin Reverin, Transcycline, Velacycline Ropinirole* ReQuip Roxithromycin Rulid S Salazosulfapyridine = sulfasalazine Azaline, Azulfidine, S.A.S.-500, Salazopyrin Salbutamol (= Albuterol) Proventil, Novosalmol, Ventolin Salicylic acid Acnex, Sebcur, Soluver, Trans-Ver-Sal Sameterol Serevent Saquinavir Fortovase, Invirase Scopolamine Transderm Scop, Triptone Selegeline Carbex, Deprenyl, Eldepryl Senna Black Draught, Fletcher’s Castoria, Genna, Gentle Nature, Nytilax, Senokot, Senolax Sertindole* Serlect Sibutramine Reductil Sildenafil Viagra Simethicone Gas.X, Mylicon, Phazyme, Silain Simvastatin Zocor Sitosterol Sito-Lande Sotalol Sotacor Spectinomycin Trobicin Spiramicin Rovamycin, Selectomycin Spironolactone Aldactone Stavudine (d4T) Zerit Streptokinase Kabikinase, Streptase Streptomycin Strepolin, Streptosol Streptozocin Zanosar Succinylcholine Anectine, Quelicin, Succostrin Sucralfate Carafate, Sulcrate Sufentanil Sufenta Sulfacetamide AK-Sulf Forte, Cetamide, Sulamyd, Sulair, Sulfex, Sulten Sulfacytine Renoquid Sulfadiazine Microsulfon Sulfadoxine + Pyrimethamine Proklar Sulfamethoxazole Gamazole, Gantanol, Methanoxanol Sulfapyridine Dagenan Sulfisoxazole Gantrisin, Gulfasin Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Sulfasalazine Azaline, Azulfidine, Salazopyrin Sulfinpyrazone Anturan, Aprazone Sulprostone Nalador Sulthiame Ospolot Sumatriptan Imitrex T t-PA (= alteplase) Activase Tacrine Cognex Tacrolimus Prograf Tamoxifen Nolvadex, Tamofen Temazepam Euhypnos, Restoril Teniposide Vumon Terazosin Hytrin Terbutalin Brethine, Bricanyl Terfenadine Seldane Testosterone cypionate Androcyp, Andronate, Duratest, Testoject Testosterone enantate Andro, Delatestryl, Everone, Testone Testosterone propionate Testex Testerone undecanoate Andriol Tetracaine Anethaine, Pontocaine Tetryzoline (= tetrahydrozoline) Collyrium, Murine, Tyzine, Visine Thalidomide Contergan, Synovir Theophylline Aerolate, Bronkodyl, Constant-T, Elixophyllin, Quibron- T, Slo-bid, Somophyllin-T, Sustaire, Theolair, Uniphyl Thiabendazole Mintezol Thiamazole (= Methimazole) Tapazole, Mercazol Thiopental Pentothal, Trapanal Thio-TEPA Thiotepa Lederle Thrombin Thrombinar, Thrombostat Thyroxine Choloxin Tiagabine Gabitril Ticarcillin Ticar Ticlopidine Ticlid Timolol Blocadren, Timoptic Tinidazol Fasigyn(CH), Simplotan, Sorquetan Tinzaparin* Innohep Tirofiban Aggrastat Tizanidine Zanaflex Tobramycin Nebcin, Tobrex Tocainide Tonocard Tolbutamide Mobenol, Oramide, Orinase Tolcapone Tasmar Tolmetin Tolectin Tolnaftate Pitrex, Tinactin Tolonium chloride Klot, Toazul Tolterodine tartrate Detrol Topiramate Topamex Tramadol Tramal Trandolapril Mavik Tranexamic acid Cyklocapron Tranylcypromine Parnate 348 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 349 Trazodone Desyrel, Trialodine Triamcinolone Aristocort, Azmacort, Kenacort, Ledercort(CH), Volon Triamcinolone acetonide Adicort, Azmacort, Kenalog, Kenalone, Triam-A Triamterene Dyrenium Triazolam Halcion Trichlormethiazide Metahydrin, Naqua, Trichlorex Trifluoperazine Stelazine Trifluridine Viroptic Trihexipheidyl Aparkane, Artane, Tremin, Trihexane Triiodothyronine (= Liothyronine) Cytomel Trimethaphan Arfonad Trimethoprim Proloprim, Trimpex Triptorelin Decapeptyl Troglitazone Rezulin Tropicamide Mydriacyl, Mydral Tropisetron Navoban d-Tubocurarine Tubarine Tyrothricin Hydrotricin U Urokinase Abbokinase, Ukidan Ursodeoxycholic acid = ursodiol Actigall, Destolit, Ursofalk V Valacyclovir Valtrex Valproic Acid Depakene Valsartan Diovan Vancomycin Vancocin, Vancomycin CP Lilly Vasopressin Pitressin Vecuronium Norcuron Venlafaxine Effexor Verapamil Calan, Isoptin, Verelan Vidarabine Vira-A Vigabatrin* Sabril Vinblastine Velban, Velbe Vincamine Cerebroxine Vincristine Oncovin Viomycine Celiomycin,Vinactane, Viocin, Vionactane Vit. B12 Bay-Bee, Berubigen, Betalin 12, Cabadon, Cobex, Cyanoject, Cyomin, Pemavit, Redisol, Rubesol, Sytobex, Vibal Vit. B6 Bee Six, Hexa-Betalin, Pyroxine Vit. D Calciferol, Drisdol W Warfarin Coumadin, Panwarfin, Sofarin Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. X Xanthinol nicotinate Complamin Xylometazoline Chlorohist, Neosynephrine II, Sinutab, Sustaine Z Zafirlukast Accolate Zalcitabine Hivid Zidovudine Retrovir Zileuton Zyflo Zolpidem Ambien Zopiclone Amoban, Amovane, Imovane, Zimovane 350 Drug Name → Trade NameDrug Name → Trade Name 350 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 351 A Abbokinase Urokinase Acantex Ceftriaxone Accolate Zafirlukast Accupril Quinapril Acediur Captopril Acephen Paracetamol = acetami- nophen Acepril Captopril Acnex Salicylic acid Acthar ACTH Acthar Corticotropin Acti-B 12 Hydroxocobalamin Actigall Ursodeoxycholic acid = ursodiol Actimmune Interferon-γ Actiprophen Ibuprofen Activase t-PA (= alteplase) Actulin Repaglinide Acular Ketorolac Acutane Roche Isotretinoin Acylanid Acetyldigoxin Adalat Nifedipine Adapin Doxepin Adicort Triamcinolone aceto- nide Adrenalin Epinephrine Adriamycin Doxorubicin Adriblastin Doxorubicin Adrucil 5-Fluorouracil Advil Ibuprofen Aerobid Flunisolide Aerolate Theophylline Afibrin ε-Aminocaproic acid Afrin Oxymetazoline Aggrastat Tirofiban Airbron Acetylcysteine Akarpine Pilocarpine Akineton Biperiden Akinophyl Biperiden AK-Sulf Forte Sulfacetamide Alazine Hydralazine Albalon Naphazoline Albego Camazepam Albiotic Lincomycin Alcoban Flucytosine Aldactone Spironolactone Aldecin Beclomethasone Aldinamide Pyrazinamide Aldocorten Aldosterone Aldomet Methyl-Dopa Aldrox Aluminium hydroxide Alfenta Alfentanil Alflorone Fludrocortisone Alfoten Alfuzosin Algocalmin Metamizol (= Dipyrone) Algocor Gallopamil Algoverine Phenylbutazone Alkeran Melphalan Allerdryl Diphenhydramine Allerest Oxymetazoline Alloferin Alcuronium Alloprin Allopurinol Allvoran Diclofenac Almocarpine Pilocarpine Alocort Cortisol (Hydrocortiso- ne) Alophen Phenolphthalein Alopresin Captopril Alpha-redisol Hydroxocobalamin Altace Ramipril Altracin Bacitracin Alu-Tab Aluminium hydroxide Aludrin Isoprenaline (= Isopro- terenol) Alupent Metaproterenol Alzapam Lorazepam Amaryl Glimepiride Ambien Zolpidem Ambril Ambroxol Amcill Ampicillin Amen Medroxyprogesterone- acetate Americaine Benzocaine Amicar e-Aminocaproic acid Amidate Etomidate Amidonal Aprindine Amikin Amikacin Aminomux Pamidronate Drug Name Trade Name Drug Name Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Amitril Amitriptyline Ammuno Indomethacin Amoban Zopiclone Amodopa Methyl-Dopa Amovane Zopiclone Amoxil Amoxicillin Amphojel Aluminium hydroxide Amphozone Amphotericin B Amycor Bifonazole Anabactyl(A) Carbenicillin Anabolin Nandrolone Anacaine Benzocaine Anacin-3 Paracetamol = acetami- nophen Anacobin Cyanocobalamin Anaesthesin Benzocaine Anamid Kanamycin Anarexol Cyproheptadine Ancef Cefazolin Ancotil Flucytosine Andriol Testerone undecanoate Andro Testosterone enantate Androcur Cyproterone-acetate Androcyp Testosterone cypionate Android Methyltestosterone Androlone Nandrolone Andronate Testosterone cypionate Androviron Mesterolone Anectine Succinylcholine Anergan Promethazine Anethaine Tetracaine Anexate Flumazenil Ang-O-Span Glyceryltrinitrate (= nitroglycerin) Angionorm Dihydroergotamine Antilirium Physostigmine Antiminth Pyrantel Pamoate Antivert Meclizine (meclozine) Antrizine Meclizine (meclozine) Anturan Sulfinpyrazone Anzemet Dolasetron Aparkane Trihexiphenidyl Apaurin Diazepam Apocretin Etilefrine Aprazone Sulfinpyrazone Apresoline Hydralazine Aprobal Alprenolol Aprozide Hydrochlorothiazide Aptine Alprenolol Aralen Chloroquine Arava Leflunomide Arduan Pipecuronium Arfonad Trimethaphan Aristocort Triamcinolone Arm-a-Med Isoetharine Armazid Isoniazid Artane Trihexiphenidyl Arteoptic Carteolol Arterenol Noradrenalin (= Nore- pinephrine) Arthrisin Acetylsalicylic acid Articulose Prednisolone Arumil Amiloride Arvin Ancrod Arwin Ancrod Asacol Mesalamine Asadrine Acetylsalicylic acid Aspenon Aprindine Aspirin Acetylsalicylic acid Astramorph Moiphine sulfate Atabrine Quinacrine Atacand Candesartan Atempol Nitrazepam Atensine Diazepam Ativan Lorazepam Atromid-S Clofibrate Atropisol Atropine Atrovent Ipratropium Augmentin Clavulanic Acid + Amo- xicillin Aureotan Aurothioglucose Auromyose Aurothioglucose Aurorix Moclobemide Auxit Bromhexine Avapro Irbesartan Avicel Cellulose Avloclor Chloroquine Avlosulfone Dapsone Axid Nizatidine Azactam Aztreonam Azaline Salazosulfapyridine = sulfasalazine Azanin Azathioprine Azlin Azlocillin Azmacort Triamcinolone Azmacort Triamcinolone aceto- nide Azolid Phenylbutazone Azulfidine Salazosulfapyridine = sulfasalazine Azulfdine Sulfasalazine B Baciguent Bacitracin Bactidan Enoxacin 352 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 353 Bactocill Oxacillin Bactrim Cotrimoxazole Barbita Phenobarbital Baxedin Chlorhexidine Bay-Bee Vit. B12 Baycol Cerivastatin Bayotensin Nitrendipine Baypress Nitrendipine Beclovent Beclomethasone Beconase Beclomethasone Becotide Beclomethasone Bedoz Cyanocobalamine Bedriol Bifonazole Bee Six Vit. B6 Pyridoxine Befizal Bezafbrate Benadryl Diphenhydramine Benemid Probenecid Berofor alpha 2 Interferon-a2 Berotec Fenoterol Berubigen Vit. B12 Bestcall Cefmenoxime Betadran Bupranolol Betadrenol Bupranolol Betagon Mepindolol Betalin 12 Vit. B12 Betaloc Metoprolol Betapen-VK Pencillin V Betoptic Betaxolol Bextra Bucindolol* Bezalip Bezafibrate Bezatol Bezafibrate Biaxin Clarithromycin Bicillin Benzathine-Penicillin G Bicol Bisacodyl Biltricide Praziquantel Biogastrone Carbenoxolone Bioplex Carbenoxolone Bisolvon Bromhexine Bisorine Isoetharine Black Draught Senna Blenoxane Bleomycin Blocadren Timolol Bofedrol Ephedrine Bolvidon Mianserin Bonamine Meclizine (meclozine) Bonpyrin Metamizol (= Dipyrone) Bopen-VK Pencillin V Borotropin Atropine Brethine Terbutalin Brevibloc Esmolol Brevital Methohexital Bricanyl Terbutalin Briclin Amikacin Bromo-Seltzer Paracetamol = acetami- nophen Bronalide Flunisolide Bronchaid Epinephrine Bronchopront Ambroxol Bronkodyl Theophylline Bronkosol Isoetharine Broxalax Bisacodyl Bumex Bumetanide Bunitrolol Bumetanide Buprene Buprenorphine Burinex Bumetanide Buscopan N-Butyl-scopolamine Buspar Buspirone Butagen Phenylbutazone Butazolidin Phenylbutazone Butylone Pentobarbital C C-Pak Doxycycline Cabadon Vit. B12 Calan Verapamil Calciferol Vit.D Calcimer Calcitonin Calcimux Etidronate Calderol Calcifediol Calsan Calcium carbonate Calsynar Calcitonin Caltidren Carteolol Caltrate Calcium carbonate Camoquin Amodiaquine Canesten Clotrimazole Capastat Capreomycin Capoten Captopril Capramol ε-Aminocaproic acid Caprolin Capreomycin Carafate Sucralfate Carbex Selegeline Carbocaine Mepivacaine Carbolite Lithium carbonate Cardene Nicardipine Cardioqin Quinidine Cardiorhythmino Ajmaline Cardizem Diltiazem Cardura Doxazosin Carduran Doxazosin Caridian Mepindolol Carindapen Carbenicillin Carteol Carteolol Catapres Clonidine Cedocard Isosorbide dinitrate Cedur Bezafibrate Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. CeeNu Lomustine Cefmax Cefmenoxime Cefobis Cefmenoxime Cefoperazone Cefmenoxime Ceftin Cefuroxime axetil Celevac Methylcellulose Celiomycin Viomycine CellCept Mycophenolate Mofetil Cellothyl Methylcellulose Cemix Cefmenoxime Centrax Prazepam Cepexin(A) Cephalexin Cephulac Lactulose Ceporex Cephalexin Cerebid Papaverine Cerebroxine Vincamine Cerespan Papaverine Cerubidine Daunorubicin Cesamet Nabilone Cesplon Captopril Cetamide Sulfacetamide Chenix Chenodeoxycholic acid Chlor-hex Chlorhexidine Chloraminophene Chlorambucil Chlorohist Xylometazoline Chloromycetin Chloramphenicol Chloroptic Chloramphenicol Cholestabyl Colestipol Cholestid Colestipol Choloxin Thyroxine Chorex HCG (= chorionic gona- dotropin) Choron HCG (= chorionic gona- dotropin) Chronulac Lactulose Cibacalcin Calcitonin Cidomycin Gentamicin Cillimycin Lincomycin Cimetrin Erythromycin-propio- nate Cin-Quin Quinidine Cipro Ciprofloxacin Ciprobay Ciprofloxacin Circupon Etilefrine Citanest Prilocaine Citrucel Methylcellulose Claforan Cefotaxime Clamoxyl Amoxicillin Claripex Clofibrate Claritin Loratidine Clasteon Clodronate* Cleocin Clindamycin Clobazam Clindamycin Clomid Clomiphene Clonopin Clonazepam Clont Metronidazole Clopra Metoclopramide Clotrimaderm Clotrimazole Cloxacillin Clotrimazole Clozan Clotiazepam Clozaril Clozapine Cobex Vit. B12 Cocillin-VK Pencillin V Codelsol Prednisolone Codicept Codeine Cogentin Benztropine Cognex Tacrine Coleb 5-Isosorbide mono- nitrate Colectril Amiloride Collyrium Tetryzoline (= tetrahy- drozoline) Cologel Methylcellulose Complamin Xanthinol nicotinate Comprecin Enoxacin Comtan Entacapone* Concor Bisoprolol Conducton Carazolol Constant-T Theophylline Contergan Thalidomide Coradus Isosorbide dinitrate Cordarex Amiodarone Cordarone Amiodarone Coreg Carvedilol Corgal Gallopamil Corgard Nadolol Coricidin Oxymetazoline Corindblan Mepindolol Corlopam Fenoldopam Coronex Isosorbide dinitrate Correctol Phenolphthalein Cortalone Prednisolone Cortate Cortisol (Hydrocortiso- ne) Cortef Cortisol (Hydrocortiso- ne) Cortelan Cortisone Cortenema Cortisol (Hydrocortiso- ne) Cortigel Corticotropin Cortogen Cortisone Cortone Cortisone Cortrophin Corticotropin Corvaton Molsidomine Coscopin Noscapine (= Narcoti- ne) 354 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 355 Coscotab Narcotine (= Noscapi- ne) Coscotab Noscapine (= Narcoti- ne) Cosmegen Actinomycin D Coumadin Warfarin Coversum Perindopril Cozaar Losartan Crixivan Indinavir Cryspen Penicillin G Crystodigin Digitoxin Cuemid Colestyramine Cuprimine D-Penicillamine Cutivate Fluticasone Cuvalit Lisuride Cyanoject Vit. B 12 Cyklocapron Tranexamic acid Cyomin Vit. B 12 Cystospaz-M Hyoscyamine sulfate Cytomel Triiodothyronine (= Liothyronine) Cytosar Cytarabine Cytotec Misoprostol Cytovene Ganciclovir Cytoxan Cyclophosphamide D D-Tabs Cholecalciferol D.E.H.45 Dihydroergotamine DDAVP Desmopressin Dagenan Sulfapyridine Dalacin Clindamycin Dalcaine Lidocaine Dalmane Flurazepam Daneral Pheniramine Dantrium Dantrolene Daonil Glibenclamide (= gly- buride) Daraprim Pyrimethamine Datril Paracetamol = acetami- nophen Daunoblastin Daunorubicin Deca-Durabolin Nandrolone Decadron Dexamethasone Decapeptyl Triptorelin Decapryn Doxylamine Dedrogyl Calcifediol Degest-2 Naphazoline Delapav Papaverine Delatestryl Testosterone enantate Delestrogen Estradiol-valerate Delta-Cortef Prednisolone Deltapen Penicillin G Deltastab Prednisoloneduisolme Demerol Meperidine Demerol Pethidine = Meperidine Denavir Penciclovir Dendrid Idoxuridine Depakene Valproic Acid Depen D-Penicillamine Depixol Flupentixol Depo-Provera Medroxyprogesterone- acetate Deprenyl Selegeline Deronil Dexamethasone Desferal Deferoxamine Desoxyn Methamphetamine Destolit Ursodeoxycholic acid = ursodiol Desuric Benzbromarone Desyrel Trazodone Detensiel Bisoprolol Detensol Propranolol Detrol Tolteridine tartrate Dexedrine d-Amphetamine Dey-Lute Isoetharine DiaBeta Glibenclamide (= gly- buride) Diabex Metformin Diamox Acetazolamide Diapid Lypressin Diaqua Hydrochlorothiazide Diarsed Diphenoxylate Diastat Diazepam Dibenzyline Phenoxybenzamine Diclocil Dicloxacillin Diclophlogont Diclofenac Diflucan Fluconazole Digacin Digoxin Digibind Digoxin immune FAB Digicor Digitoxin Digimerck Digitoxin Digitaline Digitoxin Dihydergot Dihydroergotamine Dihyzin Dihydralazine Dilantin Phenytoin Dilaudid Hydromorphone Dimetab Dimenhydrinate Dinaplex Flunarizine Diodronel Etidronate Dioval Estradiol-valerate Diovan Valsartan Diphenasone Dapsone Diphos Etidronate Diprivan Propofol Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Distraneurin Clomethiazole Diuchlor Hydrochlorothiazide Divarine Metamizol (= Dipyrone) Divegal Dihydroergotamine Dixarit Clonidine Dizac Diazepam Dobutrex Dobutamine Dolantin Pethidine = Meperidine Dolophine Methadone Donnagel-MB Kaolin + Pectin (= atta- pulgite) Dopaidan Levodopa Dopamet Methyl-Dopa Dopar Levodopa Dopastat Dopamine Dopergin Lisuride Doral Quazepam Doryl Carbachol Dowmycin Erythromycin-estolate Doxicin Doxycycline Doxylamine Doxycycline Dramamine Dimenhydrinate Drisdol Ergocalciferol Vit. D Dristan Oxymetazoline Drogenil Flutamide Droleptan Droperidol Dulcolax Bisacodyl Duoralith Lithium carbonate Duphalac Lactulose Duracoron Molsidomine Duralutin Hydroxyprogesterone caproate Duramorph Morphine sulfate Duranest Etidocaine Duratest Testosterone cypionate Durazanil Bromazepam Durolax Bisacodyl Dymenate Dimenhydrinate DynaCirc Isradipine Dynapen Dicloxacillin Dynaprin Imipramine Dyneric Clomiphene Dyrenium Triamterene E Econopred Prednisolone Enbrel Etanercept E-mycin Erythomcyin Ecostatin Econazole Ecotrin Acetylsalicylic acid Edecrin Ethacrynic acid Efedron Ephedrine Effectin Bitolterol Effexor Venlafaxine Effontil Etilefrine Effortil Etilefrine Effudex 5-Fluorouracil Effurix 5-Fluorouracil Elantan 5-Isosorbide mono- nitrate Elavil Amitriptyline Eldepryl Selegeline Elimite Permethrin Elixophyllin Theophylline Emcor Bisoprolol Emex Metoclopramide Endak Carteolol Endep Amitriptyline Endophleban Dihydroergotamine Endoxan Cyclophosphamide Enoram Enoxacin Enovil Amitriptyline Entromone HCG (= chorionic gona- dotropin) Entrophen Acetylsalicylic acid EpiPen Epinephrine Epifin Epinephrine Epimorph Morphine sulfate Epinal Epinephrine Epitol Carbamazepine Epitrate Epinephrine Epivir Lamivudine (3TC) Epogen Erythropoietin (= epoe- tin alfa) Eporal Dapsone Ergocalm Lormetazepam Ergomar Ergotamine Ergotrate Ergonovine Ergotrate Maleate Ergometrine (= Ergono- vine) Eridan Diazepam Ermalate Ergometrine (= Ergono- vine) Eryc Erythromcyin Erymycin Erythromycin-stearate Erythrocin Erythromycin-estolate Erythromid Erythomcyin Esidrex Hydrochlorothiazide Eskalith Lithium carbonate Espotabs Phenolphthalein Estinyl Ethinylestradiol Estrace Estradiol Ethrane Enflurane Ethyl Adrianol Etilefrine Etibi Ethambutol 356 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 357 Euciton Domperidone* Eudemine Diazoxide Euglucon Glibenclamide (= gly- buride) Euhypnos Temazepam Eulexin Flutamide Eunal Lisuride Evac-U-Lax Phenolphthalein Evac-U-gen Phenolphthalein Everone Testosterone enantate Evipal Hexobarbital Evista Raloxifene Evoxin Domperidone* Ex-Lax Phenolphthalein F F-Cortef Fludrocortisone Fabrol Acetylcysteine Factrel Gonadorelin Fansidar Pyrimethamine + Sulfa- doxine Fasigyn(CH) Tinidazol Faverin Fluvoxamine Felbatol Felbamate Felden Piroxicam Femazole Metronidazole Feminone Ethinylestradiol Femogex Estradiol-valerate Femotrone Progesterone Fertodur Cyclofenil Feverall Metamizol (= Dipyrone) Fiblaferon 3 Interferon-b Fibocil Aprindine Flagyl Metronidazole Flavoquine Amodiaquine Flaxedil Gallamine Fletcher’s Castoria Senna Flixonase Fluticasone Flonase Fluticasone Florinef Fludrocortisone Flovent Fluticasone Floxifral Fluvoxamine Fluagel Aluminium hydroxide Fluanxol Flupentixol Fluclox Flucloxacillin Flugeral Flunarizine Fluothane Halothane Foldine Folic acid Folex Methotrexate Follutein HCG (= chorionic gona- dotropin) Folvite Folic acid Fontego Bumetanide Forane Isoflurane Fordiuran Bumetanide Fortaz Ceftazidime Fortovase Saquinavir Fortral Pentazocine Fortum Ceftazidime Fosamax Alendronate Foscavir Foscarnet Fragmin Dalteparin Fraxiparine Nadroparin* Frisium Clobazam Fulvicin Griseofulvin Fungilin Amphotericin B Fungizone Amphotericin B Fusid Furosemide G Gabitril Tiagabine Gabren(e) Progabide Gamazole Sulfamethoxazole Ganal Fenfluramine Ganphen Promethazine Gantanol Sulfamethoxazole Gantrisin Sulfisoxazole Garamycin Gentamicin Gardenal Phenobarbital Gas. X Simethicone Gastrozepin Pirenzepine Gelafundin Gelatin-colloids Genna Senna Gentle Nature Senna Geopen Carbenicillin Gestafortin Chlormadinone acetate Gesterol L.A. Hydroxyprogesterone caproate Gilurytmal Ajmaline Glaupax Acetazolamide Glucophage Metformin Glucotrol Glipizide Gonic HCG (= chorionic gona- dotropin) Gramoderm Gramicidin Grisovin Griseofulvin Gubernal Alprenolol Gulfasin Sulfisoxazole Gumbix Aminomethylbenzoic acid Gyne-Lotrimin Clotrimazole Gynergen Ergotamine Gyno-Pevaryl Econazole Gyno-Travogen Isoconazole Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. H Haemaccel Gelatin-colloids Halcion Triazolam Haldol Haloperidol Halfan Halofantrine Hemineurin Clomethiazole Hepalean HCG (= chorionic gona- dotropin) Heparin HCG (= chorionic gona- dotropin) Herplex Idoxuridine Hespan Hetastarch Hydroxy- ethyl starch (HES) Hexa-Betalin Pyridoxine Vit. B6 Hexadrol Dexamethasone Hexit Chlorhexidine Hidroferol Calcifediol Hismanal Astemizole Hivid Zalcitabine Honvol Diethylstilbestrol Humalog Insulin Humatin Paromomycin Humulin Insulin Hybolin Decanoate Nandrolone Hydeltrasol Prednisolone Hyderm Cortisol (Hydrocortiso- ne) Hydromal Hydrochlorothiazide Hydromedin Ethacrynic acid Hydrotricin Tyrothricin Hygroton Chlorthalidone Hylutin Hydroxyprogesterone caproate Hymorphan Hydromorphone Hyocort Cortisol (Hydrocortiso- ne) Hyoscin-N-Butyl- bromid N-Butyl-scopolamine Hyperstat Diazoxide Hypertensin Angiotensin II Hypertil Captopril Hypnosedon Flunitrazepam* Hyroxon Hydroxyprogesterone caproate Hyskon Dextran Hytrin Terazosin I I-Pilopine Pilocarpine Ifex Ifosfamide Ifosfamide Idoxuridine Iktorivil Clonazepam Iletin Insulin Ilosone Erythromycin-estolate Imitrex Sumatriptan Imodium Loperamide Imovane Zopiclone Impril Imipramine Imuran Azathioprine Imurek Azathioprine Inapsine Droperidol Inderal Propranolol Indocid Indomethacin Indocin Indomethacin Indome Indomethacin Inflamase Prednisolonechnisolove Inhibace Cilazapril Inhiston Pheniramine Innohep Tinzaparin* Innovar Fentanyl + Droperidol Inocor Amrinone Insommal Diphenhydramine Intal Cromoglycate Integriline Eptifibatide Intron A Interferon-a2b Intropin Dopamine Invirase Saquinavir Isicom Carbidopa + Levodopa Ismelin Guanethidine Ismo 5-Isosorbide mono- nitrate Isocaine Mepivacaine Isoptin Verapamil Isopto-Carpine Pilocarpine Isordil Isosorbide dinitrate Isotamine Isoniazid Isoten Bisoprolol Isotol Mannitol Isuprel Isoprenaline (= Isopro- terenol) Itrop Ipratropium J Janimine Imipramine K Kabikinase Streptokinase Kabolin Nandrolone Kanrenol Canrenone Kantrex Kanamycin 358 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 359 Kaopectate Kaolin + Pectin (= atta- pulgite) Kaopectate II Loperamide Karil Calcitonin Keflex Cefalexin Keflex Cephalexin Keftab Cefalexin Kemadrin Procyclidine Kenacort Triamcinolone Kenalog Triamcinolone aceto- nide Kenalone Triamcinolone aceto- nide Kerecid Idoxuridine Kerlone Betaxolol Kertasin Etilefrine Ketalar Ketamine Ketzol Cefazolin Key-Pred Prednisolone Kildane Lindane Klebcil Kanamycin Klot Tolonium chloride Konakion Phytomenadione Korostatin Nystatin Kryptocur Gonadorelin Kwell Lindane Kytril Granisetron L Lacril Methylcellulose Lamiazid Isoniazid Lamictal Lamotrigine Lampren Clofazimine Lanacillin Penicillin G Lanacillin-VK Penicillin V Lanicor Digoxin Lanoxin Digoxin Largactil Chlorpromazine Lariam Mefloquine Larodopa Levodopa Lasix Furosemide Laxanin Bisacodyl Laxbene Bisacodyl Lectopam Bromazepam Ledercillin VK Pencillin V Ledercort(CH) Triamcinolone Lembrol Diazepam Lendorm(A) Brotizolam Lendormin Brotizolam Lenoxin Digoxin Lentin Carbachol Lescol Noradrenalin (= Nore- pinephrine) Levoprome Levomepromazine Levsin Hyoscyamine sulfate Lexotan Bromazepam Lidopen Lidocaine Likuden Griseofulvin Lincocin Lincomycin Lindane Hexachlorophane Lioresal Baclofen Lipitor Atorvastatin Liquamar Phenprocoumon Liquemin HCG (= chorionic gona- dotropin) Litec Pizotifen = Pizotyline Lithane Lithium carbonate Lithobid Lithium carbonate Lithotabs Lithium carbonate Lodine Etodolac Lomotil Diphenoxylate Loniten Minoxidil Looser Bupranolol Lopantrol Lorcainide Lopid Gemfibrozil Lopirin Captopril Lopressor Metoprolol Loramet Lormetazepam Loraz Lorazepam Lorinal Chloralhydrate Lorivox Lorcainide Losec Omeprazole Losporal Cephalexin Lotensin Benazepril Lovelco Probucol Lovenox Enoxaparin Lozide Indapamide Lozol Indapamide Ludiomil Maprotiline Lupron Leuprorelide Luvox Fluvoxamine Lynoral Ethinylestradiol Lyophrin Epinephrine Lysenyl Lisuride M Macrobin Clostebol Madopar Levodopa + Benserazi- de Madopar (plus Levodopa) Benserazide Malgesic Phenylbutazone Mallergan Promethazine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Marcumar Phenprocoumon Marinol Dronabinol Marmine Dimenhydrinate Marvelon Desogestrel + Ethinyle- stradiol Mavik Trandolapril Maxeran Metoclopramide Maxolan Metoclopramide Mazepine Carbamazepine Mazonor Mazindol Meclomen Meclofenamate Mefoxin Cefoxitin Megacillin Benzathine-Penicillin G Megaphen Chlorpromazine Melipramin Imipramine Menophase Mestranol Mercazol Thiamazole (= Methi- mazole) Mesnex Mesna Mestinon Pyridostigmine Metacen Indomethacin Metahydrin Trichlormethiazide Metalone Prednisolone Metandren Methyltestosterone Metaprel Metaproterenol Metenarin Methylcellulose Methadose Methadone Methampex Methamphetamine Methanoxanol Sulfamethoxazole Methofane Methoxyflurane Methylergobrevin Methylcellulose Methylergometrine Methylcellulose Meticorten Prednisone Metilon Metamizol (= Dipyrone) Metreton Prednisolone Metronid Metronidazole Mevacor Lovastatin Meval Diazepam Mevaril Amitriptyline Mevinacor Lovastatin Mexate Methotrexate Mexitil Mexiletin Mezlin Mezlocillin Micatin Miconazole Micronase Glibenclamide (= gly- buride) Micronor Norethisterone Microsulfon Sulfadiazine Midamor Amiloride Mielucin Busulfan Migril Ergotamine Minipress Prazosin Minirin Desmopressin Minocin Minocycline Minprog Alprostadil (= PGE1) Minprostin F2a Dinoprost Mintezol Thiabendazole Miocarpine Pilocarpine Miostat Carbachol Mithracin Mithramycin, Plicamy- cin Mitosan Busulfan Mobenol Tolbutamide Modane Phenolphthalein Moditen Fluphenazine Moduret Amiloride + Hydrochlo- rothiazide Mogadon Nitrazepam Molsidolat Molsidomine Monistat Miconazole Monitan Acebutolol Monomycin Erythromycin-succina- te Monopril Fosinopril Moronal Amphotericin B Morphitec Morphine hydrochlori- de Mosegor Pizotifen = Pizotyline Motilium Domperidone* Motrin Ibuprofen Moxacin Amoxicillin Mucomyst Acetylcysteine Mucosolvan Ambroxol Murine Tetryzoline (= tetrahy- drozoline) Murocel Methylcellulose Mustargen Mechlorethamine Mutabase Diazoxide Myambutol Ethambutol Mycelex Clotrimazole Mycifradin Neomycin Myciguent Neomycin Mycobutin Rifabutin Mycospor Bifonazole Mycosporan Bifonazole Mycostatin Nystatin Mydral Tropicamide Mydriacyl Tropicamide Myidone Primidone Mykinac Nystatin Myleran Busulfan Mylicon Simethicone Myobid Papaverine Mysoline Primidone 360 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 361 N Nacom Carbidopa + Levodopa Nadopen-V Pencillin V Naftin Naftifin Nalador Sulprostone Nalcrom Cromoglycate Nalfon Fenoprofen Nalgesic Fenoprofen Nalorex Naltrexone Naprosyn Naproxen Naqua Trichlormethiazide Narcan Naloxone Narcaricin Benzbromarone Narcozep Flunitrazepam* Narkotan Halothane Nasalide Flunisolide Natrilix Indapamide Natulan Procarbazine Nautamine Diphenhydramine Nauzelin Domperidone* Navidrix Cyclopenthiazide Naxen Naproxen Nebcin Tobramycin Negram Nalidixic acid Nembutal Pentobarbital Neo Epinin Isoprenaline (= Isopro- terenol) Neo-Codema Hydrochlorothiazide Neo-Mercazole Carbimazole Neo-Synephrine Oxymetazoline Neo-Thyreostat Carbimazole Neogel Carbenoxolone Neoral Cyclosporine Neosynephrine II Xylometazoline Nepresol Dihydralazine Netromycin Netilmicin Neurontin Gabapentin Niclocide Niclosamide Nigalax Bisacodyl Nilstat Nystatin Nilurid Amiloride Nimotop Nimodipine Nipride Nitroprusside sodium Nitrocap Glyceryltrinitrate (= nitroglycerin) Nitrogard Glyceryltrinitrate (= nitroglycerin) Nitroglyn Glyceryltrinitrate (= nitroglycerin) Nitrolingual Glyceryltrinitrate (= nitroglycerin) Nitrong Glyceryltrinitrate (= nitroglycerin) Nitropress Nitroprusside sodium Nitrostat Glyceryltrinitrate (= nitroglycerin) Nix Permethrin Nizoral Ketoconazol Noan Diazepam Noctamid Lormetazepam Noctec Chloralhydrate Nogram Nalidixic acid Noludar Methylprylon Nolvadex Tamoxifen Nor-Q D Norethindrone Norcuron Vecuronium Norlutin Norethindrone Normiflo Ardeparin Normodyne Labetalol Normurat Benzbromarone Noroxin Norfloxacin Norpace Disopyramide Norpramin Desipramine Norquen Mestranol Norval Mianserin Norvir Ritonavir Novalgin Metamizol (= Dipyrone) Novamin Amikacin Novamoxin Amoxicillin Novantrone Mitoxantrone Novarectal Pentobarbital NovoNorm Repaglinide Novocaine Procaine Novoclopate Clorazepate Novodigoxin Digoxin Novolin Insulin Novomedopa Methyl-Dopa Novopen-VK Pencillin V Novopurol Allopurinol Novorythro Erythromycin-estolate Novosalmol Salbutamol (= Albute- rol) Novotrimel Cotrimoxazole Nozinan Levomepromazine Nu-Cal Calcium carbonate Nubain Nalbuphine Nulicaine Lidocaine Nuprin Ibuprofen Nuran Cyproheptadine Nuromax Doxacurium Nydrazid Isoniazid Nystex Nystatin Nytilax Senna Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. O O-V Statin Nystatin Octapressin Felypressin Oculinum Botulinum Toxin Type A Ocupress Carteolol Omifin Clomiphene Omnipen Amphotericin B Oncovin Vincristine Ondena Daunorubicin Ondogyne Cyclofenil Ondonid Cyclofenil Ophthosol Bromhexine Opticrom Cromoglycate Optipranolol Metipranolol Oragest Medroxyprogesterone- acetate Oramide Tolbutamide Orasone Prednisone Oretic Hydrochlorothiazide Orgaran Danaparoid Orinase Tolbutamide Orthoclone OKT3 Muromonab-CD3 Osmitrol Mannitol Ospolot Sulthiame Ossiten Clodronate* Ostac Clodronate* Ovastol Mestranol Oxistat Oxiconazole Oxpam Oxazepam P POR 8 Ornipressin Pamba Aminomethylbenzoic acid Pamelor Nortriptyline Panasol Prednisone Panimit Bupranolol Pantolac Pantoprazole* Panwarfin Warfarin Papacon Papaverine Paralgin Metamizol (= Dipyrone) Paraplatin Carboplatin Paraxin Chloramphenicol Parcillin Penicillin G Paregoric Opium Tincture (lauda- num) Parlodel Bromocriptine Parnate Tranylcypromine Paromomycin Paracetamol = acetami- nophen Parsitan Ethopropazine Parsitol Ethopropazine Partergin Methylcellulose Partusisten Fenoterol Parvolex Acetylcysteine Pathocil Dicloxacillin Pavabid Papaverine Pavadur Papaverine Paveral Codeine Pavulon Pancuronium Paxil Paroxetine Pectokay Kaolin + Pectin (= atta- pulgite) Pediapred Prednisolone Pemavit Vit. B12 Penapar VK Pencillin V Penbec-V Pencillin V Penbritin Amphotericin B Pensorb Penicillin G Pentanca Pentobarbital Pentasa Mesalamine Pentazine Promethazine Penthrane Methoxyflurane Pentids Penicillin G Pentothal Thiopental Pepcid Famotidine Pepdul Famotidine Pepto-Bismol Bismuth subsalicylate Peptol Cimetidine Pergotime Clomiphene Periactin Cyproheptadine Peridon Domperidone* Peritol Cyproheptadine Permanone Permethrin Permapen Penicillin G Permax Pergolide Pertofran Desipramine Petinimid Ethosuximide Pfizerpin Penicillin G Phazyme Simethicone Phenazine Promethazine Phenergan Promethazine Phospholine Iodide Ecothiopate Physoseptone Methadone Pilokair Pilocarpine Pipracil Piperacillin Pitocin Oxytocin Pitressin ADH (= Vasopressin) Pitrex Tolnaftate Plak-out Chlorhexidine Plaquenil Hydroxychloroquine Platinex Cisplatin 362 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 363 Platinol Cisplatin Plavix Clopidogrel Plendil Felodipine Polycillin Amphotericin B Ponderal Fenfluramine Pondimin Fenfluramine Pontocaine Tetracaine Posicor Mibefradil Prandin Repaglinide Pravachol Pravastatin Pravidel Bromocriptine Predate Prednisolone Predcor Prednisolone Precose Acarbose Pregnesin HCG (= chorionic gona- dotropin) Pregnyl HCG (= chorionic gona- dotropin) Prelone Prednisolone Prenormine Atenolol Prepidil Dinoprostone Presinol Methyl-Dopa Pressunic Dihydralazine Presyn ADH (= Vasopressin) Prevacid Lansoprazole Primacor Milrinone Primaquine Primaquine Principen Amphotericin B Prinivil Lisinopril Privine Naphazoline Pro-Depo Hydroxyprogesterone caproate Probalan Probenecid Procan SR Procainamide Procardia Nifedipine Procorum Gallopamil Procytox Cyclophosphamide Profasi HCG (= chorionic gona- dotropin) Progestasert Progesterone Proglicem Diazoxide Prograf Tacrolimus Progynon B Estradiol-benzoate Progynova Estradiol-valerate Proklar Sulfamethizole Prolixan Azapropazone Prolixin Fluphenazine Prolopa Levodopa + Benserazi- de Proloprim Trimethoprim Prometh Promethazine Promine Procainamide Pronestyl Procainamide Propasa 5-Aminosalicylic acid Propecia Finasteride Propulsid Cisapride Propyl-Thyracil Propylthiouracil Prorex Promethazine Proscar Finasteride Prostaphlin Oxacillin Prostarmon Dinoprost Prostigmin Neostigmine Prostin E2 Dinoprostone Prostin F2 Dinoprost Prostin VR Alprostadil (= PGE1) Protostat Metronidazole Protrin Septra Cotrimoxazole Proventil Salbutamol (= Albute- rol) Provigan Promethazine Proviron Mesterolone Prozac Fluoxetine Prulet Phenolphthalein Pulmicort Budesonide Pulsamin Etilefrine Purinethol 6-Mercaptopurine Purodigin Digitoxin Pyopen Carbenicillin Pyrilax Bisacodyl Pyronoval Acetylsalicylic acid Pyroxine Pyridoxine, Vit. B6 Q Quelicin Succinylcholine Questran Colestyramine Quibron-T Theophylline Quinachlor Chloroquine Quinalan Quinidine Quinaminoph Quinine Quinamm Quinine Quine Quinine Quinidex Quinidine Quinite Quinine Quinora Quinidine R RU 486 Mifepristone ReQuip Ropinirole* Rebetol Ribavirin Reclomide Metoclopramide Rectocort Cortisol (Hydrocortiso- ne) Redisol Vit. B12 Refludan Lepirudin Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Refobacin Gentamicin Regitin Phentolamine Reglan Metoclopramide Regonol Pyridostigmine Relefact Gonadorelin Remicade Infliximab Remivox Lorcainide Remsed Promethazine Renoquid Sulfacytine ReoPro Abciximab Reomax Ethacrynic acid Rescriptor Delavirdine Restoril Temazepam Retardin Diphenoxylate Retrovir Azidothymidine, Zido- vudine Reverin Rolitetracyclin Revia Naltrexone Rezipas 5-Aminosalicylic acid Rezulin Troglitazone Rhinalar Flunisolide Rhumalgan Diclofenac Rhythmin Procainamide Rhythmol Propafenone Ridaura Auranofin Rifadin Rifampin Rimactan Rifampin Rimifon Isoniazid Ritalin Methylphenidate Rivotril Clonazepam Rize Clotiazepam Roaccutan Isotretinoin Robinul Glycopyrrolate Rocaltrol Calcitriol Rocephin Ceftriaxone Roferon A3 Interferon-a2a Rogaine Minoxidil Rogitin Phentolamine Rohypnol Flunitrazepam* Rolisox Isoxsuprine Romazicon Flumazenil Rovamycin Spiramicin Rowasa Mesalamine Roxanol Moiphine sulfate Rubesol Vit. B12 Rubion Cyanocobalamin Rubramin Cyanocobalamin Rulid Roxithromycin Ryegonovin Methylcellulose Rynacrom Cromoglycate Rythmodan Disopyramide S S.A.S.-500 Salazosulfapyridine = sulfasalazine Sabril Vigabatrin* Salazopyrin Salazosulfapyridine = sulfasalazine Salimid Cyclopenthiazide Saltucin Butizid Sandimmune Cyclosporine Sandomigran Pizotifen = Pizotyline Sandostatin Octreotide Sandril Reserpine Sang-35 Cyclosporine Sanocrisin Cyclofenil Sanodin Carbenoxolone Sanorex Mazindol Sansert Methysergide Satric Metronidazole Saventrine Isoprenaline (= Isopro- terenol) Scabene Lindane Sebcur Salicylic acid Sectral Acebutolol Securopen Azlocillin Seguril Furosemide Seldane Terfenadine Selectomycin Spiramicin Sembrina Methyl-Dopa Senokot Senna Senolax Senna Serax Oxazepam Serenace Haloperidol Serevent Sameterol Serlect Sertindole* Sernyl Phencyclidine Serono-Bagren Bromocriptine Serophene Clomiphene Serpalan Reserpine Serpasil Reserpine Sertan Primidone Sexovid Cyclofenil Sibelium Flunarizine Silain Simethicone Simplene Epinephrine Simplotan Tinidazol Simulect Basiliximab Sinarest Oxymetazoline Sinemet Levodopa + Carbidopa Sinequan Doxepin Singulair Montelukast Sintrom Acenocoumarin (= Ni- coumalone) 364 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 365 Sinutab Xylometazoline Sirtal Carbamazepine Sito-Lande Sitosterol Skleromexe Clofibrate Slo-bid Theophylline Sobelin Clindamycin Sofarin Warfarin Soldactone Canrenone Solfoton Phenobarbital Solganal Aurothioglucose Solu-Contenton Amantadine Soluver Salicylic acid Somnos Chloralhydrate Somophyllin-T Theophylline Sopamycetin Chloramphenicol Soprol Bisoprolol Sorbitrate Isosorbide dinitrate Sorquetan Tinidazol Sotacor Sotalol Spametrin-M Methylcellulose Spersadex Dexamethasone Spersanicol Chloramphenicol Spirocort Budesonide Sporanox Itroconazole Sprecur Buserelin Statex Morphine sulfate Stelazine Trifluoperazine Steranabol Clostebol Stimate Desmopressin Stoxil Idoxuridine Strepolin Streptomycin Streptase Streptokinase Streptosol Streptomycin Stresson Bumetanide Suacron Carazolol Sublimaze Fentanyl Succostrin Succinylcholine Sufenta Sufentanil Sulair Sulfacetamide Sulamyd Sulfacetamide Sular Nisoldipine Sulcrate Sucralfate Sulfabutin Busulfan Sulfex Sulfacetamide Sulmycin Gentamicin Sulpyrin Metamizol (= Dipyrone) Sulten Sulfacetamide Supasa Acetylsalicylic acid Suprarenin Epinephrine Suprax Cefixime Suprefact Buserelin Surfactal Ambroxol Sustaine Xylometazoline Sustaire Theophylline Suxinutin Ethosuximide Symmetrel Amantadine Synatan d-Amphetamine Synkayvit Menadione Synovir Thalidomide Syntocinon Oxytocin Sytobex Hydroxocobalamin Sytobex Vit. B12 T Tacef Cefmenoxime Tacicef Ceftazidime Tagamet Cimetidine Talwin Pentazocine Tambocor Flecainide Tamofen Tamoxifen Tapazole Methimazole Tapazole Thiamazole (= Methi- mazole) Taractan Chlorprothixene Tarasan Chlorprothixene Tardigal Digitoxin Tardocillin Benzathine-Penicillin G Tarivid Ofloxacin Tasmar Tolcapone Tavist Clemastine Taxol Paclitaxel Taxotere Docetaxel Tebrazid Pyrazinamide Teebaconin Isoniazid Tegison Etretinate Tegopen Clotrimazole Tegretol Carbamazepine Telemin Bisacodyl Temgesic Buprenorphine Tempra Paracetamol = acetami- nophen Tenalin Carteolol Tenex Guanfacine Tenormin Atenolol Tensium Diazepam Tensobon Captopril Testex Testosterone propiona- te Testoject Testosterone cypionate Testone Testosterone enantate Testred Methyltestosterone Teveten Eprosartan Theelol Estratriol = Estriol Theolair Theophylline Thesit Polidocanol Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Thiotepa Lederle Thio-TEPA Thorazine Chlorpromazine Thrombinar Thrombin Thrombostat Thrombin Ticar Ticarcillin Ticlid Ticlopidine Tienor Clotiazepam Tigason Etretinate Tilade Nedocromil Timonil Carbamazepine Timoptic Timolol Tinactin Tolnaftate Tinset Oxatomide Toazul Tolonium chloride Tobrex Tobramycin Tofranil Imipramine Tolectin Tolmetin Tomabef Cefmenoxime Tonocard Tocainide Topamex Topiramate Topitracin Bacitracin Toposar Etoposide Toradol Ketorolac Tornalate Bitolterol Totacillin Amphotericin B Tracrium Atracurium Tramal Tramadol Trandate Labetalol Trans-Ver-Sal Salicylic acid Transcycline Rolitetracyclin Transderm Scop Scopolamine Tranxene Clorazepate Tranxilium N Nor-Diazepam Trapanal Thiopental Trasicor Oxprenolol Travogen Isoconazole Trecalmo Clotiazepam Trecator Ethionamide Tremblex Dexetimide Tremin Trihexiphenidyl Trendar Ibuprofen Trental Pentoxifylline Trexan Naltrexone Triadapin Doxepin Trialodine Trazodone Triam-A Triamcinolone aceto- nide Triamterene Triamcinolone aceto- nide Trichlorex Trichlormethiazide Tricor Fenofibrate* Trihexane Trihexiphenidyl Trimpex Trimethoprim Trimysten Clotrimazole Triostat Liothyronine Triptone Scopolamine Trobicin Spectinomycin Trusopt Dorzolamide Truxal Chlorprothixene Tubarine d-Tubocurarine Tylenol Paracetamol = acetami- nophen Typramine Imipramine Tyzine Tetryzoline (= tetrahy- drozoline) U Udicil Cytarabine Udolac Dapsone Ukidan Urokinase Ulcolax Bisacodyl Ultair Pranlukast* Ultiva Remifentanil Ultracain Articaine Unicort Cortisol (Hydrocortiso- ne) Uniphyl Theophylline Uricovac Benzbromarone Uritol Furosemide Uromitexan Mesna Urosin Allopurinol Ursofalk Ursodeoxycholic acid = ursodiol V Va-tro-nol Ephedrine Valadol Paracetamol = acetami- nophen Valium Diazepam Valorin Paracetamol = acetami- nophen Valtrex Valacyclovir Vancocin Vancomycin Vancomycin Vancomycin CP Lilly Vaponefrine Epinephrine Vasal Papaverine Vasocon Naphazoline Vasodilan Isoxsuprine Vasopressin Lypressin Sandoz Vasoprine Isoxsuprine Vasotec Enalapril Vatran Diazepam 366 Drug Name → Trade Name Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug Name → Trade Name 367 VePesid Etoposide Vectrin Minocycline Vegesan Nor-Diazepam Velacycline Rolitetracyclin Velban Vinblastine Velbe Vinblastine Velosulin Insulin Venactone Canrenone Ventolin Salbutamol (= Albute- rol) Veratran Clotiazepam Verelan Verapamil Vermox Mebendazole Versed Midazolam Viagra Sildenafil Vibal Vit. B12 Vibramycin Doxycycline Videx Didanosine (ddI) Vigantol Cholecalciferol Vigorsan Cholecalciferol Vimicon Cyproheptadine Vinactane Viomycine Viocin Viomycine Vionactane Viomycine Viprinex Ancrod Vira-A Vidarabine Viracept Nelfinavir Viramune Nevirapine Virazole Ribavirin Virilon Methyltestosterone Virofral Amantadine Viroptic Trifluridine Visine Tetryzoline (= tetrahy- drozoline) Visken Pindolol Vistacrom Cromoglycate Visutensil Guanethidine Vitrasert Ganciclovir Vivol Diazepam Volon Triamcinolone Voltaren Diclofenac Voltarol Diclofenac Vumon Teniposide W Wellbatrin Bupropion Wellbutrin Bupropion Whevert Meclizine (meclozine) Wincoram Amrinone Wingom Gallopamil Winpred Prednisone Wyamycin Erythromycin-estolate Wytensin Guanabenz X Xanax Alprazolam Xanef Enalapril Xatral Alfuzosin Xylocain Lidocaine Xylocard Lidocaine Xylonest Prilocaine Y Yomesan Niclosamide Yutopar Ritodrine Z Zaditen Ketotifen Zanaflex Tizanidine Zanosar Streptozocin Zantac Ranitidine Zapex Oxazepam Zarontin Ethosuximide Zebeta Bisoprolol Zemuron Rocuronium Zenapax Daclizumab Zepine Reserpine Zerit Stavudine (d4T) Zestril Lisinopril Ziagen Abacavir* Zimovane Zopiclone Zithromax Azithromycin Zocor Simvastatin Zofran Ondansetron Zoladex Goserelin Zovirax Aciclovir Zyflo Zileuton Zyloprim Allopurinol Zyloric Allopurinol Zyprexa Olanzapine Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. A abacavir, 288 abciximab, 150 Abel, John J., 3 abortifacients, 126 absorption, 10, 11, 46, 47 speed of, 18, 46 accommodation, eye, 98 accumulation, 48, 49, 50, 51 accumulation equilibrium, 48 ACE, see Angiotensin-con- verting enzyme ACE inhibitors, 118, 124 diuretics and, 158 heart failure treatment, 132 hypertension treatment, 312, 313 myocardial infarction therapy, 310 acebutolol, 94 acetaminophen, 198, 199 biotransformation, 36 common cold treatment, 324, 325 intoxication, 302 migraine treatment, 322 acetazolamide, 162 N-acetyl-cysteine, 302 acetylcholine (ACh), 82, 98, 166, 182 binding to nicotinic re- ceptor, 64 ester hydrolysis, 34, 35 muscle relaxant effects, 184–187 release, 100, 101, 108 synthesis, 100 see also cholinoceptors acetylcholinesterase (AChE), 100, 182 inhibition, 102 acetylcoenzyme A, 100 acetylcysteine, 324, 325 acetyldigoxin, 132 N-acetylglucosamine, 268 N-acetylmuramyl acid, 268 acetylsalicylic acid (ASA), 198, 199, 200 biotransformation, 34, 35 common cold treatment, 324, 325 migraine treatment, 322 myocardial infarction therapy, 310 platelet aggregation in- hibition, 150, 151, 310 acipimox, 156 acrolein, 298 acromegaly, 242, 243 action potential, 136, 182, 186 active principle, 4 acyclovir, 284, 285, 286, 287 acylaminopenicillins, 270 acyltransferases, 38 Addison’s disease, 248 adenohypophyseal (AH) hormones, 242, 243 adenylate cyclase, 66 adrenal cortex (AC), 248 insufficiency, 248 adrenal medulla, nicotinic stimulation, 108, 109, 110 adrenaline, see epineph- rine adrenergic synapse, 82 adrenoceptors, 82, 230 agonists, 84, 86, 182 subtypes, 84 adrenocortical atrophy, 250 adrenocortical suppres- sion, 250 adrenocorticotropic hor- mone (ACTH), 242, 243, 248, 250, 251 adriamycin, 298 adsorbent powders, 178 adverse drug effects, 70–75 aerosols, 12, 14 affinity, 56 enantioselectivity, 62 agitation, 106 agonists, 60, 61 inverse, 60, 226 partial, 60 agranulocytosis, 72 AIDS treatment, 288–289 ajmaline, 136 akathisia, 238 akinesia, 188 albumin, drug binding, 30 albuterol, 326, 328 alcohol dehydrogenase (ADH), 44 alcohol elimination, 44 alcuronium, 184 aldosterone, 158, 164, 165, 248, 249 antagonists, 164 deficiency, 314 purgative use and, 172 alendronate, 318 alfuzosin, 90 alkaloids, 4 alkylating cytostatics, 298 allergic reactions, 72–73, 196, 326–327 allopurinol, 298, 316, 317 allosteric antagonism, 60 allosteric synergism, 60 α-blockers, 90 alprostanil, 118 alteplase, 146, 310 Alzheimer’s disease, 102 amantadine, 188, 286, 287 amikacin, 278, 280 amiloride, 164, 165 6-amino-penicillanic acid, 268 γ-aminobutyric acid, see GABA ε-aminocaproic acid, 146 aminoglycosides, 267, 276–279 368 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Index 369 p-aminomethylbenzoic acid (PAMBA), 146 aminopterin, 298 aminopyrine, 198 aminoquinuride, 258 5-aminosalicylic acid, 272 p-aminosalicylic acid, 280 amiodarone, 136 amitriptyline, 230, 232, 233 amodiaquine, 294 amorolfine, 282 amoxicillin, 168, 270, 271 cAMP, 66, 150 amphetamines, 88, 89, 230 see also specific drugs amphotericin B, 282, 283 ampicillin, 270 ampules, 12 amrinone, 118, 128, 132 anabolic steroids, 252 analgesics, 194–203 antipyretic, 4, 196–199, 202–203, 324 see also opioids anaphylactic reactions, 72, 73, 152 treatment, 84, 326, 327 ancrod, 146, 147 Ancylostoma duodenale, 292 androgens, 252 anemia, 138–141, 192 megaloblastic, 192 pernicious, 138 anesthesia balanced, 216, 217 conduction, 204 dissociative, 220 infiltration, 90, 204 premedication, 104, 106, 226 regional, 216 spinal, 204, 216 surface, 204 total intravenous (TIVA), 216 see also general anes- thetics; local anesthetics angina pectoris, 128, 306–308, 311, 312 prophylaxis, 308, 311 treatment, 92, 118, 120, 122, 308, 311 angiotensin II, 118, 124, 158, 248 antagonists, 124 biotransformation, 34, 35 formation, 34 angiotensin-converting enzyme (ACE), 34, 124, 158 see also ACE inhibitors angiotensinase, 34 Anopheles mosquitoes, 294 anorexiants, 88 antacids, 166–168 antagonists, 60, 61 anthraquinone derivatives, 170, 174, 176, 177 antiadrenergics, 95–96, 128 antianemics, 138–141 antiarrhythmics, 134–137 electrophysiological ac- tions, 136, 137 antibacterial drugs, 266–282 cell wall synthesis inhib- itors, 268–271 DNA function inhibitors, 274–275 mycobacterial infections, 280–281 protein synthesis inhibi- tors, 276–279 tetrahydrofolate synthe- sis inhibitors, 272–273 antibiotics, 178, 266 broad-spectrum, 266 cystostatic, 298 narrow-spectrum, 266 see also antibacterial drugs; antifungal drugs; antiviral drugs antibodies, 72, 73 monoclonal, 300 anticancer drugs, 296–299 anticholinergics, 188, 202 anticoagulants, 144–147 anticonvulsants, 190–193, 226 antidepressants, 88, 230–233 tricyclic, 230–232 antidiabetics, 262, 263 antidiarrheals, 178–179 antidiuretic hormone (ADH), see vasopressin antidotes, 302–305 antiemetics, 114, 310, 330–331 antiepileptics, 190–193 antiflatulents, 180 antifungal drugs, 282–283 antigens, 72, 73 antihelmintics, 292 antihistamines, 114–116 allergic disorder treat- ment, 326, 327 common cold treatment, 324, 325 motion sickness prophy- laxis, 330 peptic ulcer treatment, 166–168 sedative activity, 222 antimalarials, 294–295 antiparasitic drugs, 292–295 antiparkinsonian drugs, 188–190 antipyretic analgesics, 4, 196–199, 324 thermoregulation and, 202–203 antiseptics, 290, 291 antithrombin III, 142, 144 antithrombotics, 142–143, 148–151 antithyroid drugs, 246, 247 antiviral drugs, 284–289 AIDS treatment, 288–289 interferons, 284, 285 virustatic antimetab- olites, 284–287 anxiety states, 226 anxiolytics, 128, 222, 226, 228, 236 apolipoproteins, 154, 155 apoptosis, 296 aprotinin, 146 appetite suppressants, 88 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. arachidonic acid, 196, 201, 248 area postrema, 110, 130, 212, 330 area under the curve (AUC), 46 arecoline, 102 arthritis chronic polyarthritis, 320 rheumatoid, 302, 320–321 Arthus reaction, 72 articaine, 208, 209 Ascaris lumbricoides, 292, 293 aspirin, see acetylsalicylic acid aspirin asthma, 198 astemizole, 114–116 asthma, 126, 127, 326–329 β-blockers and, 92 treatment, 84, 104 astringents, 178 asymmetric center, 62 atenolol, 94, 95, 322 atherosclerosis, 154, 306 atorvastatin, 156 atracurium, 184 atrial fibrillation, 130, 134 atrial flutter, 122, 130, 131, 134 atropine, 104, 107, 134, 166, 216 lack of selectivity, 70, 71 poisoning, 106, 202, 302 auranofin, 320 aurothioglucose, 320 aurothiomalate, 320 autonomic nervous system, 80 AV block, 92, 104 axolemma, 206 axoplasm, 206 azapropazone, 200 azathioprine, 36, 300, 320 azidothymidine, 288 azithromycin, 276 azlocillin, 270 azomycin, 274 B B lymphocytes, 72, 300 bacitracin, 267, 268, 270 baclofen, 182 bacterial infections, 178, 266, 267 resistance, 266, 267 see also antibacterial drugs bactericidal effect, 266, 267 bacteriostatic effect, 266, 267 balanced anesthesia, 216, 217 bamipine, 114 barbiturates, 202, 203, 220, 222 dependence, 223 baroreceptors, nicotine ef- fects, 110 barriers blood-tissue, 24–25 cell membranes, 26–27 external, 22–23 basiliximab, 300 Bateman function, 46 bathmotropism, negative, 134 beclomethasone, 14, 250, 326 benazepril, 124 benign prostatic hyperpla- sia, 90, 252, 312 benserazide, 188 benzathiazide, 162 benzathine, 268 benzatropine, 106, 107, 188 benzbromarone, 316 benzocaine, 208, 209, 324 benzodiazepines, 182, 220, 226–229 antagonists, 226 dependence, 223, 226, 228 epilepsy treatment, 190, 192 myocardial infarction treatment, 128 pharmacokinetics, 228, 229 receptors, 226, 228 sleep disturbances and, 222, 224 benzopyrene, 36 benzothiadiazines, see thi- azide diuretics benzylpenicillin, 268 Berlin Blue, 304 β-blockers, 92–95, 128, 136 angina treatment, 308, 311 hypertension treatment, 312–313 migraine prophylaxis, 322 myocardial infarction treatment, 309, 310 sinus tachycardia treat- ment, 134 types of, 94, 95 bezafibrate, 156 bifonazole, 282 bile acids, 180 bilharziasis, 292 binding assays, 56 binding curves, 56–57 binding forces, 58–59 binding sites, 56 bioavailability, 18, 42 absolute, 42 determination of, 46 relative, 42 bioequivalence, 46 biogenic amines, 114–118 biotransformation, 34–39 benzodiazepines, 228, 229 in liver, 32, 42 biperiden, 188, 238 biphosphonates, 318 bisacodyl, 174 bisoprolol, 94 bladder atonia, 100, 102 bleomycin, 298 blood pressure, 314 see also hypertension; hypotension blood sugar control, 260, 261 blood-brain barrier, 24 blood-tissue barriers, 24–25 370 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Index 371 bonds, types of, 58, 59 botulinum toxin, 182 bowel atonia, 100, 102 bradycardia, 92, 104, 134 bradykinin, 34 brain, blood-brain barrier, 24 bran, 170 bromocriptine, 114, 126, 188, 242, 243 bronchial asthma, see asthma bronchial carcinoma, to- bacco smoking and, 112 bronchial mucus, 14 bronchitis, 324, 328 chronic obstructive, 104 tobacco smoking and, 112 bronchoconstriction, 196, 198 bronchodilation, 84, 104, 127, 196, 326 bronchodilators, 126, 328 brotizolam, 224 buccal drug administra- tion, 18, 19, 22 Buchheim, Rudolf, 3 budesonide, 14, 250, 326 bufotenin, 240 bulk gels, 170, 171 bumetanide, 162 buprenorphine, 210, 214 buserelin, 242, 243 buspirone, 116 busulfan, 298 N-butylscopolamine, 104, 126 butyrophenones, 236, 238 butyryl cholinesterase, 100 C cabergolide, 126, 188, 242 caffeine, 326 calcifediol, 264 calcineurin, 300 calcitonin, 264, 265, 318, 322 calcitriol, 264 calcium antagonists, 122–123, 128 angina treatment, 308, 311 hypertension treatment, 312–313 calcium channel blockers, 136, 234 see also calcium antago- nists calcium chelators, 142 calcium homeostasis, 264, 265 calmodulin, 84 cancer, 296–299 see also carcinoma Candida albicans, 282 canrenone, 164 capillary beds, 24 capreomycin, 280 capsules, 8, 9, 10 captopril, 34, 124 carbachol, 102, 103 carbamates, 102 carbamazepine, 190, 191, 192, 234 carbenicillin, 270 carbenoxolone, 168 carbidopa, 188 carbimazole, 247 carbonic acids, 200 carbonic anhydrase (CAH), 162 inhibitors, 162, 163 carbovir, 288 carboxypenicillins, 270 carcinoma bronchial, 112 prostatic, 242 cardiac arrest, 104, 134 cardiac drugs, 128–137 antiarrhythmics, 134–137 glycosides, 128, 130, 131, 132, 134 modes of action, 128, 129 cardioacceleration, 104 cardiodepression, 134 cardioselectivity, 94 cardiostimulation, 84, 85 carminatives, 180, 181 carotid body, nicotine ef- fects, 110 case-control studies, 76 castor oil, 170, 174 catecholamines actions of, 84, 85 structure-activity rela- tionships, 86, 87 see also epinephrine; norepinephrine catecholmin-O-methyl- transferase (COMT), 82, 86, 114 inhibitors of, 188 cathartics, 170, 172 cefmenoxin, 270 cefoperazone, 270 cefotaxime, 270 ceftazidime, 270 ceftriaxone, 270 cell membrane, 20 membrane stabilization, 94, 134, 136 permeation, 26–27 cells, 20 cellulose, 170 cephalexin, 270, 271 cephalosporinase, 270, 271 cephalosporins, 267, 268, 270, 271 cerivastatin, 156 ceruletide, 180 cestode parasites, 292 cetrizine, 114–116 chalk, 178 charcoal, medicinal, 178 chelating agents, 302, 303 chemotherapeutic agents, 266 chenodeoxycholic acid (CDCA), 180 chirality, 62 chloral hydrate, 222 chlorambucil, 298 chloramphenicol, 267, 276–279 chlorguanide, 294 chloride channels, 226 chlormadinone acetate, 254 chloroquine, 294, 295, 320 chlorpheniramine, 114 chlorphenothane (DDT), 292, 293 chlorpromazine, 208, 236, 238 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. lack of selectivity, 70, 71 chlorprothixene, 238 chlorthalidone, 162 cholecalciferol, 264 cholecystokinin, 180 cholekinetics, 180 cholelithiasis, 180 choleretics, 180 cholestasis, 238 cholesterol, 154–157 gallstone formation, 180 metabolism, 155 choline, 100 choline acetyltransferase, 100 cholinergic synapse, 100 cholinoceptors, 98, 100, 184 antacid effects, 166 antagonists, 188 muscarinic, 100, 188, 230 nicotinic, 64, 65, 100, 108, 182 chronic polyarthritis, 320 chronotropism, 84 negative, 134 chylomicrons, 154 cilazapril, 124 cimetidine, 116, 168 ciprofloxacin, 274 cisapride, 116 cisplatin, 298 citrate, 142 clarithromycin, 168, 276 Clark, Alexander J., 3 clavulanic acid, 270 clearance, 44 clemastine, 114 clemizole, 268 clindamycin, 267, 276 clinical testing, 6 clinical trials, 76 clobazam, 192 clodronate, 264, 318 clofazimine, 280, 281 clofibrate, 156 clomethiazole, 192 clomiphene, 256 clonazepam, 192 clonidine, 96, 182, 312 clopidogrel, 150 clostebol, 252 Clostridium botulinum, 182 Clostridium difficile, 270 clotiazepam, 222 clotrimazole, 282 clotting factors, 142 clozapine, 238, 239, 240 co-trimoxazole, 272, 273 coagulation cascade, 142, 143 coated tablets, 8, 9, 10 cocaine, 88, 89, 208 codeine, 210, 212, 214, 324, 325 colchicine, 316, 317 colds, 324–325 colestipol, 154 colestyramine, 130, 154 colic, 104, 127 common cold, 324–325 competitive antagonists, 60, 61 complement activation, 72, 73 compliance, 48 concentration time course, 46–47, 68, 69 during irregular intake, 48, 49 during repeated dosing, 48, 49 concentration-binding curves, 56–57 concentration-effect curves, 54, 55 concentration-effect rela- tionship, 54, 55, 68, 69 conformation change, 60 congestive heart failure, 92, 128, 130, 158, 312 conjugation reactions, 38, 39, 58 conjunctival decongestion, 90 constipation, 172, 173 atropine poisoning and, 106 see also laxatives contact dermatitis, 72, 73, 282 controlled trials, 76 coronary sclerosis, 306, 307 corpus luteum, 254 corticotropin, 242 corticotropin-releasing hormone (CRH), 242, 250, 251 cortisol, 36, 248, 249, 250, 251 receptors, 250 cortisone, biotransforma- tion, 36 coryza, 90 cotrimoxazole, 178 cough, 324, 325 coumarins, 142, 144, 145 covalent bonds, 58 cranial nerves, 98 creams, 16, 17 cromoglycate, 116 cromolyn, 14, 116, 326 cross-over trials, 76 curare, 184 Cushing’s disease, 220, 248, 300, 318 prevention of, 248 cyanide poisoning, 304, 305 cyanocobalamin, 138, 304, 305 cyclic endoperoxides, 196 cyclofenil, 256 cyclooxygenases, 196, 248 inhibition, 198, 200, 328 cyclophilin, 300 cyclophosphamide, 298, 300, 320 cycloserine, 280 cyclosporin A, 300 cyclothiazide, 162 cyproterone, 252 cyproterone acetate, 254 cystinuria, 302, 303 cystostatic antibiotics, 298 cytarabine, 298 cytochrome P450, 32 cytokines, 300 cytomegaloviruses, 286 cytostatics, 296, 297, 299, 300, 320 cytostatics, alkylating, 298 cytotoxic reactions, 72, 73 372 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Index 373 D daclizumab, 300 dantrolene, 182 dapsone, 272, 280, 281, 294 daunorubicin, 298 dealkylations, 36 deamination, 36 decarbaminoylation, 102 decongestants, 90 deferoxamine, 302, 303 dehalogenation, 36 delavirdine, 288 delirium tremens, 236 dementia, 102 N-demethyldiazepam, 228 demulcents, 178 deoxyribonucleic acid (DNA), 274 synthesis inhibition, 298, 299 dependence benzodiazepines, 223, 226, 228 hypnotics, 222, 223 laxatives, 172, 173 opioids, 210–212 dephosphorylation, 102 depolarizing muscle relax- ants, 184, 186, 187 deprenyl, 88 depression, 226, 230 endogenous, 230–233 manic-depressive illness, 230 treatment, 88, 230–233 dermatologic agents, 16, 17 as drug vehicles, 16, 17 dermatophytes, 282 descending antinocicep- tive system, 194 desensitization, 66 desflurane, 218 desipramine, 230, 232, 233 desmopressin, 164, 165 desogestrel, 254 desulfuration, 36, 37 dexamethasone, 192, 248, 249, 330 dexazosin, 90 dexetimide, 62, 63 dextran, 152 diabetes mellitus hypoglycemia, 92 insulin replacement therapy, 258 insulin-dependent, 260–261 non-insulin-dependent, 262–264 diacylglycerol, 66 diarrhea, 178 antidiarrheals, 178–179 chologenic, 172 diastereomers, 62 diazepam, 128, 228 diazoxide, 118, 312 dicationic, 268 diclofenac, 200, 320 dicloxacillin, 270 didanosine, 288 diethlystilbestrol, 74 diethylether, 216 diffusion barrier to, 20 membrane permeation, 26, 27 digitalis, 130, 131, 302 digitoxin, 132 enterohepatic cycle, 38 digoxin, 132 dihydralazine, 118, 312 dihydroergotamine, 126, 322 dihydropyridines, 122, 308 dihydrotestosterone, 252 diltiazem, 122, 136, 308 dimenhydrinate, 114 dimercaprol, 302, 303 dimercaptopropanesulfon- ic acid, 302, 303 dimethicone, 180, 181 dimethisterone, 254 2,5-dimethoxy-4-ethyl amphetamine, 240 3,4-dimethoxyampheta- mine, 240 dimetindene, 114 dinoprost, 126 dinoprostone, 126 diphenhydramine, 114, 222, 230 diphenolmethane deriva- tives, 170, 174, 177 diphenoxylate, 178 dipole-dipole interaction, 58 dipole-ion interaction, 58 dipyridamole, 150 dipyrone, 198, 199 disinfectants, 290, 291 disintegration, of tablets and capsules, 10 disopyramide, 136 disorientation, atropine poisoning and, 106 Disse’s spaces, 24, 32, 33 dissolution, of tablets and capsules, 9, 10 distribution, 22–31, 46, 47 diuretics, 158–165, 313 indications for, 158 loop, 162, 163 osmotic, 160, 161 potassium-sparing, 164, 165 sulfonamide type, 162, 163 thiazide, 132, 162, 163, 312 dobutamine, enantioselec- tivity, 62 docetaxel, 296 docosahexaenoate, 156 domperidone, 322, 330 L-dopa, 114, 188 DOPA-decarboxylase, 188 dopamine, 88, 114, 115, 132 agonists, 242 antagonists, 114 in norepinephrine syn- thesis, 82 mimetics, 114 Parkinson’s disease and, 188 dopamine receptors, 114, 322 agonists, 188 blockade, 236, 238 dopamine-β-hydroxylase, 82 doping, 88, 89 dorzolamide, 162 dosage forms, 8 dosage schedule, 50, 51 dose-linear kinetics, 68, 69 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. dose-response relation- ship, 52–53 dosing irregular, 48, 49 overdosing, 70, 71 repeated, 48, 49 subliminal, 52 double-blind trials, 76 doxorubicin, 298 doxycycline, 277, 278, 294 doxylamine, 22 dromotropism, negative, 134 dronabinol, 330 droperidol, 216, 236 drops, 8, 9 drug interactions, 30, 32 anticonvulsants, 192 drug-receptor interaction, 58–69 drugs active principle, 4 administration, 8–19 adverse effects, 70–75 approval process, 6 barriers to, 22–27 biotransformation, 32, 34–39 concentration time course, 46–47, 48–49, 68, 69 development, 6–7 distribution in body, 22–31, 46, 47 liberation of, 10 protein binding, 30–31 retarded release, 10, 11 sites of action, 20–21 sources, 4 see also elimination of drugs; specific types of drugs duodenal ulcers, 104, 166 dusting powders, 16 dynorphins, 210 dyskinesia, 238 dysmenorrhea, 196 dystonia, 238 E Emax, 54 E. coli, 270, 271 EC50, 54, 60 econazole, 282 ecothiopate, 102 ecstasy, 240 ectoparasites, 292 edema, 158, 159 EDTA, 142, 264, 302, 303 efavirenz, 288 effervescent tablets, 8 efficacy, 54, 60, 61 Ehrlich, P., 3 eicosanoids, 196 eicosapentaenoate, 156 electromechanical coupling, 128, 182 electrostatic attraction, 58, 59 elimination of drugs, 32–43, 46, 47 β-blockers, 94 biotransformation, 34–39, 42 changes during drug therapy, 50, 51 exponential rate pro- cesses, 44, 45 hydrophilic drugs, 42, 43 in kidney, 40–41, 44 in liver, 18, 32–33, 44 lipophilic drugs, 42, 43 emesis, 330–331 emulsions, 8, 16 enalapril, 34 enalaprilat, 34, 124 enantiomers, 62, 63 enantioselectivity, 62 endocytosis, 24 receptor-mediated, 26, 27 endoneural space, 206 endoparasites, 292 β-endorphin, 210, 211, 212 endothelium-derived re- laxing factor (EDRF), 100, 120 enflurane, 218 enkephalins, 34, 210, 211 enolic acids, 200 enoxacin, 274 entacapone, 188 Entamoeba histolytica, 274 Enterobius vermicularis, 292 enterohepatic cycle, 38, 39 enzyme induction, 32 ephedrine, 86, 87 epilepsy, 190, 191, 226 antiepileptics, 190–193 childhood, 192 treatment, 162 epinephrine, 82, 83, 260 anaphylactic shock treat- ment, 84, 326, 327 β-blockers and, 92 cardiac arrest treatment, 134 local anesthesia and, 206 nicotine and, 108, 109, 110 structure-activity rela- tionships, 86, 87 epipodophyllotoxins, 298 epoxidations, 36 epoxides, 36 Epsom salts, 170 eptifibatide, 150 ergocornine, 126 ergocristine, 126 ergocryptine, 126 ergolides, 114 ergometrine, 126, 127 ergosterol, 282, 283 ergot alkaloids, 126 ergotamine, 126, 127, 322 erythromycin, 34, 267, 276, 277 erythropoiesis, 138, 139 erythropoietin, 138 ester hydrolysis, 34 estradiol, 254, 255, 257 estriol, 254, 255 estrogen, 254, 318 estrone, 254, 255 ethacrynic acid, 162 ethambutol, 280, 281 ethanol, 202, 203, 224 elimination, 44 ethinylestradiol (EE), 254, 255, 256 ethinyltestosterone, 255 ethionamide, 280 ethisterone, 254 ethosuximide, 191, 192 ethylaminobenzoate, 324 ethylenediaminetetraacet- ic acid (EDTA), 142 374 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Index 375 etilefrine, 86, 87 etofibrate, 156 etomidate, 220, 221 etoposide, 298 etretinate, 74 euphoria, 88, 210 expectorants, 324, 325 exponential rate processes, 44, 45 extracellular fluid volume (EFV), 158 extracellular space, 28 extrapyramidal distur- bances, 238 eye drops, 8, 9 F factor VII, 142 factor XII, 142 famcyclovir, 286 famotidine, 116, 168 fatty acids, 20 felbamate, 190, 191 felodipine, 122 felypressin, 164, 206 fenestrations, 24 fenfluramine, 88 fenoldopam, 114, 312 fenoterol, 86, 87 allergic disorder treat- ment, 326 asthma treatment, 328 tocolysis, 84, 126 fentanyl, 210, 212–216 ferric ferrocyanide, 304, 305 ferritin, 140 fever, 202, 203, 324 fexofenadine, 114–116 fibrillation, 122 atrial, 130, 131, 134 fibrin, 34, 142, 146 fibrinogen, 146, 148, 149 fibrinolytic therapy, 146 Fick’s Law, 44 finasteride, 252 first-order rate processes, 44–45 first-pass hepatic elimina- tion, 18, 42 fish oil supplementation, 156 fleas, 292, 293 flecainide, 136 floxacillin, 270 fluconazole, 282 flucytosine, 282 fludrocortisone, 248, 314 flukes, 292 flumazenil, 226, 302 flunarizine, 322 flunisolide, 14, 250 fluoride, 318 5-fluorouracil, 298 fluoxetine, 116, 230, 232, 233 flupentixol, 236, 238, 239 fluphenazine, 236, 238, 239 flutamide, 252 fluticasone dipropionate, 14, 250 fluvastatin, 156, 157 fluvoxamine, 232 folic acid, 138, 139, 272, 273 deficiency, 138 follicle-stimulating hor- mone (FSH), 242, 243, 254 deficiency, 252 suppression, 256 follicular maturation, 254 foscarnet, 286, 287 fosinopril, 124 Frazer, T., 3 frusemide, 162 functional antagonism, 60 fungal infections, 282–283 fungicidal effect, 282 fungistatic effect, 282 furosemide, 162, 264 G G-protein-coupled recep- tors, 64, 65, 210 mode of operation, 66–67 G-proteins, 64, 66 GABA, 190, 224, 226 GABA receptors, 64, 226 gabapentin, 190, 191, 192 Galen, Claudius, 2 gallamine, 184 gallopamil, 122 gallstones, 180 dissolving of, 180, 181 ganciclovir, 285, 286 ganglia nicotine action, 108, 110 paravertebral, 82 prevertebral, 82 ganglionic blockers, 108, 128 gastric secretion, 196 gastric ulcers, 104, 166 gastrin, 166–168, 242 gastritis, atrophic, 138 gelatin, 152 gels, 16 gemfibrozil, 156 general anesthetics, 216–221 inhalational, 216, 218–219 injectable, 216, 220–221 generic drugs, 94 gentamicin, 276, 278, 279 gestoden, 254 gingival hyperplasia, 192 Glauber’s salts, 170 glaucoma, 106 treatment, 92, 102, 162 β-globulins, drug binding, 30 glomerular filtration, 40 glucagon, 242 glucocorticoids, 200, 248–251 allergic disorder treat- ment, 326 asthma treatment, 328 cytokine inhibition, 300 gout treatment, 316 hypercalcemia treat- ment, 264 rheumatoid arthritis treatment, 320 glucose metabolism, 260, 261 see also diabetes mellit- us glucose-6-phosphate de- hydrogenase deficiency, 70 glucuronic acid, 36, 38, 39 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. β-glucuronidases, 38 glucuronidation, 38 opioids, 212 glucuronides, 38 glucuronyl transferases, 32, 38 glutamate, 64, 190 receptors, 190 glutamine, in conjugation reactions, 38 glyburide, 262 glyceraldehyde enantiom- ers, 62 glycerol, 20 glycine, 64, 182, 183 in conjugation reactions, 38 glycogenolysis, 66, 84 glycosuria, 162 cGMP, 120 goiter, 244, 245, 247 gold compounds, 320 gonadorelin superagonists, 242 gonadotropin-releasing hormone (GnRH), 242, 243, 252, 256 goserelin, 242 gout, 316–317 GPIIB/IIIA, 148, 149, 150 antagonists, 150 granisetron, 116, 330 Graves’ disease, 246, 247 griseofulvin, 282, 283 growth hormone (GH), 242, 243 growth hormone recep- tors, 64 growth hormone release inhibiting hormone (- GRIH), 242 growth hormone-releasing hormone (GRH), 242 guanethidine, 96 guanylate cyclase, 120 gynecomastia, 164, 168 gyrase inhibitors, 274, 275 H Hahnemann, Samuel, 76 half-life, 44 hallucinations, atropine poisoning and, 106 hallucinogens, 240, 241 halofantrine, 294, 295 haloperidol, 236, 238, 239 halothane, 218, 219 haptens, 72, 73 hay fever, 326 HDL particles, 154 heart β-blockers and, 92 cardiac arrest, 104, 134 cardiac drugs, 128–137 cardioacceleration, 104 cardiodepression, 134 cardiostimulation, 84, 85 see also angina pectoris; myocardial infarction; myocardium heart failure β-blockers and, 92 congestive, 92, 128, 130, 158, 312 treatment, 118, 124, 132, 158 Helicobacter pylori, 166 eradication of, 168, 169 hemoglobin, 138 hemolysis, 70, 72 hemosiderosis, 140 hemostasis, 142, 148 heparin, 142–146, 309, 310 hepatic elimination, 18, 32–33, 44 exponential kinetics, 44 hepatocytes, 32, 33, 154 heroin, 212 Herpes simplex viruses, 284, 286 hexamethonium, 108 hexobarbital, 222 high blood pressure, see hypertension hirudin, 150 histamine, 72, 114, 115, 166, 326 antagonists, 114 inhibitors of release, 116 receptors, 114, 230, 326 see also antihistamines HMG CoA reductase, 154, 156, 157 Hohenheim, Theophrastus von, 2 homatropine, 107 homeopathy, 76, 77 hookworm, 292 hormone replacement therapy, 254 hormones, 20 hypophyseal, 242–243 hypothalamic, 242–243 see also specific hor- mones human chorionic gonado- tropin (HCG), 252, 256 human immunodeficiency virus (HIV), 288–289 human menopausal gona- dotropin (HMG), 252, 256 hydrochlorothiazide, 162, 164 hydrocortisone, 248 hydrogel, 16, 17 hydrolysis, 34, 35 hydromorphone, 210, 214 hydrophilic colloids, 170, 171 hydrophilic cream, 16 hydrophilic drug elimina- tion, 42, 43 hydrophobic interactions, 58, 59 hydroxyapatite, 264, 318 4-hydroxycoumarins, 144 hydroxyethyl starch, 152 hydroxylation reactions, 36, 37 17-β-hydroxyprogesterone caproate, 254 5-hydroxytryptamine (5HT), see serotonin hypercalcemia, 264 hyperglycemia, 162, 258, 260 hyperkalemia, 186 hyperlipoproteinemia, 154–157 treatment, 154 hyperpyrexia, 202 hypersensitivity, 70 376 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Index 377 hypertension therapy, 312–313 α-blockers, 90 ACE inhibitors, 124, 312 β-blockers, 92, 312 calcium antagonists, 122, 312 diuretics, 158, 312 in pregnancy, 312 vasodilators, 118, 312 hyperthermia, atropine poisoning and, 106, 202 hyperthyroidism, 244, 246–247 hypertonia, 226 hyperuricemia, 162, 316 hypnotics, 222–225 dependence, 222, 223 hypoglycemia, 92, 260 hypokalemia, 162, 163, 172, 173 hypophysis, 242–243, 250 hypotension, 118, 119, 314 treatment, 90, 314–315 hypothalamic releasing hormones, 242, 243 hypothalamus, 242, 250, 251 hypothermia, 238 hypothyroidism, 244 hypovolemic shock, 152 I ibuprofen, 198, 200 idiopathic dilated cardio- myopathy, 92 idoxuridine, 286 ifosfamide, 298 iloprost, 118 imidazole derivatives, 282, 283 imipramine, 208, 230–232, 233 immune complex vascu- litis, 72, 73 immune modulators, 300–301 immune response, 72, 73, 300 immunogens, 72 immunosuppression, 300–301, 320 indinavir, 288 indomethacin, 200, 316, 320 infertility, 242 inflammation, 72, 196, 326 asthma, 328, 329 glucocorticoid therapy, 248, 249 rheumatoid arthritis, 320 inflammatory bowel dis- ease, 272 influenza virus, 286, 287, 324 infusion, 12, 50 inhalation, 14, 15, 18, 19 injections, 12, 18, 19 inosine monophosphate dehydrogenase, 300 inositol trisphosphate, 66, 84 inotropism, 92 negative, 134 insecticides, 292 poisoning, 304, 305 insomnia, 224, 226 insulin, 242, 258–259 diabetes mellitus treat- ment, 260–261, 262 preparations, 258, 259 regular, 258 resistance to, 258 insulin receptors, 64 insulin-dependent dia- betes mellitus, 260–261 interferons (IFN), 284, 285 interleukins, 300 interstitial fluid, 28 intestinal epithelium, 22 intramuscular injection, 18, 19 intravenous injection, 18, 19 intrinsic activity, 60 enantioselectivity, 62 intrinsic factor, 138 intrinsic sympathomimetic activity (ISA), 94 intubation, 216 inulin, 28 inverse agonists, 60, 226 inverse enantioselectivity, 62 iodine, 246, 247 deficiency, 244 iodized salt prophylaxis, 244 ionic currents, 136 ionic interaction, 58 ipratropium, 14, 107 allergic disorder treat- ment, 326 bronchodilation, 126, 328 cardiaoacceleration, 104, 134 iron compounds, 140 iron deficiency, 138, 140 iron overload, 302 isoconazole, 282 isoflurane, 218 isoniazid, 190, 280, 281 isophane, 258 isoprenaline, 94 isoproterenol, 14, 94, 95 structure-activity rela- tionships, 86, 87 isosorbide dinitrate (ISDN), 120, 308, 311 5-isosorbide mononitrate (ISMN), 120 isotretinoic acid, 74 isoxazolylpenicillins, 270 itraconazole, 282 J josamycin, 276 juvenile onset diabetes mellitus, 260 K K + channels, see potassium channel activation kanamycin, 276, 280 kaolin, 178 karaya gum, 170 ketamine, 220, 221 ketanserin, 116 ketoconazole, 282 ketotifen, 116 kidney, 160, 161 drug elimination, 40–41, 44 kinetosis, 106, 330, 331 kyphosis, 318 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. L β-lactam ring, 268, 270 β-lactamases, 270 lactation, drug toxicity, 74, 75 lactulose, 170 lamivudine, 288 lamotrigine, 190, 191 Langendorff preparation, 128 Langley, J., 3 lansoprazole, 168 laryngitis, 324 law of mass action, 3, 56 laxatives, 170–177 bulk, 170, 171 dependence, 172, 173 irritant, 170, 172–174, 175, 177 lubricant, 174 misuse of, 170–172 osmotically active, 170, 171 LDL particles, 154–157 lead poisoning, 302, 303 Lennox-Gastaut syndrome, 192 leprosy, 274, 280 leuenkephalin, 212 leukotrienes, 196, 320, 326, 327, 328 NSAIDS and, 200, 201 leuprorelin, 242, 243 levetimide, 62, 63 levodopa, 188 levomepromazine, 330 lice, 292, 293 lidocaine, 134, 136, 208, 209 biotransformation, 36, 37 digitoxin intoxication treatment, 130 myocardial infarction treatment, 309, 310 ligand-gated ion channel, 64, 65 ligand-operated enzymes, 64, 65 lincomycin, 276 lindane, 292, 293 linseed, 170 lipid-lowering agents, 154 lipocortin, 248 lipolysis, 66, 84 lipophilic cream, 16 lipophilic drug elimina- tion, 42, 43 lipophilic ointment, 16 lipoprotein metabolism, 154, 155 lipoxygenases, 196 liquid paraffin, 174 liquid preparations, 8, 9 lisinopril, 124 lisuride, 114, 188 lithium ions, 234, 235, 246, 247 liver biotransformation, 32, 42 blood supply, 32 drug elimination, 18, 32–33, 44 drug exchange, 24 enterohepatic cycle, 38, 39 lipoprotein metabolism, 154–157 loading dose, 50 local anesthetics, 128, 134, 204–209 chemical structure, 208–209 diffusion and effect, 206–207 mechanism of action, 204–206 lomustine, 298 loop diuretics, 162, 163 loperamide, 178, 212 loratidine, 116 lorazepam, 220, 330 lormetazepam, 224 lotions, 16, 17 lovastatin, 156, 157 low blood pressure, see hypotension LSD, see lysergic acid di- ethylamide Lugol’s solution, 246 luteinizing hormone (LH), 242, 243, 252, 254 deficiency, 252 lymphocytes, 72 lymphokines, 72 lynestrenol, 254 lypressin, 164 lysergic acid, 126 lysergic acid diethylamide (LSD), 126, 240, 241 M macrophages, 300 activation, 72 magnesium sulfate, 126 maintenance dose, 50 major histocompatibility complex (MHC), 300 malaria, 294–295 malignant neuroleptic syn- drome, 238 mania, 230, 234, 235 manic-depressive illness, 230 mannitol, 160, 161, 170 maprotiline, 232 margin of safety, 70 mass action, law of, 3, 56 mast cells, 72 inhibitors of histamine release, 116 stabilization, 326, 328 matrix-type tablets, 9, 10 maturity-onset diabetes mellitus, 262–264 mazindole, 88 mebendazole, 292, 293 mebhydroline, 114 mecamylamine, 108 mechlorethamine, 298 meclizine, 114, 330 medicinal charcoal, 178 medroxyprogesterone ace- tate, 254 mefloquine, 294, 295 megakaryocytes, 148 megaloblastic anemia, 192 melphalan, 298 membrane permeation, 26–27 membrane stabilization, 94, 134, 136 memory cells, 72 menstrual cycle, 254 menstruation, 196 378 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Index 379 meperidine, 126, 210, 214, 215 mepivacaine, 209 6-mercaptopurine, 298 mesalamine, 272 mescaline, 116, 240 mesterolone, 252 mestranol, 254, 256 metamizole, 198 metastases, 296 metenkephalin, 212, 213 metenolone, 252 meteorism, 180 metformin, 262 l-methadone, 210, 214, 215 methamphetamine, 86, 87, 88 methemoglobin, 304, 305 methimazole, 247 methohexital, 220 methotrexate, 298, 300, 320 methoxyflurane, 218 methoxyverapamil, 122 4-methyl-2,5-dimethoxy- amphetamine, 240 methylation reactions, 36, 37 methyldigoxin, 132 methyldopa, 96, 114, 312 methylenedioxy metham- phetamine (MDMA), 240 methylergometrine, 126 methylprednisolone, 330 17-α-methyltestosterone, 252 methylxanthines, 326 methysergide, 322 metoclopramide, 322, 330 metoprolol, 94, 322 metronidazole, 168, 274 mexiletine, 134, 136 mezclocillin, 270 mianserin, 232 mibefradil, 122, 308 miconazole, 282 Micromonospora bacteria, 276 micturition, 98 midazolam, 220, 221, 228 mifepristone, 126, 256 migraine treatment, 116, 126, 322–323 milieu interieur, 80 milrinone, 132 mineralocorticoids, 248, 249 minimal alveolar concen- tration (MAC), 218 minipill, 256, 257 minocycline, 278 minoxidil, 118, 312 misoprostol, 126, 168, 169, 200 mites, 292, 293 mixed-function oxidases, 32 mixtures, 8 moclobemide, 88, 232, 233 molsidomine, 120, 308 monoamine oxidase (MAO), 82, 86, 88, 114 inhibitors of, 88, 89, 188, 230, 232 monoclonal antibodies, 300 mood change, 210 morning-after pill, 256 morphine, 4, 5, 178, 210–215, 310 antagonists, 214 increased sensitivity, 70 metabolism, 212, 213 overdosage, 70, 71 Straub tail phenomenon, 52, 53 Morton, W.T.G., 216 motiline, 276 motion sickness, 106, 330, 331 motor endplate, 182 nicotine and, 110 motor systems, drugs act- ing on, 182–193 mountain sickness, 162 moxalactam, 270 mucociliary transport, 14 mucolytics, 324, 325 mucosal administration, 12, 14, 18, 22 mucosal block, 140 mucosal disinfection, 290, 291 murein, 268 muromonab CD3, 300 muscarinic cholinoceptors, 100, 188, 230 muscimol, 240 muscle relaxants, 182, 184–187, 226 myasthenia gravis, 102 mycobacterial infections, 274, 280–281 M. leprae, 280 M. tuberculosis, 280 mycophenolate mofetil, 300 mycoses, 282–283 mydriatics, 104 myocardial infarction, 128, 148, 226, 309–310 myocardial insufficiency, 92, 132 myocardium contraction, 128, 129 oxygen demand, 306, 307 oxygen supply, 306, 307 relaxation, 128, 129 myometrial relaxants, 126 myometrial stimulants, 126 myosin kinase, 84 N Na channel blockers, 128, 134–137, 204 nabilone, 330 NaCl reabsorption, kidney, 160, 161 nadolol, 322 naftidine, 282 nalbuphine, 212, 215 nalidixic acid, 274 naloxone, 210, 211, 214, 215, 302 naltrexone, 214 nandrolone, 252 naphazoline, 90, 326 naproxene, 200 nasal decongestion, 90 Naunyn, Bernhard, 3 nausea, 330–331 see also antiemetics; motion sickness nazatidine, 116 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. nebulizers, 13, 14 Necator americanus, 292 nedocromil, 116 negative bathmotropism, 134 negative chronotropism, 134 negative dromotropism, 134 negative inotropism, 134 nelfinavir, 288 nematode parasites, 292 neomycin, 278, 279 neoplasms, see cancer; carcinoma neostigmine, 102, 103, 184 nephron, 160, 161 netilmicin, 278 neurohypophyseal (NH) hormones, 242 neurohypophysis, 242, 243 nicotine effects, 110 neuroleptanalgesia, 216, 236 neuroleptanesthesia, 216 neuroleptics, 114, 216, 240 epilepsy and, 190 mania treatment, 234 schizophrenia treatment, 236–238 thermoregulation and, 202, 203 neuromuscular transmis- sion, 182, 183 blocking, 184 neurotic disorders, 226 neutral antagonists, 60 neutrophils, 72 nevirapine, 288 nicotine, 108–113 effects on body func- tions, 110–111 ganglionic action, 108 ganglionic transmission, 108, 109 nicotinic acid, 118, 156 nicotinic cholinoceptors, 64, 65, 100, 108, 182 nifedipine, 122, 123, 126, 308 hypertension treatment, 312 mania treatment, 234 nimodipine, 122, 234 nitrate tolerance, 120 nitrates, organic, 120–121 nitrazepam, 222 nitrendipine, 122 nitric acid, 120 nitric oxide (NO), 100, 116, 120, 148 nitroglycerin, 120, 308, 311, 312 nitroimidazole, 274, 275 nitrostigmine, 102 nitrous oxide (N2O), 218, 219 nizatidine, 168 nociceptors, 194, 196 non-insulin-dependent di- abetes mellitus, 262–264 noncovalent bonds, 58 nondepolarizing muscle relaxants, 184, 185 nonsteroidal antiinflam- matory drugs (NSAIDS), 38, 198, 200–201 gout treatment, 316 pharmacokinetics, 200 rheumatoid arthritis treatment, 320 noradrenaline, see norepi- nephrine nordazepam, 228 norepinephrine, 82, 83, 88, 118 biotransformation, 36, 37 local anesthesia and, 206 neuronal re-uptake, 82, 230 release of, 90, 91 structure-activity rela- tionships, 86, 87 synthesis, 82, 88 norethisterone, 254 norfloxacin, 274 nortriptyline, 232 noscapine, 212, 324 nose drops, 8, 9 nucleoside inhibitors, 288, 289 nystatin, 282, 283 O obesity, diabetes mellitus and, 262, 263 obidoxime, 304, 305 octreotide, 242 ofloxacin, 274 ointments, 12, 13, 16, 17 olanzapine, 238 omeprazole, 168 ondansetron, 116, 330 opioids, 178, 210–215, 302 effects, 210–212 metabolism, 212, 213 mode of action, 210 tolerance, 214 opium, 4 tincture, 4, 5, 178 oral administration, 8–11, 18, 19, 22 dosage schedule, 50 oral contraceptives, 254, 256–257 biphasic preparations, 256, 257 minipill, 256, 257 monophasic prepara- tions, 256, 257 morning-after pill, 256 oral rehydration solution, 178 orciprenaline, 86, 87 organ preparation studies, 54 organophosphate insecti- cide poisoning, 304, 305 organophosphates, 102 ornipressin, 164, 165 osmotic diuretics, 160, 161 osteomalacia, 192 osteopenia, 318 osteoporosis, 264, 318–319 ouabain, 132 overdosage, 70, 71 ovulation, 254 inhibition, 256 stimulation, 256 oxacillin, 270, 271 oxalate, 142 oxatomide, 116 oxazepam, 228 oxiconazole, 282 380 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Index 381 oxidases, mixed-function, 32 oxidation reactions, 36, 37 oxymetazoline, 326 oxytocin, 126, 242, 243 P p-aminobenzoic acid (PA- BA), 272, 273 paclitaxel, 296, 297 pain, 194, 195 see also analgesics palliative therapy, 296 pamidronate, 318 pancreatic enzymes, 180, 181 pancreozymin, 180 pancuronium, 184, 185 pantoprazole, 168 Papaver somniferum, 4 papaverine, 210 Paracelsus, 2 paracetamol, see acetami- nophen paraffinomas, 174 paraoxon, 36, 102, 103 parasitic infections, 292–295 parasympathetic nervous system, 80, 98–107 anatomy, 98 drugs acting on, 102–107 responses to activation, 98, 99 parasympatholytics, 104–107, 128, 134, 324 contraindications for, 106 parasympathomimetics, 102–103, 128 direct, 102, 103 indirect, 102, 103 parathion, 102 biotransformation, 36, 37 parathormone, 264, 265 paravertebral ganglia, 82 parenteral administration, 12, 13 Parkinsonism antiparkinsonian drugs, 188–190 pseudoparkinsonism, 238 treatment, 88, 106, 114 paromomycin, 278 paroxetine, 232 partial agonists, 60 pastes, 12, 13, 16, 17 patient compliance, 48 pectin, 178 penbutolol, 94 penciclovir, 286 D-penicillamine, 302, 303, 320 penicillinase, 270, 271 penicillins, 267–270, 271 elimination, 268 penicillin G, 72, 266, 268–270, 271 penicillin V, 270, 271 Penicillium notatum, 268 pentazocine, 210, 212, 214, 215 pentobarbital, 223 biotransformation, 36, 37 peptic ulcers, 104, 106, 166–169 peptidases, 34 peptide synthetase, 276 peptidoglycan, 268 perchlorate, 246, 247 pergolide, 114, 126, 188 perindopril, 124 perineurium, 206 peristalsis, 170, 171, 173 permethrin, 292 pernicious anemia, 138 perphenazine, 330 pethidine, 210 pharmacodynamics, 4 pharmacogenetics, 70 pharmacokinetics, 4, 6, 44–51 accumulation, 48, 49, 50, 51 concentration time course, 46–49, 68, 69 protein binding, 30 see also elimination of drugs pharmacology, history of, 2–4 pharyngitis, 324 α-phase, 46 β-phase, 46 phase I reactions in drug biotransformation, 32, 34 phase II reactions in drug biotransformation, 32, 34 phenacetin, 36 phencyclidine, 240 pheniramine, 114 phenobarbital, 138, 190, 191, 192, 222 enzyme induction, 32, 33 phenolphthalein, 174 phenothiazines, 236, 238, 330 phenoxybenzamine, 90 phenoxymethylpenicillin, 270 phentolamine, 90, 312 phenylbutazone, 200, 316 phenylephrine, 86 phenytoin, 130, 136 epilepsy treatment, 190, 191, 192 folic acid absorption and, 138 phobic disorders, 226 phosphodiesterase, 66 inhibitors, 128 phospholipase A2, 248 phospholipase C, 66, 100, 150 phospholipid bilayer, 20, 26 as barrier, 22 phospholipids, 20, 26 phosphoric acid, 20 physostigmine, 102, 103, 106, 302 pilocarpine, 102 pindolol, 94, 95 pinworm, 292, 293 pipecuronium, 184 piperacillin, 270 piperazine, 236, 238 pirenzepine, 104, 107, 166 piretanide, 162 piroxicam, 200, 320 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. pizotifen, 322 placebo effect, 76, 77 placebo-controlled trials, 76 placental barrier, 24 Plantago, 170 plasma volume expanders, 152–153 plasmalemma, 20 plasmin, 146 inhibitors, 146 plasminogen, 144, 146 activators, 146 Plasmodium falciparum, 294 Plasmodium ovale, 294 Plasmodium vivax, 294 platelet activating factor (PAF), 148, 150 platelet cyclooxygenase, 150, 151 platelet factor 3 (PF3), 142 platelets, 148, 149, 196 inhibitors of aggregation, 150, 151 plicamycin, 264 poisoning antidotes, 302–305 atropine, 106, 202, 302 polidocanol, 208 polyarthritis, chronic, 320 polyene antibiotics, 282, 283 polymyxins, 266, 267 portal vein, 32, 33 potassium (K + ) channel ac- tivation, 66 potassium-sparing diuret- ics, 164, 165 potency, 54, 60, 61 potentiation, 76 powders, 12, 13, 16, 17 pramipexole, 188 pravastatin, 156 praziquantel, 292, 293 prazosin, 90 preclinical testing, 6 prednisolone, 36, 248, 249 prednisone, biotransfor- mation, 36 pregnancy drug toxicity, 74, 75 hypertension treatment, 312 vomiting, 330, 331 pregnandiol, 254, 255 premedication, 104, 106, 226 prevertebral ganglia, 82 prilocaine, 208, 209 biotransformation, 34, 35 primaquine, 294, 295 primary biliary cirrhosis, 180 primidone, 138, 192 pro-opiomelanocortin, 210, 211 probenecid, 268, 269, 316, 317 probucol, 156 procainamide, 134, 136 procaine, 134, 208, 209, 268 biotransformation, 34, 35 prodrugs, 34 prodynorphin, 210 proenkephalin, 210, 211 progabide, 190 progesterone, 254, 255, 257 progestin preparations, 254 oral contraceptives, 256 proguanil, 294, 295 prokinetic agents, 116 prolactin, 242, 243 prolactin release inhibiting hormone (PRIH), 242 prolactin-releasing hor- mone (PRH), 242 promethazine, 114 propafenone, 136 propofol, 220, 221 propranolol, 94, 95, 322 biotransformation, 36, 37 enantioselectivity, 62 propylthiouracil, 247 propyphenazone, 198 prospective trials, 76 prostacyclin, 116, 118, 148, 150, 196 prostaglandin synthase in- hibitors, 320 prostaglandins, 126, 168, 196, 197, 320 NSAIDS and, 200, 201 prostate benign hyperplasia, 90, 252, 312 carcinoma, 242 hypertrophy, 106 protamine, 144 protease inhibitors, 288, 289 protein binding, of drugs, 30–31 protein kinase A, 66 protein synthesis, 276 inhibitors, 276–279 protein synthesis-regulat- ing receptors, 64, 65 protirelin, 242 pseudocholinesterase defi- ciency, 186 pseudoparkinsonism, 238 psilocin, 240 psilocybin, 116, 240 psychedelic drugs, 116–118, 240, 241 psychological dependence, 210–212 psychomimetics, 240, 241 psychopharmacologicals, 226–241 psychosomatic un- coupling, 232, 236 purgatives, 170–177 dependence, 172, 173 pyrazinamide, 280, 281 pyridostigmine, 102 pyridylcarbinol, 156 pyrimethamine, 294, 295 pyrogens, 202, 203 Q quinapril, 124 quinidine, 136, 295 quinine, 294 4-quinolone-3-carboxylic acid, 274, 275 382 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Index 383 R racemates, 62, 63 raloxifen, 254 ramipril, 124 ranitidine, 116, 168 rapid eye movement (REM) sleep, 222, 223 reactive hyperemia, 90, 91 receptor-mediated endo- cytosis, 26, 27 receptors, 20 drug binding, 56 types of, 64–65 rectal administration, 12, 18, 19 reduction reactions, 36, 37 renal failure, prophylaxis, 158 renal tubular secretion, 40 renin, 124, 158 renin-angiotensin-aldoste- rone (RAA) system, 118, 125, 158 inhibitors of, 124–125 reserpine, 96, 114 resistance, 266, 267 respiratory tract, 22 inhalation of drugs, 14, 15, 18, 19 retarded drug release, 10, 11 reteplase, 146 retrospective trials, 76 reverse transcriptase, 288 inhibitors, 288, 289 Reye’s syndrome, 198 rheumatoid arthritis, 302, 320–321 rhinitis, 324 ribonucleic acid (RNA), 274 synthesis inhibition, 298, 299 ribosomes, 276 ricinoleic acid, 174, 175 rifabutin, 274 rifampin, 267, 274, 280, 281 risk:benefit ratio, 70 risperidone, 238, 240 ritodrine, 126 ritonavir, 288 rocuronium, 184 rolitetracycline, 278 ropinirole, 188 rosiglitazone, 262 rough endoplasmic reticu- lum (rER), 32, 33 roundworms, 292, 293 S salazosulfapyridine, 272 salbutamol, 86, 328 salicylates, 200 salicylic acid, 34 see also acetylsalicylic acid salmeterol, 328 Salmonella typhi, 270, 271 saluretics, see diuretics saquinavir, 288, 289 sarcoplasmic reticulum, 182 Sarcoptes scabiei, 292 sartans, 124 Schistosoma, 292 schizophrenia, 118, 236, 237 Schmiedeberg, Oswald, 3 scopolamine, 106, 107, 240, 330 sea sickness, 106, 330, 331 sedation, 222, 226 scopolamine, 106 seizures, 190, 226 selectivity, lack of, 70, 71 selegiline, 88, 188 senna, 174, 176 sensitivity increased, 70, 71 variation, 52 sensitization, 72 serotonin, 88, 116–118 actions, 116 neuronal reuptake, 230 platelet activation, 148, 150 receptors, 116, 230, 322 serotonin-selective reup- take inhibitors (SSRI), 230, 232 sertindole, 238 sertraline, 232 Sertümer, F.W., 4 serum sickness, 72 sibutramine, 88 side effects, 70–75 signal transduction, 64, 66 lithium ion effects, 234 simethicone, 180 simile principle, 76 simvastatin, 156 sinus bradycardia, 134 sinus tachycardia, 92, 134 sisomycin, 278 skin as barrier, 22 disinfection, 290, 291 protection, 16, 17 transdermal drug deliv- ery systems, 12, 13, 18, 19 sleep, 222, 223 disturbances, 118, 222, 224 sleep-wake cycle, 224, 225 slow-release tablets, 10 smoking, 112–113 see also nicotine smooth endoplasmic retic- ulum (sER), 32, 33 smooth muscle acetylcholine effects, 100, 101 adrenoceptor activation effects, 84 drugs acting on, 126–127 relaxation of, 104, 120, 122, 326 vascular, 118, 120, 122, 196, 326 sodium channel blockers, 128, 134–137, 204 sodium chloride reabsorp- tion, kidney, 160, 161 sodium citrate, 264 sodium methohexital, 221 sodium monofluorophos- phate, 318 sodium nitroprusside, 120, 312 sodium picosulfate, 174 sodium thiopental, 221 solutions, 8, 17 concentration of, 28 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. injectable, 12 somatic nervous system, 80 somatocrinin, 242 somatostatin, 242 somatotropic hormone (STH), 242, 243 soporifics, 222 sorbitol, 160, 170 sore throat, 324, 325 sotalol, 136 spasmolytics, 126, 127 spasticity, 226 spermatogenesis stimula- tion, 252 spiramycin, 276 spironolactone, 164, 165 stage fright, 92 stanozolol, 252 Staphylococcus bacteria, 270 statins, 156 status epilepticus, 190, 192 stavudine, 288 steady state, 48 steal effect, 306 stereoisomerism, 62 sterilization, 290 steroid receptors, 64 steroids, anabolic, 252 Straub tail phenomenon, 52, 53 streptokinase, 144, 310 Streptomyces bacteria, 276, 277, 300, 302 streptomycin, 276, 280, 281 stress, sleep disturbances and, 224, 225 stroke, 148 Strongyloides stercoralis, 292 strychnine, 182 subcutaneous injection, 18, 19 subliminal dosing, 52 sublingual drug adminis- tration, 18, 19, 22 succinylcholine, 186 sucralfate, 168, 169 sulbactam, 270 sulfadoxine, 294, 295 sulfamethoxazole, 272, 273 sulfapyridine, 272 sulfasalazine, 272, 320 sulfinpyrazone, 316 sulfonamides antibacterial, 267, 272, 273 diuretics, 162, 163 sulfonylurea, 262 sulfotransferases, 38 sulfoxidations, 36 sulprostone, 126 sulthiame, 162 sumatriptan, 116, 322 suppositories, 12, 13 suspensions, 8 swallowing problems, 324 sweat glands atropine poisoning and, 106 sympathetic innervation, 80 sympathetic nervous system, 80–97 drugs acting on, 84–97 responses to activation, 80, 81 structure of, 82 sympatholytics α-sympatholytics, 90, 91 β-sympatholytics, 92, 93, 94, 95 non-selective, 90 selective, 90 sympathomimetics, 90, 91, 128, 132, 314 allergic disorder treat- ment, 326 asthma treatment, 328 bronchodilation, 126 common cold treatment, 324, 325 direct, 84, 86 indirect, 86, 88, 89 intrinsic activity (IS), 94 sinus bradycardia and, 134 structure-activity rela- tionships, 86, 87 synapse adrenergic, 82 cholinergic, 100 synapsin, 100 synovectomy, 320 syrups, 8 T T lymphocytes, 72, 300 tablets, 8–10 vaginal, 12, 13 tachycardia, 134 atropine poisoning and, 106 treatment, 92, 122, 134 tachyphylaxis, 88 tacrine, 102 tacrolimus, 300 tamoxifen, 254 tape worms, 292, 293 tardive dyskinesia, 238 tazobactam, 270 temazepam, 222, 224 teniposide, 298 teratogenicity, 74 terazosin, 90 terbutaline, 84, 86, 326, 328 testing clinical, 6 preclinical, 6 testosterone, 34, 242, 252, 253 esters, 252 testosterone heptanoate, 252 testosterone propionate, 252 testosterone undecanoate, 34, 252 tetanus toxin, 182, 183 tetracaine, 208, 324 tetracyclines, 266, 267, 276–279 tetrahydrocannabinol, 240 tetrahydrofolic acid (THF), 272, 298, 299 tetrahydrozoline, 90, 326 thalidomide, 74 thallium salt poisoning, 304 theophylline, 118, 126, 127, 326, 328 thermoregulation, 196, 202–203 384 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Index 385 thiamazole, 247 thiazide diuretics, 132, 162, 163, 312 thiazolidinediones, 262–264 thio-TEPA, 298 thioamides, 246, 247 thiopental, 220 thiourea derivatives, 246 thioureylenes, 246 thioxanthenes, 236, 238 thrombasthenia, 148 thrombin, 150 thrombocytopenia, 72 thromboses, 142, 148, 158 prophylaxis, 142–143, 146, 148–151 thromboxane, 148, 150, 196 thymeretics, 230, 232 thymidine kinase, 286 thymoleptics, 230, 238 thyroid hormone recep- tors, 64 thyroid hormone therapy, 244–245 thyroid hyperfunction, 202 thyroid peroxidase, 246 thyroid stimulating hor- mone (TSH), 242, 243, 244 thyrotropin, 242 thyrotropin-releasing hor- mone (TRH), 242 thyroxine, 244, 245, 246 tiagabin, 190 ticarcillin, 270 ticlopidine, 150 tight junctions, 22, 24 timed-release capsules, 10 timidazole, 274 timolol, 94 tincture, 4 tirofiban, 150 tissue plasminogen activa- tor (t-PA), 146 tizanidine, 182 tobacco smoking, 112–113 see also nicotine tobramycin, 277, 278 tocainide, 136 tocolysis, 84, 127 tocolytics, 126 tolbutamide, 262 tolonium chloride, 304, 305 Toluidine Blue, 304, 305 tonsillitis, 324 topiramate, 191, 192 topoisomerase II, 274 total intravenous anesthe- sia (TIVA), 216 toxicological investiga- tions, 6 tracheitis, 324 tramadol, 210 trandolapril, 124 tranexamic acid, 16 transcytosis, 24, 26 transdermal drug delivery systems, 12, 13, 18, 19 estrogen preparations, 254 transferrin, 140 transmitter substances, 20 cholinergic synapse, 100 sympathetic, 82 transpeptidase, 268 inhibition of, 268, 270 transport membrane permeation, 26, 27 mucociliary, 14 transport proteins, 20 tranylcypromine, 88, 232 travel sickness, 106 trials, clinical, 76 triamcinolone, 248, 249 triamterene, 164, 165 triazolam, 222, 223, 224, 226 triazole derivatives, 282 Trichinella spiralis, 292, 293 trichlormethiazide, 162 Trichomonas vaginalis, 274, 275 Trichuris trichiura, 292 tricyclic antidepressants, 230–232 trifluperazine, 236, 238, 239 triflupromazine, 236, 238, 239 triglycerides, 154–156, 248 triiodothyronine, 244, 245 trimeprazine, 330 trimethaphan, 108 trimethoprim, 267, 272, 273 triptorelin, 242 troglitazone, 262–264 trolnisetron, 330 tropisetron, 116 tuberculosis, 274, 276, 280 d-tubocurarine, 184, 185 tumours, see cancer; carci- noma tyramine, 232 L-tyrosine, 82 tyrosine kinase activity, 64 tyrothricin, 266, 267 U ulcers, peptic, 104, 106, 166–169 ultralente, 258 uricostatics, 316, 317 uricosurics, 316, 317 urine, drug elimination, 40 urokinase, 146 ursodeoxycholic acid (UDCA), 180 V vaccinations, 284 vaginal tablets, 12, 13 vagus nerve, 98 valacyclovir, 286 valproate, 190, 192, 234 valproic acid, 191, 192 van der Waals’ bonds, 58, 59 vancomycin, 267, 268, 270 vanillylmandelic acid, 82 varicosities, 82 vasculitis, 72 vasoactive intestinal pep- tide (VIP), 242 vasoconstriction, 84, 90 nicotine and, 110 serotonin actions, 116 vasoconstrictors, local an- esthesia and, 206 vasodilation, 84 local anesthesia and, 206 Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. serotonin actions, 116 vasodilators, 118–123, 312 calcium antagonists, 122–123 organic nitrates, 120–121 vasopressin, 148, 160, 164, 165, 242 nicotine and, 110 vecuronium, 184 vegetable fibers, 170 verapamil, 122, 123, 136 angina treatment, 308 hypertension and, 312 mania treatment, 234 ventricular rate modifi- cation, 134 Vibrio cholerae, 178 vidarabine, 285, 386 vigabatrin, 190, 191 vinblastine, 296 vincristine, 296 viomycin, 280 viral infections, 178, 284–289 AIDS, 288–289 common cold, 324–325 virustatic antimetabolites, 284–287 vitamin A derivatives, 74 vitamin B12, 138, 139 deficiency, 138 vitamin D, 264 vitamin D hormone, 264, 265 vitamin K, 144, 145 VLDL particles, 154 volume of distribution, 28, 44 vomiting drug-induced, 330 pregnancy, 330, 331 see also antiemetics; motion sickness Von-Willebrandt factor, 148, 149 W Wepfer, Johann Jakob, 3 whipworm, 292 Wilson’s disease, 302 wound disinfection, 290, 291 X xanthine oxidase, 316, 317 xanthinol nicotinate, 156 xenon, 218 xylometazoline, 90 Z zafirlukast, 328 zalcitabine, 288 zero-order kinetics, 44 zidovudine, 289 zinc insulin, 258 Zollinger-Ellison syn- drome, 168 zolpidem, 222 zonulae occludentes, 22, 24, 206 zopiclone, 222 386 Index Lüllmann, Color Atlas of Pharmacology ? 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.