沈阳药科大学药物化学教研室
Antiarrhythmic
Therapy
Antiarrhythmic Therapy
Empiric
Arrhythmia Diagnosis
Interventions
Clinical Outcomes
Interventions
Clinical Outcomes
Pathophysiologic
Arrhythmia Diagnosis
Known or suspected
mechanisms
Critical components
Vulnerable parameters
Targeted subcellular units
BLACK BOX
Antiarrhythmic Therapy
Pathophysiologic
Arrhythmia Diagnosis
Interventions
Clinical Outcomes
Known or suspected
mechanisms
Critical components
Vulnerable parameters
Targeted subcellular units
AV node reentrant tachycardia
AV node reentry
Anatomical fast/slow
pathway
AV node (slow conduction)AV nodal action potential
L-type Ca++ channel
Ca++ channel blocker
-blocker
Sinus rhythm
Vaughn-Williams
Classification
Based on cellular properties of normal
His-Purkinje cells
Classified on drug’s ability to block
specific ionic currents (i.e,Na+,K+,Ca++)
and beta-adrenergic receptors
Advantages:
– Physiologically based
– Highlights beneficial/deleterious effects
of specific drugs
Antiarrhythmic Therapy
Empiric
Arrhythmia Diagnosis
Interventions
Clinical Outcomes
BLACK BOX
Goals
Identify the type of
dysrhythmia
Be familiar with more
common
antiarrhythmics and
their Vaughn-Williams
Classification
Arrhythmia Types
Slow
Fast
Fast wide
Fast narrow
Too fast
Arrhythmia-focused
Therapy
Fast Narrow
Supraventricular tachycardias
– Re-entry type
Orthodromic SVT
– Automatic
A.E.T.,Atrial Flutter
J.E.T.
Arrhythmia-focused
Therapy
Fast Wide
– (rare) Antidromic SVT or SVT with
abberancy
– Ventricular tachycardia
Inappropriate automaticity of
ventricular or His-Purkinje tissue
Arrhythmia-focused
Therapy
Select one antiarrhythmic or
a limited group of
antiarrhythmics to treat the
disorder.
Antiarrhythmic Agents
Vaughn-Williams Classification
Class I - Na+ - channel blockers (direct
membrane action)
Class II - Sympatholytic agents
Class III - Prolong repolarization
Class IV- Ca++ - channel blockers
Purinergic agonists
Digitalis glycosides
The Action Potential
Phase 0
Phase 4
Phase 3
Phase 2
Phase 1
- 90 mV
0 mV
30 mV
Class I
Na+ Channel Blockers
IA - Quinidine/Procainamide/Disopyramide
IB - Lidocaine/Mexiletine/Phenytoin
IC - Flecainide/Propafenone/Ethmozine
1
0
2
3
4
ERP RRP
Affects
Phase 0
Class IA - Na+ Channel Blockers
Procainamide/Quinidine/Disopyramide
Mode of action
– Depress conduction and prolong
refractoriness
Atrial,His-Purkinje,ventricular tissue
– Peripheral alpha block
– Vagolytic
– Negative inotrope
ECG changes
– Increase PR,QRS (Diso,PR? > QRS? )
– Toxicity,QTc increases by 30% or QT > 0.5 sec
– Ca++ channel blockade / potent anticholinergic
(Diso)
Class IA - Na+ Channel
Blockers Procainamide
Uses
– SVT (reentry) or VT
– Afib/flutter (on digoxin)
Drug interactions-Decrease metabolism of
Amiodarone
Dose
– IV,load 15 mg/kg over 1 hour,then 30-80
g/kg/min
– (level 5-10 ng/ml)
– PO,30-70 mg/kg/day
Side effects,Lupus- in slow acetylators
– ANA +,50-90% Symptoms,20-30 %
Arrhythmia-focused
Therapy
Procainamide has been a long-used intravenous
infusion for a wide range of dysrhythmias:
– Narrow complex tachycardia,
Atrial tachycardia,resistant re-entrant
tachycardia
– Wide-complex tachycardia,
Ventricular tachycardia
Downside,
Side effects,negative inotrope,pro-
arrhythmic
Class IB
Lidocaine/Mexiletine/Phenytoin
Mode of action
– Little effect on normal tissues
– Decreases Purkinje ERP/ automaticity
– Increases Ventricular fibrillation
threshold
– Depresses conduction,esp,at high rates
(Mexiletine)
– Suppresses dig-induced delayed
afterdepolarizations (Phenytoin)
ECG changes
– Slight? QTc (Lidocaine/Phenytoin)
Class IB
Lidocaine
Use,VT (acute)
– Acts rapidly; no depression of contractility/AV
conduction
Kinetics
– t1/2,5-10 min (1st phase); 80-110 min (2nd
phase)
Drug interactions
– Decreased metabolism w/ CHF/hepatic failure,
propranolol,cimetidine
– Increased metabolism w/ isuprel,phenobarbital,
phenytoin
Class IB
Lidocaine
Dose
– 1 mg/kg,then 20-50?g/kg/min (level,2-5
g/ml)
Side effects
– CNS toxicity w/ levels > 5?g/ml
Class IB
Mexiletine
Use,VT (post-op CHD)
Kinetics,t1/2 = 8 - 12 hrs
Drug interactions- rare
Dose
– 3-5 mg/kg/dose (adult 200-300mg/dose) po q
8 hrs
Side effects
– Nausea (40%)
– CNS - dizziness/tremor (25%)
Class IB
Phenytoin
Uses
– VT (post-op CHD),digoxin-induced
arrhythmias
Drug interactions
– Coumadin-? PT; Verapamil-? effect
(displaces from protein)
Dose
– PO,4 mg/kg q 6 hrs x 1 day,then 5-6
mg/kg/day ÷q 12hr
– IV,bolus 15 mg/kg over 1 hr; level 15-20
g/ml
Side effects
– Hypotension,gingival hyperplasia,rash
Arrhythmia-focused
Therapy
Class IB antiarrhythmics are very effective
and very safe.
Little or no effect on,normal” tissues
First line for ischemic,automatic
arrhythmia's (Ventricular tachycardia)
Not a lot of effect on normal conduction
tissue – not a good medicine for reentry
and atrial tachycardias.
Class IC
Flecainide/Propafenone/Ethmozine
Mode of action
– Depresses abnormal automaticity
(Flec/Ethmozine)
– Slows conduction in AV node,AP,ventricle
(Flec/Prop)
– Shortens repolarization (Ethmozine)
– Negative inotrope (Propafenone)
– Prolongs atrial/ventricular refractoriness
(Propafenone)
ECG changes
PR,QRS
QTc (Propafenone)
Class IC
Flecainide
Uses,PJRT,AET,CAT,SVT,VT,Afib
Kinetics
– t1/2 = 13 hrs (shorter if between 1-15 mos old)
Drug interactions
– Increases digoxin levels (slight)
– Amiodarone,increases flecainide levels
Class IC
Flecainide
Dose
– 70-225 mg/m2/day ÷q 8-12 hr
– Level,0.2-1.0?g/ml
Side effects
– Negative inotrope- use in normal hearts only
(NO POST-OPs)
– PROARRHYTHMIA - 5-12% (CAST)
Arrhythmia –focused
Therapy
IC’s have a lot of side effects
that make them appropriate for
use only by experienced
providers.
Class II Agents
Beta-blockers
Propranolol
Atenolol
Metoprolol
Nadolol
Esmolol
d,l-Sotalol
Class II
Propranolol
Uses
– SVT (reentry,ectopic)
– Sinus tachycardia (thyrotoxicosis)
– VT (exercise-induced)
Kinetics
– t1/2 = 3 hrs (increased if cyanotic)
Drug interactions
– Verapamil
Hypotension
Decreased LV function
Class II
Propranolol
Dose
– PO,2-4 mg/kg/day? q 6 hrs
– IV,0.05-0.15 mg/kg
Side effects
– Avoid in asthma/diabetes
– CNS effects
Nonpolar - crosses BBB
–? BP
Suppresses renin-aldo-angiotensin axis
Arrhythmia-focused
Therapy
Beta-blockers are good for re-
entry circuits and automatic
dysrhythmias,
Their effect of decreasing
contractility may be limiting.
Class III
K+ - channel blockers
Properties
– Prolong repolarization
– Prolong action potential duration
– Contractility is unchanged or increased
Agents
– Amiodarone
– Sotalol
– Bretylium
– N-acetyl Procainamide (NAPA)
Arrhythmia-focused
Therapy
Can be very powerful antiarrhythmics
but limited indications for first-line use –
beyond the spectrum of primary care
providers
Amiodarone,may become a first-line
medicine for a broad spectrum of
arrhythmias,currently still high-risk
Purinergic Agonists
Adenosine
Mode of action
– Vagotonic
– Anti-adrenergic
– Depresses slow inward Ca++ current
– Increases K+ conductance
(hyperpolarizes)
ECG/EP changes
– Slows AV node conduction
Purinergic Agonists
Adenosine
Uses
– SVT- termination of reentry
– Aflutter- AV block for diagnosis
Kinetics
– t1/2 = < 10 secs
– Metabolized by RBCs and vascular
endothelial cells
Dose
– IV,100-300?g/kg IV bolus
Purinergic Agonists
Adenosine
Drug interactions
– Methylxanthines (caffeine/theophylline)
Side effects
– AFib/ sinus arrest/ sinus bradycardia
– Bronchospasm
– Flushing/headache
– Nausea
Great medicine,quick onset,
quick degradation.
Digoxin
Mode of action
– Na-K ATPase
inhibition
– Positive inotrope
– Vagotonic
ECG changes
– Increases PR interval
– Depresses ST
segment
– Decreases QT interval
Digoxin
Use,SVT (not WPW)
Kinetics
– t1/2 = preemie (61hrs),neonate (35hrs),infant
(18hrs),child (37hrs),adult (35-48hrs )
Interactions
Coumadin-? PT
Digoxin level
Quinidine,amiodarone,verapamil
renal function/renal tubular excretion
(Spironolactone)
Worse with? K+,? Ca++
Digoxin Toxicity
Nausea/vomiting,lethargy,visual changes
Metabolic
– Hyper K+,Ca++
– Hypo K+,Mg++
– Hypoxemia
– Hypothyroidism
Proarrhythmia
– AV block- decreased conduction
– SVT- increased automaticity
– VT- delayed afterdepolarizations
Digoxin Toxicity
Treatment
GI decontamination
– Ipecac/lavage/charcoal w/ cathartic
Arrhythmias
– SA node /AV node depression- Atropine; if
dig > 6,may need pacing
– SVT- Phenytoin or? -blocker
– VT- Lidocaine (1 mg/kg) or Phenytoin
DC Cardioversion may cause
refractory VT/VF!!
Proarrhythmia
Torsades de Pointes
Class IA
– Quinidine 2-8%
– Procainamide 2-3%
– Disopyramide 2-3%
Class III
– d,l-Sotalol 1-5%
– d-Sotalol 1-2%
– NAPA 3-4%
– Amiodarone < 1%
Summary
SVT,Initial
– Adenosine
–?Propranolol
– Procainamide
SVT,Long Term
– Nothing
– Propranolol
– Digoxin
Summary
VT,Initial
– Lidocaine
– Procainamide
VT,Long Term
– Lidocaine/Procainamide
– Beta-blockers
– Cardiologist
60 Cycle Interference
Atrial Flutter
SVT
Ventricular Tachycardia
Ventricular Fibrillation
Antiarrhythmic
Therapy
Antiarrhythmic Therapy
Empiric
Arrhythmia Diagnosis
Interventions
Clinical Outcomes
Interventions
Clinical Outcomes
Pathophysiologic
Arrhythmia Diagnosis
Known or suspected
mechanisms
Critical components
Vulnerable parameters
Targeted subcellular units
BLACK BOX
Antiarrhythmic Therapy
Pathophysiologic
Arrhythmia Diagnosis
Interventions
Clinical Outcomes
Known or suspected
mechanisms
Critical components
Vulnerable parameters
Targeted subcellular units
AV node reentrant tachycardia
AV node reentry
Anatomical fast/slow
pathway
AV node (slow conduction)AV nodal action potential
L-type Ca++ channel
Ca++ channel blocker
-blocker
Sinus rhythm
Vaughn-Williams
Classification
Based on cellular properties of normal
His-Purkinje cells
Classified on drug’s ability to block
specific ionic currents (i.e,Na+,K+,Ca++)
and beta-adrenergic receptors
Advantages:
– Physiologically based
– Highlights beneficial/deleterious effects
of specific drugs
Antiarrhythmic Therapy
Empiric
Arrhythmia Diagnosis
Interventions
Clinical Outcomes
BLACK BOX
Goals
Identify the type of
dysrhythmia
Be familiar with more
common
antiarrhythmics and
their Vaughn-Williams
Classification
Arrhythmia Types
Slow
Fast
Fast wide
Fast narrow
Too fast
Arrhythmia-focused
Therapy
Fast Narrow
Supraventricular tachycardias
– Re-entry type
Orthodromic SVT
– Automatic
A.E.T.,Atrial Flutter
J.E.T.
Arrhythmia-focused
Therapy
Fast Wide
– (rare) Antidromic SVT or SVT with
abberancy
– Ventricular tachycardia
Inappropriate automaticity of
ventricular or His-Purkinje tissue
Arrhythmia-focused
Therapy
Select one antiarrhythmic or
a limited group of
antiarrhythmics to treat the
disorder.
Antiarrhythmic Agents
Vaughn-Williams Classification
Class I - Na+ - channel blockers (direct
membrane action)
Class II - Sympatholytic agents
Class III - Prolong repolarization
Class IV- Ca++ - channel blockers
Purinergic agonists
Digitalis glycosides
The Action Potential
Phase 0
Phase 4
Phase 3
Phase 2
Phase 1
- 90 mV
0 mV
30 mV
Class I
Na+ Channel Blockers
IA - Quinidine/Procainamide/Disopyramide
IB - Lidocaine/Mexiletine/Phenytoin
IC - Flecainide/Propafenone/Ethmozine
1
0
2
3
4
ERP RRP
Affects
Phase 0
Class IA - Na+ Channel Blockers
Procainamide/Quinidine/Disopyramide
Mode of action
– Depress conduction and prolong
refractoriness
Atrial,His-Purkinje,ventricular tissue
– Peripheral alpha block
– Vagolytic
– Negative inotrope
ECG changes
– Increase PR,QRS (Diso,PR? > QRS? )
– Toxicity,QTc increases by 30% or QT > 0.5 sec
– Ca++ channel blockade / potent anticholinergic
(Diso)
Class IA - Na+ Channel
Blockers Procainamide
Uses
– SVT (reentry) or VT
– Afib/flutter (on digoxin)
Drug interactions-Decrease metabolism of
Amiodarone
Dose
– IV,load 15 mg/kg over 1 hour,then 30-80
g/kg/min
– (level 5-10 ng/ml)
– PO,30-70 mg/kg/day
Side effects,Lupus- in slow acetylators
– ANA +,50-90% Symptoms,20-30 %
Arrhythmia-focused
Therapy
Procainamide has been a long-used intravenous
infusion for a wide range of dysrhythmias:
– Narrow complex tachycardia,
Atrial tachycardia,resistant re-entrant
tachycardia
– Wide-complex tachycardia,
Ventricular tachycardia
Downside,
Side effects,negative inotrope,pro-
arrhythmic
Class IB
Lidocaine/Mexiletine/Phenytoin
Mode of action
– Little effect on normal tissues
– Decreases Purkinje ERP/ automaticity
– Increases Ventricular fibrillation
threshold
– Depresses conduction,esp,at high rates
(Mexiletine)
– Suppresses dig-induced delayed
afterdepolarizations (Phenytoin)
ECG changes
– Slight? QTc (Lidocaine/Phenytoin)
Class IB
Lidocaine
Use,VT (acute)
– Acts rapidly; no depression of contractility/AV
conduction
Kinetics
– t1/2,5-10 min (1st phase); 80-110 min (2nd
phase)
Drug interactions
– Decreased metabolism w/ CHF/hepatic failure,
propranolol,cimetidine
– Increased metabolism w/ isuprel,phenobarbital,
phenytoin
Class IB
Lidocaine
Dose
– 1 mg/kg,then 20-50?g/kg/min (level,2-5
g/ml)
Side effects
– CNS toxicity w/ levels > 5?g/ml
Class IB
Mexiletine
Use,VT (post-op CHD)
Kinetics,t1/2 = 8 - 12 hrs
Drug interactions- rare
Dose
– 3-5 mg/kg/dose (adult 200-300mg/dose) po q
8 hrs
Side effects
– Nausea (40%)
– CNS - dizziness/tremor (25%)
Class IB
Phenytoin
Uses
– VT (post-op CHD),digoxin-induced
arrhythmias
Drug interactions
– Coumadin-? PT; Verapamil-? effect
(displaces from protein)
Dose
– PO,4 mg/kg q 6 hrs x 1 day,then 5-6
mg/kg/day ÷q 12hr
– IV,bolus 15 mg/kg over 1 hr; level 15-20
g/ml
Side effects
– Hypotension,gingival hyperplasia,rash
Arrhythmia-focused
Therapy
Class IB antiarrhythmics are very effective
and very safe.
Little or no effect on,normal” tissues
First line for ischemic,automatic
arrhythmia's (Ventricular tachycardia)
Not a lot of effect on normal conduction
tissue – not a good medicine for reentry
and atrial tachycardias.
Class IC
Flecainide/Propafenone/Ethmozine
Mode of action
– Depresses abnormal automaticity
(Flec/Ethmozine)
– Slows conduction in AV node,AP,ventricle
(Flec/Prop)
– Shortens repolarization (Ethmozine)
– Negative inotrope (Propafenone)
– Prolongs atrial/ventricular refractoriness
(Propafenone)
ECG changes
PR,QRS
QTc (Propafenone)
Class IC
Flecainide
Uses,PJRT,AET,CAT,SVT,VT,Afib
Kinetics
– t1/2 = 13 hrs (shorter if between 1-15 mos old)
Drug interactions
– Increases digoxin levels (slight)
– Amiodarone,increases flecainide levels
Class IC
Flecainide
Dose
– 70-225 mg/m2/day ÷q 8-12 hr
– Level,0.2-1.0?g/ml
Side effects
– Negative inotrope- use in normal hearts only
(NO POST-OPs)
– PROARRHYTHMIA - 5-12% (CAST)
Arrhythmia –focused
Therapy
IC’s have a lot of side effects
that make them appropriate for
use only by experienced
providers.
Class II Agents
Beta-blockers
Propranolol
Atenolol
Metoprolol
Nadolol
Esmolol
d,l-Sotalol
Class II
Propranolol
Uses
– SVT (reentry,ectopic)
– Sinus tachycardia (thyrotoxicosis)
– VT (exercise-induced)
Kinetics
– t1/2 = 3 hrs (increased if cyanotic)
Drug interactions
– Verapamil
Hypotension
Decreased LV function
Class II
Propranolol
Dose
– PO,2-4 mg/kg/day? q 6 hrs
– IV,0.05-0.15 mg/kg
Side effects
– Avoid in asthma/diabetes
– CNS effects
Nonpolar - crosses BBB
–? BP
Suppresses renin-aldo-angiotensin axis
Arrhythmia-focused
Therapy
Beta-blockers are good for re-
entry circuits and automatic
dysrhythmias,
Their effect of decreasing
contractility may be limiting.
Class III
K+ - channel blockers
Properties
– Prolong repolarization
– Prolong action potential duration
– Contractility is unchanged or increased
Agents
– Amiodarone
– Sotalol
– Bretylium
– N-acetyl Procainamide (NAPA)
Arrhythmia-focused
Therapy
Can be very powerful antiarrhythmics
but limited indications for first-line use –
beyond the spectrum of primary care
providers
Amiodarone,may become a first-line
medicine for a broad spectrum of
arrhythmias,currently still high-risk
Purinergic Agonists
Adenosine
Mode of action
– Vagotonic
– Anti-adrenergic
– Depresses slow inward Ca++ current
– Increases K+ conductance
(hyperpolarizes)
ECG/EP changes
– Slows AV node conduction
Purinergic Agonists
Adenosine
Uses
– SVT- termination of reentry
– Aflutter- AV block for diagnosis
Kinetics
– t1/2 = < 10 secs
– Metabolized by RBCs and vascular
endothelial cells
Dose
– IV,100-300?g/kg IV bolus
Purinergic Agonists
Adenosine
Drug interactions
– Methylxanthines (caffeine/theophylline)
Side effects
– AFib/ sinus arrest/ sinus bradycardia
– Bronchospasm
– Flushing/headache
– Nausea
Great medicine,quick onset,
quick degradation.
Digoxin
Mode of action
– Na-K ATPase
inhibition
– Positive inotrope
– Vagotonic
ECG changes
– Increases PR interval
– Depresses ST
segment
– Decreases QT interval
Digoxin
Use,SVT (not WPW)
Kinetics
– t1/2 = preemie (61hrs),neonate (35hrs),infant
(18hrs),child (37hrs),adult (35-48hrs )
Interactions
Coumadin-? PT
Digoxin level
Quinidine,amiodarone,verapamil
renal function/renal tubular excretion
(Spironolactone)
Worse with? K+,? Ca++
Digoxin Toxicity
Nausea/vomiting,lethargy,visual changes
Metabolic
– Hyper K+,Ca++
– Hypo K+,Mg++
– Hypoxemia
– Hypothyroidism
Proarrhythmia
– AV block- decreased conduction
– SVT- increased automaticity
– VT- delayed afterdepolarizations
Digoxin Toxicity
Treatment
GI decontamination
– Ipecac/lavage/charcoal w/ cathartic
Arrhythmias
– SA node /AV node depression- Atropine; if
dig > 6,may need pacing
– SVT- Phenytoin or? -blocker
– VT- Lidocaine (1 mg/kg) or Phenytoin
DC Cardioversion may cause
refractory VT/VF!!
Proarrhythmia
Torsades de Pointes
Class IA
– Quinidine 2-8%
– Procainamide 2-3%
– Disopyramide 2-3%
Class III
– d,l-Sotalol 1-5%
– d-Sotalol 1-2%
– NAPA 3-4%
– Amiodarone < 1%
Summary
SVT,Initial
– Adenosine
–?Propranolol
– Procainamide
SVT,Long Term
– Nothing
– Propranolol
– Digoxin
Summary
VT,Initial
– Lidocaine
– Procainamide
VT,Long Term
– Lidocaine/Procainamide
– Beta-blockers
– Cardiologist
60 Cycle Interference
Atrial Flutter
SVT
Ventricular Tachycardia
Ventricular Fibrillation
