Chapter 16 Cholinesterase Inhibitors

Report
Chapter 49
Antidysrhythmic Drugs
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Dysrhythmia

Dysrhythmia

An abnormality in the rhythm of the heartbeat
(also known as arrhythmias)
 Arises from impulse formation disturbances
• Tachydysrhythmias: SVT and ventricular
• Bradydysrhythmias

Virtually all drugs that treat dysrhythmias can
also cause dysrhythmias
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Antidysrhythmic Drugs





Electrical properties of the heart
Generation of dysrhythmias
Classification of antidysrhythmic drugs
Prodysrhythmic effects of antidysrhythmic
drugs
Overview of common dysrhythmias and their
treatment
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Electrical Properties of the Heart

Impulse conduction: pathways and timing



Sinoatrial (SA) node: pacemaker of heart
Atrioventricular (AV) node
His-Purkinje system
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Fig. 49–1. Cardiac conduction pathways.
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Cardiac Action Potentials

Fast potentials

Occur in fibers of the His-Purkinje system and in
atrial and ventricular muscle
 Five distinct phases
• Phase 0: depolarization
• Phase 1: (partial) repolarization
• Phase 2: plateau
• Phase 3: repolarization
• Phase 4: stable potential
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Cardiac Action Potentials

Slow potentials


Occur in cells of the SA node and AV node
Three features of special significance
• Phase 0: slow depolarization

Mediated by calcium influx

Phase 1 absent
Phases 2 and 3 not significant
• Phases 1, 2, and 3

• Phase 4: depolarization
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Fig. 49–2. Ion fluxes during cardiac action potentials and effects of
antidysrhythmic drugs.
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The Electrocardiogram


Provides a graphic representation of cardiac
electrical activity
Major components of an ECG




P wave
• Depolarization in the atria
QRS complex
• Depolarization of the ventricles
T wave
• Repolarization of the ventricles
Three other components



PR interval
QT interval
ST segment
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Fig. 49–3. The electrocardiogram.
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Generation of Dysrhythmias



Two fundamental causes
Disturbances of automaticity
Disturbances of conduction


Atrioventricular block
Reentry (recirculating activation)
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Classification of
Antidysrhythmic Drugs

Vaughan Williams classification





Class I: sodium channel blockers
Class II: beta blockers
Class III: potassium channel blockers
Class IV: calcium channel blockers
Other: adenosine, digoxin, and ibutilide
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Common Dysrhythmias
and Their Treatment

Supraventricular




Impulse arises above the ventricle
Atrial fibrillation
Atrial flutter
Sustained supraventricular tachycardia (SVT)
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Common Dysrhythmias
and Their Treatment

Ventricular





Sustained ventricular tachycardia
Ventricular fibrillation
Ventricular premature beats
Digoxin-induced ventricular dysrhythmias
Torsades de pointes
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Principles of Antidysrhythmic
Drug Therapy

Balancing risks and benefits



Consider properties of dysrhythmias
• Sustained vs. nonsustained
• Asymptomatic vs. symptomatic
• Supraventricular vs. ventricular
Acute and long-term treatment phases
Minimizing risk
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Class I: Sodium Channel Blockers



Class IA agents
Class IB agents
Class IC agents
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Fig. 49-4. Reentrant activation: mechanism and drug effects.
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Class IA Agents

Quinidine



Effects on the heart
• Blocks sodium channels
• Slows impulse conduction
• Delays repolarization
• Blocks vagal input to the heart
Effects on ECG
• Widens the QRS complex
• Prolongs the QT interval
Therapeutic uses
• Used against supraventricular and ventricular
dysrhythmias
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Class IA Agents

Quinidine (cont’d)

Adverse effects
• Diarrhea
• Cinchonism
• Cardiotoxicity
• Arterial embolism
• Alpha-adrenergic blockade, resulting in hypotension
• Hypersensitivity reactions
 Drug interactions
• Digoxin
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Other Class IA Agents

Procainamide (Procanbid)




Similar to quinidine
Only weakly anticholinergic
Adverse effects: symptoms of systemic lupus
erythematosus
Disopyramide (Norpace)


Similar to quinidine
Prominent side effects have limited its use
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Class IB Agents

Lidocaine (Xylocaine)

Effects on the heart and ECG
• Blocks cardiac sodium channels

Slows conduction in the atria, ventricles, and His-Purkinje
system
• Reduces automaticity in the ventricles and His-Purkinje
system
• Accelerates repolarization

Adverse effects
• CNS effects
• Drowsiness
• Confusion
• Paresthesias
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Class IB Agents

Other class IB agents

Phenytoin
• Antiseizure medication also used to treat digoxin-induced
dysrhythmias

Mexiletine
• Oral analog of lidocaine
• Used for symptomatic ventricular dysrhythmias
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Class IC Agents




Block cardiac sodium channels
Delay ventricular repolarization
All class IC agents can exacerbate existing
dysrhythmias and create new ones
Two class IC agents


Flecainide
Propafenone
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Class II: Beta Blockers

Beta-adrenergic blocking agents

Only four approved for treating dysrhythmias
1.
2.
3.
4.
Propranolol
Acebutolol
Esmolol
Sotalol
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Class II: Beta Blockers

Propranolol (Inderal): nonselective betaadrenergic antagonist


Effects on the heart and ECG
• Decreased automaticity of the SA node
• Decreased velocity of conduction through the AV node
• Decreased myocardial contractility
Therapeutic use
• Dysrhythmias caused by excessive sympathetic
stimulation
• Supraventricular tachydysrhythmias


Suppression of excessive discharge
Slowing of ventricular rate
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Class II: Beta Blockers

Propranolol (Inderal) (cont’d)


Adverse effects
• Heart block
• Heart failure
• AV block
• Sinus arrest
• Hypotension
• Bronchospasm (in asthma patients)
Other class II: beta blockers


Acebutolol (Sectral)
Esmolol (Brevibloc)
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Class III: Potassium
Channel Blockers

Amiodarone (Cordarone, Pacerone)

Therapeutic use
• For life-threatening ventricular dysrhythmias only
• Recurrent ventricular fibrillation
• Recurrent hemodynamically unstable ventricular
tachycardia
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Class III: Potassium
Channel Blockers

Amiodarone (Cordarone, Pacerone) (cont’d)

Effects on the heart and ECG
• Reduced automaticity in the SA node
• Reduced contractility
• Reduced conduction velocity
• QRS widening
• Prolongation of the PR and QT intervals
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Class III: Potassium
Channel Blockers

Amiodarone (Cordarone, Pacerone) (cont’d)

Adverse effects
• Protracted half-life
• Pulmonary toxicity
• Cardiotoxicity
• Toxicity in pregnancy and breast-feeding
• Corneal microdeposits
• Optic neuropathy
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Class III: Potassium
Channel Blockers

Amiodarone (Cordarone, Pacerone) (cont’d)

Drug interactions (increases levels)
• Quinidine
• Diltiazem
• Cyclosporine
• Digoxin
• Procainamide
• Diltiazem
• Phenytoin
• Warfarin
• Lovastatin, simvastatin, atorvastatin
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Class III: Potassium
Channel Blockers


Amiodarone levels can be increased by
grapefruit juice and by inhibitors of CYP3A4.
Toxicity can result
Amiodarone levels can be reduced by
cholestyramine (which decreases
amiodarone absorption) and by agents that
induce CYP3A4 (eg, St. John’s wort, rifampin)
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Class III: Potassium
Channel Blockers


The risk of severe dysrhythmias is increased
by diuretics (because they can reduce levels
of potassium and magnesium) and by drugs
that prolong the QT interval, of which there
are many (see Chapter 7)
Combining amiodarone with a beta blocker,
verapamil, or diltiazem can lead to excessive
slowing of heart rate
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Class III: Potassium
Channel Blockers


Dronedarone (Multaq)
Derivative of amiodarone approved in 2009




Effects on the heart and ECG
Pharmacokinetics
Adverse effects
• Common side effects
• Cardiac effects in severe heart failure
• Liver toxicity
• Toxicity in pregnancy and breast-feeding
Drug interactions
• Multiple—many involve CYP3A4
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Class III: Potassium
Channel Blockers

Sotalol (Betapace)



Dofetilide (Tikosyn)



Combined class II and class III properties
Beta blocker that also delays repolarization
Oral class III antidysrhythmic
Predisposes patient to torsades de pointes
Ibutilide (Covert)


Class III agent
IV agent used to terminate atrial flutter/fibrillation
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Class IV: Calcium
Channel Blockers

Verapamil (Calan, Isoptin, Verelan) and
diltiazem (Cardizem)




Reduce SA nodal automaticity
Delay AV nodal conduction
Reduce myocardial contractility
Therapeutic uses
• Slow ventricular rate (atrial fibrillation or atrial flutter)
• Terminate SVT caused by an AV nodal reentrant circuit
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Class IV: Calcium
Channel Blockers

Verapamil (Calan, Isoptin, Verelan) and
diltiazem (Cardizem) (cont’d)

Adverse effects
• Bradycardia
• Hypotension
• AV block
• Heart failure
• Peripheral edema
• Constipation
• Can elevate digoxin levels
• Increased risk when combined with a beta blocker
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Other Antidysrhythmic Drugs

Adenosine (Adenocard)


Effects on the heart and ECG
• Decreases automaticity in the SA node
• Slows conduction through the AV node
• Prolongation of PR interval
Therapeutic use: termination of paroxysmal SVT
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Other Antidysrhythmic Drugs

Adenosine (Adenocard) (cont’d)


Adverse effects
• Sinus bradycardia
• Dyspnea
• Hypotension
• Facial flushing
• Chest discomfort
Drug interactions
• Methylxanthines
• Dipyridamole
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Other Antidysrhythmic Drugs

Digoxin (Lanoxin)


Primary indication is heart failure
Also used to treat supraventricular dysrhythmias
(inactive against ventricular dysrhythmias)
• Suppresses dysrhythmias by decreasing conduction
through AV node and automaticity in the SA node
• QT interval may be shortened

Adverse effect: cardiotoxicity
• Risk increased by hypokalemia
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Nondrug Treatment
of Dysrhythmias


Implantable cardioverter-defibrillators
Radiofrequency catheter ablation
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