Chapter 49

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 49

Antidysrhythmic Drugs

2Copyright © 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


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


Electrical Properties of the Heart

Impulse conduction: pathways and timing Sinoatrial (SA) node: pacemaker of heart Atrioventricular (AV) node His-Purkinje system


Fig. 49–1. Cardiac conduction pathways.


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


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

• Phases 1, 2, and 3 Phase 1 absent Phases 2 and 3 not significant

• Phase 4: depolarization


Fig. 49–2. Ion fluxes during cardiac action potentials and effects of antidysrhythmic drugs.


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


Fig. 49–3. The electrocardiogram.


Generation of Dysrhythmias

Two fundamental causes Disturbances of automaticity Disturbances of conduction

Atrioventricular block Reentry (recirculating activation)


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


Common Dysrhythmias and Their Treatment

Supraventricular Impulse arises above the ventricle Atrial fibrillation Atrial flutter Sustained supraventricular tachycardia (SVT)


Common Dysrhythmias and Their Treatment

Ventricular Sustained ventricular tachycardia Ventricular fibrillation Ventricular premature beats Digoxin-induced ventricular dysrhythmias Torsades de pointes


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


Class I: Sodium Channel Blockers

Class IA agents Class IB agents Class IC agents


Fig. 49-4. Reentrant activation: mechanism and drug effects.


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


Class IA Agents

Quinidine (cont’d) Adverse effects

• Diarrhea• Cinchonism• Cardiotoxicity• Arterial embolism• Alpha-adrenergic blockade, resulting in hypotension• Hypersensitivity reactions

Drug interactions• Digoxin


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


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


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


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


Class II: Beta Blockers

Beta-adrenergic blocking agents Only four approved for treating dysrhythmias

1. Propranolol2. Acebutolol3. Esmolol4. Sotalol



Propranolol (Inderal): nonselective beta-adrenergic 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



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)


Class III: Potassium Channel Blockers

Amiodarone (Cordarone, Pacerone) Therapeutic use

• For life-threatening ventricular dysrhythmias only• Recurrent ventricular fibrillation• Recurrent hemodynamically unstable ventricular

tachycardia



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



Amiodarone (Cordarone, Pacerone) (cont’d) Adverse effects

• Protracted half-life• Pulmonary toxicity• Cardiotoxicity• Toxicity in pregnancy and breast-feeding• Corneal microdeposits• Optic neuropathy



Amiodarone (Cordarone, Pacerone) (cont’d) Drug interactions (increases levels)

• Quinidine• Diltiazem• Cyclosporine• Digoxin• Procainamide• Diltiazem• Phenytoin• Warfarin• Lovastatin, simvastatin, atorvastatin



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)



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



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



Sotalol (Betapace) Combined class II and class III properties Beta blocker that also delays repolarization

Dofetilide (Tikosyn) Oral class III antidysrhythmic Predisposes patient to torsades de pointes

Ibutilide (Covert) Class III agent IV agent used to terminate atrial flutter/fibrillation


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


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


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



Adenosine (Adenocard) (cont’d) Adverse effects

• Sinus bradycardia• Dyspnea• Hypotension• Facial flushing• Chest discomfort

Drug interactions• Methylxanthines• Dipyridamole



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


Nondrug Treatment of Dysrhythmias

Implantable cardioverter-defibrillators Radiofrequency catheter ablation

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Chapter 49