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Chapter 49
Antidysrhythmic Drugs
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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
• Phases 1, 2, and 3 Phase 1 absent Phases 2 and 3 not significant
• 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. Propranolol2. Acebutolol3. Esmolol4. Sotalol
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Class II: Beta Blockers
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
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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) 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
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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