Pharmacology for Nursing Care:, 8thth Edition

49-2Key Points: Print

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

Copyright 2013, 2010 by Saunders, an imprint of Elsevier Inc.Lehne: Pharmacology for Nursing Care, 8th Edition

Chapter 49: Antidysrhythmic Drugs

Key Points: Print

Chapter 49 begins with a discussion of the electrical properties of the heart and the factors that lead to the generation of dysrhythmias.

A dysrhythmia is defined as an abnormality in the rhythm of the heartbeat.The two basic types of dysrhythmias are tachydysrhythmias (dysrhythmias in which heart rate is increased) and bradydysrhythmias (dysrhythmias in which heart rate is slowed).The tachydysrhythmias are by far the largest group of dysrhythmias and the group that responds best to drugs.Although they are not addressed in the chapter, bradydysrhythmias are few in number and are commonly treated with electronic pacing. When drugs are indicated, atropine and isoproterenol usually are the agents of choice.It is important to appreciate that virtually all the drugs used to treat dysrhythmias can also cause dysrhythmias.Dysrhythmias result from alteration of the electrical impulses that regulate cardiac rhythm. Antidysrhythmic drugs control rhythm by correcting or compensating for these alterations.In the healthy heart, impulses originate in the sinoatrial (SA) node, spread rapidly through the atria, pass slowly through the atrioventricular (AV) node, and then spread rapidly through the ventricles via the His-Purkinje system.Cardiac cells can initiate and conduct action potentials, consisting of self-propagating waves of depolarization followed by repolarization.In the heart, two kinds of action potentials occur: fast potentials and slow potentials. These potentials differ with respect to the mechanisms by which they are generated, the kinds of cells in which they occur, and the drugs to which they respond.Fast potentials occur in fibers of the His-Purkinje system and in atrial and ventricular muscle.Fast potentials have five distinct phases, labeled 0, 1, 2, 3, and 4.In phase 0, the cell undergoes rapid depolarization in response to an influx of sodium ions. Drugs that reduce the rate of phase 0 depolarization (by blocking sodium channels) slow impulse conduction though the His-Purkinje system and myocardium.During phase 1, rapid (but partial) repolarization takes place. Phase 1 has no relevance to antidysrhythmic drugs.Phase 2 consists of a prolonged plateau in which the membrane potential remains relatively stable. During this phase, calcium enters the cell and promotes contraction of atrial and ventricular muscle.Drugs that reduce calcium entry during phase 2 do not influence cardiac rhythm. However, because calcium influx is required for contraction, these drugs can reduce myocardial contractility.In phase 3, rapid repolarization takes place. This repolarization is caused by extrusion of potassium from the cell. Phase 3 is relevant in that delay of repolarization prolongs the action potential duration, thereby prolonging the effective refractory period (ERP). Phase 3 repolarization can be delayed by drugs that block potassium channels.During phase 4, two types of electrical activity are possible: (1) the membrane potential may remain stable, or (2) the membrane may undergo spontaneous depolarization. It is phase 4 depolarization that gives cardiac cells automaticity. Slow potentials occur in cells of the SA node and AV node.Slow potentials are generated by ion fluxes. However, the specific ions involved are not the same for every phase.From a physiologic and pharmacologic perspective, slow potentials have three features of special significance: (1) phase 0 depolarization is slow and mediated by calcium influx; (2) these potentials conduct slowly; and (3) spontaneous phase 4 depolarization in the SA node normally determines the heart rate.Phase 0 of slow potentials is caused by a slow influx of calcium. Because calcium influx is slow, the rate of depolarization is slow; and because depolarization is slow, these potentials conduct slowly.Phase 0 of the slow potential has therapeutic significance in that drugs that suppress calcium influx during phase 0 can slow (or stop) AV conduction.Slow potentials lack a phase 1. Phases 2 and 3 of the slow potential are not significant with respect to the actions of antidysrhythmic drugs.Cells of the SA node and AV node undergo spontaneous phase 4 depolarization.Two classes of drugs (beta blockers and calcium channel blockers) can suppress phase 4 depolarization. By doing so, these agents can reduce automaticity in the SA node.

The chapter then discusses the components of the electrocardiogram (ECG) and its role in cardiac conduction.

The ECG provides a graphic representation of cardiac electrical activity.The ECG can be used to identify dysrhythmias and to monitor responses to therapy.The P wave is caused by depolarization in the atria; therefore, the P wave corresponds to atrial contraction. The QRS complex is caused by depolarization of the ventricle; therefore, the QRS complex corresponds to ventricular contraction. If conduction through the ventricles is slowed, the QRS complex widens. The T wave is caused by repolarization of the ventricles; therefore, this wave is not associated with overt physical activity of the heart.The PR interval represents the time between the onset of the P wave and the onset of the QRS complex. PR prolongation indicates delayed AV nodal conduction.The QT interval represents the time between the onset of the QRS complex and completion of the T wave. QT prolongation indicates delayed ventricular repolarization.The ST segment is the portion of the ECG that lies between the end of the QRS complex and the beginning of the T wave. Digoxin depresses the ST segment.

The chapter then discusses the generation of dysrhythmias, including disturbances of impulse formation and disturbances of impulse conduction. It includes discussion of disturbances of automaticity and conduction.

Dysrhythmias arise from disturbances of impulse formation (automaticity) and disturbances of impulse conduction. Factors that may alter automaticity or conduction include hypoxia, electrolyte imbalance, cardiac surgery, reduced coronary blood flow, myocardial infarction, and antidysrhythmic drugs.Disturbances of automaticity can occur in any part of the heart. Cells normally capable of automaticity can produce dysrhythmias if their normal rate of discharge changes; additionally, dysrhythmias may be produced if tissues that do not normally express automaticity develop spontaneous phase 4 depolarization.Impaired conduction through the AV node produces varying degrees of AV block.Reentrant dysrhythmias result from a localized, self-sustaining circuit capable of repetitive cardiac stimulation.

The chapter then summarizes the antidysrhythmic drugs by class. It also reiterates the important fact that virtually all the drugs used to treat dysrhythmias have prodysrhythmic (proarrhythmic) effects; that is, all these drugs can worsen existing dysrhythmias and generate new ones.

According to the Vaughan Williams classification scheme, the antidysrhythmic drugs can be divided into five groups. Class I drugs block cardiac sodium channels. In doing so, these drugs slow impulse conduction in the atria, ventricles, and His-Purkinje system. Class I constitutes the largest group of antidysrhythmic drugs.Class II consists of beta-adrenergic blocking agents. These drugs reduce calcium entry (during fast and slow potentials) and depress phase 4 depolarization (in slow potentials only). Beta blockers have three prominent effects on the heart:In the SA node, they reduce automaticity.In the AV node, they slow conduction velocity.In the atria and ventricles, they reduce contractility.Class III drugs block potassium channels, thereby delaying repolarization of fast potentials. By delaying repolarization, these drugs prolong both the duration of the action potential and the effective refractory period.Class IV is made up of the calcium channel blockers, which reduce automaticity in the SA node, delay conduction through the AV node, and reduce myocardial contractility. Antidysrhythmic benefits derive from suppression of AV node conduction.Adenosine and digoxin do not fit into the four major classes of antidysrhythmic drugs. Both of these drugs suppress dysrhythmias by reducing conduction through the AV node and reducing automaticity in the SA node.It should be stated again: Virtually all the drugs used to treat dysrhythmias have prodysrhythmic (proarrhythmic) effects; that is, all these drugs can worsen existing dysrhythmias and generate new ones.Because of their prodysrhythmic actions, antidysrhythmic drugs should be used only when dysrhythmias are symptomatically significant and only when the potential benefits clearly outweigh the risks.Of the mechanisms by which drugs can cause dysrhythmias, one deserves special mention: prolongation of the QT interval. Drugs that prolong the QT interval increase the risk of torsades de pointes, a dysrhythmia that can progress to fatal ventricular fibrillation.

The chapter then reviews the common dysrhythmias and their treatments. This review is based on the location of the dysrhythmia relative to its location in the heart.

The common dysrhythmias can be divided into two major groups: supraventricular dysrhythmias and ventricular dysrhythmias. In general, ventricular dysrhythmias are more dangerous than supraventricular dysrhythmias.With either type, intervention is required only if the dysrhythmia interferes with effective ventricular pumping.Treatment often proceeds in two phases: (1) termination of the dysrhythmia (with electrical countershock, drugs, or both), followed by (2) long-term suppression with drugs.Supraventricular dysrhythmias are dysrhythmias that arise in areas of the heart above the ventricles (atria, SA node, AV node). These include atrial fibrillation, atrial flutter, and sustained supraventricular tachycardia (SVT).In the treatment of supraventricular tachydysrhythmias, the objective frequently is to slow the ventricular rate (by blocking impulse conduction through the AV node), rather than to eliminate the dysrhythmia itself. Atrial fibrillation occurs when multiple atrial ectopic foci fire randomly; each focus stimulates a small area of atrial muscle, producing a highly irregular atrial rhythm.Treatment of atrial fibrillation has two goals: to improve ventricular pumping and to prevent stroke. Pumping can be improved either by (1) restoring normal sinus rhythm or by (2) slowing the ventricular rate.The ventricular rate can be slowed with long-term therapy with a beta blocker or cardioselective calcium channel blocker, both of which impede conduction through the AV node.To prevent stroke, most patients are treated with warfarin.Ventricular dysrhythmias can cause significant disruption of cardiac pumping; therefore, the usual objective is to abolish the dysrhythmia. Cardioversion often is the treatment of choice. When antidysrhythmic drugs are indicated, agents in class I or class III are usually used. These dysrhythmias include sustained ventricular tachycardia, ventricular fibrillation, ventricular premature beats, digoxin-induced ventricular dysrhythmias, and torsades de pointes.

The chapter then briefly reviews the principles of antidysrhythmic drug therapy.

Therapy with antidysrhythmic drugs is based on a simple but important concept: Treat only if there is a clear benefit, and then only if the benefit outweighs the risks. As a rule, this means that intervention is needed only when the dysrhythmia interferes with ventricular pumping.Treatment has two phases: acute and long term. The goal of acute treatment is to terminate the dysrhythmia. Drug selection can be aided with electrophysiologic testing.Holter monitoring can be used to evaluate treatment. A Holter monitor is a portable ECG device that is worn by the patient around the clock. If Holter monitoring indicates that dysrhythmias are still occurring with the current drug, a different drug should be tried.

The chapter then discusses the pharmacology of the antidysrhythmic drugs, beginning with class I, the sodium channel blockers. It covers their indications and their side effects.

Class I antidysrhythmic drugs block cardiac sodium channels, thereby slowing impulse conduction through the atria, ventricles, and His-Purkinje system.Quinidine is the oldest, best studied, and most widely used class IA drug; it serves as prototype for the group.By blocking sodium channels, quinidine slows impulse conduction in the atria, ventricles, and His-Purkinje system. In addition, it delays repolarization at these sites, apparently by blocking potassium channels. Quinidine is strongly anticholinergic (atropine-like) and blocks vagal input to the heart. The resultant increase in SA node automaticity and AV conduction can drive the ventricles at an excessive rate. To prevent excessive ventricular stimulation, patients usually are pretreated with digoxin, verapamil, or a beta blocker.Quinidine has two pronounced effects on the ECG: It widens the QRS complex (by slowing depolarization of the ventricles), and it prolongs the QT interval (by delaying ventricular repolarization).Quinidine is a broad-spectrum agent active against supraventricular and ventricular dysrhythmias. The drugs principal indication is long-term suppression of dysrhythmias, including SVT, atrial flutter, atrial fibrillation, and sustained ventricular tachycardia.Quinidine causes diarrhea and other gastrointestinal (GI) symptoms in 33% of patients. These reactions can be immediate and intense, frequently forcing discontinuation of treatment.Quinidine can cause cinchonism, which is characterized by tinnitus (ringing in the ears), headache, nausea, vertigo, and disturbed vision. These can develop with just one dose.

At high concentrations, quinidine can cause severe cardiotoxicity (sinus arrest, AV block, ventricular tachydysrhythmias, asystole). As cardiotoxicity develops, the ECG changes. Important danger signals are widening of the QRS complex (by 50% or more) and excessive prolongation of the QT interval. Embolism is a potential complication of the treatment of atrial fibrillation. During atrial fibrillation, thrombi may form in the atria. When sinus rhythm is restored, these thrombi may be dislodged and cause embolism.Quinidine can cause alpha-adrenergic blockade, resulting in vasodilation and subsequent hypotension. In rare cases, quinidine has caused hypersensitivity reactions, including fever, anaphylactic reactions, and thrombocytopenia.Quinidine can double digoxin levels. The increase is caused by displacement of digoxin from plasma albumin and by reduction of digoxin elimination. When these drugs are used concurrently, the digoxin dosage must be reduced.Class IB agents differ from class IA agents in two ways: they accelerate repolarization, and they have little or no effect on the ECG.Lidocaine is used only for ventricular dysrhythmias. Lidocaine has three significant effects on the heart: (1) it blocks cardiac sodium channels, thereby slowing conduction in the atria, ventricles, and His-Purkinje system; (2) it reduces automaticity in the ventricles and His-Purkinje system by a mechanism that is poorly understood; and (3) it accelerates repolarization (shortens the action potential duration and ERP).Lidocaine undergoes rapid inactivation by the liver. As a result, the drug must be administered by continuous intravenous (IV) infusion.The therapeutic range for lidocaine is 1.5 to 5 mcg/mL.Lidocaine is generally well tolerated. However, adverse central nervous system (CNS) effects can occur. High therapeutic doses can cause drowsiness, confusion, and paresthesias. Toxic doses may produce convulsions and respiratory arrest.

The chapter continues the discussion of antidysrhythmics with class II agents, the beta blockers.

Class II consists of beta-adrenergic blocking agents. At this time only four beta blockerspropranolol, acebutolol, esmolol, and sotalolhave been approved for the treatment dysrhythmias.Propranolol is considered a nonselective beta-adrenergic antagonist in that it blocks both beta1- and beta2-adrenergic receptors. By blocking cardiac beta1 receptors, propranolol attenuates sympathetic stimulation of the heart. The result is (1) decreased automaticity of the SA node, (2) decreased velocity of conduction through the AV node, and (3) decreased myocardial contractility.Propranolol is especially useful for treating dysrhythmias caused by excessive sympathetic stimulation of the heart.In patients with supraventricular tachydysrhythmias, propranolol has two beneficial effects: (1) suppression of excessive discharge of the SA node and (2) slowing of the ventricular rate by reducing transmission of atrial impulses through the AV node.Beta blockers are generally well tolerated. Principal adverse effects concern the heart and bronchi. By blocking cardiac beta1 receptors, propranolol can cause heart failure, AV block, and sinus arrest. Hypotension can occur secondary to reduced cardiac output. In patients with asthma, blocking beta2 receptors in the lung can cause bronchospasm

The chapter next discusses class III agents, the potassium channel blockers.

Five class III antidysrhythmics are available: amiodarone, dronedarone, dofetilide, ibutilide, and sotalol (which is also a beta blocker). All five delay repolarization of fast potentials.Amiodarone has complex effects on the heart. The drug is highly effective against both atrial and ventricular dysrhythmias.Unfortunately, serious toxicities (e.g., lung damage, visual impairment) are common and may persist for months after treatment has stopped. Because of toxicity concerns, amiodarone is approved only for life-threatening ventricular dysrhythmias that have been refractory to safer agents.In the United States, oral amiodarone is approved only for long-term therapy of two life-threatening ventricular dysrhythmias: recurrent ventricular fibrillation and recurrent hemodynamically unstable ventricular tachycardia.Amiodarone is the most effective drug available for atrial fibrillation and is widely prescribed to treat this dysrhythmia, even though it is not approved for this use.Amiodarone delays repolarization, thereby prolonging the duration of the action potential and ERP. The underlying cause of these effects may be blockade of potassium channels.Additional cardiac effects include reduced automaticity in the SA node, reduced contractility, and reduced conduction velocity in the AV node, ventricles, and His-Purkinje system. These occur secondary to blockade of sodium channels, calcium channels, and beta receptors. Prominent effects on the ECG are QRS widening and prolongation of the PR and QT intervals. Amiodarone also acts on coronary and peripheral blood vessels to promote dilation.Amiodarone produces many serious adverse effects. Furthermore, because the drugs half-life is protracted, toxicity can continue for weeks or months after drug withdrawal.Lung damagehypersensitivity pneumonitis, interstitial/alveolar pneumonitis, pulmonary fibrosisis the greatest concern.Amiodarone may cause a paradoxical increase in dysrhythmic activity. In addition, by suppressing the SA and AV nodes, the drug can cause sinus bradycardia and AV block.Amiodarone may cause hypothyroidism or hyperthyroidism.Amiodarone can injure the liver.In rare cases, amiodarone has been associated with optic neuropathy and optic neuritis, sometimes progressing to blindness.Amiodarone crosses the placental barrier and enters breast milk and thus can harm the developing fetus and breast-feeding infant.Patients frequently experience photosensitivity reactions.Possible CNS reactions include ataxia, dizziness, tremor, mood alteration, and hallucinations. Gastrointestinal reactions (anorexia, nausea, vomiting) are common.Amiodarone is subject to significant interactions with many drugs. The result can be toxicity or reduced therapeutic effects.Dronedarone, a derivative of amiodarone, was approved in 2009. The drug is indicated for oral therapy of atrial fibrillation and atrial flutter. The manufacturer hoped to create a drug with the high efficacy of amiodarone but with less toxicity. Unfortunately, although dronedarone is somewhat less toxic than amiodarone, it is also less effective.

The chapter then discussions class IV agents, the calcium channel blockers.

Only two calcium channel blockersverapamil and diltiazemare able to block calcium channels in the heart. Accordingly, they are the only calcium channel blockers used to treat dysrhythmias.Blockade of cardiac calcium channels has three effects:Slow delay of AV nodal conductionDelay of AV nodal conductionReduction of myocardial contractilityVerapamil and diltiazem can slow the ventricular rate in patients with atrial fibrillation or atrial flutter and can terminate SVT caused by an AV nodal reentrant circuit. In both cases, benefits derive from suppression of AV node conduction.Although generally safe, these drugs can cause undesired effects. Blockade of cardiac calcium channels can cause bradycardia, AV block, and heart failure. Blockade of calcium channels in vascular smooth muscle can cause vasodilation, resulting in hypotension and peripheral edema. Blockade of calcium channels in intestinal smooth muscle can produce constipation.

The chapter then considers the family of other antidysrhythmic drugs by reviewing adenosine and its role in the management of SVT.

Adenosine is a drug of choice for terminating paroxysmal SVT. Adenosine has an extremely short half-life and therefore must be administered IV.Adenosine reduces automaticity in the SA node and greatly slows conduction through the AV node.Adenosine works in part by inhibiting cyclic adenosine monophosphate (AMP)induced calcium influx, thereby suppressing calcium-dependent action potentials in the SA and AV nodes.Adenosine is approved only for termination of paroxysmal SVT, including Wolff-Parkinson-White syndrome. The drug is not active against atrial fibrillation, atrial flutter, or ventricular dysrhythmias.Adverse effects are short lived, lasting less than 1 minute. The most common are sinus bradycardia, dyspnea (from bronchoconstriction), hypotension and facial flushing (from vasodilation), and chest discomfort (perhaps from stimulation of pain receptors in the heart).

Finally, the chapter provides a brief review of the nondrug treatment of dysrhythmias.

Implantable cardioverter/defibrillators (ICDs) are surgically implanted devices that monitor and analyze cardiac rhythm and, by delivering electrical shocks to the heart, terminate any dysrhythmias that develop. Termination is accomplished with either (1) a series of pacing stimuli, which usually are imperceptible, or (2) a defibrillating shock, which can be painful.Radiofrequency (RF) catheter ablation is a technique in which the cardiac tissue responsible for causing a dysrhythmia is identified and destroyed.