Lehne: Pharmacology for Nursing Care, 8th Edition

Chapter 49: Antidysrhythmic Drugs

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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 selfpropagating 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
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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.
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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:
o In the SA node, they reduce automaticity.
o In the AV node, they slow conduction velocity.
o 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.
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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.
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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

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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
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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 HisPurkinje 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.
o Lung damagehypersensitivity pneumonitis, interstitial/alveolar pneumonitis,
pulmonary fibrosisis the greatest concern.
o 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.
o Amiodarone may cause hypothyroidism or hyperthyroidism.
o Amiodarone can injure the liver.
o In rare cases, amiodarone has been associated with optic neuropathy and optic
neuritis, sometimes progressing to blindness.

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o Amiodarone crosses the placental barrier and enters breast milk and thus can
harm the developing fetus and breast-feeding infant.
o Patients frequently experience photosensitivity reactions.
o Possible CNS reactions include ataxia, dizziness, tremor, mood alteration,
and hallucinations.
o 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:
o Slow delay of AV nodal conduction
o Delay of AV nodal conduction
o Reduction of myocardial contractility
Verapamil 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 WolffParkinson-White syndrome. The drug is not active against atrial fibrillation, atrial
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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.

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