Antiarrhythmic Drugs

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Chapter 22 Antiarrhythmic Drugs

MAJOR DRUG CLASSES

Na⁺ channel blockers

β adrenergic receptor antagonists

Action potential prolonging agents

Ca⁺⁺ channel blockers

Abbreviations
ATP	Adenosine triphosphate
AV	Atrioventricular
CNS	Central nervous system
GI	Gastrointestinal
IV	Intravenous
NAPA	N-acetylprocainamide
NE	Norepinephrine
SA	Sinoatrial

Therapeutic Overview

The heart is a four-chambered pump that circulates blood to the body. During normal function blood is circulated in quantities sufficient to provide adequate O₂ and nutrients to maintain aerobic metabolism. To function efficiently, the heart needs to contract sequentially (atria and then ventricles) and in a synchronized manner. It also needs adequate time between contractions for chamber filling (diastole). This need for relaxation distinguishes cardiac from smooth and skeletal muscle, which can contract tetanically. The heart has an electrical system that allows rapid and organized spread of activation, which can convert the electrical signal into mechanical energy.

Electrical activation originates in specialized pacemaker cells of the sinoatrial (SA) node, located in the high right atrium near the junction with the superior vena cava (Fig. 22-1). After exiting the SA node, the electrical signal spreads rapidly throughout the atrium, leading to contraction. However, the atria are electrically isolated from the ventricles by the fibrous atrioventricular (AV) ring, with electrical propagation between atrium and ventricles occurring solely through the AV node and His-Purkinje system. The AV node delays the electrical impulse as it passes from atrium to ventricles, providing additional filling time before ejection. The signal then rapidly spreads throughout the ventricles using the Purkinje system, allowing a synchronized contraction.

FIGURE 22–1 The heart depicting the atria and ventricles and electrical system including the SA node where the impulse is initiated, the AV node that dampens the signal from the atria before it enters the ventricles, and the His-Purkinje network that transmits the impulse to the ventricles.

When orderly propagation of the electrical signal is perturbed, the function of the heart may be adversely affected. Slowed electrical conduction through some cardiac regions, as occurs with first-degree heart block or bundle branch block in the ventricles, is generally well tolerated. Other abnormalities may lead to clinical symptoms, and in its most extreme form, cardiovascular collapse. Abnormalities in heart rhythm are called arrhythmias and may result in abnormally fast or slow heart rates. Options for clinical management of arrhythmias have been rapidly expanding and include drugs, mechanical devices such as pacemakers and defibrillators, and transcatheter therapies such as radiofrequency ablation.

Currently available antiarrhythmic drugs work by one of two mechanisms. They either directly alter

the function of ion channels that participate in a normal heartbeat, or they interfere with neuronal control. Although antiarrhythmic drugs are intended to restore normal sinus rhythm, suppress initiation of abnormal rhythms, or both, their use is hampered by the omnipresent risk of proarrhythmias. In the most famous example, the Cardiac Arrhythmia Suppression Trial showed that, even though ventricular arrhythmias predictive of sudden death could be suppressed by Na⁺ channel-blocking

Therapeutic Overview
Goal: To treat abnormal cardial impulse formation or conduction
Effects: Modify ion fluxes, block Na⁺, K⁺, or Ca⁺⁺ channels modify β adrenergic receptor-activated processes
Drug Action	Uses
Na⁺ channel blockade	Paroxysmal supraventricular tachycardia, atrial fibrillation or flutter, ventricular tachycardia; digoxin-induced arrhythmias
β Adrenergic receptor blockade	Paroxysmal supraventricular tachycardia, atrial or ventricular premature beats, atrial fibrillation or flutter
Prolong action potentials and repolarization	Ventricular tachycardia, atrial fibrillation or flutter*
Ca⁺⁺ channel blockade	Paroxysmal supraventricular tachycardia, atrial fibrillation or flutter
Other
Adenosine	Paroxysmal supraventricular tachycardia
Digitalis glycosides	Atrial fibrillation or flutter with increased ventricular rate

* Only amiodarone.

drugs, their use was associated with an increased incidence of sudden death.

Antiarrhythmic drugs are used for all forms of tachycardia, and are ineffective for long-term therapy of symptomatic bradycardia. Although mechanical therapies are preferred for many patients, drugs continue to be used as adjunctive therapy, and their complex interactions with these mechanical devices must be appreciated. A summary of the agents used for specific arrhythmias is presented in the Therapeutic Overview Box.

Mechanisms of Action

An understanding of the mechanisms by which antiarrhythmic drugs act requires an understanding of normal cardiac electrophysiology, because many channels, pumps, and ion exchangers are targets for these drugs.

Cardiac Electrophysiology

Resting Potential

Cardiac myocytes, like other excitable cells, maintain a transmembrane electrical gradient, with the interior of the cell negative with respect to the exterior. This transmembrane potential is generated by an unequal distribution of charged ions between intracellular and extracellular compartments (Table 22-1). Ions can traverse the sarcolemmal membrane only through selective channels or via pumps and exchangers. The resting potential is an active, energy-dependent process, relying on these channels, pumps and exchangers, and large intracellular immobile anionic proteins. Critical components include the Na⁺/K⁺-adenosine triphosphatase (ATPase) and the inwardly rectifying K⁺ channel (I_K). The Na⁺/K⁺-ATPase exchanges 3 Na⁺ ions from inside of the cell for 2 K⁺ ions outside, resulting in a net outward flow of positive charge.

TABLE 22–1 Typical Ion Concentrations

The unequal distribution of these ions across the membrane leads to both electrical and chemical forces causing charged ions to move into or out of the cell. If a membrane is permeable to only a single ion, then for that ion, there is an “equilibrium potential” at which there is no net driving force. This can be calculated using the Nernst equation;

(22-1)

where R = the gas constant; T = absolute temperature; F = the Faraday constant; and X is the ion in question. Because the usual intracellular and extracellular concentrations of K⁺ are 140 and 4 mM, respectively, its equilibrium potential is -94 mV. At rest, the sarcolemmal membrane is nearly impermeable to Na⁺ and Ca⁺⁺ but highly permeable to K⁺. Therefore the resting potential of most cardiac myocytes approaches the equilibrium potential for K⁺ (-80 to -90 mV). However, the sarcolemmal membrane is dynamic, with a constantly changing permeability to various ions and resultant changes in membrane potential. The membrane potential at any given moment can be calculated based on knowledge of ion concentrations and permeabilities.

Action Potentials

The cardiac action potential is divided into five phases as illustrated in Figure 22-2. The injection of current into a cardiac myocyte, or local current flow from an adjoining cell, can cause the membrane potential to depolarize (become less negative). If the resting potential exceeds a certain threshold, voltage-gated Na⁺ channels open (Fig. 22-3). Electrical and chemical gradients drive Na⁺ into the cell, making the membrane potential less negative. During phase 0, there is rapid depolarization of the action potential, Na⁺ influx is the dominant conductance, and the membrane potential approaches the equilibrium potential for Na⁺ (+64 mV). However, Na⁺ channels are open for only a very short time and close quickly. They also cycle through an inactivated state in which they are unable to open and participate in another action potential. Therefore, if a significant percentage of Na⁺ channels are in the inactivated state, the cell is refractory to further stimulation. The maximal rate of depolarization defines how fast electrical impulses can be passed from cell to cell, determining conduction velocity within a tissue. Slowing of conduction caused by inhibition of Na⁺ channels is the basis for the actions of Class I antiarrhythmic drugs. Action potentials in nonpacemaker cells are referred to as fast responses because their rate of depolarization is extremely rapid.

FIGURE 22–2 Phase of action potential (with respect to potential on extracellular side of cell membrane) in a nonpacemaker cell (left) and in a pacemaker cell (right). Numbers refer to phases. Nonpacemaker cell: 0, rapid depolarization: 1, initial repolarization; 2, action potential plateau; 3, repolarization; 4, resting potential. Pacemaker cell: 0, rapid depolarization; 3, plateau and repolarization; 4, slow diastolic depolarization (pacemaker potential).

FIGURE 22–3 Postulated conformational arrangements of cardiac Na⁺ channels compatible with concept of resting, activated, and inactivated states. Transitions among resting, activated, and inactivated states are dependent on membrane potential and time. Activation gate is shown as I and inactivation gate as II. Potentials typical for each state are shown under each channel schema as a function of time.

In pacemaker cells, like those in the SA and AV nodes, the resting membrane potential is less negative, and Na⁺ channels are inactivated and do not participate in initiation of the action potential. In these cells phase 0 is mediated almost entirely by increased conductance of Ca⁺⁺ through opening of voltage-gated Ca⁺⁺ channels. These “slow” action potentials exhibit much slower depolarization.

The voltage and time dependence of currents through individual ion channels are unique. Na⁺ channels open at more negative voltages than Ca⁺⁺ channels, and current kinetics are quite different. Physical structures, known as activation and inactivation gates, help regulate the flow of ions. Because of these gates, Na⁺ channels are believed to exist in at least three distinct states during the cardiac action potential, as shown in Figure 22-3. At the resting potential, most Na⁺ channels are in a resting state, available for activation. Upon depolarization, most channels become activated, allowing Na⁺ to flow into the cell and cause a rapid depolarization. Na⁺ channels quickly become inactivated, limiting the time for Na⁺ entry to a few milliseconds or less.

Near the end of phase 0, an overshoot of the action potential occurs. This is the most positive potential achieved and represents an abrupt transition between the end of depolarization and the onset of repolarization, known as phase 1 or initial rapid repolarization. This phase of initial repolarization is caused by two factors: inactivation of the inward Na⁺ current and activation of a transient outward current, which is composed of both a K⁺ and Cl⁻ component.

Phase 2, or the plateau phase of the cardiac action potential, is one of its most distinguishing features. In contrast to action potentials in nerves and other cells (see Chapter 13), the cardiac action potential has a relatively long duration of 200 to 500 msec, depending on the cell (see Fig. 22-2). The plateau results from a voltage-dependent decrease in K⁺ conductance (the inward rectifier) and is maintained by the influx of Ca⁺⁺ through Ca⁺⁺ channels that inactivate only slowly at positive membrane potentials. During this phase, another outward K⁺ current, the delayed rectifier, is slowly activated, which nearly balances the maintained influx of Ca⁺⁺. As a result, there is only a small change in potential during the plateau, because net current flow is small.

As the plateau phase transitions to repolarization, the voltage-activated Ca⁺⁺ channels close, leaving the outward hyperpolarizing K⁺ current unopposed, known as phase 3 repolarization. The hyperpolarizing current during phase 3 is carried through three distinct K⁺ channels, the slowly activating delayed rectifier (I_Ks), the rapidly activating delayed rectifier (I_Kr), and the ultra-rapidly activating delayed rectifier (I_Kur). The importance of these currents to ventricular repolarization is underscored by the clinical significance of abnormalities of these channels. The potentially lethal “long QT syndrome” results from abnormalities in the ion channels responsible for repolarization, causing a delay in repolarization and producing an arrhythmic substrate in the ventricles.

In a nonpacemaker cell, phase 4, or the resting potential, is characterized by a return of the membrane to its resting potential. Atrial and ventricular myocytes maintain a constant resting potential awaiting the next depolarizing stimulus, established by a voltage-activated K⁺ channel, I_K1. The resting potential remains slightly depolarized relative to the equilibrium potential of K⁺, due to an inward depolarizing leak current likely carried by Na⁺. During the terminal portions of phase 3, and all of phase 4, voltage-gated Na⁺ channels are transitioning from the inactivated to the resting state and preparing to participate in another action potential. In a pacemaker cell, however, there is a slow depolarization during diastole. This brings the membrane potential near threshold for activation of a regenerative inward current, which initiates a new action potential (see Fig. 22-2). This is called phase 4 depolarization. In a pacemaker cell in the SA node, phase 4 depolarization brings the membrane potential to a level near the threshold for activation of the inward Ca⁺⁺ current.

Mechanisms Underlying Cardiac Arrhythmias

Arrhythmias result from disorders of impulse formation, conduction, or both. Several factors may contribute, such as ischemia with resulting pH and electrolyte abnormalities, excessive myocardial fiber stretch, excessive discharge of or sensitivity to autonomic transmitters, and exposure to chemicals or toxic substances. Disorders of impulse formation can involve either a change in the pacemaker site (e.g., sinus bradycardia or tachycardia) or the development of an ectopic pacemaker. Ectopic activity may arise as a consequence of the emergence of a latent pacemaker, because many cells of the conduction system are capable of rhythmic spontaneous activity. Normally these latent pacemakers are prevented from spontaneously discharging because of the dominance of the rapidly firing SA nodal pacemaker cells. Under some conditions, however, they may become dominant because of abnormal slowing of SA firing rate or abnormal acceleration of latent pacemaker firing rate. Such ectopic activity may result from injury due to ischemia or hypoxia, causing depolarization. Two areas of cells with different membrane potentials may result in current flow between adjacent regions (injury current), which can depolarize normally quiescent tissue to a point where ectopic activity is initiated. Finally, development of oscillatory afterdepolarizations can initiate spontaneous activity in normally quiescent tissue. These afterdepolarizations can occur at the end of phase 3 (Fig. 22-4) and, if large enough in amplitude, reach threshold and initiate a burst of spontaneous activity. Toxic concentrations of digitalis or norepinephrine (NE) can initiate such effects. This mechanism has also been proposed to explain ventricular arrhythmias in patients with the long QT syndrome.

FIGURE 22–4 Development of oscillatory delayed afterdepolarization (arrow) that leads to spontaneous activity, as observed with cardiac glycosides. First five action potentials were elicited by electrical stimuli (bottom trace), followed by an afterdepolarization, which was subthreshold initially but attained threshold subsequently, leading to spontaneous discharges.

Disorders of impulse conduction can result in either bradycardia, as occurs with AV block, or in tachycardia, as when a reentrant circuit develops. Figure 22-5 shows an example of a hypothetical reentrant circuit. For a reentrant circuit to develop, a region of unidirectional block must exist, and the conduction time around the alternative pathway must exceed the refractory period of the tissue adjacent to the block. Before development of unidirectional block (see Fig. 22-5, A), impulse propagation initially branches as a result of the anatomical properties of the circuit. Some of these impulses collide and extinguish on the other side of the branch point. If an area of unidirectional block develops, impulses around the branch do not collide and become extinguished but may reexcite tissue proximal to the site of block, establishing a circular pathway for continuous reentry (see Fig. 22-5, B). Clinical examples include AV reentrant tachycardia (Wolff-Parkinson-White syndrome), AV nodal tachycardia, atrial flutter, and incisional/scar (atrial or ventricular) tachycardia. A long reentry pathway, slow conduction, and a short effective refractory period all favor reentrant circuits.

FIGURE 22–5 Hypothetical reentrant circuit. A, Normally electrical excitation branches around the circuit and becomes extinguished because of collision. B, An area of unidirectional block develops in one of the branches, allowing excitation of the blocked area by an impulse traveling from the opposite direction. This can lead to reexcitation and reentry.

ANTIARRHYTHMIC DRUGS

Antiarrhythmic drugs affect normal cardiac function and therefore have the potential for many serious adverse effects. In the most dramatic example, antiarrhythmic drugs have the potential to actually be proarrhythmic. Therefore treatment of a tachycardia, which is a nuisance clinically but not life-threatening, may initiate a life-threatening ventricular arrhythmia—truly a case of the cure being worse than the disease. Such potentially serious side effects require vigilance to ensure proper dosing, proper serum levels, a thorough knowledge of drug-drug interactions, and close follow-up.

There is no universally accepted classification scheme for antiarrhythmic agents. The most commonly used scheme, the Vaughan-Williams classification, is based on the presumed primary mechanism of action of individual drugs (Table 22-2). This scheme classifies agents that block voltage-gated Na⁺ channels in class I, those with sympathetic blocking actions in class II, those that prolong action potential duration and refractoriness in class III, and those with Ca⁺⁺ channel-blocking properties in class IV. However, classification is complicated by the fact that many drugs have multiple actions. As shown in Table 22-3, these drugs often have multiple effects on various targets. Although this scheme is useful in learning the properties of antiarrhythmic agents, all classifications are of limited use for treatment of arrhythmias because of their complex pathophysiology.

TABLE 22–2 Classification of Antiarrhythmic Agents

TABLE 22–3 Antiarrhythmic Drug Actions^*

Class I Antiarrhythmics

Class I agents are subdivided into three groups based on their effects (Table 22-4). Class IA agents slow the rate of rise of phase 0 of the action potential (and slow conduction velocity) and prolong the ventricular refractory period, although they do not alter resting potential. They are also defined on the basis of recovery from drug-induced blockade and directly decrease the slope of phase 4 depolarization in pacemaker cells, especially those arising outside the SA node. Class IB drugs slow conduction and shorten the action potential in nondiseased tissue. The IB agents preferentially act on depolarized myocardium, binding to Na⁺ channels in the inactivated state. Drugs in class IC markedly depress the rate of rise of phase 0 of the action potential. They shorten the refractory period in Purkinje fibers, although not altering the refractory period in adjacent myocardium.

TABLE 22–4 Differences Among Class I Antiarrhythmic Drugs

Class IA

Quinidine was one of the first antiarrhythmic agents used clinically. It has a wide spectrum of activity and has been used to treat both atrial and ventricular arrhythmias. However, its use has significantly diminished because of its high incidence of proarrhythmias and availability of other agents. Quinidine shares most properties with quinine (see Chapter 52). In addition to blocking voltage-gated Na⁺ channels, quinidine inhibits the delayed rectifier K⁺ channel. The effect of quinidine on the heart depends on dose and the level of parasympathetic input. A slight increase in heart rate is seen at low doses due to cholinergic blockade, whereas higher concentrations depress spontaneous diastolic depolarization in pacemaker cells, overwhelming its anticholinergic actions and slowing heart rate.

Quinidine administration results in a dose-dependent depression of responsiveness in atrial and ventricular muscle fibers. The maximum rate of phase 0 depolarization and its amplitude are depressed equally at all membrane potentials. Quinidine also decreases excitability; actions that are often referred to as local anesthetic properties.

Quinidine also prolongs repolarization in Purkinje fibers and ventricular muscle, resulting in an increase in action potential duration. An increased refractoriness known as post-repolarization refractoriness has been observed. The indirect anticholinergic properties of quinidine are not a factor in its actions on ventricular muscle and Purkinje fibers.

Procainamide, like quinidine, increases the effective refractory period and decreases conduction velocity in the atria, His-Purkinje system, and ventricles. Although having weaker anticholinergic actions than quinidine, it also has variable effects on the AV node. Procainamide increases the threshold for excitation in atrium and ventricle and slows phase 4 depolarization, a combination that decreases abnormal automaticity. Procainamide is used in the treatment of atrial arrhythmias, such as premature atrial contractions, paroxysmal atrial tachycardia, and atrial fibrillation of recent onset, in addition to being effective for most ventricular arrhythmias. Because of proarrhythmia risks, treatment should be limited to hemodynamically significant arrhythmias. Long-term therapy is complicated by the need for frequent dosing and side effects.

Disopyramide suppresses atrial and ventricular arrhythmias and has a longer duration of action than other drugs in its class. Although effective in treating atrial arrhythmias, disopyramide is only approved to treat ventricular arrhythmias in the United States. Despite prominent anticholinergic effects, disopyramide has a pronounced negative inotropic effect, which is so prominent it has been used in therapy of hypertrophic cardiomyopathy. The electrophysiological effects of disopyramide are nearly identical to those of quinidine and procainamide. However, its anticholinergic effects are far more prominent and limit its utility. Disopyramide blocks voltage-gated Na⁺ channels, thereby depressing action potentials. Disopyramide also reduces conduction velocity and increases the refractory period in atria. Post-repolarization refractoriness does not occur. Interestingly, abnormal atrial automaticity may be abolished at disopyramide concentrations that fail to alter conduction velocity or refractoriness. Conduction velocity slows and the refractory period increases in the AV node via a direct action, which is offset to a variable degree by its anticholinergic actions. Action potential duration is prolonged, which results in an increase in refractory period of the His-Purkinje and ventricular muscle tissue. Slowed conduction in accessory pathways has been demonstrated. Like quinidine, the effect of disopyramide on conduction velocity depends on extracellular K⁺ concentrations. Hypokalemic patients may respond poorly to its antiarrhythmic action, whereas hyperkalemia may accentuate its actions.

Class IB

Lidocaine is a local anesthetic (see Chapter 13) that has long been used to treat arrhythmias. Unlike quinidine, lidocaine rapidly blocks both activated and inactivated Na⁺ channels. Block of Na⁺ channels in the inactivated state leads to greater effects on myocytes with long action potentials, such as Purkinje and ventricular cells, compared with atrial cells. The rapid kinetics of lidocaine at normal resting potentials result in recovery from block between action potentials, with no effect on conduction velocity. In partially depolarized cells (such as those injured by ischemia) lidocaine significantly depresses membrane responsiveness, leading to conduction delay and block. Lidocaine also elevates the ventricular fibrillation threshold.

Mexiletine is a derivative of lidocaine that is orally active. Its actions and side effects are similar to those of lidocaine. As with other members of class IB, mexiletine slows the maximal rate of depolarization of the cardiac action potential and exerts a negligible effect on repolarization. Mexiletine also blocks the Na⁺ channel with rapid kinetics, making it more effective in control of rapid, as opposed to slow, ventricular tachyarrhythmias and ineffective in treating atrial arrhythmias.

Phenytoin is an anticonvulsant (see Chapter 34) that has been used as an antiarrhythmic agent for decades. Its actions are similar to those of lidocaine. It depresses membrane responsiveness in the ventricular myocardium and His-Purkinje system to a greater extent than in the atrium.

Class IC

Flecainide was initially developed as a local anesthetic and subsequently was found to have antiarrhythmic effects. Flecainide blocks Na⁺ channels, causing slowing of conduction in all parts of the heart, most notably in the His-Purkinje system and ventricles. It has minor effects on repolarization. Flecainide also inhibits abnormal automaticity.

Propafenone also results in conduction slowing due to Na⁺ channel blockade. Propafenone is also a weak β adrenergic receptor antagonist with a much lower potency than propranolol, as well as an L-type Ca⁺⁺ channel blocker.

Class II Antiarrhythmics: β Adrenergic Receptor Antagonists

The antiarrhythmic properties of β receptor antagonists result from two major actions: (1) blockade of myocardial β₁ receptors, and (2) direct membrane-stabilizing effects at higher concentrations related to blockade of Na⁺ channels. Propranolol is the prototypical β receptor blocker, and, in addition to blocking β₁ receptors in the heart, also has direct membrane-stabilizing effects in atrium, ventricle, and His-Purkinje system. It causes a slowing of SA nodal and ectopic pacemaker automaticity and decreases AV nodal conduction velocity by virtue of its ability to block intrinsic sympathetic activity. There is little change in action potential duration and refractoriness in atrium, ventricle, or AV node. The β receptor antagonists currently used for arrhythmias (see Table 22-2) may be differentiated by their pharmacokinetics, selectivity for β₁ receptors, lipophilicity, and intrinsic sympathomimetic effects. A more complete discussion of these drugs is provided in Chapter 11.

Class III Antiarrhythmics

Amiodarone is a class III agent that prolongs action potentials as a result of blockade of several types of K⁺ channels. However, amiodarone has an extremely complex and incompletely understood spectrum of actions and also blocks both Na⁺ and Ca⁺⁺ channels (class I and IV effects) and is a noncompetitive β adrenergic receptor antagonist (class II effect). The acute effects of amiodarone administration also differ from chronic effects, which may in part be explained by its complex pharmacokinetics.

Sotalol prolongs the action potential by inhibiting the delayed rectifier K⁺ channel. Sotalol is available as either the isolated d-isomer or as the racemic d,l-mixture. In addition to its ability to prolong action potentials, d,l-sotalol is a nonselective β receptor antagonist (class II effect) most evident at low doses, with action potential prolonging effects predominating at high doses. The d-isomer, which is a pure class III agent devoid of β receptor antagonist effects, was thought to selectively block myocardial K⁺ channels involved in initiating action potential repolarization. However, development of d-sotalol was halted when it was found to be associated with increased mortality in patients after infarction.

Ibutilide is structurally related to sotalol, and like other class III agents, it leads to action potential prolongation. However, in addition to blocking the delayed rectifier K⁺ channel, ibutilide is unique because it activates a slow inward Na⁺ channel, both of which delay repolarization.

Dofetilide is a “pure” class III agent that selectively blocks the rapid component of the delayed rectifier K⁺ current (I_Kr). At clinically relevant concentrations, dofetilide does not affect any other K⁺, Na⁺, or Ca⁺⁺ channels and has no antagonist action at adrenergic receptors. The increase in effective refractory period is observed in both atria and ventricles. Dofetilide is approved for use in atrial arrhythmias. Its effects are dependent on the concentration of extracellular K⁺ and are exaggerated by hypokalemia, which is important in patients receiving diuretics. Conversely, hyperkalemia decreases its effects, which may limit its efficacy in conditions such as myocardial ischemia.

Bretylium is a unique class III agent that was first introduced for treatment of essential hypertension but was subsequently shown to suppress ventricular fibrillation associated with acute myocardial infarction. Bretylium selectively accumulates in sympathetic ganglia and postganglionic adrenergic neurons and inhibits NE release. Bretylium has been demonstrated experimentally to increase action potential duration and effective refractory period without changing heart rate.

Class IV Antiarrhythmics

Calcium channel-blocking drugs are used to slow the rate of AV conduction in patients with atrial fibrillation or to slow ectopic atrial pacemakers. Calcium channel blockers have also been used for treating idiopathic left ventricular tachycardia arising from the posterior fascicle. These agents are discussed extensively in Chapter 20.

Nonclassified Antiarrhythmics

Adenosine is an endogenous nucleoside produced from the metabolism of adenosine triphosphate. Adenosine activates the same G-protein coupled outward K⁺ current as acetylcholine (see Chapter 10). Adenosine receptors are located on atrial myocytes and myocytes in the SA and AV nodes, and stimulation leads to hyperpolarization of the resting potential. Effects include a decrease in slope of phase 4 spontaneous depolarizations and shortening of action potential durations. Effects are most dramatic in the AV node and result in transient conduction block. This effect terminates tachycardias, which use the AV node as a limb of a reentrant circuit. There is no effect on the ventricular myocardium, because this K⁺ channel is not expressed in the ventricle.

Pharmacokinetics

Pharmacokinetic parameters of selected antiarrhythmic drugs are summarized in Table 22-5. The pharmacokinetics of β receptor blockers are discussed in Chapter 11 and Ca⁺⁺ channel blocking drugs in Chapter 20.

TABLE 22–5 Selected Pharmacokinetic Parameters

Quinidine is readily absorbed from the gastrointestinal (GI) tract. It is metabolized in liver and excreted by the kidneys. Therefore both hepatic and renal functions must be assessed in patients to prevent the accumulation of toxic concentrations in plasma.

Procainamide is metabolized in the liver by acetylation to N-acetylprocainamide (NAPA), which has class III actions and a longer serum t_1/2 than procainamide. In the United States, approximately half of the population (90% of Asians) is homozygous for the N-acetyltransferase gene and are termed rapid acetylators (see Chapter 2). These individuals have a higher concentration of plasma NAPA than procainamide at steady-state. When its concentration exceeds 5 ng/mL, NAPA can contribute to the antiarrhythmic actions of procainamide because of its class III actions that prolong repolarization. Concentrations greater than 20 ng/mL have been associated with adverse effects, including torsades de pointes.

Lidocaine is inactive when administered orally because of a high first-pass metabolism. It is therefore usually given by IV administration for acute treatment of cardiac arrhythmias. Because most drug is metabolized, liver function is important. The main route of metabolism is N-dealkylation, which produces metabolites with only mild antiarrhythmic activity but potent central nervous system (CNS) toxicity.

Mexiletine does not have a large first-pass effect, with a bioavailability in the range of 90% to 100%. However, its t_1/2 is approximately 35% less in smokers than nonsmokers, probably due to induction of hepatic enzymes. Other inducers, such as barbiturates, phenytoin, and rifampin, also increase metabolism of mexiletine. Antacids, cimetidine, and narcotic analgesics slow its absorption from the GI tract.

The long plasma t_1/2 of phenytoin shows considerable variation, which can be markedly influenced by drugs that alter hepatic microsomal drug metabolism.

Therapy with several antiarrhythmic drugs is complicated by the fact that they are predominantly metabolized by a specific cytochrome P450 that exhibits genetic polymorphisms, with a bimodal pattern of distribution in Caucasians. Seven percent of Caucasians (1% of Asians and African-Americans) are homozygous for mutations that result in low levels of, or no, active enzyme. These individuals, usually termed poor metabolizers, show a very slow elimination of many drugs, including several antiarrhythmics (e.g., flecainide, mexiletine, propafenone, disopyramide, metoprolol, timolol). They also show greater β receptor blockade when given usual doses of β receptor antagonists and have higher plasma concentrations of flecainide or mexiletine and exhibit greater Na⁺ channel blockade when given usual doses. Because these individuals are not identified routinely before initiation of therapy, all patients must be started at low doses.

The pharmacokinetics of amiodarone are extremely complex. It is metabolized by N-deethylation by cytochrome P450s (CYP3A4) to N-desethylamiodarone. Serum concentrations of this potentially active metabolite are highly variable and may relate to the large variability in CYP3A4 activity among individuals. Amiodarone is eliminated by biliary excretion with negligible excretion in urine. Amiodarone and its metabolite cross the placenta and appear in breast milk.

Ibutilide has a highly variable pharmacokinetic profile. Because of extensive first-pass metabolism, ibutilide must be given IV, and its progressive oxidation yields eight metabolites, one of which has antiarrhythmic effects.

Adenosine is taken up by erythrocytes and vascular endothelial cells and metabolized to inosine and adenosine monophosphate. Hepatic and renal dysfunction do not affect its metabolism. Its actions are potentiated by nucleoside transport blockers, such as dipyridamole, and antagonized by methylxanthines, such as caffeine and theophylline.

Relationship of Mechanisms of Action to Clinical Response

Class I Antiarrhythmics

Quinidine has potent anticholinergic properties that cause effects opposite to those due to its direct effects in parasympathetically innervated regions of the heart. After initial administration, there may be a small SA nodal tachycardia and an increase in AV nodal conduction velocity (decrease in PR interval) as a result of its indirect anticholinergic effects. These are usually followed by direct effects, including a decrease in heart rate and a slowing of AV nodal conduction velocity (increase in PR interval). At therapeutic concentrations the QRS complex often shows slight widening as a result of a decrease in ventricular conduction velocity. The QT interval is lengthened because of the prolonged action potential in the ventricular myocardium.

Procainamide and disopyramide depress automaticity in SA nodal cells and ectopic pacemakers. Procainamide has much less of an anticholinergic effect than quinidine. Therefore its effects on heart rate and AV nodal conduction velocity are more direct and usually involve a decrease in heart rate and a slight prolongation of the PR interval. Disopyramide, however, has similar, if not more, potent anticholinergic properties than quinidine. Therefore it has the same indirect and direct effects on heart rate and AV conduction velocity as quinidine. When disopyramide is given for treatment of atrial flutter or fibrillation, a digitalis glycoside will often be coadministered to minimize its anticholinergic properties. Procainamide and disopyramide block Na⁺ channels and slightly prolong the QRS complex. However, the major metabolite of procainamide, NAPA, is a potent class III agent and prolongs the QT interval during oral therapy. Therefore a widening of the QRS complex and a lengthening of the QT interval are also observed after administration of these agents. Both compounds are broad-spectrum antiarrhythmics used to treat supraventricular and ventricular arrhythmias.

Lidocaine has little effect on automaticity within the SA node over a relatively large concentration range, and hence heart rate remains relatively normal. Conversely, lidocaine suppresses automaticity in ectopic ventricular pacemakers and Purkinje fibers. Shortening of the action potential and effective refractory period is possible and is more prominent in Purkinje fibers than in ventricular myocardium. Lidocaine has little effect on AV nodal conduction and at therapeutic concentrations has minimal effect on the resting electrocardiogram. Lidocaine is used exclusively for ventricular arrhythmias, especially those associated with acute myocardial infarction. It has no efficacy in treatment of supraventricular arrhythmia, such as atrial flutter or fibrillation. Lidocaine is also used for the treatment of digitalis-induced arrhythmias.

Phenytoin depresses the automaticity of both SA nodal cells and ectopic pacemakers. Though devoid of anticholinergic properties, it increases AV nodal conduction velocity by an unknown mechanism. Phenytoin results in a small decrease in the PR and QT intervals on electrocardiogram. Its use is limited to management of postoperative arrhythmias and digitalis toxicity in pediatric patients.

Flecainide and propafenone depress SA nodal automaticity and slow AV nodal conduction. They may produce conduction block in patients with preexisting AV nodal conduction disturbances. At therapeutic concentrations, prolongation of the PR and QRS intervals are seen. Both drugs also cause conduction slowing in accessory pathways, contributing to their effectiveness in treating AV reentrant tachycardia. Drugs in class IC should be used with extreme caution in patients with structural heart disease and anyone with concerns about myocardial ischemia.

Class II Antiarrhythmics

The β receptor blockers at therapeutic doses prolong the PR interval with occasional shortening of the QT interval. These drugs are reasonably efficacious in suppressing ventricular ectopic pacemakers and are first-line therapy for most supraventricular and ventricular arrhythmias. They have been demonstrated to be effective in decreasing overall mortality rate after a myocardial infarction. Agents such as metoprolol and acebutolol (but not propranolol) have a greater selectivity for β₁ receptors than for β₂ receptors (see Chapter 11). There are also differences between these compounds with regard to their effects on cardiac channels and their intrinsic sympathomimetic activities. Esmolol, a short-acting agent, may be used for acute conversion or ventricular rate control.

Class III Antiarrhythmics

Amiodarone profoundly depresses SA nodal automaticity and that of ectopic pacemakers. Effects on the electrocardiogram include prolongation of the PR, QRS, and QT intervals. Amiodarone has become perhaps the most widely used agent because of its effectiveness in suppressing ventricular and supraventricular arrhythmias refractory to other drugs. However, its systemic toxicity and highly variable t_1/2 make it necessary to use extreme caution during therapy.

Sotalol is marketed as the racemic mixture for treatment of life-threatening ventricular arrhythmias. At low doses its predominant antiarrhythmic effect results from β receptor blockade. At higher doses its effects on K⁺ channels predominate, thereby increasing atrial and ventricular refractoriness. Sotalol prolongs repolarization and increases the QT interval. The risk for a drug-induced, potentially life-threatening ventricular arrhythmia (torsades des pointes) is 3% to 5% and necessitates initiation of therapy in an inpatient setting. Like amiodarone, sotalol has a profound effect on SA node activity and can magnify SA node dysfunction. It is used in treatment of supraventricular arrhythmias and ventricular arrhythmias but should be reserved for use in life-threatening arrhythmias because of its high risk of ventricular proarrhythmias.

Ibutilide is used for conversion of atrial fibrillation or flutter. It is an alternative to electrical cardioversion and is effective in 60% to 80% of patients. Like other QT prolonging drugs, its use is associated with a relatively high incidence of torsades des pointes.

Bretylium is used in emergency treatment of ventricular fibrillation.

Class IV Antiarrhythmics

Ca⁺⁺ channel blockers are most effective in treating supraventricular arrhythmias, which involve reentry and may also be effective in treating arrhythmias resulting from enhanced automaticity. Their ability to slow AV nodal conduction velocity and refractoriness makes them useful for controlling ventricular rate. Ca⁺⁺ channel blockers are rarely used to treat ventricular arrhythmias, although they may be effective for treating a form of idiopathic fascicular ventricular tachycardia.

Nonclassified Antiarrhythmics

Digitalis glycosides slow conduction velocity and increase the refractory period in the AV node. They may be useful in treatment of supraventricular tachycardias, such as atrial flutter and fibrillation, by slowing conduction through the AV node and helping to control ventricular rate.

Adenosine is useful for terminating reentrant supraventricular tachycardias that involve the AV node, where it causes conduction block. Adenosine has a serum t_1/2 of approximately 5 seconds, limiting its clinical usefulness to bolus IV therapy.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Major problems associated with the use of the antiarrhythmic agents are summarized in the Clinical Problems Box.

Class I Antiarrhythmics

The use of quinidine is limited by adverse side effects that are generally dose-related and reversible. Common effects include diarrhea, upper GI distress, and lightheadedness. The most worrisome side effects are related to cardiac toxicity and include AV and intraventricular conduction block, ventricular tachyarrhythmias, and depression of myocardial contractility. “Quinidine syncope,” which is a loss of consciousness resulting from ventricular tachycardia, may be fatal. This devastating side effect is more common in women and may occur at therapeutic or subtherapeutic concentrations. Quinidine is a potent inhibitor of CYP2D6 and CYP3A4 and interacts with many other drugs.

Procainamide administration may result in hypotension, AV or intraventricular block, ventricular tachyarrhythmias, and complete heart block. If severe depression of conduction (severe prolongation of the QRS interval) or repolarization (severe prolongation of the QT interval) occurs, the dose must be decreased or the drug discontinued. Long-term treatment is problematic because of induction of a lupus-like syndrome. Increased antinuclear antibody titers are present in greater than 80% of patients treated for more than 6 months, whereas 30% of patients develop a clinical lupus-like syndrome. Symptoms may disappear within a few days of cessation of therapy, although clinical tests remain positive for several months. Prolonged administration should be accompanied by hematological studies because agranulocytosis may occur. Procainamide has little potential to produce CNS toxicity.

The negative inotropic effects of disopyramide may precipitate heart failure in patients with or without preexisting depression of left ventricular function. Parasympatholytic effects, including urinary retention, dry mouth, blurred vision, constipation, and worsening of preexisting glaucoma (see Chapter 10), may require discontinuation of therapy. Disopyramide should not be used in patients with uncompensated congestive heart failure, glaucoma, hypotension, urinary retention, and baseline prolonged QT interval.

Lidocaine does not have negative hemodynamic effects at therapeutic concentrations and is well tolerated, even in significant ventricular dysfunction. However, excessively rapid injection or high doses may cause asystole. Most toxic side effects are caused by its local anesthetic effects on the CNS and include drowsiness, tremor, nausea, hearing disturbances, slurred speech paresthesias, disorientation, and at high doses, psychosis, respiratory depression, and convulsions (see Chapter 13).

Mexiletine and tocainamide have similar actions and side effects as lidocaine, but pharmacokinetic differences allow their oral use. At higher concentrations mexiletine may produce reversible nausea and vomiting and CNS effects (dizziness/light-headedness, tremor, nervousness, coordination difficulties, changes in sleep habits, paresthesias/numbness, weakness, fatigue, tinnitus, and confusion/clouded sensorium). Most effects are manageable with downward dose titration. Mexiletine can inhibit ventricular escape rhythms and is contraindicated in the presence of preexisting second- or third-degree AV block, unless the patient has an indwelling pacemaker.

Phenytoin at high levels can produce adverse CNS effects, including vertigo, nystagmus, ataxia, tremors, slurring of speech, and sedation. Because of its long t_1/2 and the nonlinear relationship between dose and clearance, considerable variations in response to an oral dose are typical. Rapid IV administration may produce transient hypotension from peripheral vasodilation and direct negative inotropic effects (see Chapter 34).

The side effects of flecainide include dizziness, blurred vision, headache, and nausea. Data from the Cardiac Arrhythmia Suppression Trial suggest that all class IC drugs are thought to carry an added proarrhythmic risk, and their use has been reserved for life-threatening arrhythmias, particularly in structural heart disease. Flecainide may also slow conduction in a reentrant circuit without terminating it. This may lead to accelerating the ventricular rate during atrial flutter, because fewer atrial beats are blocked as a result of the slower cycle length, and it may also lead to converting a rapid but self-limited AV-reentrant (accessory pathway mediated) tachycardia into a slower but persistent arrhythmia.

Propafenone may cause new or worsened arrhythmias. Similar to flecainide, most proarrhythmic events occur during the first week of therapy, although late events have been observed, suggesting that an increased risk is present throughout treatment. Agranulocytosis has been reported in patients receiving propafenone, generally within the first 2 months of therapy, and resolving upon discontinuation. Liver metabolism necessitates careful administration to patients with hepatic dysfunction. Also, a small segment of the population has a genetic abnormality of CYP2D6, which is responsible for the metabolism of propafenone.

Class II Antiarrhythmics

The β receptor antagonists should be used with caution when combined with other drugs that also slow AV nodal conduction velocity, because their effects may be synergistic. These agents are generally contraindicated in patients with existing AV nodal conduction disturbances, congestive heart failure, or bronchial asthma. Their toxicity and side effects are described in Chapter 11.

Class III Antiarrhythmics

Amiodarone therapy is fraught with multiple complications, both cardiac and systemic, after IV or oral administration. Major side effects of IV administration include hypotension, heart block, and bradycardia. The most feared noncardiac complication is pulmonary fibrosis, which has an insidious onset and may occur as early as 7 weeks or as late as years after starting treatment. It is more frequent in patients receiving doses exceeding 400 mg but has been seen in a patient taking 200 mg/day. Close monitoring of pulmonary status is required during chronic amiodarone therapy, because this is a potentially fatal condition that may not resolve with discontinuation. Other serious side effects include thyroid abnormalities, photosensitivity, rash, slate-blue skin discoloration, severe nausea, and chemical hepatitis. Although amiodarone prolongs the QT interval dramatically, the risk of torsades des pointes is relatively low compared with other class III agents. Amiodarone magnifies any sinus node dysfunction and may require pacemaker placement, if ongoing therapy is necessary.

Sotalol has fewer systemic side effects than amiodarone but a higher incidence of ventricular proarrhythmias. In patients with a history of ventricular tachycardia, the use of sotalol was associated with a 4% risk of torsades des pointes; the risk in patients with no history of ventricular arrhythmias was approximately 1%. Because of this risk, therapy should be initiated as an inpatient. Sotalol is contraindicated in patients with asthma as a consequence of its β receptor blocking action. Sotalol exacerbates sinus node dysfunction and may aggravate second-and third-degree AV block with suppression of ectopic ventricular pacemakers. Therefore its use for patients with such conditions should be restricted unless a functioning pacemaker is present. Other contraindications include congenital or acquired long QT syndromes, cardiogenic shock, and uncontrolled congestive heart failure.

Dofetilide prolongs repolarization and the QT interval, which increases the risk of torsades des pointes. The risk of torsades des pointes in patients treated for atrial fibrillation is 0.8%. Dofetilide should not be used in patients with a prolonged QT interval at baseline. A clinical trial evaluating the use of dofetilide in patients after myocardial infarction demonstrated no increased mortality, different from results from trials with sotalol or flecainide and encainide.

Bretylium is not considered a first-choice antiarrhythmic agent because of its toxicity and side effects. It is primarily used to stabilize cardiac rhythm in patients with ventricular fibrillation or recurrent tachycardia resistant to other treatments. Its most severe side effect is persistent hypotension, caused by peripheral vasodilation due to adrenergic nerve blockade. Also, catecholamine release can transiently enhance ectopic pacemaker activity and cause increases in myocardial O₂ consumption in patients with ischemic heart disease. Nausea and vomiting are also common side effects.

Nonclassified Antiarrhythmics

Adenosine leads to transient AV block, which is generally well tolerated. Prolonged AV block may be observed

CLINICAL PROBLEMS

Quinidine	Diarrhea, precipitates arrhythmias; torsades de pointes, elevates digoxin concentrations, vagolytic effects
Procainamide	Arrhythmias, granulocytopenia, fever, rash, lupus-like syndrome
Disopyramide	Precipitates congestive heart failure, anticholinergic effects
Lidocaine	CNS effects (dizziness, seizures), first-pass metabolism
Phenytoin	CNS effects, hypotension
Mexiletine	CNS effects
Flecainide	Negative inotropic effect, proarrhythmogenic, CNS side effects
Propafenone	CNS effects, proarrhythmogenic
β receptor blockers	Negative inotropic and chronotropic effects; precipitates congestive heart failure, AV conduction block
Amiodarone	Hypotension, pneumonitis, bradycardia; precipitates congestive heart failure, photosensitivity, thyroid abnormalities
Sotalol	Modest negative inotropic and chronotropic effects, torsades des pointes
Dofetilide	Torsades de pointes
Ibutilide	Torsades de pointes
Bretylium	Hypotension, nausea
Verapamil	Hypotension, negative inotropic and chronotropic effects
Adenosine	Atrial fibrillation, bronchospasm, prolonged AV block, flushing

in patients with AV node disease, and profound sinus bradycardia may be observed in patients with sick sinus syndrome. Heart transplantation patients have also been documented to have a prolonged effect from adenosine. Adenosine shortens the refractory period of atrial myocytes, which may lead to initiation of atrial fibrillation. In patients with Wolff-Parkinson-White syndrome, this may result in rapid conduction across the accessory pathway, which is not blocked by adenosine and ventricular fibrillation. Adenosine may also trigger bronchospasm in patients with asthma. Although the t_1/2 of adenosine is less than 10 seconds, bronchospasm may persist for up to 30 minutes by an unknown mechanism.

New Horizons

Antiarrhythmic therapy is changing rapidly. Increasingly, mechanical therapy via transcatheter methods such as radiofrequency ablation, or implanted devices such as pacemakers and defibrillators, are being used to control abnormal heart rhythms. Antiarrhythmic drug therapy is being used in conjunction with these therapies, and an appreciation of the interactions between drugs and devices is important. Antiarrhythmic drugs can dramatically affect the performance of implanted devices. Certain compounds may increase the amount of energy devices need to either

pace or defibrillate the heart. Amiodarone, flecainide, lidocaine, propafenone, and mexiletine all lead to increased defibrillation thresholds, whereas sotalol and dofetilide cause them to decrease.

All antiarrhythmic drugs interact with ion channels that participate in the normal action potential and therefore interfere with the normal function of the heart. Identification of ion channels that may participate in pathological states only would make ideal drug targets. One possibility is the ATP-gated K⁺ channel. This large conductance K⁺ channel is found in many tissues, including heart, pancreas, and vasculature. It is normally tonically inhibited by physiological intracellular concentrations of ATP. When intracellular ATP falls and the ATP/ADP ratio is altered, the channel opens, leading to rapid repolarization and a shortened refractory period. This predisposes the tissue to reentrant arrhythmias. The ability to block this channel, which does not participate in the normal action potential, is an attractive target.