401

INTRODUCTION �

The human heart is both a mechanical and an electrical organ. To perfuse the body adequately with blood, the mechanical and electrical components of the heart must work in precise concert with each other. The mechanical component pumps the blood; the electrical component controls the rhythm of the pump. When the mechanical component fails despite a normal rhythm, heart failure can result (see Chapter 25, Integrative Cardiovascular Pharmacology: Hypertension, Ischemic Heart Disease, and Heart Failure). When the electrical component goes awry (called an arrhythmia), cardiac myocytes fail to contract in synchrony, and effective pumping is compromised. Changes in the mem-brane potential of cardiac cells directly affect cardiac rhythm, and most antiarrhythmic drugs act by modulating the activity of ion channels in the plasma membrane. This chapter discusses the ionic basis of electric rhythm formation and conduction in the heart, the pathophysiology of electrical dysfunction, and the pharmacologic agents used to restore a normal cardiac rhythm.

ELECTRICAL PHYSIOLOGY OF THE HEART �

Electrical activity in the heart, leading to rhythmic cardiac contraction, is a manifestation of the heart’s exquisite control

of cell depolarization and impulse conduction. Once initi-ated, a cardiac action potential is a spontaneous event that proceeds based on the characteristic responses of ion chan-nels to changes in membrane voltage. At the completion of a cycle, the spontaneous depolarization of pacemaker cells ensures that the process repeats without interruption.

Pacemaker and Nonpacemaker Cells The heart contains two types of cardiac myocytes—those that can spontaneously initiate action potentials and those that cannot. Cells possessing the ability to initiate spontane-ous action potentials are termed pacemaker cells . All pace-maker cells possess automaticity , the ability to depolarize above a threshold voltage in a rhythmic fashion. Automa-ticity results in the generation of spontaneous action poten-tials. Pacemaker cells are found in the sinoatrial node (SA node), the atrioventricular node (AV node), and the ventricu-lar conducting system (bundle of His, bundle branches, and Purkinje fi bers). Together, the pacemaker cells constitute the specialized conducting system that governs the electri-cal activity of the heart. The second type of cardiac cells, the nonpacemaker cells , includes the atrial and ventricular myocytes. The nonpacemaker cells contract in response to depolarization and are responsible for the majority of cardiac

Classes of Antiarrhythmic Agents . . . . . . . . . . . . . . . . . . . 409Class I Antiarrhythmic Agents: Fast Na� Channel Blockers . . . . . . . . . . . . . . . . . . . . . 409Class II Antiarrhythmic Agents: �-Adrenergic Antagonists . . . . . . . . . . . . . . . . . . . . . . 413Class III Antiarrhythmic Agents: Inhibitors of Repolarization . . . . . . . . . . . . . . . . . . . . . 413Class IV Antiarrhythmic Agents: Ca 2� Channel Blockers . . . . . . . . . . . . . . . . . . . . . . . . 415Other Antiarrhythmic Agents . . . . . . . . . . . . . . . . . . . . 416

CONCLUSION AND FUTURE DIRECTIONS . . . . . . . . . . . . . . 416Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417

INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . 401-402ELECTRICAL PHYSIOLOGY OF THE HEART . . . . . . . . . . . . . 401

Pacemaker and Nonpacemaker Cells . . . . . . . . . . . . . . . . 401Cardiac Action Potentials . . . . . . . . . . . . . . . . . . . . . . . . . 402Determination of Firing Rate . . . . . . . . . . . . . . . . . . . . . . 406

PATHOPHYSIOLOGY OF ELECTRICAL DYSFUNCTION . . . . . . 406Defects in Impulse Formation (SA Node) . . . . . . . . . . . . . 406

Altered Automaticity . . . . . . . . . . . . . . . . . . . . . . . . . . 406Triggered Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406

Defects in Impulse Conduction . . . . . . . . . . . . . . . . . . . . . 407Re-entry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407Conduction Block . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408Accessory Tract Pathways . . . . . . . . . . . . . . . . . . . . . . 408

PHARMACOLOGIC CLASSES AND AGENTS . . . . . . . . . . . . . 408General Mechanisms of Action of Antiarrhythmic Agents . . . . . . . . . . . . . . . . . . . . . . . . . 408

Pharmacology of Cardiac Rhythm

Ehrin J. Armstrong, April W. Armstrong, and David E. Clapham

23

CHAPTER 23 / Pharmacology of Cardiac Rhythm 403

FIGURE 23-2. SA node action potential and ion currents. A. SA nodal cells are depolarized slowly by the pacemaker current ( I f ) (phase 4), which consists of an inward fl ow of sodium (mostly) and calcium ions. Depolarization to the thresh-old potential opens highly selective voltage-gated calcium channels, which drive the membrane potential toward E Ca (phase 0). As the calcium channels close and potassium channels open (phase 3 ), the membrane potential repolarizes. B. The fl ux of each ion species correlates roughly with each phase of the action potential. Positive currents indicate an outward fl ow of ions ( blue and purple ), while nega-tive currents are inward ( gray and black ).

A SA node action potentialM

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B Ion currents of SA node action potential

myocyte remains near E K until the cell is stimulated by a wave of depolarization that is initiated by nearby pacemaker cells. The fi ve phases of the ventricular myocyte action po-tential result from an intricately woven cascade of channel openings and closings; the phases are numbered from 0 to 4 (Fig. 23-3 and Table 23-1).

SA node action potential, the kinetics of this depolarization are modulated by voltage-gated Na � channels that are also expressed in the node. There are gradients of expression of I f channels and of the more selective voltage-gated Na � and Ca 2 � channels within the SA node, such that cells at the bor-der of the node express relatively more voltage-gated Na � channels and cells in the center of the node express relatively more I f and voltage-gated Ca 2 � channels. The expression of voltage-gated Na � channels in the SA node is partly respon-sible for the effect of certain antiarrhythmics on the automa-ticity of SA nodal cells (see below).

Unlike SA nodal cells, ventricular myocytes do not de-polarize spontaneously under physiologic conditions. As a result, the membrane potential of the resting ventricular

FIGURE 23-1. SA node and ventricular muscle cell action potentials. The resting membrane potential of a sinoatrial (SA) node cell is approximately � 55 mV, while that of a ventricular muscle cell is � 85 mV. The shaded areas represent the approximate depolarization required to trigger an action potential in each cell type. Together, the cardiac action potentials last for approximately half a second. SA node cells (A) depolarize to a peak of � 10 mV, and ventricular muscle cells (B) depolarize to a peak of � 45 mV. Note that the ventricular action potential has a much longer plateau phase. This long plateau ensures that ventricular myo-cytes have adequate time to contract before the onset of the next action potential. The Nernst equilibrium potentials of the major ions ( E Ca , E Na , E K ) are shown as dashed horizontal lines . E m , membrane potential.

A SA node cell

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406 Principles of Cardiovascular Pharmacology

number of Ca 2 � channels, and thereby shifts the threshold to more negative potentials. Both of these mechanisms increase heart rate. The parasympathetic vagus nerve affects the SA node by a number of mechanisms that oppose the sympathetic regulation of heart rate. Vagus nerve release of acetylcholine initiates an intracellular signaling cascade that: (1) reduces the pacemaker current by decreasing pacemaker channel opening; (2) shifts the threshold to more positive potentials by reducing Ca 2 � channel opening; and (3) makes the maximum diastolic potential (analogous to the resting membrane potential in these spontaneously fi ring cells) more negative by increasing K � channel opening. The SA node, atria, and AV node are highly innervated and are thus more sensitive than the ventricular con-ducting system to the effects of vagal stimulation.

In pathologic conditions, automaticity can be altered when latent pacemaker cells take over the SA node’s role as the pacemaker of the heart. When the SA nodal fi ring rate becomes pathologically slow or when conduction of the SA impulse is impaired, an escape beat may occur as a latent pacemaker initiates an impulse. A series of escape beats, known as an escape rhythm , may result from prolonged SA nodal dys-function. On the other hand, an ectopic beat occurs when la-tent pacemaker cells develop an intrinsic rate of fi ring that is faster than the SA nodal rate , in some cases despite the pres-ence of a normally functioning SA node. A series of ectopic beats, termed an ectopic rhythm , can result from ischemia, electrolyte abnormalities, or heightened sympathetic tone.

Direct tissue damage (such as can occur after a myocar-dial infarction) also results in altered automaticity. Tissue injury can cause structural disruption of the cell membrane. Disrupted membranes are unable to maintain ion gradients, which are critical for maintaining appropriate membrane potentials. If the resting membrane potential becomes suf-fi ciently positive (more positive than � 60 mV), nonpace-maker cells may begin to depolarize spontaneously. Another mechanism by which tissue damage leads to altered automa-ticity is through the loss of gap junction connectivity. Direct electrical connectivity is important for the effective delivery of overdrive suppression from the SA node to the rest of the cardiac myocytes. When connectivity is disrupted due to tis-sue injury, overdrive suppression is not effi ciently relayed, and the unsuppressed cells can initiate their own rhythm. This abnormal rhythm can lead to cardiac arrhythmia.

Triggered Activity Afterdepolarizations occur when a normal action potential triggers extra abnormal depolarizations. That is, the fi rst (normal) action potential triggers additional oscillations of membrane potential, which may lead to arrhythmia. There are two types of afterdepolarizations—early afterdepolariza-tions and delayed afterdepolarizations.

If the afterdepolarization occurs during the inciting ac-tion potential , it is termed an early afterdepolarization (Fig. 23-5). Conditions that prolong the action potential (e.g., drugs that prolong the QT interval, such as procain-amide and ibutilide) tend to trigger early afterdepolariza-tions. Specifi cally, an early afterdepolarization can occur during the plateau phase (phase 2) or the rapid repolariza-tion phase (phase 3). During the plateau phase, because most of the Na � channels are inactivated, an inward Ca 2 � cur-rent is responsible for the early afterdepolarization. On the other hand, during the rapid repolarization phase, partially recovered Na � channels can conduct an inward Na � current

Determination of Firing Rate The specialized conduction system of the heart consists of the SA node, AV node, bundle of His, and Purkinje system. These different populations of cells have different intrin-sic rates of fi ring. Three factors determine the fi ring rate. First, as the rate of spontaneous depolarization in phase 4 increases, the rate of fi ring increases because the threshold potential (the minimum potential necessary to trigger an ac-tion potential) is reached more quickly at the end of phase 4. Second, if the threshold potential becomes more negative, the rate of fi ring increases because the threshold potential is reached more quickly at the end of phase 4. Third, if the maximum diastolic potential (the resting membrane poten-tial) becomes more positive, the rate of fi ring increases be-cause less time is needed to repolarize the membrane fully at the end of phase 3.

Because the various populations of pacemaker cells pos-sess different intrinsic rates of fi ring, the pacemaker popula-tion with the fastest fi ring rate sets the heart rate. The SA node possesses the fastest intrinsic fi ring rate—60–100 times per minute—and is the native pacemaker of the heart. The cells of the atrioventricular (AV) node and bundle of His fi re intrinsically between 50 and 60 times per minute, and the cells of the Purkinje system have the slowest intrinsic fi ring rate—30–40 times per minute. The cells of the AV node, bun-dle of His, and Purkinje system are termed latent pacemak-ers , because their intrinsic rhythm is overridden by the faster SA-node automaticity. In a mechanism termed overdrive suppression , the SA node suppresses the intrinsic rhythm of the other pacemaker populations and entrains them to fi re at the SA nodal fi ring rate.

PATHOPHYSIOLOGY OF ELECTRICAL �DYSFUNCTION

Causes of electrical dysfunction in the heart can be divided into defects in impulse formation and defects in impulse conduction. In the former case, SA-node automaticity is in-terrupted or altered, leading to missed beats or ectopic beats, respectively. In the latter case, impulse conduction is altered (for example, in the case of re-entrant rhythms), and sus-tained arrhythmias can result.

Defects in Impulse Formation (SA Node) As the native pacemaker of the heart, the SA node has a pivotal role in normal impulse formation. Electrical events that alter SA nodal function or disturb overdrive suppression can lead to impaired impulse formation. Two mechanisms commonly associated with defective impulse formation are altered automaticity and triggered activity.

Altered Automaticity Some mechanisms that alter automaticity of the SA node are physiologic. In particular, the autonomic nervous system often modulates automaticity of the SA node as part of a physi-ologic response. In sympathetic stimulation during exercise, an increased concentration of catecholamines leads to greater � 1 -adrenergic receptor activation. Activation of � 1 receptors causes the opening of a greater number of pacemaker chan-nels ( I f channels); a larger pacemaker current is then conducted through these channels; and faster phase 4 depolarization results. Sympathetic stimulation also causes the opening of a greater

CHAPTER 23 / Pharmacology of Cardiac Rhythm 407

Defects in Impulse Conduction The second type of electrical disturbance of the heart involves defects in impulse conduction. Normal cardiac function re-quires unobstructed and timely propagation of an electrical impulse through the cardiac myocytes. In pathologic condi-tions, altered impulse conduction can result from one or a combination of three mechanisms: re-entry, conduction block, and accessory tract pathways.

Re-entry Normal cardiac conduction is initiated at the SA node and propagated to the AV node, bundle of His, Purkinje system, and myocardium in an orderly fashion. The cellular refrac-tory period ensures that stimulated regions of the myocar-dium depolarize only once during propagation of an impulse. Figure 23-7A depicts normal impulse conduction, in which an impulse arriving at point a travels synchronously down two parallel pathways, 1 and 2.

Re-entry of an electrical impulse occurs when a self- sustaining electrical circuit stimulates an area of the myocar-dium repeatedly and rapidly. Two conditions must be present

that contributes to the early afterdepolarization. If an early afterdepolarization is sustained, it can lead to a type of ven-tricular arrhythmia termed torsades de pointes . Torsades de pointes, French for “twisting of the points,” is characterized by QRS complexes of varying amplitudes as they “twist” along the baseline; this rhythm is a medical emergency that can lead to death if not treated emergently with antiarrhyth-mics and/or defi brillation.

In contrast to early afterdepolarizations, delayed afterdepo-larizations occur shortly after the completion of repolarization (Fig. 23-6). The mechanism of delayed afterdepolarizations is not well understood; it has been proposed that high intracellu-lar Ca 2 � concentrations lead to an inward Na � current, which, in turn, triggers the delayed afterdepolarization.

FIGURE 23-5. Early afterdepolarization. Early afterdepolarizations gener-ally occur during the repolarizing phase of the action potential, although they can also occur during the plateau phase. Repetitive afterdepolarizations can trigger an arrhythmia.

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FIGURE 23-6. Delayed afterdepolarization. Delayed afterdepolarizations occur shortly after repolarization. Although the mechanism has not been fi rmly elucidated, it appears that intracellular Ca 2 � accumulation activates the Na � /Ca 2 � exchanger, and the resulting electrogenic infl ux of 3 Na � for each extruded Ca 2 � depolarizes the cell.

Slow upstrokevelocity

A delayed afterdepolarizationthat reached threshold voltage

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FIGURE 23-7. Normal and re-entrant electrical pathways. A. In normal im-pulse conduction, an impulse traveling down a pathway arrives at point a , where it is able to travel down two alternate pathways, 1 and 2. In the absence of re-entry, the impulses continue on and depolarize different areas of the ventricle. B. A re-entrant circuit can develop if one of the branch pathways is pathologically disrupted. When the impulse arrives at point a , it can travel only down pathway 1 because pathway 2 is blocked unidirectionally (i.e., the effective refractory period of the cells in pathway 2 is prolonged to such an extent that anterograde conduction is prohibited). The impulse conducts through pathway 1 and proceeds to point b . At this point, the cells in path-way 2 are no longer refractory, and the impulse conducts in a retrograde fashion up pathway 2 toward point a . When the retrograde impulse arrives at point a , it can initiate re-entry. Re-entry can result in a sustained pattern of rapid depolarizations that trigger tachyarrhythmias. This mechanism can occur over small or large regions of the heart.

A Normal conduction

Cardiacaction

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Unidirectionalconduction block

Abnormally slowretrogradeconduction

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(damaged or partiallydepolarized cells)

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Cardiacaction

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408 Principles of Cardiovascular Pharmacology

initiated. After the impulse travels through the AV node, it again propagates quickly throughout the ventricles to trigger ventricular contraction.

Some individuals possess accessory electrical pathways that bypass the AV node. One common accessory pathway is the bundle of Kent , a band of myocardium that conducts im-pulses directly from the atria to the ventricles, bypassing the AV node (Fig. 23-8). In these individuals, an impulse originat-ing in the SA node is conducted through the bundle of Kent to the ventricles more rapidly than the same impulse would be conducted through the AV node. Because the bundle of Kent is an accessory pathway, the ventricular tissue receives impulses from both the normal conduction pathway and the accessory pathway. As a result, electrocardiograms from these individuals typically exhibit a wider-than-normal QRS com-plex and an earlier-than-normal ventricular upstroke. More importantly, because the two conduction tracts have different conduction velocities, the presence of an accessory tract can set up the conditions for a re-entrant loop, and thereby predis-pose the individual to tachyarrhythmias.

PHARMACOLOGIC CLASSES �AND AGENTS

Ion currents across the plasma membrane induce changes in the membrane potential of cells. Changes in the membrane poten-tial of cardiac pacemaker cells underlie the timely contraction of cardiac myocytes. Defects in impulse formation and altered impulse conduction can lead to disturbances in cardiac rhythm. Antiarrhythmic agents are used to restore normal cardiac rhythm by targeting proarrhythmic regions of the heart.

General Mechanisms of Action of Antiarrhythmic Agents Although there are many different antiarrhythmic agents, there are surprisingly few mechanisms of antiarrhythmic action. In general, drugs that affect cardiac rhythm act by altering: (1) the maximum diastolic potential in pacemaker cells (and/or the resting membrane potential in ventricular cells); (2) the rate of phase 4 depolarization; (3) the threshold potential; or (4) the action potential duration. The specifi c effect of a par-ticular channel blocker follows directly from the role of the current carried by that channel in the cardiac action potential. For example, Na � and Ca 2 � channel blockers typically alter the threshold potential, while K � channel blockers tend to pro-long action potential duration. These drugs generally block the pore from inside the cell; they can access their sites of action by either traversing the pore of the channel or diffusing across the lipid bilayer within which the channel is embedded.

State-dependent ion channel block is an important con-cept in antiarrhythmic drug action. Ion channels are capable of switching among various conformational states, and changes in the permeability of the membrane to a particular ion are mediated by conformational changes in the channels that pass that ion. Antiarrhythmic drugs often have different affi nities for different conformational states of the ion channel; that is, these drugs bind to one conformation of the channel with higher affi nity than they do to other conformations of the chan-nel. This type of binding is referred to as “state-dependent.”

Na � channel blockers serve as an excellent example to illustrate the concept of state-dependent ion channel block. The Na � channel undergoes three major state changes

for a re-entrant electrical circuit to occur: (1) unidirectional block (anterograde conduction is prohibited, but retrograde conduction is permitted); and (2) slowed retrograde con-duction velocity . Figure 23-7B shows a re-entrant electrical circuit. As the impulse arrives at point a , it can travel only down pathway 1 (the left branch), because pathway 2 (the right branch) is blocked unidirectionally in the anterograde direction. The impulse conducts through pathway 1 and travels to point b . At this junction, the impulse travels in a retrograde fashion up pathway 2 toward point a . The con-duction time from point b to point a is slowed because of cell damage or the presence of cells that are still in the refractory state. By the time the impulse reaches point a , the cells in pathway 1 have had adequate time to repolarize, and these cells are stimulated to continue conducting the action poten-tial toward point b . In this manner, tachyarrhythmias result from the combination of unidirectional block and decreased conduction velocity in the abnormal pathway.

Conduction Block Conduction block occurs when an impulse fails to propagate because of the presence of an area of inexcitable cardiac tis-sue. This area of inexcitable tissue could consist of normal tissue that is still refractory, or it could represent tissue that has been damaged by trauma, ischemia, or scarring. In either case, the myocardium is unable to conduct an impulse. Be-cause conduction block removes overdrive suppression by the SA node, the cardiac myocytes are free to beat at their intrinsically slower frequency. For this reason, conduction block can be manifested clinically as bradycardia.

Accessory Tract Pathways During the normal cardiac cycle, the SA node initiates an impulse that travels quickly through the atrial myocardium and arrives at the AV node. Impulse conduction then slows through the AV node, allowing suffi cient time for fi lling of the ventricles with blood before ventricular contraction is

SA node

AV node Bundle of His

Purkinjefibers

Bypass tract(Bundle of Kent)

FIGURE 23-8. Bundle of Kent. The bundle of Kent is an accessory electrical pathway that conducts impulses directly from the atria to the ventricles, bypassing the AV node. Impulse conduction through this accessory tract is more rapid than conduc-tion through the AV node, setting up the conditions for re-entrant tachyarrhythmias.

410 Principles of Cardiovascular Pharmacology

0 100 200 300 400 500 600 700

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FIGURE 23-9. Effects of class I antiarrhythmics and natural agonists on the SA-node action potential. A. The normal SA-node action potential is shown as a solid curve. Class I antiarrhythmics (Na � channel blockers) alter SA-node automaticity by affecting two aspects of the SA nodal action potential: (1) the threshold is shifted to more positive potentials; and (2) the slope of phase 4 depolarization is decreased. B. Acetylcholine and adenosine slow the SA nodal fi ring rate by opening K � channels that hyperpolarize the cell and decrease the slope of phase 4 depolarization.

phase 0 upstroke velocity, Na � channel blockers decrease the conduction velocity through cardiac tissue. Ideally, conduc-tion velocity is reduced to such an extent that the propagat-ing wavefront is extinguished before it is able to restimulate myocytes in a re-entrant pathway. However, if conduction velocity is not suffi ciently decreased, and the impulse is not extinguished, then the slowed impulse can support re-entry as it reaches cells that are no longer refractory (see above), and thereby precipitate an arrhythmia. In addition to decreasing phase 0 upstroke velocity, class IA Na � channel blockers prolong repolarization. Prolonged repolarization increases the effective refractory period, so that cells in a re-entrant circuit cannot be depolarized by the re-entrant action potential. In summary, Na � channel blockers decrease the likelihood of re-entry, and thereby prevent arrhythmia, by: (1) decreasing conduction velocity, and (2) increasing the refractory period of ventricular myocytes.

Although the three subclasses of class I antiarrhythmics (class IA, IB, and IC) have similar effects on the action po-tential in the SA node, there are important differences in their effects on the ventricular action potential.

Class IA Antiarrhythmics Class IA antiarrhythmics exert a moderate block on Na � channels and prolong the repolarization of both SA nodal cells and ventricular myocytes. By blocking Na � chan-nels, these agents decrease the phase 0 upstroke velocity, which decreases conduction velocity through the myocar-dium. Class IA antiarrhythmics also block K � channels, and thereby reduce the outward K � current responsible for re-polarization of the membrane. This prolongation of repolar-ization increases the effective refractory period of the cells. Together, the decreased conduction velocity and increased effective refractory period decrease re-entry.

Quinidine is often considered the prototypical drug among the class IA antiarrhythmics, but it is becoming less frequently used due to its adverse effects. In addition to the pharmacologic actions described above for all class IA antiar-rhythmics, quinidine exerts an anticholinergic (vagolytic) ef-fect, most likely by blocking the K � channels that are opened upon vagal stimulation of M 2 muscarinic receptors in the AV node (see Fig. 23-9B, Fig. 9-1). The anticholinergic effect is signifi cant clinically because it can increase conduction velocity through the AV node. Increased AV nodal conduc-tion can have potentially detrimental effects in patients with atrial fl utter. Such patients manifest an average atrial fi ring rate of 280–300 beats per minute. Because some of these im-pulses reach the AV node while it is still refractory, not all of the impulses are transmitted to the ventricles. Therefore, the atria fi re much faster than the ventricles—there is typically a 2:1 or 4:1 ratio of atrial to ventricular fi ring rates. When quinidine is administered to patients with atrial fl utter, the atrial fi ring rate decreases because of quinidine’s pharma-cologic action in slowing conduction velocity through the myocardium. At the same time, however, AV nodal conduc-tion velocity increases because of the vagolytic effects of the drug. The increase in AV nodal conduction velocity abolishes the 2:1 or 4:1 ratio of atrial to ventricular fi ring rates, and a 1:1 ratio of atrial to ventricular fi ring rates is often estab-lished. For example, with an atrial fl utter rate of 300 and 2:1 “A–V block,” the ventricles are driven at a rate of 150, which most individuals can tolerate. If the fl utter rate is slowed to 200 and A–V conduction is enhanced to 1:1, however, the

(Fig. 23-9). The block of Na � channels leaves fewer chan-nels available to open in response to membrane depolariza-tion, thereby raising the threshold for action potential fi ring and slowing the rate of depolarization. Both of these effects extend the duration of phase 4, and thereby decrease heart rate. Furthermore, the shift in threshold potential means that, in patients with implanted defi brillators who are treated with Na � channel blockers, a higher voltage is needed to defi bril-late the heart. Therefore, it is important to take into account the effect of Na � channel blockers when choosing appropri-ate settings for implanted defi brillators.

In addition to decreasing SA-node automaticity, Na � channel blockers act on ventricular myocytes to decrease re-entry. This is achieved mainly by decreasing the upstroke velocity of phase 0 and, for some Na � channel blockers, by prolonging repolarization (Fig. 23-10). By decreasing

CHAPTER 23 / Pharmacology of Cardiac Rhythm 411

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FIGURE 23-10. Effects of class IA, IB, and IC antiarrhythmics on the ventricular action potential. Class I antiarrhythmics (Na � channel blockers) act on ven-tricular myocytes to decrease re-entry. All subclasses of the class I antiarrhythmics block the Na � channel to some degree: class IA agents exhibit moderate Na � channel block, class IB agents rapidly bind to (block) and dissociate from (unblock) Na � channels, and class IC agents produce marked Na � channel block. Class IA, IB, and IC agents also differ in the degree to which they affect the duration of the ventricular action potential.

ventricles are driven at a rate of 200, which is usually too fast for effective ventricular pumping. For this reason, an agent that slows AV nodal conduction—such as a � -adrenergic an-tagonist or verapamil (a Ca � channel blocker)—should be used in conjunction with quinidine to prevent an excessively rapid ventricular response in patients with atrial fl utter.

The most common adverse effects of quinidine are diar-rhea, nausea, headache, and dizziness. These effects make it diffi cult for patients to tolerate chronic therapy with quini-dine. Quinidine is contraindicated in patients with QT pro-longation and in patients who are taking medications that predispose to QT prolongation, because of the increased risk of torsades de pointes . Relative contraindications to quini-dine use include sick sinus syndrome, bundle branch block, myasthenia gravis (because of quinidine’s anticholinergic action), and liver failure.

Quinidine is administered orally and metabolized by cy-tochrome P450 enzymes in the liver. Quinidine increases plasma levels of digoxin (an inotropic agent), most likely by competing for the P450 enzymes that are responsible for digoxin metabolism. Because digoxin has a narrow thera-peutic index (see Chapter 24, Pharmacology of Cardiac Contractility), quinidine-induced digoxin toxicity occurs in a signifi cant fraction of patients. The plasma potassium level must be carefully monitored in patients treated with quinidine, because hypokalemia decreases quinidine effi -cacy, exacerbates QT prolongation, and, most importantly, predisposes to torsades de pointes . It is hypothesized that torsades de pointes is the mechanism most likely responsible for quinidine-induced syncope. Because of quinidine’s nu-merous adverse effects and contraindications, this drug has largely been replaced by class III agents—such as ibutilide and amiodarone—for the pharmacologic conversion of atrial fl utter or atrial fi brillation to normal sinus rhythm.

Procainamide is a class IA antiarrhythmic agent that is effective in the treatment of many types of supraventricular and ventricular arrhythmias. Procainamide is often used in the pharmacologic conversion of new-onset atrial fi brillation to normal sinus rhythm, although with less effi cacy than intra-venous ibutilide. Procainamide can be used safely to decrease the likelihood of re-entrant arrhythmias in the setting of acute

myocardial infarction, even in the presence of decreased car-diac output. Procainamide can also be administered by slow intravenous infusion to treat acute ventricular tachycardia.

Unlike quinidine, procainamide has few anticholinergic effects and does not alter plasma levels of digoxin. Pro-cainamide can cause peripheral vasodilation via inhibition of neurotransmission at sympathetic ganglia. With chronic therapy, almost all patients develop a lupus-like syndrome and positive antinuclear antibodies; the precise mecha-nism of this reaction is not known, but it remits if the drug is discontinued. Procainamide is acetylated in the liver to N-acetyl-procainamide (NAPA); this active metabolite pro-duces the pure class III antiarrhythmic effects of prolonging the refractory period and lengthening the QT interval. NAPA does not appear to cause the lupus-like adverse effects of procainamide.

Disopyramide is similar to quinidine in its electrophysi-ologic and antiarrhythmic effects; the difference between the two drugs lies in their adverse effects. Disopyramide causes fewer gastrointestinal problems but has even more profound anticholinergic effects than quinidine, producing such adverse effects as urinary retention and dry mouth. The profound anticholinergic effects of disopyramide appear to be related to the drug’s action as an antagonist at muscarinic acetylcholine receptors. Disopyramide is contraindicated in patients with obstructive uropathy or glaucoma. Disopy-ramide is also contraindicated in patients with conduction block between the atria and ventricles and in patients with sinus-node dysfunction. Disopyramide has the prominent but unexplained effect that it depresses cardiac contractil-ity, which has led to its use in the treatment of hypertrophic obstructive cardiomyopathy and neurocardiogenic syncope. Because of its negative inotropic effects, disopyramide is absolutely contraindicated in patients with decompensated heart failure. Oral disopyramide is approved only for the treatment of life-threatening ventricular arrhythmias; oral or intravenous disopyramide is sometimes used to convert su-praventricular tachycardia to normal sinus rhythm. The cur-rent trend in the treatment of life-threatening arrhythmias, however, is away from class I antiarrhythmic agents and to-ward class III agents and electrical devices.

412 Principles of Cardiovascular Pharmacology

Mexiletine , an analogue of lidocaine, is available in oral formulation. While the effi cacy of mexiletine is similar to that of quinidine, mexiletine does not prolong the QT interval and it lacks vagolytic effects. In addition, little hemodynamic depression has been reported with the use of mexiletine. The primary indication for mexiletine is life-threatening ventricu-lar arrhythmia. In practice, however, mexiletine is often used as an adjunct to other antiarrhythmic agents. For example, mexiletine is used in combination with amiodarone in pa-tients with implantable cardioverter-defi brillators (ICDs) and in patients with recurrent ventricular tachycardia. Mexiletine is also used in combination with quinidine or sotalol to in-crease antiarrhythmic effi cacy while reducing adverse effects. There are no data supporting reduced mortality with the use of mexiletine or any of the other class IB antiarrhythmic agents. Major adverse effects of mexiletine include dose- related nausea and tremor, which can be ameliorated when the medi-cation is taken with food. Mexiletine undergoes hepatic me-tabolism, and its plasma levels may be altered by inducers of hepatic P450 enzymes such as phenytoin and rifampin.

While phenytoin is usually considered an antiepileptic medication, its effects on the myocardium also allow it to be classifi ed as a class IB antiarrhythmic agent. The phar-macologic properties of phenytoin are discussed in detail in Chapter 15, Pharmacology of Abnormal Electrical Neu-rotransmission in the Central Nervous System. Although the use of phenytoin as an antiarrhythmic agent is limited, it has been found to be effective in ventricular tachycardia of young children. Specifi cally, phenytoin has been used in the treatment of congenital prolonged QT syndrome when therapy with � -adrenergic antagonists alone has failed; it is also used to treat ventricular tachycardia after congenital heart surgery. Phenytoin maintains AV conduction in digox-in-toxic arrhythmias, and it is especially useful in the rare patient who has concurrent epilepsy and cardiac arrhythmia. Phenytoin is an inducer of hepatic enzymes including P450 3A4, and thus affects plasma levels of other antiarrhythmic agents such as mexiletine, lidocaine, and quinidine.

Class IC Antiarrhythmics Class IC antiarrhythmics are the most potent Na � channel blockers, and they have little or no effect on action potential duration (Fig. 23-10). By markedly decreasing the rate of phase 0 upstroke of ventricular cells, these drugs suppress premature ventricular contractions. Class IC antiarrhythmics also prevent paroxysmal supraventricular tachycardia and atrial fi brillation. However, these drugs have marked depres-sive effects on cardiac function and, thus, must be used with discretion. In addition, the CAST (Cardiac Arrhythmia Sup-pression Trial) and other studies have brought attention to the proarrhythmic effects of these agents.

Flecainide is the prototypical class IC drug; other members of this class include encainide , moricizine , and propafenone . Flecainide illustrates the principle that antiar-rhythmic agents can also cause arrhythmia. When fl ecain-ide is administered to patients with preexisting ventricular tachyarrhythmias and to those with a history of myocardial infarction, it can worsen the arrhythmia even at normal doses. Currently, fl ecainide is approved for use only in life- threatening situations; for example, when paroxysmal su-praventricular or ventricular arrhythmia is unresponsive to other measures. Flecainide is eliminated very slowly from the body; it has a plasma half-life of 12–30 hours. Because

Class IB Antiarrhythmics Class IB antiarrhythmics include lidocaine , mexiletine , and phenytoin . Lidocaine is the prototypical class IB agent. These drugs alter the ventricular action potential by block-ing Na � channels and sometimes by shortening repolariza-tion; the latter effect may be mediated by the drugs’ ability to block the few Na � channels that inactivate late during phase 2 of the cardiac action potential (Fig. 23-10). In compari-son to class IA antiarrhythmics, which preferentially bind to open Na � channels, class IB drugs bind to both open and inactivated Na � channels . Therefore, the more time Na � channels spend in the open or inactivated state, the more blockade the class IB antiarrhythmics can exert. The major distinguishing characteristic of the class IB antiarrhythmics is their fast dissociation from Na � channels. Because Na � channels recover quickly from class IB blockade, these drugs are most effective in blocking depolarized or rapidly driven tissues, where there is a higher likelihood of the Na �

channels being in the open or inactivated state. Thus, class IB antiarrhythmics exhibit use-dependent block in diseased myocardium, where the cells have a tendency to fi re more frequently; these antiarrhythmics have relatively little effect on normal cardiac tissue.

Myocardial ischemia provides an example of the therapeu-tic utility of the use-dependent block exerted by class IB an-tiarrhythmics. The increase in extracellular H � concentration in ischemic tissue activates membrane pumps that cause an increase in the extracellular K � concentration. This increase in extracellular K � shifts E K to a more depolarized (more positive) value; for example, E K may shift from � 94 mV to � 85 mV. The altered electrochemical K � gradient provides a smaller driving force for K � ions to fl ow out of cells, and depolarization of the membrane leads to a higher likelihood of action potential fi ring. Because ischemic cardiac myocytes tend to fi re more frequently, the Na � channels spend more time in the open or inactivated state, serving as a better target for blockade by class IB antiarrhythmics.

Lidocaine is commonly used to treat ventricular arrhyth-mias in emergency situations. This drug is not effective in treat-ing supraventricular arrhythmias. In hemodynamically stable patients, lidocaine is reserved for treatment of ventricular tach-yarrhythmias or frequent premature ventricular contractions (PVCs) that are bothersome or hemodynamically signifi cant.

Lidocaine has a short plasma half-life (approximately 20 minutes), and it is metabolically de-ethylated in the liver. Its metabolism is governed by two factors, liver blood fl ow and liver cytochrome P450 activity. For patients whose liver blood fl ow is decreased by old age or heart failure, or whose P450 enzymes are acutely inhibited, for example, by cimet-idine (see Chapter 4, Drug Metabolism), a lower dose of lido-caine should be considered. For patients whose P450 enzymes are induced by drugs such as barbiturates, phenytoin, or ri-fampin, the dose of lidocaine should be increased.

Because lidocaine shortens repolarization, possibly by blocking the few Na � channels that inactivate late during phase 2 of the cardiac action potential, it does not prolong the QT interval. Therefore, the drug is safe for use in patients with long QT syndrome. However, because lidocaine also blocks Na � channels in the central nervous system (CNS), it can produce CNS adverse effects such as confusion, dizziness, and seizures. In addition to its use as an acute in-travenous therapy for ventricular arrhythmias, lidocaine is used as a local anesthetic (see Chapter 11).

CHAPTER 23 / Pharmacology of Cardiac Rhythm 413

� 1 -Antagonists are the most frequently used agents in the treatment of supraventricular and ventricular arrhythmias pre-cipitated by sympathetic stimulation. � 1 -Adrenergic antago-nists have been shown to reduce mortality after myocardial infarction, even in patients with relative contraindications to this therapy such as severe diabetes mellitus or asthma. Because of their wide spectrum of clinical application and es-tablished safety record, � -adrenergic antagonists are the most useful antiarrhythmic agents currently available.

There are several generations of � -antagonists, each characterized by slightly different pharmacologic properties. First-generation � -antagonists, such as propranolol , are nonselective � -adrenergic antagonists that antagonize both � 1 -adrenergic and � 2 -adrenergic receptors. They are widely used to treat tachyarrhythmias caused by catecholamine stimulation during exercise or emotional stress. Because propranolol does not prolong repolarization in ventricular tissue, it can be used in patients with long QT syndrome. Second- generation agents, including atenolol , metoprolol , acebutolol , and bisoprolol , are relatively selective for � 1 -adrenergic receptors when administered in low doses. Third-generation � -antagonists cause vasodilation in addi-tion to � 1 -receptor antagonism. Labetalol and carvedilol induce vasodilation by antagonizing � -adrenergic receptor-mediated vasoconstriction; pindolol is a partial agonist at the � 2 -adrenergic receptor; and nebivolol stimulates endothelial production of nitric oxide.

The different generations of � -antagonists produce vary-ing degrees of adverse effects. Three general mechanisms are responsible for the adverse effects of � -blockers. First, antagonism at � 2 -adrenergic receptors causes smooth mus-cle spasm, leading to bronchospasm, cold extremities, and impotence. These effects are more commonly caused by the nonselective fi rst-generation � -antagonists. Second, exag-geration of the therapeutic effects of � 1 -receptor antagonism can lead to excessive negative inotropic effects, heart block, and bradycardia. Third, drug penetration into the CNS can produce insomnia and depression.

Class III Antiarrhythmic Agents: Inhibitors of Repolarization Class III antiarrhythmic agents block K � channels. Two types of currents determine the duration of the plateau phase of the cardiac action potential: inward, depolarizing Ca 2 � currents and outward, hyperpolarizing K � currents. During a normal action potential, the hyperpolarizing K � currents eventu-ally dominate, returning the membrane potential to more hyperpolarized values. Larger hyperpolarizing K � currents shorten plateau duration, returning the membrane potential to its resting value more rapidly, while smaller hyperpolar-izing K � currents lengthen plateau duration and delay return of the membrane potential to its resting value.

When K � channels are blocked, a smaller hyperpolarizing K � current is generated. Therefore, K � channel blockers cause a longer plateau and prolong repolarization (Fig. 23-12). The ability of K � channel blockers to lengthen plateau duration is responsible for both their pharmacologic uses and their adverse effects. On the benefi cial side, prolongation of the plateau du-ration increases the effective refractory period, which, in turn, decreases the incidence of re-entry. On the toxic side, prolon-gation of the plateau duration increases the likelihood of devel-oping early afterdepolarizations and torsades de pointes . With the exception of amiodarone, K � channel blockers also exhibit the undesirable property of “ reverse use-dependency”: action

of its marked blockade of Na � channels and its suppressive effects on cardiac function, fl ecainide use is associated with adverse effects that include sinus-node dysfunction, a marked decrease in conduction velocity, and conduction block.

Class II Antiarrhythmic Agents: � -Adrenergic Antagonists Class II antiarrhythmic agents are � -adrenergic antago-nists (also called � -blockers). These agents act by inhib-iting sympathetic input to the pacing regions of the heart. ( � -Adrenergic antagonists are more extensively discussed in Chapter 10, Adrenergic Pharmacology.) Although the heart is capable of beating on its own without innervation from the autonomic nervous system, both sympathetic and parasym-pathetic fi bers innervate the SA node and the AV node, and thereby alter the rate of automaticity. Sympathetic stimula-tion releases norepinephrine, which binds to � 1 -adrenergic receptors in the nodal tissues. ( � 1 -Adrenergic receptors are the adrenergic subtype preferentially expressed in cardiac tissue.) Activation of � 1 -adrenergic receptors in the SA node triggers an increase in the pacemaker current ( I f ), which in-creases the rate of phase 4 depolarization and, consequently, leads to more frequent fi ring of the node. Stimulation of � 1 -adrenergic receptors in the AV node increases Ca 2 � and K � currents, thereby increasing the conduction velocity and decreasing the refractory period of the node.

� 1 -Antagonists block the sympathetic stimulation of � 1 -adrenergic receptors in the SA and AV nodes (Fig. 23-11). The AV node is more sensitive than the SA node to the effects of � 1 -antagonists. � 1 -Antagonists affect the action potentials of SA and AV nodal cells by: (1) decreasing the rate of phase 4 depolarization; and (2) prolonging repolariza-tion. Decreasing the rate of phase 4 depolarization results in decreased automaticity, and this, in turn, reduces myocardial oxygen demand. Prolonged repolarization at the AV node in-creases the effective refractory period, which decreases the incidence of re-entry.

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FIGURE 23-11. Effects of class II antiarrhythmics on pacemaker cell action potentials. Class II antiarrhythmics ( � -antagonists) reverse the tonic sympathetic stimulation of cardiac � 1 -adrenergic receptors. By blocking the adrenergic effects on the SA and AV nodal action potentials, these agents de-crease the slope of phase 4 depolarization (especially important at the SA node) and prolong repolarization (especially important at the AV node). These agents are useful in the treatment of supraventricular and ventricular arrhythmias that are precipitated by sympathetic stimulation.

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CHAPTER 23 / Pharmacology of Cardiac Rhythm 417

will constitute an alternative strategy to prevent or termi-nate arrhythmias.

Suggested Reading Ackerman MJ, Clapham DE. Ion channels—basic science and clinical dis-ease. N Engl J Med 1997;336:1575–1586. ( Broad review of ion channels. )

Delacretaz E. Clinical practice. Supraventricular tachycardia. N Engl J Med 2006;354:1039–1051. ( Discussion of the clinical uses of antiarrhythmic agents in treating supraventricular tachycardia. )

Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in patients with atrial fi brillation. N Engl J Med 2009;360:668–678. ( Trial of dronedarone suggesting safety in patients with atrial fi brillation. )

McBride BF. The emerging role of antiarrhythmic compounds with atrial selectivity in the management of atrial fi brillation. J Clin Pharmacol 2009;49:258–267. ( Future directions in drug development for treatment of atrial fi brillation. )

Nash DT, Nash SBD. Ranolazine for chronic stable angina. Lancet 2008;372:1335–1341. ( Recent review of ranolazine. )

Rudy Y, Silva JR. Computational biology in the study of cardiac ion channels and cell electrophysiology. Quarterly Rev Biophys 2006;39:57–116. ( Summa-rizes the known cardiac ion channels in models of cardiac action potentials. )

models are used for the majority of ion channel research; comparatively little is known about the clinical pharmacol-ogy of ion channels expressed in humans. With the mouse and human genomes now completely sequenced, research-ers will be able to investigate the possibility that newly identifi ed gene products can serve as selective targets for new therapeutic agents. The identifi cation of ion channel gene expression in the various tissues of the human heart (SA node, AV node, atrial conduction pathways, endocar-dium, ventricular conduction pathways, etc.), both dur-ing development and in response to injury, may provide new targets that are not now known. Many of the genes are likely to encode channels that form heteromultimers, and there are likely to be many genetic variants within the population. This enormous complexity will likely represent a boon to drug development because it will allow more tai-lored strategies to be employed. For example, current re-search in atrial fi brillation has focused on the development of antiarrhythmics selective for ion channels that are ex-pressed selectively in the atria. In parallel, the development of implantable computers, stimulators, and defi brillators