Goodman and Gilman Manual of Pharmacology and Therapeutics

Section III
Modulation of Cardiovascular Function

chapter 29
Anti-Arrhythmic Drugs

Cardiac cells undergo depolarization and repolarization to form cardiac action potentials ~60 times/min. The shape and duration of each action potential are determined by the activity of ion channel protein complexes in the membranes of individual cells, and the genes encoding most of these proteins now have been identified.

Arrhythmias can range from incidental, asymptomatic clinical findings to life-threatening abnormalities. In some human arrhythmias, precise mechanisms are known, and treatment can be targeted specifically against those mechanisms. In other cases, mechanisms can be only inferred, and the choice of drugs is based largely on the results of prior experience. Anti-arrhythmic drug therapy can have 2 goals: termination of an ongoing arrhythmia or prevention of an arrhythmia. Unfortunately, anti-arrhythmic drugs not only help to control arrhythmias but also can cause them, especially during long-term therapy. Thus, prescribing anti-arrhythmic drugs requires that precipitating factors be excluded or minimized, that a precise diagnosis of the type of arrhythmia be made, and that the risks of drug therapy can be minimized.

PRINCIPLES OF CARDIAC ELECTROPHYSIOLOGY

The flow of ions across cell membranes generates the currents that make up cardiac action potentials. Most anti-arrhythmic drugs affect more than one ion current, and many exert ancillary effects such as modification of cardiac contractility or autonomic nervous system function. Thus, anti-arrhythmic drugs usually exert multiple actions and can be beneficial or harmful in individual patients.

THE CARDIAC CELL AT REST: A K+-PERMEABLE MEMBRANE

The normal cardiac cell at rest maintains a transmembrane potential ~80-90 mV negative to the exterior; this gradient is established by pumps, especially the Na+, K+-ATPase, and fixed anionic charges within cells. There are both an electrical and a concentration gradient that would move Na+ ions into resting cells (Figure 29–1). However, Na+ channels, which allow Na+ to move along this gradient, are closed at negative transmembrane potentials, so Na+ does not enter normal resting cardiac cells. In contrast, a specific type of K+ channel protein (the inward rectifier channel) is in an open conformation at negative potentials. Hence, K+ can move through these channels across the cell membrane at negative potentials in response to either electrical or concentration gradients.

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Figure 29–1 Electrical and chemical gradients for K+ and Na+in a resting cardiac cell. Inward rectifier K+ channels are open (left), allowing K+ ions to move across the membrane and the transmembrane potential to approach EK. In contrast, Na+ does not enter the cell despite a large net driving force because Na+ channel proteins are in the closed conformation (right) in resting cells.

For each individual ion, there is an equilibrium potential Ex at which there is no net driving force for the ion to move across the membrane. Ex can be calculated using the Nernst equation:

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where Zx is the valence of the ion, T is the absolute temperature, R is the gas constant, F is Faraday’s constant, [x]o is the extracellular concentration of the ion, and [x]i is the intracellular concentration. For K+, [K]o = 4 mM and [K]i = 140 mM, the calculated K+ equilibrium potential EK is –94 mV. There is thus no net force driving K+ ions into or out of a cell when the transmembrane potential is –94 mV, close to the resting potential. Thus, at rest, the normal cardiac cell is permeable to K+ (because inward rectifier channels are open) and [K]o is the major determinant of resting potential. If [K]o is elevated to 10 mM, as might occur in diseases such as renal failure or myocardial ischemia, the calculated EK rises to –70 mV.

THE CARDIAC ACTION POTENTIAL

Na+ channels have a life cycle of openings and closings that help to regulate membrane excitability (Figure 29–2). To initiate an action potential, a cardiac myocyte at rest is depolarized above a threshold potential, usually via gap junctions by a neighboring myocyte. Upon membrane depolarization, Na+ channel proteins change from the “closed” (resting) state to the “open” (conducting) state, allowing up to 107 Na+ ions/sec to enter each cell and moving the transmembrane potential toward ENa (+65 mV). This surge of Na+ ions lasts only about a millisecond, after which the Na+ channel protein rapidly moves to an “inactivated,” nonconducting state. The maximum upstroke slope of phase 0 (dV/dtmax, or Vmax) of the action potential (Figure 29–3) is largely governed by Na+ current and plays a role in the conduction velocity of a propagating action potential. Under normal conditions, Na+channels, once inactivated, cannot reopen until they reassume the closed conformation.

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Figure 29–2 Life cycle of a voltage-sensitive channel. Voltage-dependent conformational changes determine current flow through Na+ channels. At hyperpolarized potentials, the channel is in a closed conformation (C) and no current flows. As depolarization begins, the pore opens (O), allowing conduction. As depolarization is maintained, a nearby region of a channel subunit moves to block current flow, putting the channel into an inactivated, nonconducting state (I). Restoration of the normal resting Em restores the conformation to the closed state (C). See Figure 20–2 for structural details.

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Figure 29–3 The relationship between an action potential from the conducting system and the currents that generate it. The current magnitudes are not to scale; the Na+ current is ordinarily 50 times larger than any other current, although the portion that persists into the plateau (phase 2) is small. Multiple types of Ca2+ current, transient outward current (IT0), and delayed rectifier (IK) have been identified. Each represents a different channel protein, usually associated with ancillary (function-modifying) subunits. 4-AP (4-aminopyridine) is a widely used in vitro blocker of K+ channels. ITO2 may be a Clcurrent in some species. Components of IK have been separated on the basis of how rapidly they activate: slowly (IKs), rapidly (IKr), or ultra-rapidly (IKur). The voltage-activated, time-independent current may be carried by Cl (ICl) or K+ (IKp, p for plateau). The genes encoding the major pore-forming proteins have been cloned for most of the channels shown here and are included in the right-hand column. The right-hand column lists the primary genes coding for the various ion channels and transporters.

A small population of Na+ channels may continue to open during the action potential plateau in some cells, providing further inward current. Certain mutations in the cardiac isoform of the Na+ channel can further increase the number of channels that do not properly inactivate, thereby prolonging the action potential, and cause a form of the congenital long QT syndrome. In general, however, as the cell membrane repolarizes, the negative membrane potential moves Na+ channel proteins from inactivated to “closed” conformations. The relationship between Na+ channel availability and transmembrane potential is an important determinant of conduction and refractoriness in many cells.

The changes in transmembrane potential generated by the inward Na+ current produce a series of openings (and in some cases subsequent inactivation) of other channels (see Figure 29–3). For example, when a cell is depolarized by the Na+ current, “transient outward” K+ channels quickly enter an open, or conducting, state; because the transmembrane potential at the end of phase 0 is positive to EK, the opening of transient outward channels results in an outward, or repolarizing, K+ current (termed IT0), which contributes to the phase 1 “notch” seen in action potentials from these tissues. Transient outward K+ channels, like Na+ channels, inactivate rapidly. During the phase 2 plateau of a normal cardiac action potential, inward, depolarizing currents, primarily through Ca2+ channels, are balanced by outward, repolarizing currents primarily through K+ (“delayed-rectifier”) channels. Delayed-rectifier currents (collectively termed IK) increase with time, whereas Ca2+ currents inactivate (and so decrease with time); as a result, cardiac cells repolarize (phase 3) several hundred milliseconds after the initial Na+ channel opening. Mutations in the genes encoding repolarizing K+ channels are responsible for the most common forms of the congenital long QT syndrome.

ACTION POTENTIAL HETEROGENEITY IN THE HEART. The general description of the action potential and the currents that underlie it must be modified for certain cell types, primarily due to variability in the expression of ion channels and electrogenic ion transport pumps. In the ventricle, action potential duration (APD) and shape vary across the wall of each chamber, as well as apico-basally (Figure 29–4). Atrial cells have short action potentials, probably because ITO is larger, and an additional repolarizing K+ current, activated by the neurotransmitter acetylcholine, is present. As a result, vagal stimulation further shortens atrial action potentials. Cells of the sinus and atrioventricular (AV) nodes lack substantial Na+ currents. In addition, these cells, as well as cells from the conducting system, normally display the phenomenon of spontaneous diastolic, or phase 4 depolarization and thus spontaneously reach threshold for regeneration of action potentials. The rate of spontaneous firing usually is fastest in sinus node cells, which therefore serve as the natural pacemaker of the heart.

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Figure 29–4 Normal impulse propagation. A schematic of the human heart with example action potentials from different regions of the heart (top) for a normal beat and their corresponding contributions to the macroscopic ECG (bottom). AV, atrioventricular; LV, left ventricle; RV, right ventricle; SA, sinoatrial. (Used with permission from The Am Physiol Soc. Nerbonne JM, Kass RS. Physiol Rev, 2005;85:1205-1253.)

One of the pacemaking currents responsible for this automaticity is generated via specialized K+ channels, the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels that are permeable to both potassium and sodium. Another mechanism responsible for automaticity is the repetitive spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). The rise in cytosolic Ca2+ causes membrane depolarizations when Ca2+ is extruded from the cell via the electrogenic Na-Ca exchanger (NCX). In addition, sinus node cells lack inward rectifier K+ currents that are primarily responsible for protecting working myocardium against spontaneous membrane depolarizations.

MAINTENANCE OF INTRACELLULAR ION HOMEOSTASIS

With each action potential, the cell interior gains Na+ ions and loses K+ ions. The Na+, K+-ATPase (Na+ pump) is activated in most cells to maintain intracellular homeostasis, extruding 3 Na+ ions for every 2 K+ ions shuttled from the exterior of the cell to the interior; as a result, the act of pumping itself generates a net outward (repolarizing) current.

Normally, basal intracellular Ca2+ is maintained at very low levels (<100 nM). In cardiac myocytes, the entry of Ca2+ during each action potential through L-type Ca2+ channels is a signal to the SR to release its Ca2+ stores. The efflux of Ca2+ from the SR occurs through ryanodine-receptor (RyR2) Ca2+ release channels, and the resulting increase in intracellular Ca2+ subsequently triggers Ca2+-dependent contractile processes (= excitation-contraction coupling). Removal of intracellular Ca2+ occurs by both Ca2+-ATPase (which moves Ca2+ ions back into the SR) and NCX, which exchanges 3 Na+ ions from the exterior for each Ca2+ ion extruded (see Figure 28–5). Abnormal regulation of intracellular Ca2+ is increasingly well described in heart failure and contributes to arrhythmias in this setting. Furthermore, mutations that disrupt the normal activity of the RyR2 channels and the cardiac isoform of calsequestrin have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), thereby demonstrating a direct link between spontaneous SR Ca2+ release and cardiac arrhythmias.

IMPULSE PROPAGATION AND THE ELECTROCARDIOGRAM

Normal cardiac impulses originate in the sinus node. Once impulses leave the sinus node, they propagate rapidly throughout the atria, resulting in atrial systole and the P wave of the surface electrocardiogram (ECG; see Figure 29–4). Propagation slows markedly through the AV node, where the inward current (through Ca2+ channels) is much smaller than the Na+current in atria, ventricles, or the subendocardial conducting system. This conduction delay allows the atrial contraction to propel blood into the ventricle, thereby optimizing cardiac output. Once impulses exit the AV node, they enter the conducting system, where Na+ currents are larger than elsewhere and propagation is correspondingly faster, up to 0.75 m/s longitudinally. Activation spreads from the His–Purkinje system on the endocardium of the ventricles throughout the rest of the ventricles, stimulating coordinated ventricular contraction. This electrical activation manifests itself as the QRS complex on the ECG. The T wave of the ECG represents ventricular repolarization.

The ECG can be used as a rough guide to some cellular properties of cardiac tissue:

• Heart rate reflects sinus node automaticity.

• PR-interval duration reflects AV nodal conduction time.

• QRS duration reflects conduction time in the ventricle.

• The QT interval is a measure of ventricular APD.

REFRACTORINESS AND CONDUCTION FAILURE

If a single action potential is restimulated very early during the plateau, no Na+ channels are available to open, no inward current results, and no action potential is generated: the cell is termed refractory (Figure 29–5). Conversely, if a stimulus occurs after the cell has repolarized completely, Na+ channels have recovered, and a normal Na+ channel–dependent upstroke results (Figure 29–5A). When a stimulus occurs during phase 3 of the action potential, the magnitude of the resultant Na+ current depends on the number of Na+ channels that have recovered (Figure 29–5B). The recovery from inactivation is faster at more hyperpolarized membrane potentials. Thus, refractoriness is determined by the voltage-dependent recovery of Na+ channels from inactivation. The effective refractory period (ERP) is the longest interval at which a premature stimulus fails to generate a propagated response.

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Figure 29–5 Qualitative differences in responses of nodal and conducting tissues to premature stimuli. A. With a very early premature stimulus (black arrow) in ventricular myocardium, all Na+ channels still are in the inactivated state, and no upstroke results. As the action potential repolarizes, Na+ channels recover from the inactivated to the resting state, from which opening can occur. The phase 0 upstroke slope of the premature action potentials (purple) are greater with later stimuli because recovery from inactivation is voltage dependent. B. The relationship between transmembrane potential and degree of recovery of Na+ channels from inactivation. The dotted line indicates 25% recovery. Most Na+ channel–blocking drugs shift this relationship to the left. C. In nodal tissues, premature stimuli delivered even after full repolarization of the action potential are depressed; recovery from inactivation is time dependent.

The situation is different in tissue whose depolarization is largely controlled by Ca2+ channel current such as the AV node. As Ca2+ channels have a slower recovery from inactivation, these tissues often are referred to as slow response, in contrast to fast response in the remaining cardiac tissues (Figure 29–5C). Even after a Ca2+ channel–dependent action potential has repolarized to its initial resting potential, not all Ca2+ channels are available for re-excitation. Therefore, an extra stimulus applied shortly after repolarization is complete and generates a reduced Ca2+ current, which may propagate slowly to adjacent cells prior to extinction. An extra stimulus applied later will result in a larger Ca2+ current and faster propagation. Thus, in Ca2+ channel–dependent tissues, which include not only the AV node but also tissues whose underlying characteristics have been altered by factors such as myocardial ischemia, refractoriness is prolonged and propagation occurs slowly. Slow conduction in the heart, a critical factor in the genesis of reentrant arrhythmias (see next section), also can occur when Na+ currents are depressed by disease or membrane depolarization (e.g., elevated [K]o), resulting in decreased steady-state Na+ channel availability (see Figure 29–5B).

MECHANISMS OF CARDIAC ARRHYTHMIAS

When the normal sequence of impulse initiation and propagation is perturbed, an arrhythmia occurs. Failure of impulse initiation, in the sinus node, may result in slow heart rates (bradyarrhythmias), whereas failure in the normal propagation of action potentials from atrium to ventricle results in dropped beats (commonly referred to as heart block) that usually reflect an abnormality in either the AV node or the His–Purkinje system. These abnormalities may be caused by drugs (Table 29–1) or by structural heart disease; in the latter case, permanent cardiac pacing may be required.

Table 29–1

Drug-Induced Cardiac Arrhythmias

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Abnormally rapid heart rhythms (tachyarrhythmias) are common clinical problems that may be treated with anti-arrhythmic drugs. Three major underlying mechanisms have been identified: enhanced automaticity, triggered automaticity, and reentry. These often are interrelated mechanisms, as the first 2 often serve to initiate reentry.

ENHANCED AUTOMATICITY. Enhanced automaticity may occur in cells that normally display spontaneous diastolic depolarization—the sinus and AV nodes and the His–Purkinje system. β Adrenergic stimulation, hypokalemia, and mechanical stretch of cardiac muscle cells increase phase 4 slope and accelerate pacemaker rate; acetylcholine reduces pacemaker rate both by decreasing phase 4 slope and through hyperpolarization (making the maximum diastolic potential more negative). Automatic behavior may also occur in sites that ordinarily lack spontaneous pacemaker activity; e.g., depolarization of ventricular cells (e.g., by ischemia) may produce “abnormal” automaticity. When impulses propagate from a region of enhanced normal or abnormal automaticity to excite the rest of the heart, more complex arrhythmias may result from the induction of functional reentry.

AFTERDEPOLARIZATIONS AND TRIGGERED AUTOMATICITY. Under some pathophysiologic conditions, a normal cardiac action potential may be interrupted or followed by an abnormal depolarization (Figure 29–6). If this abnormal depolarization reaches threshold, it may give rise to secondary upstrokes that can propagate and create abnormal rhythms. These abnormal secondary upstrokes occur only after an initial normal, or “triggering,” upstroke and are termed triggered rhythms.

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Figure 29–6 Afterdepolarizations and triggered activityA. Delayed afterdepolarization (DAD) arising after full repolarization. DADs are typically caused by spontaneous Ca2+ release from the sarcoplasmic reticulum under conditions of Ca2+ overload. The extra cytosolic Ca2+ is removed from the cytosol by the electrogenic Na-Ca exchanger (NCX), which produces Na+ influx and causes a cell membrane depolarization in the form of a DAD. A DAD that reaches threshold results in a triggered upstroke (black arrow, right). B. Early afterdepolarization (EAD) interrupting phase 3 repolarization. Multiple ion channels and transporters can contribute to EADs (e.g., Na+ channel, L-type Ca2+ channel, NCX). Under some conditions, triggered beat(s) can arise from an EAD (black arrow, right).

In the first form of triggered rhythm, under conditions of intracellular or SR Ca2+ overload (e.g., myocardial ischemia, adrenergic stress, digitalis intoxication, heart failure), a normal action potential may be followed by a delayed afterdepolarization (DAD; Figure 29–6A). If this afterdepolarization reaches threshold, a secondary triggered beat or beats may occur. In the second type of triggered activity, the key abnormality is marked prolongation of the cardiac action potential. When this occurs, phase 3 repolarization may be interrupted by an early afterdepolarization (EAD; Figure 29–6B). EAD-mediated triggering in vitro and clinical arrhythmias are most common when the underlying heart rate is slow, extracellular K+ is low, and certain drugs that prolong APD are present. EAD-related triggered upstrokes probably reflect inward current through Na+ or Ca2+ channels. EADs are induced much more readily in Purkinje cells than in epicardial or endocardial cells. When cardiac repolarization is markedly prolonged, polymorphic ventricular tachycardia with a long QT interval, known as the torsade de pointes syndrome, may occur. This arrhythmia is thought to be caused by EADs, which trigger functional reentry owing to heterogeneity of APDs across the ventricular wall. Congenital long QT syndrome, a disease in which torsade de pointes is common, can most often be caused by mutations in the genes encoding the Na+ channels or the channels underlying the repolarizing currents IKr and IKs.

REENTRY. Reentry occurs when a cardiac impulse travels in a path such as to return to its original site and reactivate the original site and self-perpetuate rapid activation independent of the normal sinus node conduction. This abnormal activation path (or reentrant circuit) requires an isotropic conduction slowing (or failure) due to either an anatomic or functional barrier.

ANATOMICALLY DEFINED REENTRY. Reentry can occur when impulses propagate by more than 1 pathway between 2 points in the heart, and those pathways have heterogeneous electrophysiologic properties. Patients with Wolff–Parkinson–White (WPW) syndrome have accessory connections between the atrium and ventricle (Figure 29–7). With each sinus node depolarization, impulses can excite the ventricle via the normal structures (AV node) or the accessory pathway. However, the electrophysiologic properties of the AV node and accessory pathways are different: Accessory pathways usually consist of nonnodal tissue and consequently vastly differ in refractoriness with the AV node. Thus, with a premature atrial beat, conduction may fail in the accessory pathway but continue, albeit slowly, in the AV node and then through the His–Purkinje system; there, the propagating impulse may encounter the ventricular end of the accessory pathway when it is no longer refractory. The likelihood that the accessory pathway is no longer refractory increases as AV nodal conduction slows. When the impulse reenters the atrium, it then can reenter the ventricle via the AV node, reenter the atrium via the accessory pathway, and so on. Reentry of this type, referred to as AV reentrant tachycardia, is determined by:

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Figure 29–7 Atrioventricular reentrant tachycardia in the Wolff–Parkinson–White syndrome. In these patients, an accessory atrioventricular (AV) connection is present (light blue). A premature atrial impulse blocks in the accessory pathway (1) and propagates slowly through the AV node and conducting system. On reaching the accessory pathway (by now no longer refractory), the impulse reenters the atrium (2), where it then can reenter the ventricle via the AV node and become self-sustaining (see Figure 29–9C). AV nodal blocking drugs readily terminate this tachycardia. Recurrences can be prevented by drugs that prevent atrial premature beats, by drugs that alter the electrophysi-ologic characteristics of tissue in the circuit (e.g., they prolong AV nodal refractoriness), and by nonpharmacologic techniques that section the accessory pathway.

• The presence of an anatomically defined circuit

• Heterogeneity in refractoriness among regions in the circuit

• Slow conduction in one part of the circuit

Similar “anatomically defined” reentry commonly occurs in the region of the AV node (AV nodal reentrant tachycardia) and in the atrium (atrial flutter). The term paroxysmal supraventricular tachycardia(PSVT) includes both AV reentry and AV nodal reentry, which share many clinical features. It now is sometimes possible to identify and ablate critical segments of reentrant pathway (or automatic foci), thus curing the patient and obviating the need for long-term drug therapy.

FUNCTIONALLY DEFINED REENTRY. Reentry also may occur in the absence of a distinct, anatomically defined pathway (Figure 29–8). If ischemia or other electrophysiologic perturbations result in an area of sufficiently slow conduction in the ventricle, the impulses exiting from that area find the rest of the myocardium re-excitable and reentry may ensue. Atrial or ventricular fibrillation (VF) is an extreme example of “functionally defined” (or “leading circle”) reentry. Cells are re-excited as soon as they are repolarized sufficiently to allow enough Na+ channels to recover from inactivation. In this setting, neither organized activation patterns nor coordinated contractile activity is present.

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Figure 29–8 Two types of reentry. The border of a propagating wavefront is denoted by a heavy black arrowhead. In anatomically defined reentry (top), a fixed pathway is present (e.g., Figure 29–7). Theblack area denotes tissue in the reentrant circuit that is completely refractory because of the recent passage of the propagating wavefront; the gray area denotes tissue in which depressed upstrokes can be elicited (see Figure 29–5A), and the red area represents tissue in which restimulation would result in action potentials with normal upstrokes. The red area is termed an excitable gap. In functionally defined, or “leading circle,” reentry (bottom), there is no anatomic pathway and no excitable gap. Rather, the circulating wavefront creates an area of inexcitable tissue at its core. In this type of reentry, the circuit does not necessarily remain in the same anatomic position during consecutive beats, and multiple such “rotors” may be present.

COMMON ARRHYTHMIAS AND THEIR MECHANISMS

Table 29–2 lists common arrhythmias, their likely mechanisms, and approaches that should be considered for their acute termination and for long-term therapy to prevent recurrence.

Table 29–2

A Mechanistic Approach to Anti-Arrhythmic Therapy

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MECHANISMS OF ANTI-ARRHYTHMIC DRUG ACTION

Anti-arrhythmic drugs almost invariably have multiple effects in patients, and their effects on arrhythmias can be complex. A drug can modulate additional targets in addition to its primary mode of action. A single arrhythmia may result from multiple underlying mechanisms. Drugs may be anti-arrhythmic by suppressing the initiating mechanism or by altering the reentrant circuit. In some cases, drugs may suppress the initiator but nonetheless promote reentry.

Drugs may slow automatic rhythms by altering any of the 4 determinants of spontaneous pacemaker discharge (Figure 29–9):

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Figure 29–9 Four ways to reduce the rate of spontaneous discharge. The blue horizontal line represents threshold potential.

• Decrease phase 4 slope

• Increase threshold potential

• Increase maximum diastolic potential

• Increase APD

Adenosine and acetylcholine may increase maximum diastolic potential, and βreceptor antagonists may decrease phase 4 slope. Blockade of Na+ or Ca2+ channels usually results in altered threshold, and blockade of cardiac K+ channels prolongs the action potential.

Anti-arrhythmic drugs may block arrhythmias owing to DADs or EADs by 2 major mechanisms:

• Inhibition of the development of afterdepolarizations

• Interference with the inward current (usually through Na+ or Ca2+ channels), which is responsible for the upstroke

Thus, arrhythmias owing to digitalis-induced DADs may be inhibited by verapamil (which blocks the development of DAD by reducing Ca2+ influx and subsequent storage/release) or by quinidine (which blocks Na+ channels, thereby elevating the threshold required to produce the abnormal upstroke). Similarly, 2 approaches are used in arrhythmias related to EAD-triggered beats (see Tables 29–1 and 29–2). EADs can be inhibited by shortening APD; in practice, heart rate is accelerated by isoproterenol infusion or by pacing. Triggered beats arising from EADs can be inhibited by Mg2+, without normalizing repolarization in vitro or QT interval. In patients with a congenitally prolonged QT interval, torsade de pointes often occurs with adrenergic stress; therapy includes β adrenergic blockade (which does not shorten the QT interval) as well as pacing.

In anatomically determined reentry, drugs may terminate the arrhythmia by blocking propagation of the action potential. In the example of the WPW-related arrhythmia, drugs that prolong AV nodal refractoriness and slow AV nodal conduction, such as Ca2+ channel blockers, βadrenergic receptor antagonists, or digitalis glycosides, are likely to be effective. Conversely, slowing conduction in functionally determined reentrant circuits may change the pathway without extinguishing the circuit. Slow conduction generally promotes the development of reentrant arrhythmias, whereas the most likely approach for terminating functionally determined reentry is prolongation of refractoriness. In atrial and ventricular myocytes, refractoriness can be prolonged by delaying the recovery of Na+ channels from inactivation. Drugs blocking Na+ channels generally shift the voltage dependence of recovery from block (see Figure 29–5B) and so prolong refractoriness (Figure 29–10). Drugs that increase APD without direct action on Na+ channels (e.g., by blocking delayed-rectifier currents) also will prolong refractoriness. In sinoatrial or AV nodal tissues, Ca2+ channel blockade prolongs refractoriness.

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Figure 29–10 Two ways to increase refractoriness. The black dot indicates the point at which a sufficient number of Na+ channels (an arbitrary 25%; see Figure 29–5B) have recovered from inactivation to allow a premature stimulus to produce a propagated response in the absence of a drug. Block of Na+ channels (A) shifts voltage dependence of recovery (Figure 29–5B) and delays the point at which 25% of channels have recovered (red diamond), prolonging refractoriness. If the drug also dissociates slowly from the channel (see Figure 29–11), refractoriness in fast-response tissues actually can extend beyond full repolarization (“postrepolarization refractoriness”). Drugs that prolong the action potential (B) also will extend the point at which an arbitrary percentage of Na+ channels have recovered from inactivation, even without directly interacting with Na+ channels. ERP, effective refractory period.

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Figure 29–11 Recovery from block of Na+ channels during diastole. This recovery is the critical factor determining extent of steady-state Na+ channel block. Na+ channel blockers bind to (and block) Na+channels in the open and/or inactivated states, resulting in phasic changes in the extent of block during the action potential. In the middle panel, a decrease in the rate of recovery from block increases the extent of block. Different drugs have different rates of recovery, and depolarization reduces the rate of recovery. Increasing heart rate, which results in relatively less time spent in the resting state, also increases the extent of block (right panel). (Modified from Roden DM, Echt DS, Lee JT, Murray KT. Clinical pharmacology of antiarrhythmic agents. In: Josephson ME, ed. Sudden Cardiac Death. London: Blackwell Scientific; 1993:182–185, with permission from Wiley-Blackwell Publishing.)

STATE-DEPENDENT ION CHANNEL BLOCK

A key concept is that ion channel–blocking drugs bind to specific sites on the ion channel proteins to modify function (e.g., decrease current) and that the affinity of the ion channel protein for the drug on its target site will vary as the ion channel protein shuttles among functional states (see Figure 29–2). Most useful agents of this type block open and/or inactivated Na+ channels and have very little affinity for channels in the resting state. Thus, with each action potential, drugs bind to Na+ channels and block them, and with each diastolic interval, drugs dissociate, and the block is released. When heart rate increases, the time available for dissociation decreases, and steady-state Na+ channel block increases. The rate of recovery from block also slows as cells are depolarized, as in ischemia. This explains the finding that Na+ channel blockers depress Na+ current, and hence conduction, to a greater extent in ischemic tissues than in normal tissues. Open versus inactivated-state block also may be important in determining the effects of some drugs. Increased APD, which results in a relative increase in time spent in the inactivated state, may increase block by drugs that bind to inactivated channels, such as lidocaine or amiodarone.

The rate of recovery from block often is expressed as a time constant (τrecovery, the time required for ~63% of an exponentially determined process to be complete). In the case of drugs such as lidocaine, τrecovery is so short (>>1 s) that recovery from block is very rapid, and substantial Na+ channel block occurs only in rapidly driven tissues, particularly in ischemia. Conversely, drugs such as flecainide have such long τrecovery values (>10 s) that roughly the same number of Na+ channels is blocked during systole and diastole. As a result, marked slowing of conduction occurs even in normal tissues at normal rates.

CLASSIFYING ANTI-ARRHYTHMIC DRUGS

To the extent that the clinical actions of drugs can be predicted, classifying drugs by their basic electrophysiologic properties is useful. However, differences in pharmacologic effects occur even among drugs that share the same classification, some of which may be responsible for the observed clinical differences in responses to drugs of the same broad “class” (Table 29–3). Another way of approaching therapy is to classify arrhythmia mechanisms and then to target drug therapy to the electrophysiologic mechanism most likely to terminate or prevent the arrhythmia (see Table 29–2).

Table 29–3

Major Electrophysiologic Actions of Anti-Arrhythmic Drugs

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Na+ Channel Block. The extent of Na+ channel block depends critically on heart rate and membrane potential, as well as on drug-specific physicochemical characteristics that determine τrecovery (Figure 29–11). When Na+ channels are blocked, excitability is decreased (i.e., greater membrane depolarization is required to bring Na+ channels from the resting to open state). This change in the threshold of excitability probably contributes to the clinical findings that Na+ channel blockers tend to increase both pacing threshold and the energy required for defibrillation.

These deleterious effects may be important if anti-arrhythmic drugs are used in patients with pacemakers or implanted defibrillators. Na+ channel block decreases conduction velocity in nonnodal tissue and increases QRS duration. Usual doses of flecainide prolong QRS intervals by 25% or more during normal rhythm, whereas lidocaine increases QRS intervals only at very fast heart rates. Drugs with τrecoveryvalues greater than 10 s (e.g., flecainide) also tend to prolong the PR interval; it is not known whether this represents additional Ca2+ channel block (see below) or block of fast-response tissue in the region of the AV node. Drug effects on the PR interval also are highly modified by autonomic effects. For example, quinidine actually tends to shorten the PR interval largely as a result of its vagolytic properties. Action potential duration either is unaffected or shortened by Na+ channel block; some Na+ channel–blocking drugs do prolong cardiac action potentials but by other mechanisms, usually K+ channel block (see Table 29–3).

Na+ channel block decreases automaticity (Figure 29–9B) and can inhibit triggered activity arising from DADs or EADs. Many Na+ channel blockers also decrease phase 4 slope (Figure 29–9A). In anatomically defined reentry, Na+ channel blockers may decrease conduction sufficiently to extinguish the propagating reentrant wavefront. However, conduction slowing owing to Na+ channel block may exacerbate reentry. Thus, whether a given drug exacerbates or suppresses reentrant arrhythmias depends on the balance between its effects on refractoriness and on conduction in a particular reentrant circuit. Lidocaine and mexiletine have short τrecovery values and are not useful in atrial fibrillation or flutter, whereas quinidine, flecainide, propafenone, and similar agents are effective in some patients. Many of these agents owe part of their anti-arrhythmic activity to blockade of K+ channels.

Late Na+ Channel Current Block. The long QT syndrome variant 3 (LQT3) is characterized by late inward Na+ current caused by defects in the inactivation of the cardiac isoform of the Na+ channel. This late current prolongs the APD and predisposes to arrhythmia. Many drugs with local anesthetic effects, including mexiletine, preferentially block this late current and can be used to successfully treat LQT3 patients.

Na+ Channel–Blocker Toxicity. Conduction slowing in potential reentrant circuits can account for toxicity of drugs that block the Na+ channel (see Table 29–1). For example, Na+ channel block decreases conduction velocity and hence slows atrial flutter rate. Normal AV nodal function permits a greater number of impulses to penetrate the ventricle, and heart rate actually may increase (see Figure 29–9). Thus, atrial flutter rate may drop from 300/min, with 2:1 or 4:1 AV conduction (i.e., a heart rate of 150 or 75 beats/min), to 220/min, but with 1:1 transmission to the ventricle (i.e., a heart rate of 220 beats/min), with potentially disastrous consequences. This form of drug-induced arrhythmia is especially common during treatment with quinidine because the drug also increases AV nodal conduction through its vagolytic properties; flecainide and propafenone also have been implicated. Therapy with Na+ channel blockers in patients with reentrant ventricular tachycardia after a myocardial infarction (MI) can increase the frequency and severity of arrhythmic episodes. Slowed conduction allows the reentrant wavefront to persist within the tachycardia circuit. Such drug-exacerbated arrhythmia can be very difficult to manage, and deaths owing to intractable drug-induced ventricular tachycardia have been reported. In this setting, Na+ infusion may be beneficial.

Action Potential Prolongation. Most drugs that prolong the action potential do so by blocking K+ channels, although enhanced inward Na+ current also can cause prolongation. Enhanced inward current may underlie QT prolongation (and arrhythmia suppression) by ibutilide. Block of cardiac K+ channels increases APD and reduces normal automaticity (Figure 29–9D). Increased APD, seen as an increase in QT interval, increases refractoriness (see Figure 29–10) and therefore should be an effective way of treating reentry. Experimentally, K+ channel block produces a series of desirable effects: reduced defibrillation energy requirement, inhibition of VF owing to acute ischemia, and increased contractility. Most K+ channel–blocking drugs also interact with β adrenergic receptors (sotalol) or other channels (e.g., amiodarone, quinidine) (see Table 29–3). Amiodarone and sotalol appear to be at least as effective as drugs with predominant Na+ channel–blocking properties in both atrial and ventricular arrhythmias. “Pure” action potential–prolonging drugs (e.g., dofetilide, ibutilide) also are available.

Toxicity of Drugs That Prolong QT Interval. Most of these agents disproportionately prolong cardiac action potentials when underlying heart rate is slow and can cause torsade de pointes (see Table 29–1). While this effect usually is seen with QT-prolonging anti-arrhythmic drugs, it can occur more rarely with drugs that are used for noncardiac indications. For such agents, the risk of torsade de pointes may become apparent only after widespread use postmarketing. Sex hormones modify cardiac ion channels and may account for the clinically observed increased incidence of drug-induced torsade de pointes in women.

Ca2+ Channel Block. The major electrophysiologic effects resulting from block of cardiac Ca2+ channels are in nodal tissues. Dihydropyridines, such as nifedipine, which are used commonly in angina and hypertension, preferentially block Ca2+ channels in vascular smooth muscle; their cardiac electrophysiologic effects, such as heart rate acceleration, result principally from reflex sympathetic activation secondary to peripheral vasodilation. Only verapamil, diltiazem, and bepridil block Ca2+ channels in cardiac cells at clinically used doses. These drugs generally slow heart rate (Figure 29–9A), although hypotension, if marked, can cause reflex sympathetic activation and tachycardia. The velocity of AV nodal conduction decreases, so the PR interval increases. AV nodal block occurs as a result ofdecremental conduction, as well as increased AV nodal refractoriness. These latter effects form the basis of the anti-arrhythmic actions of Ca2+ channel blockers in reentrant arrhythmias whose circuit involves the AV node, such as AV reentrant tachycardia (see Figure 29–7).

Another important indication for anti-arrhythmic therapy is to reduce ventricular rate in atrial flutter or fibrillation. Rare forms of ventricular tachycardia appear to be DAD-mediated and respond to verapamil. Parenteral verapamil and diltiazem are approved for rapid conversion of PSVTs to sinus rhythm and for temporary control of rapid ventricular rate in atrial flutter or fibrillation. Oral verapamil may be used in conjunction with digoxin to control ventricular rate in chronic atrial flutter or fibrillation and for prophylaxis of repetitive PSVT. Unlike β adrenergic receptor antagonists, Ca2+ channel blockers have not been shown to reduce mortality after MI.

Verapamil and Diltiazem. The major adverse effect of intravenous verapamil or diltiazem is hypotension, particularly with bolus administration. This is a particular problem if the drugs are used mistakenly in patients with ventricular tachycardia (in whom Ca2+ channel blockers usually are not effective) misdiagnosed as AV nodal reentrant tachycardia. Hypotension also is frequent in patients receiving other vasodilators, including quinidine, and in patients with underlying left ventricular dysfunction, which the drugs can exacerbate. Severe sinus bradycardia or AV block occurs, especially in patients also receiving β blockers. With oral therapy, these adverse effects tend to be less severe.

Verapamil (CALAN, ISOPTIN, VERELAN, COVERA-HS, and others) is supplied as a racemate. L-Verapamil is a more potent calcium channel blocker than is D-verapamil. However, with oral therapy, the L-enantiomer undergoes more extensive first-pass hepatic metabolism. For this reason, a given concentration of verapamil prolongs the PR interval to a greater extent when administered intravenously (where concentrations of the L- and D-enantiomers are equivalent) than when administered orally. Diltiazem (CARDIZEM, TIAZAC, DILACOR XR, and others) also undergoes extensive first-pass hepatic metabolism, and both drugs have metabolites that exert Ca2+ channel–blocking actions. Adverse effects during therapy with verapamil or diltiazem are determined largely by underlying heart disease and concomitant therapy; plasma concentrations of these agents are not measured routinely. Both drugs can increase serum digoxin concentration, although the magnitude of this effect is variable; excess slowing of ventricular response may occur in patients with atrial fibrillation. Constipation can occur with oral verapamil.

Blockade of β Adrenergic Receptors. β Adrenergic stimulation increases the magnitude of the Ca2+ current and slows its inactivation, increases the magnitude of repolarizing K+ and Cl currents, increases pacemaker current (thereby increasing sinus rate), increases the Ca2+ stored in the SR, and under pathophysiologic conditions, can increase both DAD- and EAD-mediated arrhythmias. The increases in plasma epinephrine associated with severe stress (e.g., acute MI, resuscitation after cardiac arrest) lower serum K+, especially in patients receiving chronic diuretic therapy. β Adrenergic receptor antagonists inhibit these effects and can be anti-arrhythmic by reducing heart rate, decreasing intracellular Ca2+ overload, and inhibiting afterdepolarization-mediated automaticity. Epinephrine-induced hypokalemia appears to be mediated by a2 adrenergic receptors and is blocked by “noncardioselective” antagonists such as propranolol (see Chapter 12). In acutely ischemic tissue, blockers increase the energy required to fibrillate the heart, an anti-arrhythmic action. These effects may contribute to the reduced mortality observed in trials of chronic therapy with β blockers after MI.

As with Ca2+ channel blockers and digitalis,β blockers increase AV nodal conduction time (increased PR interval) and prolong AV nodal refractoriness; hence, they are useful in terminating reentrant arrhythmias that involve the AV node and in controlling ventricular response in atrial fibrillation or flutter. In many patients with the congenital long QT syndrome and many other patients, arrhythmias are triggered by physical or emotional stress; β blockers may be useful in these cases. β Adrenergic receptor antagonists also reportedly are effective in controlling arrhythmias Na+ channel blockers; this effect may be due in part to slowing of the heart rate, which then decreases the extent of rate-dependent conduction slowing by Na+ channel block. Adverse effects of β blockade include fatigue, bronchospasm, hypotension, impotence, depression, worsening of symptoms owing to peripheral vascular disease, and masking of the symptoms of hypoglycemia in diabetic patients (see Chapter 12). In patients with arrhythmias owing to excess sympathetic stimulation (e.g., pheochromocytoma, clonidine withdrawal), d blockers can result in unopposed α adrenergic stimulation, with resulting severe hypertension and/or α adrenergic–mediated arrhythmias. In such patients, arrhythmias should be treated with both α and β adrenergic antagonists or with a drug such as labetalol that combines α and β blocking properties. Abrupt discontinuation of chronic β blocker therapy can lead to “rebound” symptoms; thus, β receptor antagonists are tapered over 2 weeks.

Selected β Adrenergic Receptor Blockers. It is likely that most β adrenergic antagonists share anti-arrhythmic properties. Some, such as propranolol, also exert Na+ channel–blocking effects at high concentrations. Acebutolol is as effective as quinidine in suppressing ventricular ectopic beats, an arrhythmia that many clinicians no longer treat. Sotalol is more effective for many arrhythmias than other β blockers, probably because of its K+ channel–blocking actions. Esmolol is a β1-selective agent that has a very short elimination t1/2. Intravenous esmolol is useful in clinical situations in which immediate β adrenergic blockade is desired.

PRINCIPLES IN THE CLINICAL USE OF ANTI-ARRHYTHMIC DRUGS

Drugs that modify cardiac electrophysiology often have a small therapeutic index. Moreover, anti-arrhythmic drugs can induce new arrhythmias with possibly fatal consequences. Nonpharmacologic treatments, such as cardiac pacing, electrical defibrillation, or ablation of targeted regions, are indicated for some arrhythmias; in other cases, no therapy is required, even though an arrhythmia is detected. The fundamental principles of therapeutics described here must be applied to optimize anti-arrhythmic therapy.

1. IDENTIFY AND REMOVE PRECIPITATING FACTORS

Factors that commonly precipitate cardiac arrhythmias include hypoxia, electrolyte disturbances (especially hypokalemia), myocardial ischemia, and certain drugs.

For example, theophylline can cause multifocal atrial tachycardia, while torsade de pointes can arise not only during therapy with action potential–prolonging anti-arrhythmics but also with other drugs not ordinarily classified as having effects on ion channels, including erythromycin (see Chapter 55); the antiprotozoal pentamidine (see Chapter 50); some antipsychotics, notably thioridazine (see Chapter 16); some analgesics, notably methadone and celecoxib; some antiemetics (e.g., droperidol, dolasetron); antihistamines such as diphenhydramine; azole antifungals such as voriconazole and fluconazole; bronchodilators such as albuterol, formoterol, and salmeterol; prednisone; cisapride; famotidine; tacrolimus; some selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine sertraline, and venlafaxine); haloperidol; trazodone; some serotonin 5HT1 agonists (e.g., sumatriptan, zolmitriptan); some antiretrovirals (e.g., efavirenz); most quinolone antibiotics (e.g., levofloxacin); tizanidine; and certain tricyclic antidepressants (see Chapter 15).

2. ESTABLISH THE GOALS OF TREATMENT

SOME ARRHYTHMIAS SHOULD NOT BE TREATED. The mere detection of an abnormality does not equate with the need for therapy. In the Cardiac Arrhythmia Suppression Trial (CAST), patients whose ventricular ectopic beats were suppressed by the potent Na+ channel blockers encainide (no longer marketed) or flecainide were randomly assigned to receive those drugs or placebo. Unexpectedly, the mortality rate was 2- to 3-fold higher among patients treated with the drugs than those treated with placebo. This pivotal clinical trial reemphasizes the concept that therapy should be initiated only when a clear benefit to the patient can be identified. When symptoms are obviously attributable to an ongoing arrhythmia, there usually is little doubt that termination of the arrhythmia will be beneficial; when chronic therapy is used to prevent recurrence of an arrhythmia, the risks may be greater. Among the anti-arrhythmic drugs discussed here, only β adrenergic blockers and, to a lesser extent, amiodarone have been shown to reduce mortality during long-term therapy.

SYMPTOMS DUE TO ARRHYTHMIAS. If patients with an arrhythmia are asymptomatic, establishing any benefit from treatment will be difficult. Some patients may present with presyncope, syncope, or even cardiac arrest, which may be due to brady- or tachyarrhythmias. The sensation of irregular heartbeats (i.e., palpitations) can be minimally symptomatic in some individuals and incapacitating in others. The irregular heartbeats may be due to intermittent premature contractions or to sustained arrhythmias such as atrial fibrillation (which results in an irregular ventricular rate). Finally, patients may present with symptoms owing to decreased cardiac output. The most common symptom is breathlessness either at rest or on exertion. Rarely, sustained tachycardias may produce no “arrhythmia” symptoms (such as palpitations) but will depress contractile function; these patients may present with congestive heart failure that can be controlled by treating the arrhythmia.

CHOOSING AMONG THERAPEUTIC APPROACHES. In selecting therapy, establish clear therapeutic goals. For example, 3 options are available in patients with atrial fibrillation: (1) reduce the ventricular response using AV nodal blocking agents such as digitalis, verapamil, diltiazem, or β adrenergic antagonists (see Table 29–1); (2) restore and maintain normal rhythm using drugs such as quinidine, flecainide, or amiodarone; or (3) decide not to implement anti-arrhythmic therapy, especially if the patient truly is asymptomatic. Most patients with atrial fibrillation also benefit from anticoagulation to reduce stroke incidence regardless of symptoms. Factors that contribute to choice of therapy include not only symptoms but also the type and extent of structural heart disease, the QT interval prior to drug therapy, the coexistence of conduction system disease, and the presence of noncardiac diseases (Table 29–4). In the rare patient with the WPW syndrome and atrial fibrillation, the ventricular response can be extremely rapid and can be accelerated paradoxically by AV nodal blocking drugs such as digitalis or Ca2+ channel blockers; deaths owing to drug therapy have been reported.

Table 29–4

Patient-Specif c Anti-Arrhythmic Drug Contraindications

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The frequency and reproducibility of arrhythmia should be established prior to initiating therapy because inherent variability in the occurrence of arrhythmias can be confused with a beneficial or adverse drug effect. Techniques for this assessment include recording cardiac rhythm for prolonged periods or evaluating the response of the heart to artificially induced premature beats. It is important to recognize that drug therapy may be only partially effective. A marked decrease in the duration of paroxysms of atrial fibrillation may be sufficient to render a patient asymptomatic.

3. MINIMIZE RISKS

ANTI-ARRHYTHMIC DRUGS CAN CAUSE ARRHYTHMIAS. One risk of anti-arrhythmic therapy is the provoking of new arrhythmias, with potentially life-threatening consequences. Anti-arrhythmic drugs can provoke arrhythmias by different mechanisms (see Table 29–1). These drug-provoked arrhythmias must be recognized because further treatment with anti-arrhythmic drugs often exacerbates the problem. Targeting therapies at underlying mechanisms of the arrhythmias may be required.

MONITORING OF PLASMA CONCENTRATION. Some adverse effects of anti-arrhythmic drugs result from excessive plasma drug concentrations. Measuring plasma concentration and adjusting the dose to maintain the concentration within a prescribed therapeutic range may minimize some adverse effects. In many patients, serious adverse reactions relate to interactions involving anti-arrhythmic drugs (often at usual plasma concentrations), transient factors such as electrolyte disturbances or myocardial ischemia, and the type and extent of the underlying heart disease.

PATIENT-SPECIFIC CONTRAINDICATIONS. Another way to minimize the adverse effects of anti-arrhythmic drugs is to avoid certain drugs in certain patient subsets altogether. For example, patients with a history of congestive heart failure are particularly prone to develop heart failure during disopyramide therapy. In other cases, adverse effects of drugs may be difficult to distinguish from exacerbations of underlying disease. Amiodarone may cause interstitial lung disease; its use therefore is undesirable in a patient with advanced pulmonary disease in whom the development of this potentially fatal adverse effect would be difficult to detect. Specific diseases that constitute relative or absolute contraindications to specific drugs are listed in Table 29–4.

4. CONSIDER THE ELECTROPHYSIOLOGY OF THE HEART AS A “MOVING TARGET”

Cardiac electrophysiology varies dynamically in response to external influences such as changing autonomic tone, myocardial ischemia, and myocardial stretch. For example, in response to myocardial ischemia, a normal heart may display changes in resting potential, conduction velocity, intracellular Ca2+ concentrations, and repolarization, any one of which then may create arrhythmias or alter response to anti-arrhythmic therapy.

ANTI-ARRHYTHMIC DRUGS

Summaries of important electrophysiologic and pharmacokinetic features of the drugs considered here are presented in Tables 29–3 and 29–5, respectively. Ca2+ channel blockers and β adrenergic antagonists are discussed in Chapters 1227, and 28. The drugs are presented in alphabetical order.

ADENOSINE. Adenosine (ADENOCARD, others) is a naturally occurring nucleoside that is administered as a rapid intravenous bolus for the acute termination of reentrant supraventricular arrhythmias. Adenosine also has been used to produce controlled hypotension during some surgical procedures and in the diagnosis of coronary artery disease. Intravenous ATP appears to produce effects similar to those of adenosine.

Pharmacologic Effects. The effects of adenosine are mediated by its interaction with specific GPCRs. Adenosine activates acetylcholine-sensitive K+ current in the atrium and sinus and AV nodes, resulting in shortening of APD, hyperpolarization, and slowing of normal automaticity (Figure 29–9C). Adenosine also inhibits the electrophysiologic effects of increased intracellular cyclic AMP that occur with sympathetic stimulation. Because adenosine thereby reduces Ca2+ currents, it can be anti-arrhythmic by increasing AV nodal refractoriness and by inhibiting DADs elicited by sympathetic stimulation. Administration of an intravenous bolus of adenosine to humans transiently slows sinus rate and AV nodal conduction velocity and increases AV nodal refractoriness. A bolus of adenosine can produce transient sympathetic activation by interacting with carotid baroreceptors; a continuous infusion can cause hypotension.

Adverse Effects. A major advantage of adenosine therapy is that adverse effects are short lived because the drug is transported into cells and deaminated so rapidly. Transient asystole is common but usually lasts less than 5 sec and is in fact the therapeutic goal. Most patients feel a sense of chest fullness and dyspnea when therapeutic doses (6-12 mg) of adenosine are administered. Rarely, an adenosine bolus can precipitate bronchospasm or atrial fibrillation.

Clinical Pharmacokinetics. Adenosine is eliminated with a t1/2 of seconds by carrier-mediated uptake and subsequent metabolism by adenosine deaminase. Adenosine probably is the only drug whose efficacy requires a rapid bolus dose, preferably through a large central intravenous line; slow administration results in elimination of the drug prior to its arrival at the heart. The effects of adenosine are potentiated in patients receiving dipyridamole, an adenosine uptake inhibitor, and in patients with cardiac transplants owing to denervation hypersensitivity. Methylxanthines such as theophylline and caffeine block adenosine receptors; therefore, larger than usual doses are required to produce an anti-arrhythmic effect in patients who have consumed these agents in coffee and sodas or as therapy.

AMIODARONE. Amiodarone (CORDARONE, PACERONE, others) exerts myriad pharmacologic effects, none of which is clearly linked to its arrhythmia-suppressing properties. Amiodarone is a structural analog of thyroid hormone, and some of its anti-arrhythmic actions and its toxicity are due to interaction with thyroid hormone receptors.

Amiodarone is highly lipophilic, is concentrated in many tissues, and is eliminated extremely slowly; consequently, adverse effects may resolve very slowly. In the U.S., the drug is indicated for oral therapy in patients with recurrent ventricular tachycardia or fibrillation resistant to other drugs. Oral amiodarone also is effective in maintaining sinus rhythm in patients with atrial fibrillation. An intravenous form is indicated for acute termination of ventricular tachycardia or fibrillation and is supplanting lidocaine as first-line therapy for out-of-hospital cardiac arrest. Despite uncertainties about its mechanisms of action and the potential for serious toxicity, amiodarone now is used very widely in the treatment of common arrhythmias such as atrial fibrillation.

Pharmacologic Effects. Amiodarone blocks inactivated Na+ channels and has a relatively rapid rate of recovery (time constant ~1.6 s) from block. It also decreases Ca2+ current and transient outward delayed-rectifier and inward rectifier K+ currents and exerts a noncompetitive adrenergic blocking effect. Amiodarone potently inhibits abnormal automaticity and, in most tissues, prolongs APD. Amiodarone decreases conduction velocity by Na+ channel block and by a poorly understood effect on cell–cell coupling that may be especially important in diseased tissue. Prolongations of the PR, QRS, and QT intervals and sinus bradycardia are frequent during chronic therapy. Amiodarone prolongs refractoriness in all cardiac tissues; Na+ channel block, delayed repolarization owing to K+ channel block, and inhibition of cell–cell coupling all may contribute to this effect.

Adverse Effects. Hypotension owing to vasodilation and depressed myocardial performance are frequent with the intravenous form of amiodarone. Although depressed contractility can occur during long-term oral therapy, it is unusual. Despite administration of high doses that would cause serious toxicity if continued long term, adverse effects are unusual during oral drug-loading regimens, which typically require several weeks. Occasionally during the loading phase, patients develop nausea, which responds to a decrease in daily dose.

Adverse effects during long-term therapy reflect both the size of daily maintenance doses and the cumulative dose, suggesting that tissue accumulation may be responsible. The most serious adverse effect during chronic amiodarone therapy is pulmonary fibrosis, which can be rapidly progressive and fatal. Underlying lung disease, doses of 400 mg/day or more, and recent pulmonary insults such as pneumonia appear to be risk factors. Serial chest X-rays or pulmonary function studies may detect early amiodarone toxicity; monitoring plasma concentrations has not been useful. With low doses, such as 200 mg/day or less used in atrial fibrillation, pulmonary toxicity is unusual. Other adverse effects during long-term therapy include corneal microdeposits (which often are asymptomatic), hepatic dysfunction, neuromuscular symptoms (peripheral neuropathy or proximal muscle weakness), photosensitivity, and hypo- or hyperthyroidism. Treatment consists of withdrawal of the drug and supportive measures, including corticosteroids. Dose reduction may be sufficient if the drug is deemed necessary and the adverse effect is not life-threatening. Despite the marked QT prolongation and bradycardia typical of chronic amiodarone therapy, torsade de pointes and other drug-induced tachyarrhythmias are unusual.

Clinical Pharmacokinetics. Amiodarone’s oral bioavailability is ~30%, which is important in calculating equivalent dosing regimens when converting from intravenous to oral therapy. After the initiation of amiodarone therapy, increases in refractoriness, a marker of pharmacologic effect, require several weeks to develop. Amiodarone undergoes hepatic metabolism by CYP3A4 to desethyl-amiodarone, a metabolite with pharmacologic effects similar to those of the parent drug. When amiodarone therapy is withdrawn from a patient who has been receiving therapy for several years, plasma concentrations decline with a t1/2 of weeks to months. The mechanism whereby amiodarone and desethyl-amiodarone are eliminated is not well established.

A therapeutic plasma amiodarone concentration range of 0.5-2 µg/mL has been proposed. However, efficacy apparently depends as much on duration of therapy as on plasma concentration, and elevated plasma concentrations do not predict toxicity. Because of amiodarone’s slow accumulation in tissue, a high-dose oral loading regimen (e.g., 800-1600 mg/day) usually is administered for several weeks before maintenance therapy is started. If the presenting arrhythmia is life-threatening, dosages of >300 mg/day normally are used unless unequivocal toxicity occurs. On the other hand, maintenance doses of ≤200 mg/day are used if recurrence of an arrhythmia would be tolerated, as in patients with atrial fibrillation. Because of its very slow elimination, amiodarone is administered once daily, and omission of 1 or 2 doses during chronic therapy rarely results in recurrence of arrhythmia. Dosage adjustments are not required in hepatic, renal, or cardiac dysfunction. Amiodarone potently inhibits the hepatic metabolism or renal elimination of many compounds. Mechanisms identified to date include inhibition of CYP3A4, CYP2C9, and P-glycoprotein (see Chapters 5 and 6). Dosages of warfarin, other anti-arrhythmics (e.g., flecainide, procainamide, quinidine), or digoxin usually require reduction during amiodarone therapy.

DIGOXIN. Digitalis glycosides exert positive inotropic effects and are used in heart failure (see Chapter 28). Their inotropic action results from increased intracellular Ca2+ (Figure 28–5), which also forms the basis for arrhythmias related to cardiac glycoside intoxication.

Pharmacologic Effects. Cardiac glycosides increase phase 4 slope (i.e., increase the rate of automaticity), especially if [K]o is low. They also exert prominent vagotonic actions, resulting in inhibition of Ca2+ currents in the AV node and activation of acetylcholine-mediated K+ currents in the atrium. Thus, the major “indirect” electrophysiologic effects of cardiac glycosides are hyperpolarization, shortening of atrial action potentials, and increases in AV nodal refractoriness. The latter action accounts for the utility of digoxin in terminating reentrant arrhythmias involving the AV node and in controlling ventricular response in patients with atrial fibrillation.

Cardiac glycosides may be especially useful in atrial fibrillation because many such patients have heart failure, which can be exacerbated by other AV nodal blocking drugs such as Ca2+ channel blockers or β adrenergic receptor antagonists. However, sympathetic drive is increased markedly in many patients with advanced heart failure, so digitalis is not very effective in decreasing the rate; however, even a modest decrease in rate can ameliorate heart failure. Similarly, in other conditions in which high sympathetic tone drives rapid AV conduction (e.g., chronic lung disease, thyrotoxicosis), digitalis therapy may be only marginally effective in slowing the rate. In heart transplant patients, in whom innervation has been ablated, cardiac glycosides are ineffective for rate control. Increased sympathetic activity and hypoxia can potentiate digitalis-induced changes in automaticity and DADs, thus increasing the risk of digitalis toxicity. A further complicating feature in thyrotoxicosis is increased digoxin clearance. The major ECG effects of cardiac glycosides are PR prolongation and a nonspecific alteration in ventricular repolarization (manifested by depression of the ST segment), whose underlying mechanism is not well understood.

Adverse Effects. Because of the low therapeutic index of cardiac glycosides, their toxicity is a common clinical problem (see Chapter 28). Arrhythmias, nausea, disturbances of cognitive function, and blurred or yellow vision are the usual manifestations. Elevated serum concentrations of digitalis, hypoxia, and electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypercalcemia) predispose patients to digitalis-induced arrhythmias. Although digitalis intoxication can cause virtually any arrhythmia, certain types of arrhythmias that should raise a strong suspicion of digitalis intoxication are those in which DAD-related tachycardias occur along with impairment of sinus node or AV nodal function. Atrial tachycardia with AV block is classic, but ventricular bigeminy (sinus beats alternating with beats of ventricular origin), “bidirectional” ventricular tachycardia (a very rare entity), AV junctional tachycardias, and various degrees of AV block also can occur. With severe intoxication (e.g., with suicidal ingestion), severe hyperkalemia owing to poisoning of Na+, K+-ATPase and profound bradyarrhythmias are seen. In patients with elevated serum digitalis levels, the risk of precipitating VF by DC cardioversion probably is increased; in those with therapeutic blood levels, DC cardioversion can be used safely.

Minor forms of cardiac glycoside intoxication may require no specific therapy beyond monitoring cardiac rhythm until symptoms and signs of toxicity resolve. Sinus bradycardia and AV block often respond to intravenous atropine. Mg2+ has been used successfully in some cases of digitalis-induced tachycardia. Any serious arrhythmia should be treated with antidigoxin Fab fragments (DIGIBIND, DIGIFAB), which are highly effective in binding digoxin and digitoxin and greatly enhance their renal excretion (see Chapter 28). Temporary cardiac pacing may be required for advanced sinus node or AV node dysfunction. Digitalis exerts direct arterial vasoconstrictor effects, which can be deleterious in patients with advanced atherosclerosis who receive intravenous drug.

Clinical Pharmacokinetics. The only digitalis glycoside used in the U.S. is digoxin (LANOXIN). Digitoxin also is used for chronic oral therapy outside the U.S. Digoxin tablets are ~75% bioavailable. In some patients, intestinal microflora may metabolize digoxin, markedly reducing bioavailability. In these patients, higher than usual doses are required for clinical efficacy; toxicity is a serious risk if antibiotics that destroy intestinal microflora are administered. Inhibition of P-glycoprotein also may play a role in cases of toxicity. Digoxin is 20-30% protein bound. The anti-arrhythmic effects of digoxin can be achieved with intravenous or oral therapy. However, digoxin undergoes relatively slow distribution to effector site(s); therefore, even with intravenous therapy, there is a lag of several hours between drug administration and the development of measurable anti-arrhythmic effects such as PR-interval prolongation or slowing of the ventricular rate in atrial fibrillation. To avoid intoxication, a loading dose of ~0.6-1 mg digoxin is administered over 24 h. Measurement of postdistribution serum digoxin concentration and adjustment of the daily dose (0.0625-0.5 mg) to maintain concentrations of 0.5-2 ng/mL are useful during chronic digoxin therapy (see Table 29–5). Some patients may require and tolerate higher concentrations but with an increased risk of adverse effects.

Table 29–5

Pharmacokinetic Characteristics and Doses of Anti-Arrhythmic Drugs

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Digoxin is largely excreted unchanged by the kidney with an elimination t1/2 ~36 h, so maintenance doses are administered once daily. Digoxin doses should be reduced (or dosing interval increased) and serum concentrations monitored closely in patients with impaired excretion owing to renal failure or in patients who are hypothyroid. Digitoxin undergoes primarily hepatic metabolism and may be useful in patients with fluctuating or advanced renal dysfunction. Digitoxin’s elimination t1/2 is even longer than that of digoxin (~7 days); it is highly protein bound, and its therapeutic range is 10-30 ng/mL. Digitoxin metabolism is accelerated by drugs such as phenytoin and rifampin that induce hepatic metabolism. Amiodarone, quinidine, verapamil, diltiazem, cyclosporine, itraconazole, propafenone, and flecainide decrease digoxin clearance, likely by inhibiting P-glycoprotein, the major route of digoxin elimination. New steady-state digoxin concentrations are approached in about a week. Digitalis toxicity results so often with quinidine or amiodarone that it is routine to decrease the dose of digoxin if these drugs are started. In all cases, digoxin concentrations should be measured regularly and the dose adjusted if necessary. Hypokalemia will potentiate digitalis-induced arrhythmias.

DISOPYRAMIDE. Disopyramide (NORPACE, others) exerts electrophysiologic effects very similar to those of quinidine, but the drugs produce different adverse effects. Disopyramide is used to maintain sinus rhythm in patients with atrial flutter or atrial fibrillation and to prevent recurrence of ventricular tachycardia or VF.

Pharmacologic Actions and Adverse Effects. The in vitro electrophysiologic actions of S-(–)-disopyramide are similar to those of quinidine. The R-(–)-enantiomer produces similar Na+ channel block but does not prolong cardiac action potentials. Unlike quinidine, racemic disopyramide is not an α adrenergic receptor antagonist, but it does exert prominent anticholinergic actions that account for many of its adverse effects. These include precipitation of glaucoma, constipation, dry mouth, and urinary retention. Disopyramide commonly depresses contractility, which can precipitate heart failure and also can cause torsade de pointes.

Clinical Pharmacokinetics. Disopyramide is well absorbed. Binding to plasma proteins is concentration dependent, so a small increase in total concentration may represent a disproportionately larger increase in free drug concentration. Disopyramide is eliminated by both hepatic metabolism (to a weakly active metabolite) and renal excretion of unchanged drug. The dose should be reduced in patients with renal dysfunction. Higher than usual dosages may be required in patients receiving drugs that induce hepatic metabolism, such as phenytoin.

DOFETILIDE. Dofetilide (TIKOSYN) is a potent and “pure” IKr blocker that has virtually no extracardiac effects. Dofetilide is effective in maintaining sinus rhythm in patients with atrial fibrillation. Dofetilide is available through a restricted distribution system that includes only physicians, hospitals, and other institutions that have received special educational programs covering proper dosing and in-hospital treatment initiation.

Adverse EffectsTorsade de pointes occurred in 1-3% of patients in clinical trials where strict exclusion criteria (e.g., hypokalemia) were applied and continuous ECG monitoring was used to detect marked QT prolongation in the hospital. The incidence of this adverse effect during more widespread use of the drug postmarketing is unknown.

Clinical Pharmacokinetics. Most of a dose of dofetilide is excreted unchanged by the kidneys. In patients with mild to moderate renal failure, decreases in dosage based on creatinine clearance are required to minimize the risk of torsade de pointes. The drug should not be used in patients with advanced renal failure or with inhibitors of renal cation transport. Dofetilide also undergoes minor hepatic metabolism.

DRONEDARONE. Dronedarone (MULTAQ) is a derivative of amiodarone approved for the treatment of atrial fibrillation and atrial flutter. Compared to amiodarone, dronedarone treatment is associated with significantly fewer adverse events, but it also is significantly less effective in maintaining sinus rhythm. Dronedarone reduces morbidity and mortality in patients with high-risk atrial fibrillation. However, dronedarone increases mortality in patients with severe heart failure and is contraindicated in patients with NYHA class 4 heart failure and in patients with a recent decompensation of heart failure requiring hospitalization.

Pharmacologic Effects. Similar to amiodarone, dronedarone is a potent blocker of multiple ion currents, including the rapidly activating delayed-rectifier K+ current (IKr), the slowly activating delayed-rectifier K+ current (IKs), the inward rectifier K+ current (IK1), the acetylcholine activated K+ current, the peak Na+ current, and the L-type Ca2+ current. It has stronger anti-adrenergic effects than amiodarone.

Adverse Effects and Drug Interactions. The most common adverse reactions are diarrhea, nausea, abdominal pain, vomiting, and asthenia. Dronedarone causes dose-dependent prolongation of QT interval, but torsade de pointes is rare. Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A, CYP2D6, and P-glycoprotein. A potent CYP3A4 inhibitor such as ketoconazole may increase dronedarone exposure by as much as 25-fold. Dronedarone should not be coadministered with potent CYP3A4 inhibitors. Coadministration with other drugs metabolized by CYP2D6 (e.g., metoprolol) or transported by P-glycoprotein (e.g., digoxin) may result in increased drug concentrations.

ESMOLOL. (BREVIBLOC, others) is a β1-selective agent that is metabolized by erythrocyte esterases and so has a very short elimination t1/2 (9 min). Intravenous esmolol is useful in clinical situations in which immediate β adrenergic blockade is desired (e.g., for rate control of rapidly conducted atrial fibrillation).

FLECAINIDE. The effects of flecainide (TAMBOCOR, others) are likely attributable to the drug’s very long srecovery from Na+ channel block. It is approved for the maintenance of sinus rhythm in patients with supraventricular arrhythmias, including atrial fibrillation, in whom structural heart disease is absent.

Pharmacologic Effects. Flecainide blocks Na+ current, delayed-rectifier K+ current (IKr) and Ca2+ currents. APD is shortened in Purkinje cells, probably owing to block of late-opening Na+ channels, but prolonged in ventricular cells, probably owing to block of delayed-rectifier current. Flecainide does not cause EADs in vitro but has been associated with rare cases of torsade de pointes. In atrial tissue, flecainide disproportionately prolongs action potentials at fast rates, an especially desirable anti-arrhythmic drug effect; this effect contrasts with that of quinidine, which prolongs atrial action potentials to a greater extent at slower rates. Flecainide prolongs the duration of PR, QRS, and QT intervals even at normal heart rates. Flecainide also is an open channel blocker of RyR2 Ca2+ release channels and prevents arrhythmogenic Ca2+ release from the SR in isolated myocytes. The blockade of the RyR2 channel by flecainide targets directly the underlying molecular defect in patients with mutations in the ryanodine receptor and cardiac calsequestrin, which may explain why flecainide suppresses ventricular arrhythmias in CPVT patients refractory to standard drug therapy.

Adverse Effects. Dose-related blurred vision is the most common noncardiac adverse effect. It can exacerbate congestive heart failure in patients with depressed left ventricular performance. The most serious adverse effects are provocation or exacerbation of potentially lethal arrhythmias. These include acceleration of ventricular rate in patients with atrial flutter, increased frequency of episodes of reentrant ventricular tachycardia, and increased mortality in patients convalescing from MI. These may be attributed to Na+ channel block. Flecainide also can cause heart block in patients with conduction system disease.

Clinical Pharmacokinetics. Flecainide is well absorbed. Elimination occurs by both renal excretion of unchanged drug and hepatic metabolism by CYP2D6 to inactive metabolites. However, in patients who lack this pathway due to genetic polymorphism or inhibition by other drugs (i.e., quinidine, fluoxetine), renal excretion ordinarily is sufficient to prevent drug accumulation. In the rare patient with renal dysfunction and lack of active CYP2D6, flecainide may accumulate to toxic plasma concentrations. Some reports suggest that plasma flecainide concentrations greater than 1 µg/mL should be avoided to minimize the risk of flecainide toxicity; but the adverse electrophysiologic effects of flecainide therapy can occur at therapeutic plasma concentrations.

IBUTILIDE. Ibutilide (CORVERT) is an IKr blocker that in some systems also activates an inward Na+ current. The action potential–prolonging effect of the drug may arise from either mechanism.

Ibutilide is administered as a rapid infusion (1 mg over 10 min) for the immediate conversion of atrial fibrillation or flutter to sinus rhythm. The drug’s efficacy rate is higher in patients with atrial flutter (50-70%) than in those with atrial fibrillation (30-50%). In atrial fibrillation, the conversion rate is lower in those in whom the arrhythmia has been present for weeks or months compared with those in whom it has been present for days. The major toxicity with ibutilide is torsade de pointes, which occurs in up to 6% of patients and requires immediate cardioversion in up to one-third of these. The drug undergoes extensive first-pass metabolism and so is not used orally. It is eliminated by hepatic metabolism with a t1/2 of 2-12 h.

LIDOCAINE. Lidocaine (XYLOCAINE, others) is a local anesthetic that also is useful in the acute intravenous therapy of ventricular arrhythmias. Its pharmacology is presented inChapter 20. See also mexiletine, below.

Pharmacologic Effects. Lidocaine blocks both open and inactivated cardiac Na+ channels. Recovery from block is very rapid, so lidocaine exerts greater effects in depolarized (e.g., ischemic) and/or rapidly driven tissues. Lidocaine is not useful in atrial arrhythmias possibly because atrial action potentials are so short that the Na+ channel is in the inactivated state only briefly compared with long diastolic (recovery) times. Lidocaine can hyperpolarize Purkinje fibers depolarized by low [K]o or stretch; the resulting increased conduction velocity may be anti-arrhythmic in reentry. Lidocaine decreases automaticity by reducing the slope of phase 4 and altering the threshold for excitability. APD usually is unaffected or is shortened; such shortening may be due to block of the few Na+ channels that inactivate late during the cardiac action potential. Lidocaine usually exerts no significant effect on PR or QRS duration; QT is unaltered or slightly shortened. The drug exerts little effect on hemodynamic function, although rare cases of lidocaine-associated exacerbations of heart failure have been reported in patients with very poor left ventricular function.

Adverse Effects. When a large intravenous dose of lidocaine is administered rapidly, seizures can occur. When plasma concentrations of the drug rise slowly above the therapeutic range, as may occur during maintenance therapy, tremor, dysarthria, and altered levels of consciousness are more common. Nystagmus is an early sign of lidocaine toxicity.

Clinical Pharmacokinetics. Lidocaine is well absorbed but undergoes extensive though variable first-pass hepatic metabolism; thus, oral use is inappropriate and the intravenous route is preferred (see Table 29–5). Lidocaine’s metabolites, glycine xylidide (GX) and monoethyl GX, are less potent as Na+ channel blockers than the parent drug. GX and lidocaine appear to compete for access to the Na+ channel, suggesting that with infusions during which GX accumulates, lidocaine’s efficacy may be diminished. With infusions lasting longer than 24 h, the clearance of lidocaine falls—an effect that has been attributed to competition between parent drug and metabolites for access to hepatic drug-metabolizing enzymes.

The initial drop in plasma lidocaine following intravenous administration occurs rapidly, with a t1/2 of ~8 min, and represents distribution from the central compartment to peripheral tissues. The terminal elimination t1/2, usually ~110 min, represents drug elimination by hepatic metabolism. Lidocaine’s efficacy depends on maintenance of therapeutic plasma concentrations in the central compartment. Therefore, the administration of a single bolus dose of lidocaine can result in transient arrhythmia suppression that dissipates rapidly as the drug is distributed and concentrations in the central compartment fall. To avoid this distribution-related loss of efficacy, a loading regimen of 3-4 mg/kg over 20-30 min is used—e.g., an initial 100 mg followed by 50 mg every 8 min for 3 doses. Subsequently, stable concentrations can be maintained in plasma with an infusion of 1-4 mg/min, which replaces drug removed by hepatic metabolism. The time to steady-state lidocaine concentrations is ~l8-10 h. Routine measurement of plasma lidocaine concentration at the time of expected steady state is useful in adjusting the maintenance infusion rate to avoid toxicities (therapeutic range, 1.5-5 µg/mL). In heart failure, the central volume of distribution is decreased, so the total loading dose should be decreased. Lidocaine clearance also is reduced in hepatic disease, during treatment with cimetidine or β blockers, and during prolonged infusions. Lidocaine is bound to the acute-phase reactant α-1-acid glycoprotein. Diseases such as acute MI are associated with increases in α-1-acid glycoprotein and protein binding and hence a decreased proportion of free drug. These findings may explain why some patients require and tolerate higher than usual total plasma lidocaine concentrations to maintain anti-arrhythmic efficacy.

MAGNESIUM. The intravenous administration of 1-2 g MgSO4 reportedly is effective in preventing recurrent episodes of torsade de pointes, even if the serum Mg2+ concentration is normal. However, controlled studies of this effect have not been performed.

The mechanism of action is unknown because the QT interval is not shortened; an effect on the inward current, possibly a Ca2+ current, responsible for the triggered upstroke arising from EADs (black arrowFigure 29–6B) is possible. Intravenous Mg2+ also has been used successfully in arrhythmias related to digitalis intoxication.

MEXILETINE. Mexiletine (MEXITIL, others) is an analog of lidocaine that has been modified to reduce first-pass hepatic metabolism and permit chronic oral therapy. The electrophysiologic actions are similar to those of lidocaine. Tremor and nausea, the major dose-related adverse effects, can be minimized by taking the drugs with food.

Mexiletine undergoes hepatic metabolism, which is inducible by drugs such as phenytoin. Mexiletine is approved for treating ventricular arrhythmias; combinations of mexiletine with quinidine or sotalol may increase efficacy while reducing adverse effects. In vitro studies and clinical case reports suggest a role for mexiletine (or flecainide) in correcting the aberrant late inward Na+ current in congenital LQT3.

PROCAINAMIDE. Procainamide (PROCAN SR, others) is an analog of the local anesthetic procaine (see Chapter 20). It exerts electrophysiologic effects similar to those of quinidine but lacks quinidine’s vagolytic and α adrenergic blocking activity. Procainamide is better tolerated than quinidine when given intravenously. Loading and maintenance intravenous infusions are used in the acute therapy of many supraventricular and ventricular arrhythmias; long-term oral treatment is poorly tolerated and often is stopped owing to adverse effects.

Pharmacologic Effects. Procainamide is a blocker of open Na+ channels with an intermediate τrecovery from block. It also prolongs cardiac action potentials, probably by blocking outward K+ current(s). Procainamide decreases automaticity, increases refractory periods, and slows conduction. Its major metabolite, N-acetyl procainamide, lacks the Na+ channel-blocking activity of the parent drug but is equipotent in prolonging action potentials. Because the plasma concentrations of N-acetyl procainamide often exceed those of procainamide, increased refractoriness and QT prolongation during chronic procainamide therapy may be partly attributable to the metabolite. However, it is the parent drug that slows conduction and produces QRS-interval prolongation. Hypotension may occur at high plasma concentrations, this effect is attributable to ganglionic blockade rather than to any negative inotropic effect.

Adverse Effects. Hypotension and marked slowing of conduction are major adverse effects of high concentrations (>10 µg/mL) of procainamide, especially during intravenous use. Dose-related nausea is frequent during oral therapy and may be attributable in part to high plasma concentrations of N-acetyl procainamide. Torsade de pointes can occur, particularly when plasma concentrations of N-acetyl procainamide rise to -30 µg/mL. Procainamide produces potentially fatal bone marrow aplasia in 0.2% of patients. During long-term therapy, most patients will develop biochemical evidence of the drug-induced lupus syndrome, such as circulating antinuclear antibodies. Therapy need not be interrupted merely because of the presence of antinuclear antibodies. However, 25-50% of patients eventually develop symptoms of the lupus syndrome; common early symptoms are rash and small-joint arthralgias. Other symptoms of lupus, including pericarditis with tamponade, can occur, although renal involvement is unusual. The lupuslike symptoms resolve on cessation of therapy or during treatment with N-acetyl procainamide (see below).

Clinical Pharmacokinetics. Procainamide is eliminated rapidly (t1/2 = 3-4 h) by both renal excretion of unchanged drug and hepatic metabolism. The major pathway for hepatic metabolism is conjugation byN-acetyl transferase, to form N-acetyl procainamide. N-Acetyl procainamide is eliminated by renal excretion (t1/2 = 6-10 h). Oral procainamide usually is administered as a slow-release formulation. In patients with renal failure reduction dose and dosing frequency and monitoring of plasma concentrations of both compounds are required. Because the parent drug and metabolite exert different pharmacologic effects, the past practice of using the sum of their concentrations to guide therapy is inappropriate. In individuals who are “slow acetylators,” the procainamide-induced lupus syndrome develops more often and earlier during treatment than among rapid acetylators. In addition, the symptoms of procainamide-induced lupus resolve during treatment with N-acetyl procainamide. Both these findings suggest that it is chronic exposure to the parent drug (or an oxidative metabolite) that results in the lupus syndrome.

PROPAFENONE. Propafenone (RYTHMOL, others) is a Na+ channel blocker with a relatively slow time constant for recovery from block. Like flecainide, propafenone also blocks K+ channels. Its major electrophysiologic effect is to slow conduction in fast-response tissues.

The drug is prescribed as a racemate; although the enantiomers do not differ in their Na+ channel–blocking properties, S-(+)-propafenone is a β receptor antagonist. Propafenone prolongs PR and QRS durations. Chronic therapy with oral propafenone is used to maintain sinus rhythm in patients with supraventricular tachycardias, including atrial fibrillation. It also can be used in ventricular arrhythmias, but with only modest efficacy.

adverse effects. Adverse effects during propafenone therapy include acceleration of ventricular response in patients with atrial flutter, increased frequency or severity of episodes of reentrant ventricular tachycardia, exacerbation of heart failure, and the adverse effects of β adrenergic blockade, such as sinus bradycardia and bronchospasm.

Clinical Pharmacokinetics. Propafenone is well absorbed and is eliminated by both hepatic and renal routes. The activity of CYP2D6 is a major determinant of plasma propafenone concentration. In most subjects (“extensive metabolizers”), propafenone undergoes extensive first-pass hepatic metabolism to 5-hydroxy propafenone, a metabolite equipotent to propafenone as a Na+ channel blocker but much less potent as a β adrenergic receptor antagonist. A second metabolite, N-desalkyl propafenone, is formed by non–CYP2D6-mediated metabolism and is a less potent blocker of Na+ channels and β adrenergic receptors. CYP2D6-mediated metabolism of propafenone is saturable, so small increases in dose can increase plasma propafenone concentration disproportionately. In “poor metabolizer” subjects lacking functional CYP2D6, plasma propafenone concentrations will be much higher after an equal dose. The incidence of adverse effects of propafenone therapy is higher in poor metabolizers.

CYP2D6 activity can be inhibited markedly by a number of drugs, including quinidine and fluoxetine. In extensive metabolizer subjects receiving such drugs or in poor metabolizer subjects, plasma propafenone concentrations of more than 1 µg/mL are associated with clinical effects of β receptor blockade, such as reduction of exercise heart rate. Patients with moderate to severe liver disease should be reduced to ~20-30% of the usual dose, with careful monitoring. Slow-release formulation allows twice-daily dosing.

QUINIDINE. Quinidine, a diastereomer of the antimalarial quinine, is used to maintain sinus rhythm in patients with atrial flutter or atrial fibrillation and to prevent recurrence of ventricular tachycardia or VF.

Pharmacologic Effects. Quinidine blocks Na+ current and multiple cardiac K+ currents. It is an open-state blocker of Na+ channels, with a τrecovery in the intermediate (~3 s) range; as a consequence, QRS duration increases modestly, usually by 10-20%, at therapeutic dosages. At therapeutic concentrations, quinidine commonly prolongs the QT interval up to 25%, but the effect is highly variable. At concentrations as low as 1 µM, quinidine blocks Na+ current and the rapid component of delayed rectifier (IKr); higher concentrations block the slow component of delayed rectifier, inward rectifier, transient outward current, and L-type Ca2+ current.

Quinidine’s Na+ channel–blocking properties result in an increased threshold for excitability and decreased automaticity. Due to K+ channel–blocking actions, quinidine prolongs action potentials in most cardiac cells, most prominently at slow heart rates. In some cells, such as midmyocardial cells and Purkinje cells, quinidine consistently elicits EADs at slow heart rates, particularly when [K]o is low. Quinidine prolongs refractoriness in most tissues, probably as a result of both prolongation of APD and Na+ channel blockade.

Quinidine also produces β receptor blockade and vagal inhibition. Thus, the intravenous use of quinidine is associated with marked hypotension and sinus tachycardia. Quinidine’s vagolytic effects tend to inhibit its direct depressant effect on AV nodal conduction, so the effect of drug on the PR interval is variable. Moreover, quinidine’s vagolytic effect can result in increased AV nodal transmission of atrial tachycardias such as atrial flutter (see Table 29–1).

Adverse Effects—Noncardiac. Diarrhea is the most common adverse effect during quinidine therapy, occurring in 30-50% of patients, usually within the first several days of quinidine therapy but can occur later. Diarrhea-induced hypokalemia may potentiate torsade de pointes due to quinidine. A number of immunologic reactions can occur during quinidine therapy. The most common is thrombocytopenia, which can be severe but resolves rapidly with drug discontinuation. Hepatitis, bone marrow depression, and lupus syndrome occur rarely. None of these effects is related to elevated plasma quinidine concentrations. Quinidine also can produce cinchonism, a syndrome that includes headache and tinnitus. In contrast to other adverse responses to quinidine therapy, cinchonism usually is related to elevated plasma quinidine concentrations and can be managed by dose reduction.

Adverse Effects—Cardiac. Between 2-8% will develop marked QT-interval prolongation and torsade de pointes. In contrast to effects of sotalol, N-acetyl procainamide, and many other drugs, quinidine-associated torsade de pointes generally occurs at therapeutic or even subtherapeutic plasma concentrations. The reasons for individual susceptibility are not known. At high plasma concentrations of quinidine, marked Na+ channel block can occur, with resulting ventricular tachycardia. Quinidine can exacerbate heart failure or conduction system disease. However, in most patients with congestive heart failure, quinidine is well tolerated, perhaps because of its vasodilating actions.

Clinical Pharmacokinetics. Quinidine is well absorbed and is 80% bound to plasma proteins, including albumin and α-1-acid glycoprotein. As with lidocaine, greater than usual doses (and total plasma quinidine concentrations) may be required to maintain therapeutic concentrations of free quinidine in high-stress states such as acute MI. Quinidine undergoes extensive hepatic oxidative metabolism, and ~20% is excreted unchanged by the kidneys. One metabolite, 3-hydroxyquinidine, is nearly as potent as quinidine in blocking cardiac Na+ channels and prolonging cardiac action potentials. Concentrations of unbound 3-hydroxyquinidine equal to or exceeding those of quinidine are tolerated by some patients. There is substantial individual variability in the range of dosages required to achieve therapeutic plasma concentrations of 2-5 µg/mL. In patients with advanced renal disease or congestive heart failure, quinidine clearance is decreased only modestly. Thus, dosage requirements in these patients are similar to those in other patients.

Drug Interactions. Quinidine is a potent inhibitor of CYP2D6. Drugs that undergo extensive CYP2D6-mediated metabolism may result in altered drug effects. For example, inhibition of CYP2D6-mediated metabolism of codeine to its active metabolite morphine results in decreased analgesia. Conversely, inhibition of CYP2D6-mediated metabolism of propafenone results in elevated plasma propafenone concentrations and increased β adrenergic receptor blockade. Quinidine reduces the clearance of digoxin; inhibition of P-glycoprotein–mediated digoxin transport has been implicated. Quinidine metabolism is induced by drugs such as phenobarbital and phenytoin. In patients receiving these agents, very high doses of quinidine may be required to achieve therapeutic concentrations. Cimetidine and verapamil also elevate plasma quinidine concentrations, but these effects usually are modest.

SOTALOL. Sotalol (BETAPACE, BETAPACE AF) is a nonselective β adrenergic receptor antagonist that also prolongs cardiac action potentials by inhibiting delayed-rectifier and possibly other K+ currents.

Sotalol is prescribed as a racemate; the L-enantiomer is a much more potent β adrenergic receptor antagonist than the D-enantiomer, but the 2 are equipotent as K+ channel blockers. In the U.S., sotalol is an orphan drug approved for use in patients with both ventricular tachyarrhythmias (BETAPACE) and atrial fibrillation or flutter (BETAPACE AF). It is at least as effective as most Na+ channel blockers in ventricular arrhythmias. Sotalol prolongs QT interval, decreases automaticity, slows AV nodal conduction, and prolongs AV refractoriness by blocking both K+ channels and β adrenergic receptors; but it exerts no effect on conduction velocity in fast-response tissue. Sotalol causes EADs and triggered activity in vitro and can cause torsade de pointes, especially when the serum K+ concentration is low. The incidence of torsade de pointes seems to depend on the dose of sotalol. Occasional cases occur at low dosages, often in patients with renal dysfunction, because sotalol is eliminated by renal excretion. For adverse effects associated with β receptor blockade (see Chapter 12).