Chapter 29: Anti-Arrhythmic Drugs

The flow of ions across cell membranes generates the currents that make up cardiac action potentials. The factors that determine the magnitude of individual currents and their modulation by drugs can be explained at the cellular and molecular levels (Priori et al., 1999; Nerbonne and Kass, 2005). However, the action potential is a highly integrated entity wherein changes in one current almost inevitably produce secondary changes in other currents. 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 (Roden, 1994; Priori et al., 1999).

Ions move across cell membranes in response to electrical and concentration gradients, not through the lipid bilayer but through specific ion channels or transporters. 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 (Figure 29–1). For each individual ion, there is an equilibrium potential E_x at which there is no net driving force for the ion to move across the membrane. E_x can be calculated using the Nernst equation:

where Z_x 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 typical values for K⁺, [K]_o = 4 mM and [K]_i = 140 mM, the calculated K⁺ equilibrium potential E_K 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, which is close to the resting potential. If [K]_o is elevated to 10 mM, as might occur in diseases such as renal failure or myocardial ischemia, the calculated E_K rises to –70 mV. In this situation, there is excellent agreement between changes in theoretical E_K owing to changes in [K]_o and the actual measured transmembrane potential, indicating that the normal cardiac cell at rest is permeable to K⁺ (because inward rectifier channels are open) and that [K]_o is the major determinant of resting potential.

Transmembrane current through voltage-gated ion channels is the primary determinant of cardiac action potential morphology and duration. Channels are macromolecular complexes consisting of a pore-forming α subunit, as well as β subunits and further accessory proteins. These channels are transmembrane proteins consisting of a voltage-sensing domain, a selectivity filter, a conducting pore, and often an inactivating particle. In response to changes in local transmembrane potential, ion channels undergo conformational changes allowing for, or preventing, the flow of ions through the conducting pore along their electrochemical gradient (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 conformation from the "closed" (resting) state to the "open" (conducting) state (Figure 29–2), allowing up to 10⁷ Na⁺ ions/sec to enter each cell and moving the transmembrane potential toward E_Na (+65 mV). This surge of Na⁺ ions lasts only about a millisecond, after which the Na⁺ channel protein rapidly changes conformation from the "open" state to an "inactivated," nonconducting state (Figure 29–2). The maximum upstroke slope of phase 0 (dV/dt_max, or V_max) 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. However, a small population of Na⁺ channels may continue to open during the action potential plateau in some cells (Figure 29–3), 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 one form of the congenital long QT syndrome (Keating and Sanguinetti, 2001). 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, as discussed in the following discussion.

The changes in transmembrane potential generated by the inward Na⁺ current produce, in turn, a series of openings (and in some cases subsequent inactivation) of other channels (Figure 29–3). For example, when a cell is depolarized by the Na⁺ current, "transient outward" K⁺ channels quickly change conformation to enter an open, or conducting, state; because the transmembrane potential at the end of phase 0 is positive to E_K, the opening of transient outward channels results in an outward, or repolarizing, K⁺ current (termed I_TO), 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 I_K) 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 (Nerbonne and Kass, 2005). Identification of these specific channels has allowed more precise characterization of the pharmacologic effects of anti-arrhythmic drugs. A common mechanism whereby drugs prolong cardiac action potentials and provoke arrhythmias is inhibition of a specific delayed-rectifier current, I_Kr, generated by expression of the human ether-a-go-go–related gene (HERG). The ion channel protein generated by HERG expression differs from other ion channels in important structural features that make it much more susceptible to drug block; understanding these structural constraints is an important first step to designing drugs lacking I_Kr-blocking properties (Mitcheson et al., 2000). Avoiding I_Kr/HERG channel block has become a major issue in the development of new anti-arrhythmic drugs (Roden, 2004).

The diversity of action potentials seen throughout different regions of the heart plays a role in understanding the pharmacologic profiles of anti-arrhythmic drugs. This general description of the action potential and the currents that underlie it must be modified for certain cell types (Figure 29–4), 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). In the neighboring His–Purkinje system, action potentials are characterized by a more hyperpolarized plateau potential and prolongation of the action potential due to divergent ion channel expression and differences in intercellular Ca²⁺ handling (Dun and Boyden, 2008). Atrial cells have short action potentials, probably because I_TO 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, and depolarization is achieved by the movement of Ca²⁺ across the membrane. 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. Several ionic channels and transport pumps underlie pacemaker currents in the heart. 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 (Cohen and Robinson, 2006). Another major mechanism responsible for automaticity is the repetitive spontaneous Ca²⁺ release from the sarcoplasmic reticulum (SR), a specialized endoplasmic reticulum found in striated muscle cells (Vinogradova and Lakatta, 2009). 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.

Molecular biologic and electrophysiologic techniques have refined the description of ion channels important for the normal functioning of cardiac cells and have identified channels that may be particularly important under pathologic conditions. For example, the transient outward and delayed-rectifier currents actually result from multiple ion channel subtypes (Tseng and Hoffman, 1989; Sanguinetti and Jurkiewicz, 1990) (Figure 29–3). The acetylcholine-evoked hyperpolarization results from activation of a K⁺ channel formed by hetero-oligomerization of multiple, distinct channel proteins (Krapivinsky et al., 1995). The understanding that molecularly diverse entities subserve regulation of the cardiac action potential is important because drugs may target one channel subtype selectively. Furthermore, ancillary function-modifying proteins (the products of diverse genes) have been identified for most ion channels.

With each action potential, the cell interior gains Na⁺ ions and loses K⁺ ions. An ATP-requiring Na⁺–K⁺ exchange mechanism, or pump, is activated in most cells to maintain intracellular homeostasis. This Na⁺,K⁺-ATPase extrudes three Na⁺ ions for every two 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 sarcoplasmic reticulum to release its Ca²⁺ stores. The efflux of Ca²⁺ from the sarcoplasmic reticulum 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 sarcoplasmic reticulum) and NCX, which exchanges three Na⁺ ions from the exterior for each Ca²⁺ ion extruded. 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 sarcoplasmic reticulum Ca²⁺ release and cardiac arrhythmias (Mohamed et al., 2007). Inhibiting RyR2 channels with flecainide appears to prevent CPVT in mouse models and in humans (Watanabe et al., 2009). Thus, in both CPVT and heart disease, the cardiac ryanodine receptor has become an intriguing target for future anti-arrhythmic drug therapies.

Normal cardiac impulses originate in the sinus node. Impulse propagation in the heart depends on two factors: the magnitude of the depolarizing current (usually Na⁺ current) and the geometry of cell–cell electrical connections. Cardiac cells are relatively long and thin and well coupled through specialized gap junction proteins at their ends, whereas lateral ("transverse") gap junctions are sparser. As a result, impulses spread along cells two to three times faster than across cells. This "anisotropic" (direction-dependent) conduction may be a factor in the genesis of certain arrhythmias described later (Priori et al., 1999). 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; 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. Due to the aforementioned heterogeneity in ventricular APDs, the T wave of the ECG, which represents ventricular repolarization, is broader than the QRS complex and of opposite polarity to what one would expect if repolarization directly followed activation.

The ECG can be used as a rough guide to some cellular properties of cardiac tissue (Figure 29–4):

• 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.

In atrial, ventricular, and His–Purkinje cells, if a single action potential is restimulated very early during the plateau, no Na⁺ channels are available to open, so no inward current results, and no action potential is generated: At this point, the cell is termed refractory (Figure 29–5). On the other hand, if a stimulus occurs after the cell has repolarized completely, Na⁺ channels have recovered from inactivation, and a normal Na⁺ channel–dependent upstroke results with the same amplitude as the previous upstroke (Figure 29–5A). When a stimulus occurs during phase 3 of the action potential, the upstroke of the premature action potential is slower and of smaller magnitude. The magnitude depends on the number of Na⁺ channels that have recovered from inactivation (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. Refractoriness frequently is measured by assessing whether premature stimuli applied to tissue preparations (or the whole heart) result in propagated impulses. Although the magnitude of the Na⁺ current is one major determinant of propagation of premature beats, cellular geometry also is important in multicellular preparations. Propagation from cell to cell requires current flow from the first site of activation and consequently can fail if inward current is insufficient to drive activation in many neighboring cells. The effective refractory period (ERP) is the longest interval at which a premature stimulus fails to generate a propagated response and often is used to describe drug effects in intact tissue.

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. Conduction that exhibits such dependence on the timing of premature stimuli is termed decremental. Slow conduction in the heart, a critical factor in the genesis of re-entrant 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 (Figure 29–5B).

The primary therapy for anatomically defined re-entry is radiofrequency ablation, as its consistent pathway (or automatic foci) often makes it possible to identify and ablate critical segments of this pathway, effectively curing the patient and obviating the need for long-term drug therapy. Radiofrequency ablation is carried out through a catheter advanced to the interior of the heart and requires minimal convalescence.

In anatomically determined re-entry, drugs may terminate the arrhythmia by blocking propagation of the action potential. Conduction usually fails in a "weak link" in the circuit. In the example of the WPW-related arrhythmia described earlier, the weak link is the AV node, and drugs that prolong AV nodal refractoriness and slow AV nodal conduction, such as Ca²⁺ channel blockers, β adrenergic receptor antagonists, or digitalis glycosides, are likely to be effective. On the other hand, slowing conduction in functionally determined re-entrant circuits may change the pathway without extinguishing the circuit. In fact, slow conduction generally promotes the development of re-entrant arrhythmias, whereas the most likely approach for terminating functionally determined re-entry is prolongation of refractoriness (Task Force, 1991). In atrial and ventricular myocytes, refractoriness can be prolonged by delaying the recovery of Na⁺ channels from inactivation. Drugs that act by blocking Na⁺ channels generally shift the voltage dependence of recovery from block (Figure 29–5B) and so prolong refractoriness (Figure 29–11).

Drugs that increase APD without direct action on Na⁺ channels (e.g., by blocking delayed-rectifier currents) also will prolong refractoriness (Figure 29–11). Particularly in sinoatrial or AV nodal tissues, Ca²⁺ channel blockade prolongs refractoriness. Drugs that interfere with cell–cell coupling also theoretically should increase refractoriness in multicellular preparations; amiodarone may exert this effect in diseased tissue (Levine et al., 1988). Acceleration of conduction in an area of slow conduction also could inhibit re-entry; lidocaine may exert such an effect, and peptides that suppress experimental arrhythmias by increasing gap junction conductance have been described.

The rate of recovery from block often is expressed as a time constant (τ_recovery, the time required for ∼63% of an exponentially determined process to be complete; Courtney, 1987). In the case of drugs such as lidocaine, τ_recovery 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 τ_recovery 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.

Adverse effects of β blockade include fatigue, bronchospasm, hypotension, impotence, depression, aggravation of heart failure, worsening of symptoms owing to peripheral vascular disease, and masking of the symptoms of hypoglycemia in diabetic patients (Chapter 12). In patients with arrhythmias owing to excess sympathetic stimulation (e.g., pheochromocytoma, clonidine withdrawal), β 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, including hypertension, increased angina, and arrhythmias; thus, β receptor antagonists are tapered over 2 weeks prior to discontinuation of chronic therapy (Chapters 12 and 25, 26, 27, 28).

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. Similarly, drugs with intrinsic sympathomimetic activity may be less useful as anti-arrhythmics, at least in theory (Singh, 1990). Acebutolol is as effective as quinidine in suppressing ventricular ectopic beats, an arrhythmia that many clinicians no longer treat. Sotalol (see later in this chapter) is more effective for many arrhythmias than other β blockers, probably because of its K⁺ channel–blocking actions. Esmolol (see later in this chapter) is a β₁-selective agent that has a very short elimination t_1/2. Intravenous esmolol is useful in clinical situations in which immediate β adrenergic blockade is desired.

Factors that commonly precipitate cardiac arrhythmias include hypoxia, electrolyte disturbances (especially hypokalemia), myocardial ischemia, and certain drugs. Anti-arrhythmics, including cardiac glycosides, are not the only drugs that can precipitate arrhythmias (Table 29–1). For example, theophylline can cause multifocal atrial tachycardia, which sometimes can be managed simply by reducing the dose of theophylline. Torsades 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. These include the antibiotic erythromycin (Chapter 55); the antiprotozoal pentamidine (Chapter 50); some antipsychotics, notably thioridazine, ziprasidone, risperidone, and quetiapine (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, fomoterol, and salmeterol; prednisone; cisapride; famotidine; tacrolimus; some selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetin, sertraline, and venlafaxine); haloperidol; trazodone; some serotonin 5-HT1 antagonists (e.g., sumatriptan, zolmitriptan); some antiretrovirals (e.g., efavirenz); most quinolone antibiotics (e.g., levofloxacin); tizanidine; and certain tricyclic antidepressants (Chapter 15).

Some Arrhythmias Should Not Be Treated: The CAST Example. Abnormalities of cardiac rhythm are readily detectable by a variety of recording methods. However, the mere detection of an abnormality does not equate with the need for therapy. This was illustrated in the Cardiac Arrhythmia Suppression Trial (CAST). The presence of asymptomatic ventricular ectopic beats is a known marker for increased risk of sudden death owing to VF in patients convalescing from MI. In the 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 (CAST Investigators, 1989). Although the explanation for this effect is not known, several lines of evidence suggest that in the presence of these drugs, transient episodes of myocardial ischemia and/or sinus tachycardia can cause marked conduction slowing (because these drugs have a very long τ^recovery), resulting in fatal re-entrant ventricular tachyarrhythmias (Ruskin, 1989; Akiyama et al., 1991). One consequence of this pivotal clinical trial was to re-emphasize 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 (Roden, 1994). Among the anti-arrhythmic drugs discussed here, only β adrenergic blockers and, to a lesser extent, amiodarone (Connolly, 1999) have been shown to reduce mortality during long-term therapy.

Symptoms Due to Arrhythmias. Some patients with an arrhythmia may be asymptomatic; in this case, establishing any benefit for treatment will be very difficult. Some patients may present with presyncope, syncope, or even cardiac arrest, which may be due to brady- or tachyarrhythmias. Other patients may present with a sensation of irregular heartbeats (i.e., palpitations) that 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) (Figure 29–9). Finally, patients may present with symptoms owing to decreased cardiac output attributable to arrhythmias. 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 choosing among available therapeutic options, it is important to establish clear therapeutic goals. For example, three 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 (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 (Singer, 1996) (Chapter 30).

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 co-existence 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 under these circumstances.

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 even if an occasional episode still can be detected.

Anti-Arrhythmic Drugs Can Cause Arrhythmias. One well-recognized risk of anti-arrhythmic therapy is the possibility of provoking new arrhythmias, with potentially life-threatening consequences. Anti-arrhythmic drugs can provoke arrhythmias by different mechanisms (Table 29–1). These drug-provoked arrhythmias must be recognized because further treatment with anti-arrhythmic drugs often exacerbates the problem, whereas withdrawal of the causative agent often is curative. Thus, establishing a precise diagnosis is critical, and targeting therapies at underlying mechanisms of the arrhythmias may be required. For example, treating a ventricular tachycardia with verapamil not only may be ineffective but also can cause catastrophic cardiovascular collapse (Stewart et al., 1986).

Monitoring of Plasma Concentration. Some adverse effects of antiarrhythmic 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 (Ruskin, 1989; Roden, 1994). Factors such as generation of unmeasured active metabolites, variability in elimination of enantiomers (which may exert differing pharmacologic effects), and disease- or enantiomer-specific abnormalities in drug binding to plasma proteins can complicate the interpretation of plasma drug concentrations.

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.

Cardiac electrophysiology varies dynamically in response to external influences such as changing autonomic tone, myocardial ischemia, and myocardial stretch (Priori et al., 1999). For example, myocardial ischemia results in changes in extracellular K⁺ that make the resting potential less negative, inactivate Na⁺ channels, decrease Na⁺ current, and slow conduction (Weiss et al., 1991). In addition, myocardial ischemia can result in the formation and release of metabolites such as lysophosphatidylcholine, which can alter ion channel function; ischemia also may activate channels that otherwise are quiescent, such as the ATP-inhibited K⁺ channels. Thus, 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.

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 (lack of any cardiac rhythm whatsoever) is common but usually lasts less than 5 seconds 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 presumably by heterogeneously shortening atrial action potentials.

Clinical Pharmacokinetics. Adenosine is eliminated with a t_1/2 of seconds by carrier-mediated uptake, which occurs in most cell types, including the endothelium, 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 (Chapter 36) 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 beverages or as therapy.

Adverse Effects. Hypotension owing to vasodilation and depressed myocardial performance are frequent with the intravenous form of amiodarone and may be due in part to the solvent. 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 (Dusman et al., 1990). Serial chest X-rays or pulmonary function studies may detect early amiodarone toxicity, but 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 (most commonly peripheral neuropathy or proximal muscle weakness), photosensitivity, and hypo- or hyperthyroidism. The multiple effects of amiodarone on thyroid function are discussed further in Chapter 39. Treatment consists of withdrawal of the drug and supportive measures, including corticosteroids, for life-threatening pulmonary toxicity; reduction of dosage 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, torsades de pointes and other drug-induced tachyarrhythmias are unusual.

Clinical Pharmacokinetics. Amiodarone's oral bioavailability is ∼30%, presumably because of poor absorption. This incomplete bioavailability is important in calculating equivalent dosing regimens when converting from intravenous to oral therapy. The drug is distributed in lipid; e.g., heart-tissue-to-plasma concentration ratios of greater than 20:1 and lipid-to-plasma ratios of greater than 300:1 have been reported. 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 t_1/2 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 (Dusman et al., 1990). 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. Maintenance dose is adjusted based on adverse effects and the arrhythmias being treated. 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 one or two 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 (Chapters 5 and 6). Dosages of warfarin, other anti-arrhythmics (e.g., flecainide, procainamide, quinidine), or digoxin usually require reduction during amiodarone therapy.

Bretylium. Bretylium is a quaternary ammonium compound that prolongs cardiac action potentials and interferes with reuptake of norepinephrine by sympathetic neurons. In the past, bretylium was used to treat VF and prevent its recurrence; the drug is currently not available in the U.S.

Adverse Effects. Because of the low therapeutic index of cardiac glycosides, their toxicity is a common clinical problem (Chapter 28). Arrhythmias, nausea, disturbances of cognitive function, and blurred or yellow vision are the usual manifestations. Elevated serum concentrations of digitalis, hypoxia (e.g., owing to chronic lung disease), and electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypercalcemia) predispose patients to digitalisinduced arrhythmias. Although digitalis intoxication can cause virtually any arrhythmia, certain types of arrhythmias are characteristic. 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, which may be unresponsive to pacing therapy, 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, but the effect is transient. 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 (Chapter 28). Serum glycoside concentrations rise markedly with antidigitalis antibodies, but these represent bound (pharmacologically inactive) drug. Temporary cardiac pacing may be required for advanced sinus node or AV node dysfunction. Digitalis exerts direct arterial vasoconstrictor effects, which can be especially deleterious in patients with advanced atherosclerosis who receive intravenous drug; mesenteric and coronary ischemia have been reported.

Clinical Pharmacokinetics. The only digitalis glycoside used in the U.S. is digoxin (lanoxin). Digitoxin (various generic preparations) also is used for chronic oral therapy outside the U.S. Digoxin tablets are incompletely (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 (see "Adverse effects and Drug Interactions" under "Dronaderone") 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 hours. 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 (Table 29–5). Some patients may require and tolerate higher concentrations but with an increased risk of adverse effects.

The elimination t_1/2 of digoxin ordinarily is ∼36 hours, so maintenance doses are administered once daily. Renal elimination of unchanged drug accounts for less than 80% of digoxin elimination. 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 metabolism is accelerated by drugs such as phenytoin and rifampin that induce hepatic metabolism (Chapter 6). Digitoxin's elimination t_1/2 is even longer than that of digoxin (∼7 days); it is highly protein bound, and its therapeutic range is 10-30 ng/mL.

Amiodarone, quinidine, verapamil, diltiazem, cyclosporine, itraconazole, propafenone, and flecainide decrease digoxin clearance, likely by inhibiting P-glycoprotein, the major route of digoxin elimination (Fromm et al., 1999). New steady-state digoxin concentrations are approached after 4-5 t_1/2 (i.e., 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, which can be caused by many drugs (e.g., diuretics, amphotericin B, corticosteroids), will potentiate digitalis-induced arrhythmias.

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 (Lima et al., 1981). 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.

Adverse Effects. Torsades 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, marketed since 2000, is unknown. Other adverse effects were no more common than with placebo during premarketing clinical trials.

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 torsades 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.

Adverse Effects and Drug Interactions. The most common adverse reactions are diarrhea, nausea, abdominal pain, vomiting, and asthenia. Dronedarone causes dose-dependent prolongation of QTc interval, but torsades 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. Consequently, dronedarone should not be co-administered with potent CYP3A4 inhibitors (e.g., antifungals, macrolide antibiotics). Co-administration with other drugs metabolized by CYP2D6 (e.g., metoprolol) or P-glycoprotein (e.g., digoxin) may result in increased drug concentrations.

Adverse Effects. Flecainide produces few subjective complaints in most patients; 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 re-entrant ventricular tachycardia, and increased mortality in patients convalescing from MI (Crijns et al., 1988; CAST Investigators, 1989). As discussed earlier, it is likely that all these effects can be attributed to Na⁺ channel block. Flecainide also can cause heart block in patients with conduction system disease.

Clinical Pharmacokinetics. Flecainide is well absorbed. The elimination t_1/2 is shorter with urinary acidification (10 hours) than with urinary alkalinization (17 hours), but it is nevertheless sufficiently long to allow dosing twice daily (Table 29–5). Elimination occurs by both renal excretion of unchanged drug and hepatic metabolism to inactive metabolites. The latter is mediated by the polymorphically distributed enzyme CYP2D6 (Gross et al., 1989) (Chapter 6). However, even in patients in whom this pathway is absent because of 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. Flecainide is a racemate, but there are no differences in the electrophysiologic effects or disposition kinetics of its enantiomers (Kroemer et al., 1989). Some reports have suggested that plasma flecainide concentrations greater than 1 μg/mL should be avoided to minimize the risk of flecainide toxicity; however, in susceptible patients, the adverse electrophysiologic effects of flecainide therapy can occur at therapeutic plasma concentrations.

Ibutilide is administered as a rapid infusion (1 mg over 10 minutes) 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 torsades 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 and has a t_1/2 of 2-12 hours (average of 6 hours).

Pharmacologic Effects. Lidocaine blocks both open and inactivated cardiac Na⁺ channels. In vitro studies suggest that lidocaineinduced block reflects an increased likelihood that the Na⁺ channel protein assumes a nonconducting conformation in the presence of drug (Balser et al., 1996). 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 diastolic (recovery) times, which are relatively long. In some studies, lidocaine increased current through inward rectifier channels; however, the clinical significance of this effect is not known. Lidocaine can hyperpolarize Purkinje fibers depolarized by low [K]_o or stretch; the resulting increased conduction velocity may be anti-arrhythmic in re-entry.

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, especially in patients with very poor left ventricular function. For additional information on lidocaine, see Chapter 20.

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 of the drug is inappropriate. In theory, therapeutic plasma concentrations of lidocaine may be maintained by intermittent intramuscular administration, but the intravenous route is preferred (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 (Bennett et al., 1988). With infusions lasting longer than 24 hours, the clearance of lidocaine falls—an effect that has been attributed to competition between parent drug and metabolites for access to hepatic drugmetabolizing enzymes.

Plasma concentrations of lidocaine decline biexponentially after a single intravenous dose, indicating that a multicompartment model is necessary to analyze lidocaine disposition. The initial drop in plasma lidocaine following intravenous administration occurs rapidly, with a t_1/2 of ∼8 minutes, and represents distribution from the central compartment to peripheral tissues. The terminal elimination t_1/2, usually ∼110 minutes, 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 minutes is used—e.g., an initial 100 mg followed by 50 mg every 8 minutes for three 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 ∼8-10 hours. If the maintenance infusion rate is too low, arrhythmias may recur hours after the institution of apparently successful therapy. On the other hand, if the rate is too high, toxicity may result. In either case, routine measurement of plasma lidocaine concentration at the time of expected steady state is useful in adjusting the maintenance infusion rate.

In heart failure, the central volume of distribution is decreased, so the total loading dose should be decreased. Because lidocaine clearance also is decreased, the rate of the maintenance infusion should be decreased. Lidocaine clearance also is reduced in hepatic disease, during treatment with cimetidine or β blockers and during prolonged infusions (Nies et al., 1976). Frequent measurement of plasma lidocaine concentration and dose adjustment to ensure that plasma concentrations remain within the therapeutic range (1.5-5 mg/mL) are necessary to minimize toxicity in these settings. Lidocaine is bound to the acute-phase reactant α₁-acid glycoprotein. Diseases such as acute MI are associated with increases in β₁-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 (Kessler et al., 1984).

Large placebo-controlled trials of intravenous magnesium to improve outcome in acute MI have yielded conflicting results (Woods and Fletcher, 1994; ISIS-4 Collaborative Group, 1995). Although oral Mg²⁺ supplements may be useful in preventing hypomagnesemia, there is no evidence that chronic Mg²⁺ ingestion exerts a direct anti-arrhythmic action.

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 have suggested a role for mexiletine (or flecainide) in correcting the aberrant late inward Na⁺ current in congenital LQT3 (Napolitano et al., 2006).

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. Torsades 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; the mechanism is not known, but high plasma drug concentrations are not suspected.

During long-term therapy, most patients will develop biochemical evidence of the drug-induced lupus syndrome, such as circulating antinuclear antibodies (Woosley et al., 1978). 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 next section).

Clinical Pharmacokinetics. Procainamide is eliminated rapidly (t_1/2 = 3-4 hours) by both renal excretion of unchanged drug and hepatic metabolism. The major pathway for hepatic metabolism is conjugation by N-acetyl transferase, whose activity is determined genetically, to form N-acetyl procainamide. N-Acetyl procainamide is eliminated by renal excretion (t_1/2 = 6-10 hours) and is not significantly converted back to procainamide. Because of the relatively rapid elimination rates of both the parent drug and its major metabolite, oral procainamide usually is administered as a slowrelease formulation. In patients with renal failure, procainamide and/or N-acetyl procainamide can accumulate to potentially toxic plasma concentrations. Reduction of procainamide dose and dosing frequency and monitoring of plasma concentrations of both compounds are required in this situation. 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 (Woosley et al., 1978). In addition, the symptoms of procainamide-induced lupus resolve during treatment with N-acetyl procainamide. Both these findings support results of in vitro studies, suggesting that it is chronic exposure to the parent drug (or an oxidative metabolite) that results in the lupus syndrome; these findings also provided one rationale for the further development of N-acetyl procainamide and its analogs as anti-arrhythmic agents (Roden, 1993).

Adverse Effects. Adverse effects during propafenone therapy include acceleration of ventricular response in patients with atrial flutter, increased frequency or severity of episodes of re-entrant ventricular tachycardia, exacerbation of heart failure, and the adverse effects of β adrenergic blockade, such as sinus bradycardia and bronchospasm (see earlier in this chapter and Chapter 12).

Clinical Pharmacokinetics. Propafenone is well absorbed and is eliminated by both hepatic and renal routes. The activity of CYP2D6, an enzyme that functionally is absent in ∼7% of Caucasians and African Americans (Chapter 6), is a major determinant of plasma propafenone concentration and thus the clinical action of the drug. 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, in whom functional CYP2D6 is absent, firstpass hepatic metabolism is much less than in extensive metabolizers, and plasma propafenone concentrations will be much higher after an equal dose. The incidence of adverse effects during propafenone therapy is significantly 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 mg/mL are associated with clinical effects of β receptor blockade, such as reduction of exercise heart rate (Lee et al., 1990). It is recommended that dosage in patients with moderate to severe liver disease should be reduced to ∼20-30% of the usual dose, with careful monitoring. It is not known if propafenone doses must be decreased in patients with renal disease. A slow-release formulation allows twice-daily dosing.

Adverse Effects—Noncardiac. Diarrhea is the most common adverse effect during quinidine therapy, occurring in 30-50% of patients; the mechanism is not known. Diarrhea usually occurs within the first several days of quinidine therapy but can occur later. Diarrheainduced hypokalemia may potentiate torsades 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 discontinuation of the drug. 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. Of patients receiving quinidine therapy, 2-8% will develop marked QT-interval prolongation and torsades de pointes. In contrast to effects of sotalol, N-acetyl procainamide, and many other drugs, quinidine-associated torsades de pointes generally occurs at therapeutic or even subtherapeutic plasma concentrations. The reasons for individual susceptibility to this adverse effect are not known.

At high plasma concentrations of quinidine, marked Na⁺ channel block can occur, with resulting ventricular tachycardia. This adverse effect occurs when very high doses of quinidine are used to try to convert atrial fibrillation to normal rhythm; this aggressive approach to quinidine dosing has been abandoned, and quinidine-induced ventricular tachycardia is unusual.

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, like lidocaine, the acute-phase reactant β₁-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 (Kessler et al., 1984). 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. Other metabolites are less potent than quinidine, and their plasma concentrations are lower; thus, they are unlikely to contribute significantly to the clinical effects of quinidine.

There is substantial individual variability in the range of dosages required to achieve therapeutic plasma concentrations of 2–5 mg/mL. Some of this variability may be assay dependent because not all assays exclude quinidine metabolites. 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. As a result, the administration of quinidine to patients receiving drugs that undergo extensive CYP2D6-mediated metabolism may result in altered drug effects owing to accumulation of parent drug and failure of metabolite formation. For example, inhibition of CYP2D6-mediated metabolism of codeine to its active metabolite morphine results in decreased analgesia. On the other hand, 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 (Fromm et al., 1999).

Quinidine metabolism is induced by drugs such as phenobarbital and phenytoin (Data et al., 1976). In patients receiving these agents, very high doses of quinidine may be required to achieve therapeutic concentrations. If therapy with the inducing agent is then stopped, quinidine concentrations may rise to very high levels, and its dosage must be adjusted downward. Cimetidine and verapamil also elevate plasma quinidine concentrations, but these effects usually are modest.

Vernakalant is metabolized by rapidly by CYP2D6 to one major and inactive metabolite (RSD1385) via 4-O-demethylation (Mao et al., 2009). There appears to be little difference in C_max between extensive and poor 2D6 metabolizers after single-dose IV administration. However, average t_1/2 of vernakalant was much longer in two poor metabolizers (8.5 hours) than in 10 extensive metabolizers (2.7 hours). This profound difference in t_1/2 will be important if vernakalant is used chronically to prevent atrial fibrillation.