Antiarrhythmic Drugs

Individual cardiac cells undergo depolarization and repolarization to form cardiac action potentials about sixty times per minute. The shape and duration of each action potential are determined by the activity of ion channel protein complexes on the surface of individual cells, and the genes encoding many of these proteins have now been identified. Thus, each heartbeat is the result of the highly integrated electrophysiological behavior of multiple gene products on multiple cardiac cells. Ion channel function can be perturbed by factors such as acute ischemia, sympathetic stimulation, or myocardial scarring to create abnormalities of cardiac rhythm, or arrhythmias. Available antiarrhythmic drugs suppress arrhythmias by blocking flow through specific ion channels or by altering autonomic function.

Arrhythmias can range from incidental, asymptomatic clinical findings to life-threatening abnormalities. Mechanisms underlying cardiac arrhythmias have been identified in cellular and animal experiments. In some human cases, precise mechanisms are known, and treatment targeted against those mechanisms can be used. In other cases, mechanisms can be only inferred, and the choice of drugs is based largely on results of prior experience. Antiarrhythmic drug therapy can have two goals: termination of an ongoing arrhythmia or prevention of an arrhythmia. It is now well recognized that antiarrhythmic drugs not only help to control arrhythmias but also can cause them, especially during long-term therapy. Thus, prescribing antiarrhythmic drugs requires that precipitating factors be excluded or minimized, that a precise diagnosis of the type of arrhythmia (and its possible mechanisms) be made, that the prescriber has reason to believe that drug therapy will be beneficial, and that the risks of drug therapy be minimized.

In this chapter, the principles underlying normal and abnormal cardiac electrophysiology are outlined. Then, the mechanisms by which drugs modulate cardiac electrophysiology are presented, followed by a description of the important properties of individual agents.

Drugs that modify cardiac electrophysiology often have a very narrow margin between the doses required to produce a desired effect and those associated with adverse effects. Moreover, adverse effects from antiarrhythmic drug therapy can include induction of new arrhythmias, with possibly fatal consequences. Nonpharmacological treatments, such as cardiac pacing, electrical defibrillation, or ablation of targeted regions (Morady, 1999), are indicated for some arrhythmias; in other cases no therapy is required even though an arrhythmia is detected. Therefore, the fundamental principles of therapeutics described here must be applied to optimize antiarrhythmic therapy.

Identify and Remove Precipitating Factors

Factors that commonly precipitate cardiac arrhythmias include hypoxia, electrolyte disturbances (especially hypokalemia), myocardial ischemia, and certain drugs. Antiarrhythmics, including digitalis glycosides, are not the only drugs that can precipitate arrhythmias (Table 351). For example, theophylline is a common cause of 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 antiarrhythmics, but also with other drugs not ordinarily classified as having effects on ion channels. These include the antihistamines terfenadine and astemizole (Chapter 25: Histamine, Bradykinin, and Their Antagonists); the antibiotic, erythromycin (Chapter 47: Antimicrobial Agents: Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents); the antiprotozoal, pentamidine (Chapter 41: Drugs Used in the Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections); some antipsychotics, notably thioridazine (Chapter 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania); and certain tricyclic antidepressants (Chapter 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders).

Establish the Goals of Treatment

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 should not be equated with the need for therapy. This was best illustrated in the Cardiac Arrhythmias Suppression Trial (CAST). The presence of asymptomatic ventricular ectopic beats is known to be a marker for an increased risk of sudden death due to ventricular fibrillation in patients convalescing from a myocardial infarction. In the CAST, patients in whom 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 a matching placebo. Unexpectedly, the mortality rate was two-to threefold higher among patients treated with the drugs than those treated with placebo (CAST Investigators, 1989). While the explanation of this effect is not known, a number of 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 _recovery), resulting in fatal reentrant ventricular tachyarrhythmias (Ruskin, 1989; Ranger et al., 1989; Akiyama et al., 1991). One consequence of this very important clinical trial was to reemphasize 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 not much doubt that termination of the arrhythmia will be beneficial; when chronic therapy is used to prevent recurrence of an arrhythmia, risks may be greater (Roden, 1994). Among the antiarrhythmic drugs discussed here, only -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, which 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 359). Finally, patients may present with symptoms due to decreased cardiac output attributable to arrhythmias. The most common symptom is breathlessness at rest or on exertion. Rarely, patients with sustained tachycardias will present with congestive heart failure, which can be controlled by treating the arrhythmia.

Choosing Among Therapeutic Approaches

Establishing the goals of therapy is especially important when different therapeutic options are available. For example, in patients with atrial fibrillation, three options are available: (1) Reduce the ventricular response, using AV nodal blocking agents such as digitalis, verapamil, diltiazem, or -adrenergic antagonists (Table 351); (2) restore and maintain normal rhythm, using drugs such as quinidine, flecainide, or amiodarone; or (3) decide not to implement antiarrhythmic therapy, which may be the appropriate approach if the patient truly is asymptomatic. Most patients with atrial fibrillation also benefit from anticoagulation to reduce stroke incidence, regardless of symptoms (Singer, 1996; see Chapter 55: Anticoagulant, Thrombolytic, and Antiplatelet Drugs).

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 354). In the rare patient with the WPW syndrome and atrial fibrillation, the ventricular response can be extremely rapid and can be paradoxically accelerated by AV nodal blocking drugs such as digitalis or Ca²⁺ channel blockers; deaths due to drug therapy have been reported under these circumstances.

Frequency and reproducibility of arrhythmia should be established prior to initiating therapy, since 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 also 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.

Minimize Risks

Antiarrhythmic Drugs Can Cause Arrhythmias

One increasingly well-recognized risk of antiarrhythmic therapy is the possibility of provoking new arrhythmias, with potentially life-threatening consequences. Mechanistically distinct syndromes of arrhythmia provocation by antiarrhythmic drugs have been described (Table 351). These drug-provoked arrhythmias must be recognized, since further treatment with antiarrhythmic drugs often exacerbates the problem, whereas withdrawal of the causative agent often is curative. In addition, specific therapies targeted toward underlying mechanisms of these arrhythmias may be indicated. It also is critical to establish a precise diagnosis. 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 are related to excessively elevated plasma drug concentration. Thus, measuring plasma concentration and adjusting the dose to maintain the concentration within a prescribed therapeutic range may be a useful way of minimizing some adverse effects. In many patients, the occurrence of serious adverse reactions appears to be related to interactions involving drug (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; Morganroth et al., 1986; Roden, 1994). Factors such as generation of unmeasured active metabolites, variability in elimination of enantiomers (which may exert differing pharmacological effects), and disease-or enantiomer-specific abnormalities in drug binding to plasma proteins can complicate the interpretation of routine monitoring of plasma drug concentrations (see Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination).

Patient-Specific Contraindications

Another way of minimizing the adverse effects of antiarrhythmic 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. Often, adverse effects of drugs may be difficult to distinguish from exacerbations of underlying disease. Amiodarone may cause interstitial lung disease; its use is therefore 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 354.

The Electrophysiology of the Heart as a 'Moving Target'

Cardiac electrophysiology varies in a highly dynamic fashion in response to external influences such as changing autonomic tone, myocardial ischemia, or myocardial stretch. For example, myocardial ischemia results in changes in extracellular K⁺ that, in turn, 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 release of 'metabolites of ischemia,' such as lysophosphatidylcholine, which can alter ion channel function (DaTorre et al., 1991); ischemia also may activate channels that otherwise are quiescent, such as the ATP-inhibited K⁺ channels (Wilde and Janse, 1994). Thus, a normal heart may display, in response to myocardial ischemia, changes in resting potential, conduction velocity, intracellular Ca²⁺ concentrations, and repolarization, any one of which may then create arrhythmias or alter response to antiarrhythmic therapy.

Summaries of important electrophysiological and pharmacokinetic features of the drugs considered here are presented in Tables 353 and 355. Ca²⁺ channel blockers and -adrenergic antagonists have been considered above and in Chapters 32: Drugs Used for the Treatment of Myocardial Ischemia and 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, respectively. The drugs are presented in alphabetical order.

Adenosine

Adenosine ADENOCARD) is a naturally occurring nucleoside which is administered as a rapid intravenous bolus for the acute termination of reentrant supraventricular arrhythmias (Lerman and Belardinelli, 1991). Rare cases of ventricular tachycardia in patients with otherwise normal hearts are thought to be DAD-mediated and can be terminated by adenosine. 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.

Pharmacological Effects

The effects of adenosine are mediated by its interaction with specific G proteincoupled adenosine receptors. Adenosine activates acetylcholine-sensitive K⁺ current in the atrium and sinus and AV nodes, resulting in shortening of action potential duration, hyperpolarization, and slowing of normal automaticity (Figure 3510C). Adenosine also inhibits the electrophysiological effects of increased intracellular cyclic AMP, which occur with sympathetic stimulation. Because adenosine thereby reduces Ca²⁺ currents, it can be antiarrhythmic by increasing AV nodal refractoriness and by inhibiting DADs elicited by sympathetic stimulation.

Administration of an intravenous bolus of adenosine to human beings transiently slows sinus rate and AV nodal conduction velocity and increases AV nodal refractoriness. It has been shown that a bolus dose of adenosine can produce transient sympathetic activation by interacting with carotid baroreceptors (Biaggioni et al., 1991); when a continuous infusion of the drug is administered, hypotension results.

Adverse Effects

A major advantage of adenosine therapy is that adverse effects are short-lived, since the drug is eliminated so rapidly. Transient asystole (lack of any cardiac rhythm whatsoever) is common but usually lasts <5 seconds and is in fact the therapeutic goal. Most patients feel a sense of chest fullness and dyspnea when therapeutic doses (6 to 12 mg) of adenosine are administered. Rarely, an adenosine bolus can precipitate atrial fibrillation, presumably by heterogeneously shortening atrial action potentials, or bronchospasm.

Clinical Pharmacokinetics

Adenosine is eliminated with a half-life 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, due to denervation hypersensitivity. Methylxanthines (see Chapter 28: Drugs Used in the Treatment of Asthma) such as theophylline and caffeine block adenosine receptors; therefore larger-than-usual doses are required to produce an antiarrhythmic effect in patients who have consumed these agents in beverages or as therapy.

Amiodarone

Amiodarone CORDARONE PACERONE) exerts a multiplicity of pharmacological effects, none of which is clearly linked to its arrhythmia-suppressing properties (Mason, 1987). Amiodarone is a structural analog of thyroid hormone, and some of its antiarrhythmic actions and its toxicity may be attributable to interaction with nuclear thyroid hormone receptors. Amiodarone is highly lipophilic, is concentrated in many tissues, and is eliminated extremely slowly; consequently, adverse effects may be very slow to resolve. In the United States, the drug currently is indicated for oral therapy in patients with recurrent ventricular tachycardia or fibrillation resistant to other drugs. Controlled clinical trials indicate that oral amiodarone also is effective in maintaining sinus rhythm in patients with atrial fibrillation (Connolly, 1999). An intravenous form has been approved in the United States for the acute termination of ventricular tachycardia or fibrillation (Kowey et al., 1995). Trials of oral amiodarone in patients convalescing from acute myocardial infarction have shown a modest beneficial effect on mortality (Amiodarone Trials Meta-Analysis Investigators, 1997). The drug is nevertheless not widely prescribed in this population, perhaps because of concerns about its potential for long-term toxicity.

Pharmacological Effects

Studies of the acute effects of amiodarone in in vitro systems are complicated by its insolubility in water, necessitating the use of solvents such as dimethyl sulfoxide. It has been suggested that amiodarone's effects are mediated by perturbation of the lipid milieu in which ion channels are placed (Herbette et al., 1988). Amiodarone blocks inactivated Na⁺ channels and has a relatively rapid (time constant 1.6 seconds) rate of recovery from block. It also decreases Ca²⁺ current and transient outward, delayed rectifier and inward rectifier K⁺ currents and exerts a noncompetitive (see Chapter 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists) adrenergic blocking effect. Amiodarone is a potent inhibitor of abnormal automaticity, and, in most tissues, it prolongs action potential duration. Amiodarone decreases conduction velocity by Na⁺ channel block as well as by a poorly understood effect on cellcell coupling that may be especially important in diseased tissue (Levine et al., 1988). PR, QRS, and QT prolongations and sinus bradycardia are frequent during chronic therapy. Amiodarone prolongs refractoriness in all cardiac tissues; Na⁺ channel block, delayed repolarization due to K⁺ channel block, and inhibition of cellcell coupling all may contribute to this effect of amiodarone.

Adverse Effects

Hypotension due to vasodilation and depression of myocardial performance is frequent with the intravenous form of amiodarone, and may be due in part to the solvent. While depression of contractility can occur during long-term therapy, it is unusual. During oral drug-loading regimens, which usually take place over several weeks, adverse effects are unusual, despite administration of high dosages that would cause serious toxicity if continued long-term. Occasional patients develop nausea, which responds to a decrease in daily dose during the loading phase.

Adverse effects during long-term therapy have been related to both the size of daily maintenance doses as well as to cumulative dose (i.e., to duration of therapy), suggesting 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 400 mg/day, 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 used in atrial fibrillation, pulmonary toxicity is extremely unusual. Other adverse effects during long-term therapy include corneal microdeposits (which often are asymptomatic), hepatic dysfunction, hypo- or hyperthyroidism, neuromuscular symptoms (most commonly peripheral neuropathy or proximal muscle weakness), and photosensitivity. Treatment consists of withdrawal of the drug and supportive measures, including corticosteroids, for life-threatening 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 is incompletely (30%) bioavailable, presumably because of poor absorption. This reduced bioavailability is important in calculating equivalent dosing regimens when converting from intravenous to oral therapy. The drug is distributed in lipid; for example, heart tissue to plasma concentration ratios >20:1 and lipid to plasma ratios >300:1 have been reported. After the initiation of amiodarone therapy, increases in refractoriness, a marker of pharmacological effect, require several weeks to develop. Amiodarone undergoes hepatic metabolism by cytochrome P450 3A4 (CYP3A4) to desethyl-amiodarone, a metabolite with pharmacological 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 half-life 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 to 2.0 g/ml has been proposed. However, efficacy appears to depend as much on duration of therapy as on plasma concentration, and elevated plasma concentrations are not useful in predicting toxicity (Dusman et al., 1990). Because of amiodarone's slow accumulation in tissue, a high-dose oral loading regimen (e.g., 800 to 1600 mg/day) is usually administered for several weeks and then maintenance therapy started. Maintenance dose is adjusted on the basis of adverse effects and the arrhythmias being treated. If the presenting arrhythmia is life-threatening, dosages >300 mg/day normally are used unless clear 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 the drug's very slow elimination, amiodarone is administered once daily, and omission of one or two doses during chronic therapy rarely results in recurrence of arrhythmia.

Dose adjustments are not required in conditions such as hepatic, renal, or cardiac dysfunction. Amiodarone is a potent inhibitor of the hepatic metabolism or renal elimination of many compounds. Mechanisms identified to date include inhibition of CYP3A4 and CYP2C9 and of P-glycoprotein (see Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination). Dosages of warfarin, other antiarrhythmics (flecainide, procainamide, quinidine), or digoxin usually require reduction during amiodarone therapy.

Bretylium

Bretylium (bretylium tosylate; BRETYLOL) is a quaternary ammonium compound that prolongs cardiac action potentials and interferes with reuptake of norepinephrine by sympathetic neurons; both actions may be antiarrhythmic (Heissenbuttel and Bigger, 1979). Bretylium loading and maintenance infusions are used to treat ventricular fibrillation and prevent its recurrence (see Table 355 for loading and maintenance doses).

Pharmacological Effects

Bretylium prolongs action potentials in normal Purkinje cells to a greater extent than in cells that have survived a recent ischemic insult (in which action potentials already are prolonged abnormally). Thus, bretylium reduces heterogeneity of repolarization times, an effect that may suppress reentry (Cardinal and Sasyniuk, 1978). The mechanism whereby bretylium prolongs cardiac action potentials has not been established, although block of K⁺ channels seems likely. Bretylium has no effect on Na⁺ channels, except at high concentrations, and no direct effect on automaticity. In animals and human beings, administration of bretylium initially results in increased norepinephrine release from sympathetic neurons and inhibition of subsequent reuptake.

Adverse Effects

As a result of norepinephrine release, bretylium can produce transient hypertension and increased arrhythmias; this effect rarely is observed, since bretylium is used in critically ill patients who often are hemodynamically unstable. In theory, bretylium should be avoided in patients who are especially prone to increased arrhythmias with norepinephrine release, such as those with digitalis intoxication. In contrast, hypotension due to inhibition of norepinephrine reuptake is a common problem during bretylium therapy. Bretylium-induced hypotension should be managed with judicious fluid replacement if possible. Since bretylium effectively results in sympathetic denervation, the administration of normal doses of catecholamines such as dopamine may cause marked hypertension. Bretylium should be used only with great caution when the drug's vasodilating effects may be particularly hazardous, as in patients with aortic stenosis, carotid occlusive disease, or hypertrophic cardiomyopathy. The occurrence of torsades de pointes is unusual during bretylium therapy.

Clinical Pharmacokinetics

Bretylium is excreted unchanged by the kidneys without undergoing significant hepatic metabolism. Reduction of a maintenance infusion rate has been recommended in patients with renal failure, although adverse effects due to accumulation of bretylium in plasma have not been seen. A lag time of 2 hours has been reported between peak plasma bretylium concentrations and peak prolongation of ventricular refractoriness after an intravenous dose in dogs (Anderson et al., 1980). This lag time suggests that bretylium is distributed to sites in peripheral tissues prior to exerting its pharmacological effect.

An oral formulation has been investigated, but hypotension and reduced bioavailability (35%), presumably because of poor absorption, are problems. The hypotensive effects of bretylium can be inhibited by coadministration of tricyclic antidepressants such as protriptyline, which blocks bretylium's effects on sympathetic norepinephrine release and reuptake (Woosley et al., 1982). Results of a limited number of studies suggest that the antiarrhythmic effects of bretylium may be preserved during coadministration of tricyclic antidepressants.

Digitalis Glycosides

Pharmacological Effects

Digitalis glycosides exert positive inotropic effects and are widely used in heart failure (Chapter 34: Pharmacological Treatment of Heart Failure). Their inotropic action is the result of increased intracellular Ca²⁺ (Smith, 1988), which also forms the basis for arrhythmias related to digitalis intoxication. Digitalis glycosides increase phase 4 slope (i.e., increase the rate of automaticity), especially if [K]_o is low. Digitalis glycosides 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' electrophysiological effects of digitalis glycosides are hyperpolarization, shortening of atrial action potentials, and increases in AV nodal refractoriness. The latter action accounts for the utility of digitalis in termination of reentrant arrhythmias involving the AV node, and in controlling ventricular response in patients with atrial fibrillation. Digitalis preparations may be especially useful in the latter situation, since many such patients have heart failure, which can be exacerbated by other AV nodal blocking drugs such as Ca²⁺ channel blockers or -adrenergic receptor antagonists. However, in many patients with advanced heart failure, sympathetic drive is markedly increased, so digitalis is not very effective in decreasing the rate; on the other hand, even a modest decrease in rate can sometimes help ameliorate heart failure. Similarly, in other conditions in which high sympathetic tone drives rapid atrioventricular conduction (e.g., chronic lung disease, thyrotoxicosis), digitalis therapy may be only marginally effective in slowing the rate. 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 (the ST segment), whose underlying mechanism is not well understood.

Adverse Effects

Digitalis intoxication is a common clinical problem (see also Chapter 34: Pharmacological Treatment of Heart Failure). Arrhythmias, nausea, disturbances of cognitive function, and blurred or yellow vision are the usual manifestations. Often, these are not immediately recognized, since they occur frequently in patients with advanced illnesses receiving multiple drugs. Elevated serum concentrations of digitalis, hypoxia (e.g., due to chronic lung disease), and hypokalemia, hypomagnesemia, and hypercalcemia predispose patients to digitalis-induced arrhythmias. While 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 advanced intoxication (e.g., with suicidal ingestion), severe hyperkalemia due to poisoning of Na⁺,K⁺ATPase and profound bradyarrhythmias, which may be unresponsive to pacing therapy, are seen. In patients with elevated serum digitalis blood levels, the risk of precipitating ventricular fibrillation by DC cardioversion probably is increased; in those with therapeutic blood levels, DC cardioversion can be used safely.

Minor forms of digitalis 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 (Seller, 1971). Any serious arrhythmia should be treated with antidigoxin Fab fragments, which are highly effective in binding digoxin and digitoxin, greatly enhancing the renal excretion of these drugs (see Chapter 34: Pharmacological Treatment of Heart Failure). Serum glycoside concentrations rise markedly with antidigitalis antibodies, but these represent bound (nonpharmacologically active) drug. Temporary cardiac pacing may be required for advanced sinus node or AV node dysfunction. Other forms of antidotal therapy that have been used in the past, but have been largely supplanted by the use of Fab fragments, include lidocaine, phenytoin, or the cautious administration of K⁺ for ventricular arrhythmias; K⁺ can exacerbate AV block. Digitalis exerts direct arterial vasoconstrictor effects, which can be especially deleterious in patients with advanced atherosclerosis who receive intravenous drug; ischemia in the intestinal or coronary beds has been reported.

Clinical Pharmacokinetics

The most commonly used digitalis glycoside in the United States is digoxin (LANOXIN), although digitoxin (CRYSTODIGIN) is also used for chronic oral therapy. Digoxin tablets are incompletely (75%) bioavailable, but capsules are >90% bioavailable. In some patients, intestinal microflora may metabolize digoxin, causing a marked reduction in drug bioavailability. In these patients, higher-than-usual doses are required for clinical efficacy to be achieved; toxicity is a serious risk if antibiotics such as tetracycline or erythromycin, which destroy intestinal microflora, are administered. Inhibition of P-glycoprotein (see below) also may play a role. Digoxin is 20% to 30% protein-bound. The antiarrhythmic 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 pharmacological effects such as PR interval prolongation or slowing of the ventricular rate in atrial fibrillation. To avoid digitalis intoxication, a loading regimen of 1 to 1.5 mg given over 24 hours is administered. Measurement of postdistribution serum digoxin concentration and adjusting the daily dose (0.125 to 0.375 mg) to maintain concentrations of 0.5 to 2 ng/ml are useful during chronic digoxin therapy (see Table 355). Some patients may require and tolerate higher concentrations, but with an increased risk of adverse effects.

The elimination half-life of digoxin ordinarily is 36 hours, so maintenance doses are administered once daily. Renal elimination of unchanged drug accounts for <80% of digoxin elimination. Digoxin doses should be reduced (or dosing interval increased) and serum concentrations closely monitored in patients with impaired excretion due 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 or rifampin that induce hepatic metabolism (Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination). Digitoxin's elimination half-life is even longer than that of digoxin (about 7 days); it is highly protein-bound, and its therapeutic range is 10 to 30 ng/ml.

Quinidine elevates serum digoxin concentrations by decreasing clearance and volume of distribution; new steady-state digoxin concentrations are approached in 4 to 5 digoxin elimination half-lives, i.e., in about a week (Leahey et al., 1978). A similar effect has been reported with digitoxin when serum concentrations were monitored for sufficiently long periods. Digitalis toxicity results so often when quinidine is being administered that it is routine to decrease the dose of digoxin if quinidine is started. Other drugs that increase serum digoxin concentration include verapamil, diltiazem, amiodarone, cyclosporine, itraconazole, propafenone, flecainide, and spironolactone. In these cases, the effect is less predictable, and digoxin concentrations regularly are measured and the dose adjusted only if necessary. One common mechanism underlying digoxin clearance appears to involve P-glycoproteinmediated transport. Inhibition of this transport has been implicated as the mechanism whereby quinidine and other interacting drugs decrease digoxin clearance (Fromm et al., 1999). Hypokalemia, which can be caused by many drugs (e.g., diuretics, amphotericin B, corticosteroids), will potentiate digitalis-induced arrhythmias.

Disopyramide

Disopyramide NORPACE, others; Morady et al., 1982) exerts electrophysiological effects very similar to those of quinidine, but the drugs have different adverse-effect profiles. Disopyramide is used for the maintenance of sinus rhythm in patients with atrial flutter or atrial fibrillation and for the prevention of recurrence of ventricular tachycardia or ventricular fibrillation. Disopyramide is prescribed as a racemate. Its structure is given below.

Pharmacological Actions and Adverse Effects

The in vitro electrophysiological actions of S-(+)-disopyramide are similar to those of quinidine (Mirro et al., 1981). The R-()-enantiomer produces similar Na⁺ channel block but does not prolong cardiac action potentials. Unlike quinidine, racemic disopyramide is not an -adrenergic receptor antagonist, but it does exert prominent anticholinergic actions, which account for many of its adverse effects. These include precipitation of glaucoma, constipation, dry mouth, and urinary retention; the latter is most common in males with prostatism but can occur in females. Disopyramide commonly depresses contractility and can precipitate heart failure (Podrid et al., 1980), and it can cause torsades 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 proportionately 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.

Dofetilide

Dofetilide(TIKOSYN) is a potent and 'pure'I_Kr blocker. As a result of this specificity, it has virtually no extracardiac pharmacological effects. Dofetilide is effective in maintaining sinus rhythm in patients with atrial fibrillation. In the DIAMOND studies (Torp-Pedersen et al., 1999), dofetilide did not affect mortality in patients with advanced heart failure or in those convalescing from acute myocardial infarction. Dofetilide currently is available through a restricted distribution system that includes only those physicians, hospitals, and other institutions that have received special educational programs covering proper dosing and treatment initiation.

Adverse Effects

Torsades de pointes occurred in 1% to 3% of patients in clinical trials, in whom 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 in 2000, is unknown. Other adverse effects are no more common than with placebo.

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 and should not be used with inhibitors of renal cation transport. Dofetilide also undergoes minor hepatic metabolism.

Flecainide

The effects of flecainide (TAMBOCOR) therapy are thought to be attributable to the drug's very long _recovery from Na⁺ channel block (Roden and Woosley, 1986a). In the CAST study, flecainide increased mortality in patients convalescing from myocardial infarction (CAST Investigators, 1989). However, it continues to be approved for the maintenance of sinus rhythm in patients with supraventricular arrhythmias, including atrial fibrillation, in whom structural heart disease is absent (Anderson et al., 1989; Henthorn et al., 1991). Encainide, a drug with very similar electrophysiological actions, is no longer available.

Pharmacological Effects

Flecainide blocks Na⁺ current and delayed rectifier K⁺ current (I_Kr) at similar concentrations in vitro, 1 to 2 M (Ikeda et al., 1985; Follmer and Colatsky, 1990). It also blocks Ca²⁺ currents in vitro. Action potential duration is shortened in Purkinje cells (probably due to block of late-opening Na⁺ channels) but prolonged in ventricular cells, probably due to block of delayed rectifier current (Ikeda et al., 1985). Flecainide does not cause EADs in vitro or torsades de pointes. In atrial tissue, flecainide prolongs action potentials disproportionately at fast rates, an especially desirable antiarrhythmic drug effect; this effect contrasts with that of quinidine, which prolongs atrial action potentials to a greater extent at slower rates (Wang et al., 1990). Flecainide prolongs the duration of PR, QRS, and QT, even at normal heart rates.

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 reentrant ventricular tachycardia, and increased mortality in patients convalescing from myocardial infarction (Morganroth et al., 1986; Crijns et al., 1988; CAST Investigators, 1989; Ranger et al., 1989). As discussed above, 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 half-life is shorter with urinary acidification (10 hours) than with urinary alkalinization (17 hours), but it is nevertheless sufficiently long to allow dosing twice daily (see Table 355). 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 (Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination) (Gross et al., 1989). 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 electrophysiological effects or disposition kinetics of its enantiomers (Kroemer et al., 1989). Some reports have suggested that plasma flecainide concentrations >1000 ng/ml should be avoided to minimize the risk of flecainide toxicity; however, in susceptible patients, the adverse electrophysiological effects of flecainide therapy can occur at therapeutic plasma concentrations.

Ibutilide

Ibutilide CORVERT; Murray, 1998) is an I_Kr 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 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% to 70%) than in those with atrial fibrillation (30% to 50%). In atrial fibrillation, the conversion rate is lowest 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 occur 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 half-life of 2 to 12 hours (average of 6 hours).

Lidocaine

Lidocaine XYLOCAINE) is a local anesthetic that also is useful in the acute intravenous therapy of ventricular arrhythmias. When lidocaine was administered to all patients with suspected myocardial infarction, the incidence of ventricular fibrillation was reduced (Lie et al., 1974). However, survival to hospital discharge tended to be decreased (Hine et al., 1989), perhaps because of lidocaine-exacerbated heart block or congestive heart failure. Lidocaine is therefore no longer routinely administered to all patients in coronary care units.

Pharmacological Effects

Lidocaine blocks both open and inactivated cardiac Na⁺ channels. Findings from in vitro studies suggest that lidocaine-induced 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 (Hondeghem and Katzung, 1984). In some studies, lidocaine increased current through inward rectifier channels, but the clinical significance of this effect is not known. Lidocaine can hyperpolarize Purkinje fibers depolarized by low [K]_o or stretch (Arnsdorf and Bigger, 1972); the resultant increased conduction velocity may be antiarrhythmic in reentry.

Lidocaine decreases automaticity by reducing the slope of phase 4 and altering the threshold for excitability. Action potential duration 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.

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 (Thompson et al., 1973); 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 (see Table 355). Lidocaine's metabolites, glycine xylidide (GX) and mono-ethyl GX (MEGX), 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 fallsan effect that has been attributed to competition between parent drug and metabolites for access to hepatic drug-metabolizing enzymes (LeLorier et al., 1977; Suzuki et al., 1984).

Plasma concentrations of lidocaine decline biexponentially after a single intravenous dose, indicating that a multicompartment model (Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination) is necessary to analyze lidocaine disposition. The initial drop in plasma lidocaine following intravenous administration occurs rapidly, with a half-life of 8 minutes, and represents distribution from the central compartment to peripheral tissues. The terminal elimination half-life, usually 100 to 120 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, but this effect 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 to 4 mg/kg over 20 to 30 minutes is usede.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 to 4 mg/min, which replaces drug removed by hepatic metabolism. The time to steady-state lidocaine concentrations is 8 to 10 hours. If the chosen 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 maintenance infusion rate.

In heart failure, the central volume of distribution is decreased, so the total loading dose should be decreased (Thompson et al., 1973). Since lidocaine clearance also is decreased, the rate of the maintenance infusion should be decreased. Lidocaine clearance is also reduced in hepatic disease (Thompson et al., 1973), during treatment with cimetidine or -blockers, and during prolonged infusions (Nies et al., 1976; LeLorier et al., 1977; Feely et al., 1982). Frequent measurement of plasma lidocaine concentration and dose adjustment to ensure that plasma concentrations remain within the therapeutic range (1.5 to 5 g/ml) are necessary to minimize toxicity in these settings. Lidocaine is bound to the acute phase reactant, -acid glycoprotein. Diseases such as acute myocardial infarction are associated with increases in -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 antiarrhythmic efficacy (Alderman et al., 1974; Kessler et al., 1984).

Magnesium

The intravenous administration of 1 to 2 g of MgSO₄ has been reported to be effective in preventing recurrent episodes of torsades de pointes, even if serum Mg²⁺ is normal (Tzivoni et al., 1988). However, controlled studies of this effect have not been performed. The mechanism of action is unknown; since QT interval is not shortened, an effect on the inward current, possibly a Ca²⁺ current, responsible for the triggered upstroke arising from EADs (black arrow, Figure 356B) is possible (Jackman et al., 1988; Roden, 1991b). Intravenous Mg²⁺ also has been used successfully in arrhythmias related to digitalis intoxication (Seller, 1971). Large, placebo-controlled trials of intravenous magnesium to improve outcome in acute myocardial infarction have yielded conflicting results (Woods and Fletcher, 1994; ISIS-4 Collaborative Group, 1995). While oral Mg²⁺ supplements may be useful in preventing hypomagnesemia, there is no evidence that chronic Mg²⁺ ingestion exerts a direct antiarrhythmic action.

Mexiletine and Tocainide

Mexiletine MEXITIL) and tocainide (TONOCARD) are analogs of lidocaine with structures that have been modified to reduce first-pass hepatic metabolism to make chronic oral therapy effective (Roden and Woosley, 1986b; Campbell, 1987). Their electrophysiological actions are similar to those of lidocaine. Tremor and nausea are the major dose-related adverse effects; these can be minimized by taking the drugs with food. Because tocainide can cause potentially fatal bone marrow aplasia and pulmonary fibrosis, it is rarely used.

Mexiletine undergoes hepatic metabolism, which is inducible by drugs such as phenytoin. Tocainide, on the other hand, is eliminated by renal excretion. Thus, in patients with renal disease, the dose of tocainide should be decreased. Both agents have been used for ventricular arrhythmias; combinations of mexiletine or tocainide with quinidine or sotalol may increase efficacy while reducing adverse effects. In vitro studies and clinical anecdotes have suggested a role for mexiletine (or flecainide) in correcting the molecular defect in the form of congenital long QT syndrome caused by abnormal Na⁺ channel inactivation (Shimizu and Antzelevitch, 1997).

Moricizine

Moricizine ETHMOZINE) is a phenothiazine analog with Na⁺ channelblocking properties used in the chronic treatment of ventricular arrhythmias (Clyne et al., 1992). In a randomized, double-blind trial (CAST II), moricizine increased mortality in patients shortly after a myocardial infarction and did not improve survival during long-term therapy (Cardiac Arrhythmia Suppression Trial II Investigators, 1992). Moricizine undergoes extensive first-pass hepatic metabolism; despite its short elimination half-life, its antiarrhythmic effect can persist for many hours after a single dose, suggesting that some of its metabolites may be active.

Phenytoin

The anticonvulsant phenytoin (DILANTIN; Chapter 21: Drugs Effective in the Therapy of the Epilepsies) also is a blocker of inactivated cardiac Na⁺ channels. It has been used in the acute and chronic suppression of ventricular arrhythmias and in digitalis intoxication (Atkinson and Davison, 1974). Phenytoin has a short _recovery, and little QRS prolongation is observed during chronic therapy. Phenytoin undergoes extensive, saturable, first-pass hepatic metabolism; therefore, small increases in dose can produce large increases in plasma concentration and toxicity (Richens, 1979). Phenytoin is highly bound to plasma proteins, but the extent of its binding may vary. For example, in patients with renal disease, phenytoin binding falls from 90% to 80%, effectively doubling the free fraction of drug. Phenytoin toxicity may ensue if doses are adjusted on the basis of total rather than free drug concentrations. Symptoms of phenytoin toxicity include CNS complaints, such as ataxia, nystagmus, or mental confusion, and gingival hyperplasia; serious dermatological and bone marrow reactions can occur. With intravenous use, hypotension and ventricular fibrillation have been reported. Phenytoin is an inducer of the hepatic metabolism of many other drugs, including quinidine, mexiletine, digitoxin, estrogens, theophylline, and vitamin D (Richens, 1979).

Procainamide

Procainamide PROCAN SR; others) is an analog of the local anesthetic, procaine. It exerts electrophysiological effects similar to those of quinidine, but lacks quinidine's vagolytic and -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. However, long-term oral treatment is often stopped because of adverse effects.

Pharmacological Effects

Procainamide is a blocker of open Na⁺ channels, with an intermediate time constant of recovery from block. It also prolongs cardiac action potentials in most tissues, probably by blocking outward K⁺ current(s). Procainamide decreases automaticity, increases refractory periods, and slows conduction. The major metabolite, N-acetyl procainamide, lacks the Na⁺ channelblocking activity of the parent drug but is equipotent in prolonging action potentials (Dangman and Hoffman, 1981). As the plasma concentrations of N-acetyl procainamide often exceed those of procainamide, increased refractoriness and QT prolongation during chronic procainamide therapy can be attributed at least in part to the metabolite. However, it is the parent drug that slows conduction and produces QRS interval prolongation. Although hypotension may occur at high plasma concentrations, this effect usually is attributable to ganglionic blockade rather than to any negative inotropic effect, which is minimal.

Adverse Effects

Hypotension and marked slowing of conduction are major adverse effects of high concentrations (>10 g/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 g/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, many patients, perhaps as many as 25% to 50%, eventually will 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.

Clinical Pharmacokinetics

Procainamide is rapidly eliminated (t_1/2= 3 to 4 hours) by both renal excretion of unchanged drug as well as by hepatic metabolism. The major pathway for hepatic metabolism is conjugation by N-acetyl transferase (see Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination) to form N-acetyl procainamide. N-Acetyl procainamide is eliminated by renal excretion (t_1/2= 6 to 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, procainamide usually is administered as a slow-release formulation. In patients with renal failure, procainamide and/or N-acetyl procainamide can accumulate to potentially toxic plasma concentrations (Drayer et al., 1977). 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 pharmacological effects, the 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 of 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 antiarrhythmic agents (Roden, 1993).

Propafenone

Propafenone RYTHMOL) is a Na⁺ channel blocker with a relatively slow time constant for recovery from block (Funck-Brentano et al., 1990). Some data suggest that, like flecainide, propafenone also blocks K⁺ channels. Its major electrophysiological effect is to slow conduction in fast-response tissues. The drug is prescribed as a racemate; while the enantiomers do not differ in their Na⁺ channelblocking properties, S-(+)-propafenone is a -adrenergic receptor antagonist in vitro and in some patients. 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, like other Na⁺ channel blockers, it is only modestly effective.

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 -adrenergic blockade such as sinus bradycardia and bronchospasm (see above and Chapter 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists).

Clinical Pharmacokinetics

Propafenone is well absorbed and is eliminated by both hepatic and renal routes. The activity of cytochrome P450 2D6 (CYP2D6), an enzyme that functionally is absent in 7% of Caucasians and African-Americans (Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination), 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 -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 -adrenergic receptors. CYP2D6-mediated metabolism of propafenone is saturable, so small increases in dose can lead to disproportionate increases in plasma propafenone concentration. In 'poor metabolizer' subjects, in whom functional CYP2D6 is absent, the extent of first-pass hepatic metabolism is much less than in extensive metabolizers, and plasma propafenone concentrations are much higher. The incidence of adverse effects during propafenone therapy is significantly higher in poor than in extensive metabolizers. CYP2D6 activity can be markedly inhibited by a number of drugs, including quinidine and fluoxetine. In extensive metabolizer subjects receiving such inhibitors or in poor metabolizer subjects, plasma propafenone concentrations >1 g/ml are associated with clinical effects of -adrenergic receptor blockade, such as reduction of exercise heart rate (Lee et al., 1990; Mrike and Roden, 1994). It is recommended that dosage in patients with moderate to severe liver disease should be reduced to approximately 20% to 30% of the usual dose, with careful monitoring. It is not known if propafenone doses must be decreased in patients with renal disease.

Quinidine

As early as the eighteenth century, the bark of the cinchona plant was used to treat 'rebellious palpitations' (Levy and Azoulay, 1994). Studies in the early twentieth century identified quinidine, a diastereomer of the antimalarial quinine, as the most potent of the antiarrhythmic substances extracted from the cinchona plant, and by the 1920s quinidine was used as an antiarrhythmic agent (Wenckebach, 1923). Quinidine is used for the maintenance of sinus rhythm in patients with atrial flutter or atrial fibrillation and in the prevention of recurrence of ventricular tachycardia or ventricular fibrillation (Grace and Camm, 1998).

Pharmacological Effects

Quinidine (QUINAGLUTE QUINIDEX, others) blocks Na⁺ current and multiple cardiac K⁺ currents. It is an open-state blocker of Na⁺ channels, with a time constant of recovery in the intermediate (3 seconds) range; as a consequence, QRS duration increases modestly, usually from 10% to 20%, at therapeutic dosages. At therapeutic concentrations, quinidine routinely prolongs QT interval up to 25%, but the effect is highly variable. At concentrations as low as 1 M, quinidine blocks Na⁺ current and the rapid component of delayed rectifier (I_Kr); 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. As a consequence of its K⁺ channelblocking actions, quinidine prolongs action potentials in most cardiac cells. This effect is most prominent at slow 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 (Roden and Hoffman, 1985). Quinidine prolongs refractoriness in most tissues, probably as a result of both prolongation of action potential duration and its Na⁺ channel blockade.

In the intact animal and in human beings, quinidine also produces -adrenergic 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 that 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 (Table 351).

Adverse Effects

Noncardiac

Diarrhea is the most common adverse effect during quinidine therapy, occurring in 30% to 50% of patients. The mechanism is not known. Diarrhea usually occurs within the first several days of quinidine therapy, but can occur later. In mild cases of diarrhea in which quinidine therapy is deemed vital, antidiarrheal drugs can be used. Diarrhea-induced hypokalemia may potentiate torsades de pointes due to quinidine.

A number of immunological reactions can occur during quinidine therapy. The most common is thrombocytopenia, which can be severe but which resolves rapidly with discontinuation of the drug. Hepatitis, bone marrow depression, and a lupus syndrome occur rarely. None of these effects is related to elevated plasma quinidine concentrations.

Quinidine also can produce cinchonism, a symptom complex that includes headache and tinnitus. In contrast to other adverse events during quinidine therapy, cinchonism usually is related to elevated plasma quinidine concentrations, and can be managed by dose reduction.

Cardiac

It is estimated that 2% to 8% of patients who receive quinidine therapy 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 occur at therapeutic, or even subtherapeutic, plasma concentrations (Jackman et al., 1988; Roden, 1991). 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 resultant ventricular tachycardia. This adverse effect formerly occurred when very high doses of quinidine were used to try to convert atrial fibrillation to normal rhythm, but this aggressive approach to quinidine dosing has now been abandoned, and quinidine-induced ventricular tachycardia due to excess Na⁺ channel block 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, -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 myocardial infarction (Kessler et al., 1984). Quinidine undergoes extensive hepatic oxidative metabolism, and 20% is excreted unchanged by the kidneys. One metabolite, 3-hydroxy-quinidine, is nearly as potent as quinidine in blocking cardiac Na⁺ channels or 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, it is unlikely that they 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 to 5 g/ml. Some of this variability may be assay-dependent, since not all assays have excluded quinidine metabolites. Among patients with advanced renal disease or advanced congestive heart failure, quinidine clearance is only modestly decreased. 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 due 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 -adrenergic receptor blockade. Quinidine reduces the clearance of digoxin and digitoxin; inhibition of P-glycoproteinmediated digoxin transport has been implicated (Fromm et al., 1999). This interaction is particularly important during the initiation of quinidine therapy in patients with atrial fibrillation, many of whom also are receiving digoxin (Leahey et al., 1978).

Quinidine metabolism is inducible by drugs such as phenobarbital or phenytoin (Data et al., 1976). In patients receiving these agents, very high doses of quinidine may be required to achieve therapeutic concentrations. It is important to note that, 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 elevate plasma quinidine concentrations, but these effects usually are modest.

Sotalol

Sotalol BETAPACE) is a nonselective -adrenergic receptor antagonist that also prolongs cardiac action potentials by inhibiting delayed rectifier and possibly other K⁺ currents (Hohnloser and Woosley, 1994). Sotalol is prescribed as a racemate; the l-enantiomer is a much more potent -adrenergic receptor antagonist than the d-enantiomer, but the two are equipotent as K⁺ channel blockers. Its structure is shown below:

In the United States, racemic sotalol is approved for use in patients with both ventricular tachyarrhythmias and atrial fibrillation or flutter. Clinical trials suggest that it is at least as effective as most Na⁺ channel blockers in ventricular arrhythmias (Mason, 1993).

Sotalol prolongs action potential duration throughout the heart and QT interval on the ECG. It decreases automaticity, slows AV nodal conduction, and prolongs AV refractoriness both by K⁺ channel block and block of -adrenergic receptors, but it exerts no effect on conduction velocity in fast-response tissue. Sotalol causes EADs and triggered activity in vitro (Strauss et al., 1970) and can cause torsades de pointes, especially when serum K⁺ is low. Unlike the situation with quinidine, the incidence of torsades de pointes seems to depend on the dose of sotalol, and in fact torsades de pointes are the major toxicity with sotalol overdose. Occasional cases occur at low dosages, often in patients with renal dysfunction, since sotalol is eliminated by renal excretion of unchanged drug. The other adverse effects of sotalol therapy are those associated with -adrenergic receptor blockade (see above and Chapter 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists).

Recent and continuing elucidation of the mechanisms underlying normal and abnormal cardiac electrical behavior, along with clinical investigations clearly delineating the dangers of indiscriminate use of potent ion channelblocking drugs in large groups of patients, have significantly altered therapeutic strategies for the treatment of arrhythmias. In some instances, nonpharmacological therapies are increasingly used to avoid the dangers of chronic drug therapy. Techniques for ablation of areas critical for the genesis of arrhythmias are now sufficiently well developed that chronic drug therapy can be avoided in many patients. When arrhythmia recurrence would be lethal and drugs may be incompletely effective, as in patients resuscitated from an episode of ventricular fibrillation, implanted defibrillators often are an appropriate choice. Among drugs discussed here, only -blockers (and, to a lesser extent, amiodarone) reduce the incidence of sudden death. By contrast, while drugs with predominant ion channel-blocking properties can acutely terminate arrhythmias, long-term therapy has either increased or not altered the incidence of sudden death. Basic genetic, molecular, and cellular studies continue to improve our understanding of arrhythmia mechanisms; it is likely that this new knowledge will identify novel drug targets to intervene in specific ways to alleviate particular arrhythmic events and thus supplant currently available drugs.

For further discussion of cardiac arrhythmias, see Chapters 213 and 214 in Harrison's Principles of Internal Medicine, 16th ed., McGraw-Hill, New York, 2005.