Summaries of important electrophysiologic and pharmacokinetic features of the drugs considered here are presented in Tables 29–3 and 29–5, respectively. Ca2+ channel blockers and β adrenergic antagonists are discussed in Chapters 12 and 25 to 28. The drugs are presented in alphabetical order.
Table 29-5Pharmacokinetic Characteristics and Doses of Anti-Arrhythmic Drugs ||Download (.pdf) Table 29-5 Pharmacokinetic Characteristics and Doses of Anti-Arrhythmic Drugs
|DRUG ||BIOAVAILABILITY ||PROTEIN BINDING >80% ||ELIMINATION ||ELIMINATION t1/2 ||ACTIVE METABOLITE(S) ||THERAPEUTICb PLASMA CONCENTRATION ||USUAL DOSESc |
|Reduced First-Pass Metabolism ||Renal ||Hepatic ||Other ||Loading Doses ||Maintenance Doses |
|Adenosined || || || || ||√ ||<10 s ||√ || ||6–12 mg (IV only) 800–1600 mg/d × 1–3 wk (IV: 1000 mg over 24 h) || |
|Amiodarone || ||√ || ||√ || ||wk ||√ ||0.5-2 μg/mL || ||400 mg/day IV: 0.5 mg/min) |
|Digoxin ||−80% || ||√ || || ||36 h || ||0.5-2.0 ng/mL ||0.6–1 mg over 12–24 h ||0.0625–0.5 mg/24 h |
|Diltiazem ||√ || || ||√ || ||4 h ||(x) || ||0.25 mg/kg over 10 min (IV) ||5-15 mg/h (IV); 180-360 mg/d in 3-4 divided doses (immediate release); 120-180 mg/24 h (extended release)e |
|Disopyramide ||>80% || ||√ ||√ || ||4-10 h ||(x) ||2-5 μg/mL || ||150 mg/6 h (immediate release); 300 mg (controlled releasef |
|Dofetilide ||>80% || ||√ ||(x) || ||7-10 h || || || ||0.5 mg/12 h |
|Dronedarone ||√ ||>98% ||√ || || ||13-19 h ||√ || || ||400 mg/12 h |
|Esmolol || || || || ||√ ||5-10 min || || ||0.5 mg/kg over 1 min (IV) ||0.05-0.3 mg/kg/min for 4 min (IV) |
|Flecainide ||>80% || || ||√ || ||10-18 h || ||0.2-1 μg/mL || ||50-100 mg/12 h |
|Ibutilide ||√ || || || || || || || ||1 mg (IV) over 10 min; may repeat once 10 min later || |
|Lidocaine ||√ ||√ || ||√ || ||120 min ||(x) ||1.5-5 μg/mL ||50-100 mg administered at a rate of 25-50 mg/min (IV) ||1-4 mg/min (IV) |
|Mexiletine ||>80% || || ||√ || ||9-15 h || ||0.5-2 μg/mL ||400 mg ||200 mg/8 h |
|Procainamide ||>80% || ||√ ||√ || ||3-4 h ||√ ||4-8 μg/mL ||500-600 mg (IV), given at 20 mg/min ||2-6 mg/min (IV); 250 mg q3h; 500-1000 mg q6h |
|(N-Acetyl procainamide) ||(>80%) || ||(√) || || ||(6-10 h) || ||(10-20 μg/mL) || || |
|Propafenone ||√ || || ||√ || ||2-32 h ||√ ||<1 μg/mL || ||150 mg/8h (immediate release); 225 mg/12h (extended release) |
|Propranolol ||√ ||√ ||√ || || ||4 h || || ||1-3 mg administered no faster than 1 mg/min, may repeate after 2 min (IV) ||10-30 mg q6-8h (immediate release) |
|Quinidine ||>80% ||−80% ||(x) ||√ || ||4-10 h ||√ ||2-5 μg/mL || ||648 mg (gluconate) every 8h |
|Sotalol ||>80% || ||√ || || ||8 h || ||<5 μg/mL (?) || ||80-160 mg/12h |
|Verapamil ||√ ||√ || ||√ || ||3-7 h ||√ || ||5-10 mg given over 2 min or more (IV) ||40-120 mg/6-8h (immediate release) |
Adenosine. Adenosine (adenocard, others) is a naturally occurring nucleoside that is administered as a rapid intravenous bolus for the acute termination of re-entrant supraventricular arrhythmias (Lerman and Belardinelli, 1991). Adenosine also has been used to produce controlled hypotension during some surgical procedures and in the diagnosis of coronary artery disease. Intravenous ATP appears to produce effects similar to those of adenosine.
Pharmacologic Effects. The effects of adenosine are mediated by its interaction with specific G protein–coupled adenosine receptors. Adenosine activates acetylcholine-sensitive K+ current in the atrium and sinus and AV nodes, resulting in shortening of APD, hyperpolarization, and slowing of normal automaticity (Figure 29–10C). Adenosine also inhibits the electrophysiologic effects of increased intracellular cyclic AMP that occur with sympathetic stimulation. Because adenosine thereby reduces Ca2+ currents, it can be anti-arrhythmic by increasing AV nodal refractoriness and by inhibiting DADs elicited by sympathetic stimulation.
Administration of an intravenous bolus of adenosine to humans transiently slows sinus rate and AV nodal conduction velocity and increases AV nodal refractoriness. A bolus of adenosine can produce transient sympathetic activation by interacting with carotid baroreceptors (Biaggioni et al., 1991); a continuous infusion can cause hypotension.
Adverse Effects. A major advantage of adenosine therapy is that adverse effects are short lived because the drug is transported into cells and deaminated so rapidly. Transient asystole (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 t1/2 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.
Amiodarone. Amiodarone (cordarone, pacerone, others) exerts a multiplicity of pharmacologic 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 anti-arrhythmic 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 resolve very slowly. In the U.S., the drug is indicated for oral therapy in patients with recurrent ventricular tachycardia or fibrillation resistant to other drugs. Oral amiodarone also is effective in maintaining sinus rhythm in patients with atrial fibrillation (Connolly, 1999). An intravenous form is indicated for acute termination of ventricular tachycardia or fibrillation (Kowey et al., 1995) and is supplanting lidocaine as first-line therapy for out-of-hospital cardiac arrest (Dorian et al., 2002). Trials of oral amiodarone have shown a modest beneficial effect on mortality after acute MI (Amiodarone Trials Meta-Analysis Investigators, 1997). Despite uncertainties about its mechanisms of action and the potential for serious toxicity, amiodarone now is used very widely in the treatment of common arrhythmias such as atrial fibrillation (Roy et al., 2000).
Pharmacologic 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. Amiodarone's effects may be mediated by perturbation of the lipid environment of the ion channels (Herbette et al., 1988). Amiodarone blocks inactivated Na+ channels and has a relatively rapid rate of recovery (time constant ∼1.6 s) from block. It also decreases Ca2+ current and transient outward delayed-rectifier and inward rectifier K+ currents and exerts a noncompetitive adrenergic blocking effect. Amiodarone potently inhibits abnormal automaticity and, in most tissues, prolongs APD. Amiodarone decreases conduction velocity by Na+ channel block and by a poorly understood effect on cell–cell coupling that may be especially important in diseased tissue (Levine et al., 1988). Prolongations of the PR, QRS, and QT intervals and sinus bradycardia are frequent during chronic therapy. Amiodarone prolongs refractoriness in all cardiac tissues; Na+ channel block, delayed repolarization owing to K+ channel block, and inhibition of cell–cell coupling all may contribute to this effect.
Adverse Effects. Hypotension owing to vasodilation and depressed myocardial performance are frequent with the intravenous form of amiodarone 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 t1/2 of weeks to months. The mechanism whereby amiodarone and desethyl-amiodarone are eliminated is not well established.
A therapeutic plasma amiodarone concentration range of 0.5-2 μg/mL has been proposed. However, efficacy apparently depends as much on duration of therapy as on plasma concentration, and elevated plasma concentrations do not predict toxicity (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.
Digitoxin has H at C12 in place of the OH.
Pharmacologic Effects. Digitalis glycosides exert positive inotropic effects and are used in heart failure (Chapter 28). Their inotropic action results from increased intracellular Ca2+ (Smith, 1988), which also forms the basis for arrhythmias related to cardiac glycoside intoxication. Cardiac glycosides increase phase 4 slope (i.e., increase the rate of automaticity), especially if [K]o is low. These drugs (e.g., digoxin) also exert prominent vagotonic actions, resulting in inhibition of Ca2+ currents in the AV node and activation of acetylcholinemediated K+ currents in the atrium. Thus, the major "indirect" electrophysiologic effects of cardiac glycosides are hyperpolarization, shortening of atrial action potentials, and increases in AV nodal refractoriness. The latter action accounts for the utility of digoxin in terminating re-entrant arrhythmias involving the AV node and in controlling ventricular response in patients with atrial fibrillation. Cardiac glycosides may be especially useful in the latter situation because many such patients have heart failure, which can be exacerbated by other AV nodal blocking drugs such as Ca2+ channel blockers or β adrenergic receptor antagonists. However, sympathetic drive is increased markedly in many patients with advanced heart failure, so digitalis is not very effective in decreasing the rate; on the other hand, even a modest decrease in rate can ameliorate heart failure. Similarly, in other conditions in which high sympathetic tone drives rapid AV conduction (e.g., chronic lung disease, thyrotoxicosis), digitalis therapy may be only marginally effective in slowing the rate. In heart transplant patients, in whom innervation has been ablated, cardiac glycosides are ineffective for rate control. Increased sympathetic activity and hypoxia can potentiate digitalis-induced changes in automaticity and DADs, thus increasing the risk of digitalis toxicity. A further complicating feature in thyrotoxicosis is increased digoxin clearance. The major ECG effects of cardiac glycosides are PR prolongation and a nonspecific alteration in ventricular repolarization (manifested by depression of the ST segment), whose underlying mechanism is not well understood.
Adverse Effects. Because of the low therapeutic index of cardiac glycosides, their toxicity is a common clinical problem (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 t1/2 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 t1/2 is even longer than that of digoxin (∼7 days); it is highly protein bound, and its therapeutic range is 10-30 ng/mL.
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 t1/2 (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.
Disopyramide. Disopyramide (norpace, others) exerts electrophysiologic effects very similar to those of quinidine, but the drugs have different adverse effect profiles (Morady et al., 1982). Disopyramide is used to maintain sinus rhythm in patients with atrial flutter or atrial fibrillation and to prevent recurrence of ventricular tachycardia or VF. Disopyramide is prescribed as a racemate. Its structure is as follows.
Pharmacologic Actions and Adverse Effects. The in vitro electrophysiologic actions of S-(+)-disopyramide are similar to those of quinidine. The R-(−)-enantiomer produces similar Na+ channel block but does not prolong cardiac action potentials. Unlike quinidine, racemic disopyramide is not an a adrenergic receptor antagonist, but it does exert prominent anticholinergic actions that account for many of its adverse effects. These include precipitation of glaucoma, constipation, dry mouth, and urinary retention; the latter is most common in males with prostatism but also can occur in females. Disopyramide commonly depresses contractility, which can precipitate heart failure (Podrid et al., 1980) and also 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 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.
Dofetilide. Dofetilide (tikosyn) is a potent and "pure" IKr blocker. As a result of this specificity, it has virtually no extracardiac pharmacologic 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 MI. Dofetilide currently is available through a restricted distribution system that includes only physicians, hospitals, and other institutions that have received special educational programs covering proper dosing and in-hospital treatment initiation.
Adverse 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.
Dronedarone. Dronedarone (multaq) is a noniodinated benzofuran derivative of amiodarone that was approved by the FDA in 2009 for the treatment of atrial fibrillation and atrial flutter. In randomized placebocontrolled trials, it was effective in maintaining sinus rhythm and reducing the rate of ventricular response during episodes of atrial fibrillation (drug reviewed by Patel et al., 2009). Compared to amiodarone, dronedarone treatment is associated with significantly fewer adverse events, but it also is significantly less effective in maintaining sinus rhythm. Dronedarone reduces morbidity and mortality in patients with high-risk atrial fibrillation. However, dronedarone increases mortality in patients with severe heart failure and is contraindicated in patients with NYHA class 4 heart failure and in patients with a recent decompensation of heart failure requiring hospitalization.
Pharmacologic Effects. Similar to amiodarone, dronedarone is a potent blocker of multiple ion currents, including the rapidly activating delayed-rectifier K+ current (IKr), the slowly activating delayed-rectifier K+ current (IKs), the inward rectifier K+ current (IK1), the acetylcholine activated K+ current, the peak Na+ current, and the L-type Ca2+ current. It has stronger antiadrenergic effects than amiodarone.
Adverse Effects and Drug Interactions. The most common adverse reactions are diarrhea, nausea, abdominal pain, vomiting, and asthenia. Dronedarone causes dose-dependent prolongation of 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.
Esmolol. (brevibloc, others) is a β1-selective agent that is metabolized by erythrocyte esterases and so has a very short elimination t1/2 (9 minutes). Intravenous esmolol is useful in clinical situations in which immediate β adrenergic blockade is desired (e.g., for rate control of rapidly conducted atrial fibrillation). Because of esmolol's very rapid elimination, adverse effects due to β adrenergic blockade—should they occur—dissipate rapidly when the drug is stopped. Although methanol is a metabolite of esmolol, methanol intoxication has not been a clinical problem. Its pharmacology is described in detail in Chapter 12.
Flecainide. The effects of flecainide (tambocor, others) therapy are thought to be attributable to the drug's very long τrecovery from Na+ channel block (Roden and Woosley, 1986). In the CAST study, flecainide increased mortality in patients convalescing from MI (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) and for life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia.
Pharmacologic Effects. Flecainide blocks Na+ current and delayed-rectifier K+ current (IKr) in vitro at similar concentrations, 1 to 2 μM (Ikeda et al., 1985; Follmer and Colatsky, 1990). It also blocks Ca2+ currents in vitro. APD is shortened in Purkinje cells, probably owing to block of late-opening Na+ channels, but prolonged in ventricular cells, probably owing to block of delayedrectifier current (Ikeda et al., 1985). Flecainide does not cause EADs in vitro but has been associated with rare cases of torsades de pointes. In atrial tissue, flecainide disproportionately prolongs action potentials at fast rates, an especially desirable anti-arrhythmic drug effect; this effect contrasts with that of quinidine, which prolongs atrial action potentials to a greater extent at slower rates (Wang et al., 1990). Flecainide prolongs the duration of PR, QRS, and QT intervals even at normal heart rates. Flecainide also is an open channel blocker of RyR2 Ca2+ release channels and prevents arrhythmogenic Ca2+ release from the sarcoplasmic reticulum in isolated myocytes (Hilliard et al., 2010). The blockade of the RyR2 channel by flecainide targets directly the underlying molecular defect in patients with mutations in the ryanodine receptor and cardiac calsequestrin, which may explain why flecainide suppresses ventricular arrhythmias in CPVT patients refractory to standard drug therapy (Watanabe et al., 2009).
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 t1/2 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. Ibutilide (corvert) is an IKr blocker that in some systems also activates an inward Na+ current (Murray, 1998). 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 (50-70%) 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 t1/2 of 2-12 hours (average of 6 hours).
Lidocaine. Lidocaine (xylocaine, others) 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 MI, the incidence of VF was reduced (Lie et al., 1974). However, survival to hospital discharge tended to be decreased (Hine et al., 1989), perhaps because of lidocaineexacerbated heart block or congestive heart failure. Therefore, lidocaine no longer is administered routinely to all patients in coronary care units.
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 t1/2 of ∼8 minutes, and represents distribution from the central compartment to peripheral tissues. The terminal elimination t1/2, 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).
Magnesium. The intravenous administration of 1-2 g MgSO4 reportedly is effective in preventing recurrent episodes of torsades de pointes, even if the serum Mg2+ concentration is normal (Tzivoni et al., 1988). However, controlled studies of this effect have not been performed. The mechanism of action is unknown because the QT interval is not shortened; an effect on the inward current, possibly a Ca2+ current, responsible for the triggered upstroke arising from EADs (black arrow, Figure 29–6B) is possible. Intravenous Mg2+ also has been used successfully in arrhythmias related to digitalis intoxication.
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. Mexiletine (mexitil, others) is an analog of lidocaine that has been modified to reduce first-pass hepatic metabolism and permit chronic oral therapy (Campbell, 1987). The electrophysiologic actions are similar to those of lidocaine. Tremor and nausea, the major dose-related adverse effects, can be minimized by taking the drugs with food.
Procainamide. Procainamide (procan sr, others) is an analog of the local anesthetic procaine (Chapter 20). It exerts electrophysiologic effects similar to those of quinidine but lacks quinidine's vagolytic and a 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 poorly tolerated and often is stopped owing to adverse effects.
Pharmacologic Effects. Procainamide is a blocker of open Na+ channels with an intermediate τrecovery from block. It also prolongs cardiac action potentials in most tissues, probably by blocking outward K+ current(s). Procainamide decreases automaticity, increases refractory periods, and slows conduction. Its major metabolite, N-acetyl procainamide, lacks the Na+ channelblocking activity of the parent drug but is equipotent in prolonging action potentials. Because the plasma concentrations of N-acetyl procainamide often exceed those of procainamide, increased refractoriness and QT prolongation during chronic procainamide therapy may be partly attributable to the metabolite. However, it is the parent drug that slows conduction and produces QRS-interval prolongation. 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 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 (t1/2 = 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 (t1/2 = 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).
Propafenone. Propafenone (rythmol, others) 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 electrophysiologic effect is to slow conduction in fast-response tissues. The drug is prescribed as a racemate; although the enantiomers do not differ in their Na+ channel–blocking properties, S-(+)-propafenone is a β receptor antagonist 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; like other Na+ channel blockers, it also can be used in ventricular arrhythmias, but with only modest efficacy.
Adverse Effects. Adverse effects during propafenone therapy include acceleration of ventricular response in patients with atrial flutter, increased frequency or severity of episodes of 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.
Quinidine. As early as the 18th century, the bark of the cinchona plant was used to treat "rebellious palpitations" (Levy and Azoulay, 1994). Studies in the early 20th 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. Quinidine is used to maintain sinus rhythm in patients with atrial flutter or atrial fibrillation and to prevent recurrence of ventricular tachycardia or VF (Grace and Camm, 1998).
Pharmacologic Effects. Quinidine blocks Na+ current and multiple cardiac K+ currents. It is an open-state blocker of Na+ channels, with a τrecovery in the intermediate (∼3 s) range; as a consequence, QRS duration increases modestly, usually by 10-20%, at therapeutic dosages. At therapeutic concentrations, quinidine commonly prolongs the QT interval up to 25%, but the effect is highly variable. At concentrations as low as 1 μM, quinidine blocks Na+ current and the rapid component of delayed rectifier (IKr); higher concentrations block the slow component of delayed rectifier, inward rectifier, transient outward current, and l-type Ca2+ current.
Quinidine's Na+ channel–blocking properties result in an increased threshold for excitability and decreased automaticity. As a consequence of its K+ channel–blocking actions, quinidine prolongs action potentials in most cardiac cells, most prominently at slow heart rates. In some cells, such as midmyocardial cells and Purkinje cells, quinidine consistently elicits EADs at slow heart rates, particularly when [K]o is low (Priori et al., 1999). Quinidine prolongs refractoriness in most tissues, probably as a result of both prolongation of APD and Na+ channel blockade.
In intact animals and humans, quinidine also produces β receptor blockade and vagal inhibition. Thus, the intravenous use of quinidine is associated with marked hypotension and sinus tachycardia. Quinidine's vagolytic effects tend to inhibit its direct depressant effect on AV nodal conduction, so the effect of drug on the PR interval is variable. Moreover, quinidine's vagolytic effect can result in increased AV nodal transmission of atrial tachycardias such as atrial flutter (Table 29–1).
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.
Sotalol. Sotalol (betapace, betapace af) is a nonselective β adrenergic receptor antagonist that also prolongs cardiac action potentials by inhibiting delayed-rectifier and possibly other K+ currents (Hohnloser and Woosley, 1994). Sotalol is prescribed as a racemate; the l-enantiomer is a much more potent β adrenergic receptor antagonist than the d-enantiomer, but the two are equipotent as K+ channel blockers. Its structure is shown below:
In the U.S., sotalol is an orphan drug approved for use in patients with both ventricular tachyarrhythmias (betapace) and atrial fibrillation or flutter (betapace af). Clinical trials suggest that it is at least as effective as most Na+ channel blockers in ventricular arrhythmias (Mason, 1993).
Sotalol prolongs APD throughout the heart and QT interval on the ECG. It decreases automaticity, slows AV nodal conduction, and prolongs AV refractoriness by blocking both K+ channels and β adrenergic receptors, but it exerts no effect on conduction velocity in fast-response tissue. Sotalol causes EADs and triggered activity in vitro and can cause torsades de pointes, especially when the serum K+ concentration is low. Unlike the situation with quinidine, the incidence of torsades de pointes (1.5-2% incidence) seems to depend on the dose of sotalol; indeed, torsades de pointes is the major toxicity with sotalol overdose. Occasional cases occur at low dosages, often in patients with renal dysfunction, because sotalol is eliminated by renal excretion of unchanged drug. The other adverse effects of sotalol therapy are those associated with β receptor blockade (see earlier in this chapter and Chapter 12).
Vernakalant. Vernakalant (RSD1235, proposed tradename kynapid) is an investigational inhibitor of several ion channels that are preferentially expressed in the atria, in particular the ultra-rapidly activating delayed-rectifier K+ current (IKur encoded by Kv1.5). To a lesser extent, it also blocks the rapidly activating delayed-rectifier K+ current (IKr), the transient outward K+ current (Ito), the Na+ current, and the L-type Ca2+ current. Vernakalant selectively prolongs the atrial refractory period without significantly affecting ventricular refractoriness.
Vernakalant is effective for converting atrial fibrillation of short duration to sinus rhythm (Roy et al., 2008). Vernakalant (3 mg/kg) is administered as a 10-minute infusion, followed by a second infusion of 2 mg/kg 15 minutes later if AF is not terminated. Vernakalant is not effective in converting long-duration AF (>7 days) or atrial flutter. The intravenous formulation of vernakalant was recommended for approval by an FDA advisory committee in 2008, but the drug has not received FDA approval at the time of this printing. An oral formulation is currently in clinical trials for the maintenance of sinus rhythm in patients with chronic atrial fibrillation. Vernakalant seems to have little or no proarrhythmic effects, with no reported cases of torsades de pointes in phase II and III studies.
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 Cmax between extensive and poor 2D6 metabolizers after single-dose IV administration. However, average t1/2 of vernakalant was much longer in two poor metabolizers (8.5 hours) than in 10 extensive metabolizers (2.7 hours). This profound difference in t1/2 will be important if vernakalant is used chronically to prevent atrial fibrillation.