According to the original schema, drugs that have an effect on sodium channels were placed in class I. It was later recognized that the relative potency of all of these drugs varied and that some had additional electrophysiologic effects differentiating them from others. For that reason, subclasses a, b, and c were used to designate these differences. The class Ia agents, including quinidine, procainamide, and disopyramide, exert an intermediate effect to block the fast sodium current and prolong the APD by blocking outward potassium current. The class Ib agents, including lidocaine and mexiletine, are the weakest sodium blockers that produce little change in the QRS duration in normal cardiac tissues and have a negligible effect on repolarization. Class Ib drugs predominantly bind to the channel in the inactivated state. In ischemic myocardium with reduced membrane potential, voltage-dependent recovery of sodium channel from inactivation is delayed, so that binding of class Ib drugs to the channel is significantly increased. This explains the greater efficacy of class Ib antiarrhythmic drugs to inhibit ischemia-induced ventricular arrhythmias. The class Ic drugs, including flecainide and propafenone, have a more potent effect on the sodium current, leading to depression of phase 0 of the action potential and exhibiting more use dependence, that is, inhibiting the sodium current and slowing conduction during tachycardia. The varying sodium channel effects on the ventricular action potential of the three types of class I agents are illustrated in Fig. 87–3.
Effects of group I antiarrhythmic drugs on the ventricular action potential. Class Ia agents have an intermediate effect on the fast sodium current and prolong the action potential with blockade of the outward potassium current. Class Ib agents have less sodium channel blockade and bind to the sodium channel in inactivated state, having minimal effect on the action potential. Class Ic agents have a significant sodium channel blocking effect, which leads to the most marked depression of the initial phase (phase 0) of the action potential. Modified with permission from Golan DE, Tashjian, Jr. AH: Principles of Pharmacology. The Pathophysiologic Basis of Drug Therapy, 3rd Edition. Philadelphia: Lippincott Williams & Wilkins; 2012.
Class II agents act indirectly on ionic currents primarily by inhibiting sympathetic activity through β-adrenergic blockade, leading to sinus rhythm slowing and PR interval prolongation under physiologic conditions. Many of them have additional actions on the adrenergic receptors. For example, carvedilol and labetalol also have a strong α-adrenergic blocking effect, whereas pindolol and acebutolol exhibit an intrinsic sympathomimetic activity.
Class III antiarrhythmic drugs are those that extend the APD, thereby increasing the effective refractory period, which is shown in Fig. 87–4. There is a great deal of heterogeneity within this class because the drugs may act on any of several different ion channels, including sodium in addition to potassium channels, to reduce the net repolarizing current and prolong refractoriness. Most of the class III drugs demonstrate reverse use dependence, with their maximal effect on repolarization at slower heart rates, which may be counterproductive for effective arrhythmia termination. Amiodarone and ibutilide have a fairly homogeneous effect on refractoriness across a range of cycle lengths.
Effects of group III antiarrhythmic drugs on the ventricular action potential. Class III agents act on multiple ion channels, including potassium channels, and extend the action potential duration. These changes prolong repolarization with an increase in the effective refractory period. Modified with permission from Golan DE, Tashjian, Jr. AH: Principles of Pharmacology. The Pathophysiologic Basis of Drug Therapy, 3rd Edition. Philadelphia: Lippincott Williams & Wilkins; 2012.
Class IV antiarrhythmic drugs are L-type calcium channel blockers. Here again, there is substantial heterogeneity within the class. This may be particularly important because the calcium antagonists have a variable effect on slow channels in the heart versus the peripheral circulation.
The Vaughan-Williams classification schema (see Table 87–1) has been used as a conversational shorthand to facilitate exchange of information about the electrophysiologic properties of antiarrhythmic drugs. But it has a number of important drawbacks. First, many of the currently available drugs have multiple actions. Second, the metabolites of some of the drugs may be primarily responsible for at least some of the antiarrhythmic actions, such as procainamide and its metabolite NAPA. Third, the scheme does not account for important differences seen when the drugs are used in diverse patient populations, for example, the incidence and nature of proarrhythmia as it relates to presence, type, and severity of underlying structural heart diseases.
Class I Antiarrhythmic Drugs
The common electrophysiologic feature of class Ia drugs is that the drugs block the rapidly activating delayed rectifier potassium current (IKr) at relatively lower concentrations than their effect on INa. Therefore, they cause QT prolongation that may lead to TdP. At higher doses, they inhibit INa, with an intermediate time constant of dissociation from the sodium channel, leading to conduction slowing and a decrease in myocardial contractility. Consequently, the class Ia agents are relatively contraindicated in structural heart disease.
Among class Ia drugs, quinidine causes greater QT prolongation. Therefore, use of quinidine is associated with a higher incidence of TdP. Because quinidine has a larger concentration gap in blocking IKr and INa, TdP often develops when patients take lower doses of quinidine or just start to take the drug. Therefore, quinidine should be avoided in patients with heart failure or structural heart disease and in those with the congenital long QT syndrome, hypokalemia, or a history of TdP.42 At higher doses, quinidine inhibits INa, leading to conduction slowing and a decrease in myocardial contractility.
Quinidine also inhibits Ito and may thereby prevent ventricular fibrillation in J-wave syndromes, including idiopathic ventricular fibrillation with prominent J wave in ECGs leads excluding V1 to V3 and Brugada syndrome.12,43 This is also the reason why quinidine, unlike other sodium channel blockers without an effect on Ito, cannot be used for unmasking ST-segment elevation in concealed Brugada syndrome.
Quinidine can be rapidly absorbed; it reaches peak plasma concentrations in approximately 2 to 3 hours with the immediate-release formulations, but takes much longer with the sustained-release formulations. Bioavailability varies from 50% to 100% with a mean value of 70% to 80%. The mean plasma half-life is 6 hours, but the half-life may vary from 3 to 19 hours. Therapeutic plasma concentrations of quinidine range between 2 and 6 μg/mL, and it is eliminated mainly by hepatic metabolism (~80%). The renal elimination of unchanged drug is approximately 20%.
Quinidine has historically been used in the treatment of atrial fibrillation and ventricular arrhythmias.44,45 Because quinidine is associated with a relative high incidence of TdP (5%-8%) leading to syncope (quinidine syncope) or sudden cardiac death, its role in the treatment of atrial fibrillation is limited and its overall used has diminished. However, quinidine has been shown to effectively prevent ventricular fibrillation in patients with J-wave syndromes because of its inhibitory effect on Ito.12,13,14
Diarrhea is relatively common (~50% of patients). Less common adverse reactions include fever, rash, tinnitus, thrombocytopenia, and granulomatous hepatitis. Marked QT prolongation leading to TdP may occur, and is more commonly seen in females. Quinidine use simultaneously with another class Ia agent should be avoided because of an increased risk of death.46
Because the concentration gap of procainamide to block IKr and INa is relatively narrower compared with quinidine, the risk that procainamide will prolong the QT interval and lead to TdP is smaller. Unlike quinidine, procainamide has no effect on Ito.
Oral bioavailability of procainamide is approximately 83%, and drug can be administered orally or intraveneously. Procainamide is acetylated in the liver to an active metabolite, NAPA, which has a class III effect with a half-life of approximately 6 hours. The rate of acetylation varies in the population, with more than one half of the population being rapid acetylators. In rapid acetylators, NAPA levels usually exceed those of the parent compound. Therapeutic level for procainamide is 4 to 10 μg/mL and NAPA is 6 to 20 μg/mL. Short half-life of elimination (~3 hours) after oral administration in patients with normal renal function necessitates frequent dosing. Procainamide is contraindicated in patients with renal failure because the accumulation of the parent drug and its active metabolite can cause significant adverse effects including life-threatening proarrhythmias such as TdP.
Procainamide suppresses both supraventricular and ventricular tachycardia. Intravenous procainamide can be used to convert supraventricular tachycardias, including atrial fibrillation, to normal sinus rhythm. In Wolff-Parkinson-White syndrome (preexcitation of the ventricles via accessory pathway(s) between the atria and ventricles), atrial fibrillation with rapid ventricular responses may mimic ventricular tachycardia, in which AV-blocking agents are relatively contraindicated. Intravenous procainamide inhibits conduction in the accessory pathway(s) and therefore effectively slows the ventricular response to atrial fibrillation. Intravenous procainamide can be also used to unmask the concealed type of Brugada syndrome as a result of its sodium channel blocking effect.
Procainamide can cause nausea, anorexia, vomiting, rash, and granulocytosis. Intravenous administration of procainamide may result in hypotension. A systemic lupus erythematosus–like reaction is fairly common (10%-20%), particularly in slow acetylators who have a higher procainamide concentration and a lower NAPA level. Procainamide can cause QT prolongation likely via its active metabolite NAPA. However, the incidence of TdP is lower than with quinidine, and typically only occurs at high plasma concentrations (> 30 μg/mL).
Similar to procainamide, the concentration gap of disopyramide to block IKr and INa is relatively narrower than quinidine. Therefore, its effect on QT interval and conduction is comparable to procainamide. Among class Ia drugs, disopyramide has more negative inotropic and marked anticholinergic effects. Disopyramide also has a weak inhibitory effect on Ito.
More than 90% of oral disopyramide is absorbed, and its bioavailability is approximately 83%. The rate of renal elimination of unchanged disopyramide is 55%. The half-life varies from 4 to 10 hours, with a mean value of 6 hours. In patients with renal failure and congestive heart failure, the plasma half-life is significantly increased. The therapeutic levels are between 2 and 5 μg/mL. In patients with renal and/or hepatic function insufficiency, the dosage needs to be adjusted.
Disopyramide is used for treatment of ventricular and atrial arrhythmias. Because disopyramide has a strong vagolytic effect, it is useful in patients with vagally mediated atrial fibrillation. Its negative inotropic effect also makes it an effective treatment option in hypertrophic obstructive cardiomyopathy.
The adverse effects of disopyramide are largely associated with its anticholinergic activity. These include bloating, constipation, urinary retention, oropharyngeal dryness, blurred vision, and worsening of glaucoma. Disopyramide may also cause headache, muscle weakness, nausea, and fatigue. Because of its relatively strong negative inotropic activity, disopyramide should be avoided in patients with left ventricular dysfunction and heart failure. Like other class Ia drugs, disopyramide may cause TdP.
The common electrophysiologic feature of class Ib drugs is that the drugs block cardiac sodium channels in the inactive state with a rapid dissociation rate from the channels. Class Ib drugs increase the effective refractory period more significantly in the ventricles than in the atria because the action potentials of the ventricles have a relatively longer inactivated state. In addition, class Ib drugs have little effect on accessory pathways and those cardiac structures with calcium-dependent action potentials, such as the sinus node and AV node. This explains why class Ib drugs are ineffective for treatment of supraventricular tachycardias and atrial fibrillation or flutter. However, class Ib drugs inhibit ventricular tachycardias more effectively under conditions of myocardial ischemia because shifting of resting potential to more positive potential in ischemic tissues markedly prolongs the inactivated state. Class Ib drugs have no significant effect on IKr and other repolarizing currents, and therefore have a minimal influence on the QT interval. Class Ib drugs have a smaller effect on hemodynamics and myocardial contractility than class Ia and Ic drugs and can be safely used in patients with heart failure.
Lidocaine is given intravenously for treatment of ventricular arrhythmias and has a half-life of 1.5 to 2.0 hours, with a mean value of 1.8 hours in normal adults. Because lidocaine is approximately 90% metabolized in the liver by CYP1A2, its half-life may be prolonged significantly in patients with hepatic impairment. Congestive heart failure may also increase the half-life of lidocaine. Lidocaine should be loaded with an intravenous bolus of 100 to 200 mg before continuous infusion is initiated. For ventricular tachycardia or fibrillation refractory to the drug, a repeat bolus of 100 mg can be given. Although the initial loading doses do not require adjustment, the maintenance doses should be reduced in patients with hepatic impairment or heart failure.
Lidocaine is used to treat ventricular arrhythmias, particularly in setting of ischemia. However, amiodarone is now used as first-line treatment in ventricular arrhythmias in the setting of acute myocardial ischemia.
The most common adverse reactions of intravenous lidocaine are central nervous system effects that are often dose related. They include tongue numbness, visual disturbances, tremor, seizure, drowsiness, hallucinations, and even coma. These adverse effects are particularly frequent in elderly patients and those with heart failure or liver function impairment. Cardiac effects of lidocaine are infrequent, but overdosing or rapid infusion may cause asystole, hypotension, and shock.
Mexiletine is well absorbed orally and has a bioavailability of approximately 87%. Mexiletine is largely (> 75%) metabolized in the liver, and the rest is excreted unchanged through the kidneys. The peak serum concentration occurs in 2 to 3 hours, with a half-life of 9 to 12 hours, and the therapeutic plasma concentration ranges from 0.5 to 2.0 μg/mL. Clearance of mexiletine is significantly delayed in patients with congestive heart failure and hepatic impairment. Therefore, the dose needs to be reduced in these patients.
Mexiletine is considered as an oral form of lidocaine in terms of clinical application, and similarly is used in treating ventricular arrhythmia. In addition, mexiletine displays the unique property of blocking the late sodium current (INa,L).47 This property of mexiletine is the basis for its use in preventing TdP in patients with acquired long QT syndrome.48 Mexiletine can be used in patients with long QT3 syndrome because it blocks late sodium current, an inward current responsible for delayed ventricular repolarization and TdP in long QT3 syndrome.49
Gastrointestinal adverse effects of mexiletine are relatively common (30%) and include nausea, vomiting, stomach cramps, and diarrhea or constipation. Other adverse effects include blurred vision, tremor, headache, ataxia, and confusion.
Class Ic drugs block the sodium channels at their open state and dissociate from the channels with a relatively longer time constant. Therefore, class Ic drugs exhibit strong use dependence (ie, the blockade of the sodium channel is more prominent during tachycardia when the channels are “frequently used”). Class Ic drugs increase the effective refractory period in the atria, His-Purkinje system, ventricles, and accessory pathways. However, class Ic drugs slow conduction. Therefore, the effect of class Ic drugs on impulse wavelength, a key parameter that determines whether a reentrant tachycardia can occur, varies depending on the net effect of the drugs on effective refractory period and conduction velocity.50 When class Ic drugs are used for the treatment of atrial fibrillation, atrial flutter may develop. Since class Ic drugs have minimal effect on the AV node, one-to-one AV conduction may occur during atrial flutter, leading to marked tachycardia. Sometimes atrial flutter with one-to-one AV conduction may resemble ventricular tachycardia because the QRS complex widens significantly as a result of strong sodium blockade at tachycardia. This is why an AV-blocking agent, such as a calcium channel blocker or β-blocker, should normally be used in conjunction with class Ic drugs for treatment of atrial fibrillation. Class Ic antiarrhythmics should be avoided in patients with ischemic and structural heart disease because of the significant proarrhythmic risk in these patients.
Flecainide has an oral bioavailability of 60% to 86%, with a mean value of approximately 70%. The therapeutic levels range from 0.2 to 1.0 μg/mL. Although flecainide is mostly metabolized hepatically, renal clearance is important as well. Its half-life varies from 10 to 20 hours and can be significantly prolonged in patients with liver and renal impairment and congestive heart failure.
Flecainide is indicated for treatment of atrial fibrillation in patients with structurally normal heart. Flecainide is useful for treating and preventing supraventricular tachycardia, including AV nodal reentrant tachycardia, AV reentrant tachycardia, and atrial tachycardia. Because the action potential in the accessory pathways is INa dependent, flecainide is particularly effective to inhibit reentrant tachycardia using accessory pathway(s) like AV reentrant tachycardia and Wolff-Parkinson-White syndrome. Flecainide also has shown to be effective in preventing arrhythmic events in catecholaminergic polymorphic ventricular tachycardic when added to b-blocker therapy via inhibition of the ryanodine receptor.51,52
Flecainide is usually well tolerated. However, it should be avoided in patients with ischemic cardiomyopathy and congestive heart failure.15 Flecainide may cause ventricular tachycardia or fibrillation and worsen heart failure in these patients as a result of its strong use-dependent inhibition of INa. It also should be avoided in patients with J wave syndromes because it may induce ST-segment elevation and facilitate the development of ventricular fibrillation via its effect on INa in these patients. Flecainide may worsen sinus node dysfunction leading to sinus bradycardia, and in addition, it may slow conduction in His-Purkinje and cause AV block in patients with severe His-Purkinje system disease. Because flecainide blocks IKr at a concentration slightly lower than that at which it blocks INa, it may cause mild QT prolongation not related to its effect on QRS. However, TdP is extremely rare. Noncardiac adverse effects are dose related, including tremor, dizziness, blurred or double vision, headache, nausea, and dry mouth.
Propafenone is almost completely absorbed and undergoes extensive first-pass hepatic clearance. The bioavailability of propafenone is dose dependent, ranging from 5% to 50%. The half-life of the parent compound is approximately 5.5 hours, although it may be prolonged to 14 hours in poor metabolizers (~10% of patients), who are determined by genetic factors. The major metabolites of propafenone include 5-hydroxypropafenone (active) and N-debutyl propafenone. Propafenone has a weak β-blocking effect. In poor metabolizers, a relatively higher level of propafenone and lower levels of its active metabolites may be associated with a greater β-blocking effect. Because propafenone is largely eliminated via the liver, its doses should be adjusted in patients with liver disease. Propafenone also exhibits saturable kinetics, resulting in a nonlinear increase in plasma concentration during increases in oral dosing. This also results in a change in the ratio of parent drug to metabolite when the oxidative enzyme in the liver becomes saturated.
The indications of propafenone are similar to those of flecainide.53
The majority of cardiac adverse effects are similar to those of flecainide. However, propafenone does not prolong ventricular repolarization and has not been reported to induce TdP. Propafenone should be avoided in advanced heart failure because of its proarrhythmic risk. Unusual taste, nausea or vomiting, constipation, dizziness, and headache are relatively common. Propafenone toxicity can present with cardiovascular effects of hypotension, ventricular arrhythmias or bradycardia, as well as CNS depression. Patients who are poor metabolizers or are taking CYP2D6 inhibitors would be more likely to experience symptoms of propafenone toxicity. Rash is also seen in 1% to 3% of patients on propafenone. Rarely, propafenone can cause profound neutropenia or lupus-like syndrome.
Class II Drugs (β-Blockers)
β-Agonists enhance ICa,L and the pacemaker current (If). Therefore, β-receptor blockade prolongs the AV node effective refractory period and suppresses automaticity, resulting in depression of AV conduction and increase in sinus node recovery time, leading to slowing of the sinus rate. Although β-blockers per se have no clear effect on repolarization, they seem to prevent or blunt the changes in refractoriness at all levels in the heart.
Antiarrhythmic effects of β-blockers on supraventricular and ventricular tachycardias are largely a result of their counteracting action on arrhythmogenesis of catecholamines. In addition, β-blockers also increase ventricular fibrillation thresholds by reducing dispersion of repolarization, particularly in ischemic zones.
Pharmacokinetics and thus dosing differ significantly among β-blockers. β-Blockers are usually titrated based on resting heart rate.
β-Blockers effectively suppress arrhythmias in which catecholamines play an important role. These arrhythmias include catecholamine-sensitive polymorphic ventricular tachycardia and TdP in certain congenital long QT syndromes (long QT1 and long QT2 syndromes). β-Blockers slow AV nodal conduction and reduce the ventricular response to atrial fibrillation and atrial flutter. As a result of their antifibrillatory and anti-ischemic actions, β-blockers are also useful in the treatment of ischemia-related ventricular arrhythmias, such as premature ventricular beats and nonsustained ventricular tachycardia, and in prevention of sudden arrhythmic death in patients with ischemic cardiomyopathy. β-Blockers may be effective in terminating AV and AV nodal reentry or in preventing such arrhythmias. Multiple studies have demonstrated β-blockers having similar rates of prevention of atrial fibrillation recurrence as the class IA and class III antiarrhythmics.46 β-Blockers, particularly when given intravenously, are contraindicated in patients with preexcitation during atrial fibrillation.
β-Blockers are generally well tolerated, but they are contraindicated in patients with moderate-to-severe asthma. β-Blockers also exacerbate sick sinus syndrome and AV block. β-Blockers may be associated with fatigue, depression, insomnia, hallucinations, and sexual dysfunction. Abrupt withdrawal of β-blockers in patients with coronary artery disease may lead to worsening angina, myocardial infarction, and even sudden death. β-Receptor blockade may mask signs of hypoglycemia in diabetics. Initiation of β-blockers should generally be avoided in acute decompensated heart failure requiring intravenous vasoactive medications.
Ibutilide, a methanesulfonamide derivative, blocks the IKr current and enhances late slow inward sodium current, therefore exhibiting a strong effect to delay repolarization in both atrial and ventricular myocardium including accessory pathways.54,55 ECG changes associated with use of ibutilide include prolongation of the QT interval. The QT interval normally returns to baseline within 3 to 4 hours after drug infusion is discontinued. Ibutilide has minimal effects on sinus node and AV conduction.
Ibutilide is available only in an intravenous preparation because of extensive first-pass metabolism during oral administration. It has a half-life of 2 to 12 hours and is extensively metabolized by the liver to eight metabolites that are largely eliminated via the kidney. Weight-based dosing is required for patients weighing < 60 kg.
Continuous ECG telemetry monitoring during infusion and for at least 4 hours after infusion is strongly recommended because TdP can occur. The patient should not be discharged until the QT interval returns to baseline.
The indication of ibutilide is for acute termination of atrial flutter and fibrillation. Its efficacy is higher in atrial flutter or fibrillation of short duration. It is also useful in converting atrial fibrillation to sinus rhythm in patients after cardiac surgery and in those with the Wolff-Parkinson-White syndrome.
The primary adverse effect of ibutilide is TdP (4%-8%). TdP is more likely to occur in females or under conditions of hypokalemia, hypomagnesemia, bradycardia, or significant left ventricular dysfunction.
d,l-Sotalol is a racemate of d and l isomers that both exhibit antiarrhythmic actions via blocking IKr.56 In addition, the l isomer also exhibits nonselective β-blocking activity. Electrophysiologic effects of sotalol include an increase in APD in both the atria and ventricles and a decrease in sinus rate and AV conduction.
Sotalol is well absorbed with bioavailability of almost 100%. It is primarily eliminated in an unchanged form by the kidney. The half-life ranges from 10 to 16 hours. In patients with renal insufficiency, sotalol clearance is significantly delayed, and drug accumulation leading to serious toxic effects may occur. Therefore, sotalol dosage must be adjusted based on patients’ creatinine clearance. Because of the risk of TdP, sotalol should be started in hospital with QT monitoring.
Sotalol is effective in suppressing atrial and ventricular arrhythmias.57 Its common clinical use is to prevent recurrence of atrial fibrillation and ventricular tachycardia particularly related to old myocardial infarction.
Sotalol is contraindicated in patients with acquired or congenital long QT syndrome, symptomatic sinus node dysfunction, AV block, and moderate-to-severe asthma. b-blocking activity can cause bradycardia and worsening of left ventricular function. Sotalol commonly causes fatigue, and may also cause insomnia, headache, mild diarrhea, nausea, or vomiting. QTc prolongation > 500 ms in narrow QRS or a change in the QTc interval of > 15% in baseline wide QRS (> 120 ms) should prompt discontinuation of sotalol. TdP risk is approximately 2% to 4%.58
While amiodarone is designated as a class III agent, it has properties of all four classes of the Vaughan-Williams classification. The electrophysiologic effects of intravenous amiodarone differ from oral amiodarone; when given intravenously, amiodarone exhibits acute inhibitory effect on INa and ICa,L, whereas oral amiodarone has a delayed onset of action, which takes at least 2 to 3 days, that mainly targets outward currents. Chronic administration of amiodarone inhibits multiple outward potassium currents including IKr, IKs, IK1, and Ito. Although amiodarone may cause marked QT prolongation, it rarely leads to TdP.59 Amiodarone exerts its antiadrenergic effects by noncompetitive binding to β-adrenergic receptors and inhibition of agonist-induced increases in adenylate cyclase activity. These combined effects may lead to QT prolongation, a slight increase in QRS duration, and a profound inhibitory effect on sinus node and AV conduction.
Amiodarone is highly lipid soluble and has complex pharmacokinetics. The effective volume of distribution of oral amiodarone is variable, but can be quite significant (range 18-148 L/kg), and therefore, it may take many weeks or months for amiodarone to reach equilibrium in the body. Similarly, its elimination half-life is also very long, ranging from many weeks to months.60 Amiodarone is metabolized to desethylamiodarone, which has similar electrophysiologic effects to those of amiodarone.
The typical oral loading regimen is 800 to 1600 mg daily in divided doses, up to 2 to 3 weeks before dose adjustment to 200 to 400 mg per day. The goal of chronic amiodarone is to use a dose as low as possible for good efficacy and limited adverse effects. Because amiodarone is not eliminated by the kidney, dose adjustment in patients with renal insufficiency is not necessary.
Intravenous use of amiodarone typically starts with a 150-mg bolus. The standard intravenous loading regimen is then a continuous infusion of 1 mg/min for a period of 6 hours and then reduction to 0.5 mg/min for an additional 18 hours. Intravenous bolus can be repeated for refractory or recurrent arrhythmia. When given intravenously, amiodarone is distributed rapidly; its plasma level after discontinuing infusion diminishes quickly in 30 to 60 minutes.
Amiodarone may raise the plasma concentration of digoxin and warfarin, leading to serious toxicities. Therefore, doses of these two drugs often need to be adjusted when amiodarone is started.
Amiodarone has a broad spectrum of antiarrhythmic actions in a variety of supraventricular and ventricular arrhythmias.61,62 Of the currently available antiarrhythmic drugs, amiodarone has claimed supremacy in treatment and prevention of atrial fibrillation by its cardiac safety and efficacy in multiple randomized and nonrandomized trials.46,57
In addition, intravenous amiodarone has replaced intravenous lidocaine as the first-line drug for treatment and prophylaxis of ventricular fibrillation, particularly hemodynamically compromised ventricular arrhythmias refractory to other therapies.61 Amiodarone has not been demonstrated to have a clear benefit on survival for ventricular arrhythmias in patients with left ventricular dysfunction. Specifically, the SCD-HeFT (Sudden Cardiac Death in Heart Failure) trial, which looked at patients with ischemic or nonischemic cardiomyopathies, did not show a mortality benefit in either group with amiodarone therapy.63 Intravenous amiodarone is also an excellent AV-blocking agent and is effective in slowing the ventricular responses to atrial fibrillation in critically ill patients.64
Although amiodarone has an excellent efficacy and cardiac safety profile, it has potential adverse effects affecting nearly every organ system except the kidney. Even low-dose amiodarone (≤ 400 mg) has been shown to at least double a patient’s likelihood of developing a thyroid, neurologic, ocular, skin, or bradycardic adverse event.65 The odds of discontinuing amiodarone because of adverse events was almost 1.5 times that of the control group.65 Additionally, amiodarone therapy, compared with other antiarrhythmic drugs, is more sustained because of its extended half-life, and the adverse effects of the drug increase as a function of time as a result of extensive tissue accumulation.
Iodine in the amiodarone molecule is the likely cause of its extracardiac adverse effects. With a daily maintenance dose of amiodarone between 100 and 600 mg, approximately 3.5 to 31 mg of iodide are released into the systemic circulation, which is equivalent to a 35- to 140-fold excess of daily intake. In a normal-functioning thyroid gland, further iodine transport and thyroid hormone biosynthesis are inhibited, leading to hypothyroidism. However, a preexisting autonomously functioning nodule escapes the Wolff-Chaikoff effect and produces excess amounts of thyroid hormones in response to large concentrations of iodine, leading to type 1 hyperthyroidism. Conversely, amiodarone itself and excess iodide can exert direct cytotoxic effects on thyroid follicles, leading to destructive inflammatory thyroiditis and a consequent leakage of a large amount of thyroid hormone, leading to type 2 hyperthyroidism.
Additionally, iodine also renders the amiodarone molecule more lipophilic, increasing its volume of distribution. The active metabolite of amiodarone, N-desethylamiodarone, significantly accumulates in adipose tissue and highly perfused organs. Besides the previously mentioned hyperthyroidism and hypothyroidism, relatively common adverse effects of amiodarone include anorexia, nausea, vomiting, constipation, altered taste, corneal microdeposits, blue-gray skin discoloration, and photosensitivity of the skin. Liver and pulmonary toxicities, which may be dose dependent, are important extracardiac adverse effects and include elevation of hepatic enzymes, hepatic cirrhosis, chronic interstitial pneumonitis or bronchiolitis obliterans, and relatively rare acute pneumonitis. Neurologic adverse effects, including peripheral neuropathy and myopathy, may occur with use of higher-dose amiodarone. Rarely, amiodarone may cause optic neuritis.
Amiodarone may cause marked sinus bradycardia or AV block. However, TdP is rare. Its minimal risk in increasing proarrhythmia also adds to its attractiveness and wide use.
Because amiodarone may cause significant extracardiac adverse effects, hepatic, thyroid, and pulmonary functions need to be assessed on a regular basis.
Dofetilide is a pure IKr blocker that prolongs action potentials in the atria and ventricles. On the ECG, QT prolongation is not accompanied by an increase in PR and QRS. The Tp-e interval, an index of transmural dispersion of repolarization,8 may increase as well when the baseline ECG is normal (ie, there are positive T waves).
Dofetilide is well absorbed with a bioavailability of 92%.66 The free therapeutic plasma concentration is approximately 0.8 ng/mL. The elimination half-life ranges from 8 to 10 hours in patients with normal renal function. Approximately 70% to 80% of the drug is excreted in the urine, so dosing must be adjusted based on creatinine clearance. The remaining 20% to 30% is metabolized in the liver by the CYP3A4 isoenzyme of the cytochrome P450 enzyme system. Compounds that inhibit the CYP3A4 isoenzyme, such as amiodarone, erythromycin, ketoconazole, verapamil, and cimetidine, increase serum dofetilide level.
Dosage must be adjusted based on the change in the QT interval because of TdP risk, so the initiation of the drug therapy must be done in a hospital, where ECG recording and telemetry are available. QTc prolongation > 500 ms in narrow QRS or a change in the QTc interval > 15% in baseline wide QRS (> 120 ms) should prompt discontinuation of the drug.
Dofetilide is used for treatment and prevention of atrial fibrillation and atrial flutter. Because dofetilide has no deteriorating effect on ventricular contractility, it can be safely used for conversion of atrial fibrillation and prevention of its recurrence in patients with congestive heart failure. It may also have value in suppressing reentrant ventricular arrhythmias such as monomorphic ventricular tachycardia resulting from myocardial scar.
TdP is a major concern. The TdP incidence was approximately 3% to 4% in earlier clinical trials. When dofetilide is initiated in hospital and its dose is adjusted based on ECG changes, the TdP incidence appears to be lower. Dofetilide should be avoided in patients with marked renal insufficiency or baseline QT prolongation. Defetilife also has demonstrated safety in left ventricular dysfunction and recent history of myocardial infarction.67
Dronedarone was approved for the treatment of atrial fibrillation and flutter by the US Food and Drug Administration in 2009. It is an analog of amiodarone, but is a noniodinated benzofuran derivative with the most significant molecular modification being removal of iodine and the addition of a methane sulfonyl group.
Although dronedarone displays similar electrophysiologic properties as its mother compound amiodarone and has effects on multiple cardiac ion channels, its efficacy in suppressing cardiac arrhythmias is inferior to amiodarone. It has potent class I to IV antiarrhythmic activity according to the Vaughan-Williams classification scheme.26 However, dronedarone has stronger ICa,L inhibition. In addition, dronedarone has a noncompetitive antiadrenergic action. On the ECG, dronedarone prolongs the R-R and QTc intervals and may also mildly increase QRS duration.
Dronedarone is well absorbed after oral administration, with bioavailability of 15% to 20% that increases two- to three-fold when taken with food.68 It undergoes extensive first-pass metabolism and is metabolized by CYP3A4. It is expected to interact with drugs such as digoxin, calcium channel blockers, erythromycin, and ketoconazole. Dronedarone is also a CYP2D6 inhibitor and causes a modest increase in bioavailability of metoprolol in CYP2D6 extensive metabolizers.68 The clearance of dronedarone is principally nonrenal. With chronic administration at 400 mg twice daily, the steady-state plasma level is reached in approximately 2 weeks, and elimination half-life is approximately 24 hours.
Dronedarone is used for the prevention of recurrent atrial fibrillation and flutter.
Based on an adverse effect on mortality in ANDROMEDA (Antiarrhythmic Trial With Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease), dronedarone should be avoided in patients with advanced heart failure.26,69 In addition, dronedarone should not be used in patients with permanent atrial fibrillation because of an increased risk for heart failure, stroke, and death with use in this population. This recommendation is based upon data from the PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy) trial, which was terminated early as a result of excess mortality and morbidity in patients in the dronedarone treatment group versus control.70
Dronedarone is not associated with thyroid, neurologic, ocular, or pulmonary toxicity. Dronedarone leads to dose-dependent prolongation of QT interval, but no TdP has been reported. Like amiodarone, it has a very low proarrhythmic risk, differentiating it from most other antiarrhythmics. The most common adverse effects of dronedarone are gastrointestinal, including nausea, vomiting, and diarrhea. There was a reported incidence of serum creatinine elevation by about 0.1 mg/dL in approximately 2.4% of patients as a result of dronedarone-induced inhibition of tubular secretion.71
Nondihydropyridine Calcium Channel Blockers
Unlike a large number of dihydropyridine calcium channel blockers, the nondihydropyridine calcium channel blockers verapamil and diltiazem specifically inhibit calcium-dependent slow action potentials in the sinoatrial and AV nodes. These two agents slow diastolic depolarization in both nodes, therefore slowing the pacemaker rate. They also prolong the refractory period of the AV node, reducing ventricular responses to atrial fibrillation. However, verapamil and diltiazem may cause peripheral vasodilation, which may partially offset their sinus and AV nodal slowing effects.
When given intravenously with bolus, the peak effects of verapamil and diltiazem occur after approximately 15 minutes. Although both drugs are well absorbed, their bioavailability is approximately 35% (verapamil) and 45% (diltiazem) after their first-pass metabolism. Elimination by the kidney is not important. Their elimination half-life is similar, ranging from 3 to 7 hours.
Verapamil and diltiazem are used for termination of supraventricular tachycardias and prevention of their recurrence. They are also used for ventricular rate control in atrial fibrillation and flutter. Calcium channel blockers can effectively suppress focal atrial tachycardia particularly related to pulmonary diseases. Some idiopathic ventricular tachycardias, particularly in the left ventricle, are verapamil sensitive and may be successfully treated with this agent. Verapamil and diltiazem reduce both resting and exercise heart rates in patients with atrial fibrillation. Verapamil and diltiazem may also effectively prevent ventricular tachycardia or fibrillation caused by coronary artery spasm.
Both agents inhibit ICa,L and should be avoided in patients with advanced heart failure or hypotension. Both agents can cause sinus bradycardia and AV block. Verapamil and diltiazem, particularly when given intravenously, should be avoided in the Wolff-Parkinson-White syndrome complicated by atrial fibrillation because they may facilitate conduction over the accessory pathway, resulting in ventricular fibrillation. Noncardiac adverse effects include dizziness, headache, nausea, constipation, and insomnia.
Other Antiarrhythmic Drugs
Adenosine is an important physiologic regulator in many organ systems. Rapid intravenous injection of adenosine has negative dromotropic and chronotropic effects mainly on the sinoatrial and AV nodes mainly via the A1 adenosine receptor. Adenosine activates adenosine-induced inwardly rectifying K+ current (IKAdo) and inhibits the pacemaker current (If) in the atria, sinus, and AV nodes. These combined effects cause transient complete AV block and sinus bradycardia. Adenosine has no significant effect on AV accessory pathways. Adenosine can produce coronary vasodilatation via its effects on A2 receptors in the vascular smooth muscle cells.
Adenosine is rapidly cleared by cellular uptake and metabolism, with an estimated elimination half-life of 1 to 5 seconds. Aminophylline antagonizes the negative chronotropic and dromotropic effects of adenosine, whereas dipyridamole, a strong adenosine uptake inhibitor, potentiates the effects of adenosine. The dose of adenosine is 6 to 12 mg by intravenous bolus.
The main use of adenosine is to convert paroxysmal supraventricular tachycardias to normal sinus rhythm. Two common types of proximal supraventricular tachycardias (ie, AV nodal reentry and AV reentry tachycardias) use the AV node as part of the route for their circus (reentry) movement. Therefore, adenosine that transiently blocks AV conduction effectively terminates these two reentrant paroxysmal supraventricular tachycardias. Adenosine administration also has growing utility in guiding pulmonary vein isolation catheter ablations for atrial fibrillation. In this setting, adenosine testing has been utilized effectively to identify potentially at risk dormant pulmonary vein conduction during catheter ablation.72
Adenosine should be avoided in patients with sick sinus syndrome or AV block. The common adverse effects are facial flushing, chest pressure, and dyspnea, but these effects are mild and brief. In patients with asthma, adenosine can trigger an acute attack caused by bronchoconstriction. Adenosine may induce atrial fibrillation.
Digoxin augments vagal tone, leading to the prolongation of the AV node effective refractory period and a decrease in sinus rate and AV conduction. However, digoxin inhibits sarcolemmal Na+-K+-ATPase, leading to an increase in intracellular calcium that may promote triggered activities.
Digoxin is fairly well absorbed, with an oral bioavailability of 60% to 80%. It is mainly eliminated by the kidney. The elimination half-life is approximately 36 hours in patients with normal renal function and up to a week in those with renal impairment. In patients with renal failure, hepatic metabolism becomes important in digoxin clearance. Many drugs, such as amiodarone, quinidine, and verapamil, increase serum digoxin concentration. Digoxin can be given orally or intravenously, and is initially given with a weight based loading dose followed by a maintenance dose. Intravenous and oral dosing is not equivalent, with 100 μg intravenous equaling 125 μg oral dose.
Digoxin as an antiarrhythmic drug is mainly used to control the ventricular rate in atrial fibrillation/flutter or to prevent relapse of supraventricular arrhythmias using the AV node. Digoxin is particularly useful in pregnant patients with supraventricular tachycardias because many years of clinical experience has demonstrated that use of digoxin is safe during pregnancy. Digoxin has also been used routinely in ventricular rate control in atrial fibrillation in congestive heart failure. However, there is data that suggests a possible increased risk of death with the use of digoxin in this group.73 Future studies and ideally a randomized control study examining this issue will be critically important in guiding future clinical management with respect to digoxin use in heart failure patients with atrial fibrillation.
Cardiac toxicities are sinus bradycardia, AV block, and triggered atrial and ventricular arrhythmias including paroxysmal atrial tachycardia, ventricular bigeminy, junctional tachycardia, and bidirectional ventricular tachycardia. Noncardiac adverse effects include anorexia, nausea, headache, halo vision, visual scotomas, and altered color perception. Hypokalemia enhances digoxin toxicity.
Digoxin levels are routinely measured to monitor for appropriate target drug concentration as a result of its narrow toxic to therapeutic window. In patients with left ventricular dysfunction, a lower digoxin level is recommended (0.5-0.8 ng/mL).74 This is based on evidence of a possible reduced mortality at these lower digoxin levels, as well as increased mortality with a serum digoxin concentration ≥ 1.2 in this population.75,76
Ranolazine is approved for treatment of chronic angina. However, this drug has potent antiarrhythmic activity.77 Ranolazine inhibits IKr, IKs, late INa, ICa, and INa-Ca.78 Animal data revealed marked atrial selectivity in its sodium channel blockade in a rate dependent manner, which may have particularly valuable characteristics in atrial fibrillation.79 Oral bioavailability of ranolazine is 35% to 50% and it is eliminated primarily by the liver. The elimination half-life is approximately 7 hours with the extended-release formulation.
Ranolazine appears to be useful for treatment of both atrial fibrillation and ischemia-induced ventricular arrhythmias. In the MERLIN-TIMI 36 randomized controlled trial of 6351 patients with a non–ST-segment elevation acute coronary syndrome who were hospitalized and monitored with continuous ECG recording, ranolazine was associated with less ventricular tachycardia (5.3% vs 8.3%) and less new onset of atrial fibrillation (1.7% vs 2.4%) compared with the placebo group.77 The HARMONY trial showed that the addition of ranolazine to reduced dose dronedarone had a synergistic effect in providing a reduced burden of atrial fibrillation in patients with paroxysmal atrial fibrillation.80 However, there are no prospective trial data to support its usefulness to treat arrhythmias such as atrial fibrillation. Adverse effects include constipation, headache, dizziness, and nausea. Ranolazine may also cause bradycardia, orthostatic hypotension, and palpitations. QT prolongation may be present, but TdP has not been reported.
Ivabradine is approved for treatment of stable symptomatic heart failure, specifically in patients with decreased systolic function who are in sinus rhythm with a heart rate of 70 bpm of greater. It works by blocking the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel, causing a decrease in the spontaneous pacemaker activity of the sinus node through inhibition of the “f-current” (If). Its utilization has also been explored in management of inappropriate sinus tachycardia and postural tachycardia syndrome (POTS).81,82 For inappropriate sinus tachycardia, there are initial data showing its efficacy in reducing heart rate as well as providing improvement in symptoms in this patient group.83,84 Additional studies and clinical experience using ivrabadine are both necessary before being routinely used in this setting.
Ivabradine is metabolized by CYP3A4. Use of strong CYP3A4 inhibitors (eg, clarithromycin, ketoconazole, ritonavir) is contraindicated, with potential for high ivabradine concentrations and increased risk of severe bradycardia. It is contraindicated in patients with severe liver dysfunction. Adverse reactions include bradycardia, hypertension, atrial fibrillation, and visual disturbances. There are no effects on cardiac contractility.
Vernakalant hydrochloride is a novel intravenous antiarrhythmic that is designed to rapidly terminate acute-onset atrial fibrillation.85 Vernakalant’s mechanism of actions is blockade of sodium channels and early activation of potassium channels. Its activity on the sodium channel is rate dependent, and therefore has weak activity blocking the INa channel at low heart rates, but increases its INa channel blockade with increasing heart rates. Vernakalant also has an atrial selective potassium channel blocking effect. Initial data examining electrophysiologic properties revealed prolongation of the atrial refractory period and AV nodal conduction.86 Its elimination half-life is approximately 2 hours. It is predominantly cleared by the liver, and likely requires dose adjustments in advanced liver disease.
Vernakalant hydrochloride injection is under review for its use in rapid conversion of atrial fibrillation to sinus rhythm. Prior studies reveal an approximate 50% conversion rate from atrial fibrillation to sinus rhythm within 90 minutes from initial infusion.87,88 Currently, vernakalant is not approved by the Food and Drug Administration for use in the United States.