CHAPTER 87: ANTIARRHYTHMIC DRUGS

The treatment of patients with tachyarrhythmias has evolved dramatically over the past several decades. However, even with advances in catheter ablation and implantable cardioverter-defibrillators, antiarrhythmic drug therapy remains a cornerstone in the treatment of nearly every form of cardiac arrhythmia. An in-depth knowledge of the pharmacology of antiarrhythmic drugs, including their pharmacokinetics and pharmacodynamics, is essential to their successful and safe implementation (Table 87–1).

The development of cardiac arrhythmias and drug-induced proarrhythmias can be a result of abnormal impulse formation (ie, enhanced automaticity and triggered activities) and/or reentry. This section provides a brief overview of ionic and cellular mechanisms underlying the antiarrhythmic and proarrhythmic effects of the drugs.

Ion Channel Physiology

Antiarrhythmic drugs exert their effects on cardiac electrical impulse formation and propagation via their interaction with ionic channels or with membrane receptors and cellular pumps that subsequently influence ionic currents across the cell membrane. Cardiac ionic currents commonly targeted by antiarrhythmic drugs include inward sodium current (I_Na), L-type calcium current (I_Ca,L), and delayed rectifier outward potassium current (I_K), which consists of two components—a rapidly activating component (I_Kr) and a slowly activating component (I_Ks). Although transient outward potassium current (I_to) is not commonly influenced by currently available antiarrhythmic drugs, it has been shown to contribute importantly to the genesis of polymorphic ventricular tachycardia and ventricular fibrillation.¹ Therefore, antiarrhythmic drugs with selective I_to blockade will be favored in future drug development.

Antiarrhythmic drugs that block the sodium channel appear to bind selectively to the channel during designated states and dissociate from the channel during the other states. Therefore, a sodium channel blocker will block the sodium channel differently depending on pathologic conditions. The maximal velocity of change in membrane potential during phase 0 (V_max) is correlated with influx of sodium ions through opened sodium channels, and this is the major driving force for electrical conduction in atrial, His-Purkinje, and ventricular tissues. Drug binding occurs during phase 0 and phase 2 and dissociation occurs during phase 4. Class Ic drugs, which demonstrate slow dissociation kinetics, cause conduction slowing that manifests as P-wave and QRS widening on the surface electrocardiogram (ECG) during tachycardia because there is less time for dissociation and more opportunity for drug binding. Class Ib drugs have only a modest effect on action potential phase 0 under normal conditions. However, in ischemic myocardium with reduced membrane potential, voltage- and time-dependent recovery of the sodium channel from inactivation is delayed, such that binding of class Ib drugs to the channel is significantly increased. This explains the greater activity of class Ib antiarrhythmic drugs under conditions of myocardial ischemia. By contrast, repolarization in the atria is faster than in the ventricles, and is associated with rapid transition of the atrial sodium channel from the inactivated to the resting state. Therefore, class Ib drugs play little role in atrial arrhythmias.

A few channels may remain open through sustained depolarization, the so-called late (or slow) I_Na-L,² and contribute to the action potential duration (APD). Compared with the epicardium and endocardium, the submyocardium of the left ventricle (M cells) has a larger late I_Na-L.³ Increasing evidence suggests that, as a result of its slow inactivation and recovery kinetics, I_Na-L plays a central role in the rate dependence of the APD and QT duration, as well as in the reverse use-dependence of select APD/QT-prolonging agents.⁴

I_Ca,L is responsible for the prolonged plateau phase (phase 2) of the action potentials of atrial, His-Purkinje, and ventricular cells, and is the major inward current responsible for phase 0 depolarization in sinus and atrioventricular (AV) nodal cells. Consequently, calcium channel blockade causes slight action potential shortening in the atria, His-Purkinje system, and ventricles; depresses the slope of diastolic depolarization and action potential amplitude; and prolongs the effective refractory period in sinus and AV nodal cells. L-type calcium channels may reactivate during the action potential plateau under conditions of delayed ventricular repolarization (ie, long QT syndrome). This may lead to early afterdepolarization (EAD) capable of initiating a specific form of polymorphic ventricular tachycardia termed torsade de pointes (TdP).⁵ In addition, a larger calcium influx via L-type calcium channel increases the likelihood of calcium overloading in the sarcoplasmic reticulum (SR) under certain pathologic conditions. Oscillatory release of calcium from SR increases Na/Ca exchange, resulting in the genesis of delayed afterdepolarization (DAD) and triggered activity.⁶

I_Kr and I_Ks are the major repolarizing currents in the heart, and their blockade leads to an increase in APD and effective refractory period in the atria, AV node, His-Purkinje fibers, ventricles, and accessory pathways. Therefore, the drugs that inhibit I_Kr and/or I_Ks, such as sotalol and dofetilide, have value in the treatment of reentrant arrhythmias such as atrial fibrillation, atrial flutter, and monomorphic ventricular tachycardia. The majority of antiarrhythmic and noncardiac drugs that prolong the QT interval and induce TdP also block I_Kr.

The role of I_to in arrhythmogenesis has been highlighted in the past two decades. A prominent I_to-mediated action potential notch in the ventricular epicardium, but not endocardium, produces a transmural voltage gradient during early ventricular repolarization that could register as a J-wave or J-point elevation on the ECG.⁷ If the I_to-mediated notch is deep enough, epicardial action potential dome at phase 2 is sensitive to a change in the net repolarization current. An increase in the net repolarization current, resulting from either a decrease in inward currents or augmentation of outward currents, may result in partial or complete loss of the dome, leading to a transmural voltage gradient that manifests as ST-segment elevation.⁸ Heterogeneous loss of I_to-mediated action potential dome, particularly when it is complete, results in marked repolarization dispersion on the epicardium surface, leading to reentry at action potential phase 2 (ie, so-called phase 2 reentry). The extrasystole produced via phase 2 reentry occurs often on the down limb of the T wave (R-on-T phenomenon). This may, in turn, initiate polymorphic ventricular tachycardia or fibrillation.⁸ In structurally normal hearts, the I_to-mediated J wave is the intrinsic link for ST-segment elevation among early repolarization syndrome, idiopathic ventricular fibrillation, and Brugada syndrome. Therefore, these syndromes are now referred to as J-wave syndromes.^1,9,10,11 This explains why quinidine, a class IA drug that also exhibits an additional inhibitory effect on I_to, is effective in preventing ventricular fibrillations in J-wave syndromes.^12,13,14

Use Dependence

Blockade of inward currents may be use dependent. The class Ic drugs dissociate from the sodium channels in the resting state very slowly, exhibiting strong use dependence that manifests as a marked increase in sodium channel blockade during tachycardia. This is thought to be responsible for the increased efficacy of the class Ic antiarrhythmic drugs in slowing and converting tachycardia with minimal effects at normal sinus rates. However, strong use dependence of a drug on I_Na may be proarrhythmic (eg, flecainide-induced atrial flutter or ventricular tachycardia) when the effect of the drug on conduction slowing is stronger than its effect on the effective refractory period.

Reverse Use Dependence

As opposed to the use dependence observed for drugs that block the sodium and calcium channels, inhibition of I_Kr is enhanced during bradycardia when the channel is “not frequently used,” leading to more significant action potential prolongation at slow heart rates. The mechanism may be related to the dependence of I_Kr blockade on extracellular potassium concentration.¹⁵ However, reverse use dependence does occur in an extracellular environment where K⁺ concentration is unchanged, and it is likely a result of an effect on I_Na-L. Block of I_Na-L blunts the normal rate dependence of APD/QT and abolishes reverse use dependence.¹⁶

Reentry

Development of reentry using an anatomic circuit, for example around a scar tissue secondary to myocardial infarction, is determined by the wavelength of the reentrant wavefront and the size of the circuit. The wavelength of the reentrant wavefront is equal to the product of the conduction velocity times the effective refractory period of myocardial tissue in the pathway, and should be significantly shorter than the length of the reentrant circuit for maintenance of circus movement. Conduction velocity of the electrical impulse in the atria, His-Purkinje, and ventricles is largely determined by the intensity of the fast inward sodium current that contributes to the rapid upstroke (V_max) of the action potential. Therefore, class Ic antiarrhythmic drugs may predispose to the development of monomorphic ventricular tachycardia in patients with coronary artery disease as a result of the drugs’ reduction of V_max of the action potential and conduction velocity that surpasses the drugs’ effects to prolong the effective refractory period.¹⁷ However, antiarrhythmic drugs that prolong the effective refractory period without influencing conduction and, thus, the wavelength of a reentrant impulse are useful in suppressing reentrant arrhythmias.

Abnormal Impulse Formation

Abnormal Automaticity

Normal automaticity of cardiac cells is the consequence of spontaneous diastolic depolarization caused by a net inward current during phase 4 of action potential. Abnormal automaticity, which is caused by either enhanced normal automaticity or spontaneous activity in ventricular and atrial myocardium, may occur with heightened β-adrenergic tone or reduced resting membrane potentials, such as ischemia or infarction.¹⁸ β-adrenergic receptor or calcium channel blockers are useful in treatment of arrhythmias caused by abnormal automaticity. The hyperpolarization-activated “funny” current (I_f, also called pacemaker current) may play an important role in enhanced automaticity such as in inappropriate sinus tachycardia. Blockade of this current is a promising treatment option for patients with inappropriate sinus tachycardia.¹⁹

Afterdepolarizations and Triggered Activity

Afterdepolarization can be divided into two subclasses: EADs and DADs. EADs often occur in M cells or endocardium because these action potentials prolong disproportionally with drugs that block I_Kr, an ionic current targeted by most QT-prolonging drugs.^5,20 Antiarrhythmic drugs that inhibit I_Ca,L or shorten APD by blocking the sodium current, such as mexiletine, suppress EADs. Calcium channel and β-adrenergic blockers suppress DADs, and therefore DAD-mediated arrhythmias, by reducing intracellular calcium overload.

Proarrhythmia

Proarrhythmic and antiarrhythmic effects of a drug are two sides of the same coin. Antiarrhythmic drugs intended to suppress arrhythmias may potentially worsen a preexisting arrhythmia or cause a new arrhythmia. The mechanisms responsible for cardiac arrhythmias are complicated, and any intervention may be antiarrhythmic in some circumstances and proarrhythmic in others.

Atrial Proarrhythmia

When class Ic antiarrhythmic drugs are used for the treatment of supraventricular tachycardia, they can cause atrial flutter, often with slower rates (~200 bpm). This is seen in patients with atrial fibrillation treated with the class Ic drugs flecainide and propafenone. The slowed atrial flutter may be associated with 1:1 AV conduction with markedly rapid ventricular rates. Therefore, dosing with an AV nodal blocking agent should be considered with a sodium channel blocker in patients with atrial fibrillation and intact AV nodes.

Adenosine and digitalis occasionally promote the development of atrial fibrillation by shortening the atrial effective refractory period. Shortening of the refractory period reduces the wavelength of the reentrant wavefront, so that reentry can occur in smaller reentrant substrates.

Ventricular Proarrhythmia

Ventricular proarrhythmias can generally be divided into two categories based on mechanisms and ECG features: monomorphic ventricular tachycardia and TdP.

A key factor in the genesis of monomorphic ventricular tachycardia is the availability of an anatomic reentrant pathway, such as scar tissue or tricuspid and mitral rings. Any drug that causes conduction slowing greater than effective refractory period prolongation has the potential to facilitate the development of reentrant arrhythmias. Class Ic drugs have the highest risk to cause this type of proarrhythmia and to increase mortality in patients with coronary artery disease and left ventricular systolic dysfunction.^21,22,23 Myocardial ischemia seems to play a pivotal role in the genesis of proarrhythmia with class Ic drugs. Conversely, proarrhythmia rates are nearly zero when class Ic drugs are used for atrial arrhythmias in patients with a structurally normal heart.²⁴

TdP requires QT prolongation.⁸ It is widely accepted that TdP is initiated by EAD-dependent triggered activity and maintains itself via functional reentry.⁵ Class Ia and class III antiarrhythmic drugs that block I_Kr and/or increase late I_Na may facilitate the development of TdP. Interestingly, amiodarone, a commonly used class III antiarrhythmic drug, significantly prolongs the QT interval, but rarely causes TdP. Amiodarone prolongs the APD without producing EADs, and reduces transmural dispersion of repolarization, probably as a consequence of its effects on multiple ionic channels and receptors.²⁵ Dronedarone, a noniodinated benzofuran derivative of amiodarone that was approved for treatment of atrial fibrillation in 2009, also causes QT prolongation without a significant risk of TdP.²⁶

Marked QT prolongation and resultant TdP are more likely to occur in patients with reduced repolarization reserve. Clinical diseases or factors that are associated with reduced repolarization reserve include congenital long QT syndrome, bradycardia, female sex, ventricular hypertrophy, electrolyte disturbances such as hypokalemia and hypomagnesemia, and coadministration of other QT-prolonging agents or drugs that delay clearance of the drugs from the body.

Pharmacokinetics describes the relationship between drug administration and plasma concentration. It is assumed that the plasma concentration reflects, in a general sense, myocardial concentrations and thus the availability of the drug at its site of action. The pharmacokinetics of antiarrhythmic drugs are variable and not predictable by drug classification or by knowledge of the drug’s chemical structure.

Absorption/Bioavailability

Absorption describes the movement of orally administered drug from the gut lumen to the systemic circulation, and the efficiency of this absorption is defined as bioavailability. Those factors that influence passage of the drug through the gut wall into the portal circulation and through the liver will have an effect on drug bioavailability. Thus, diseases that affect bowel motility, bowel wall blood flow, gastric and bowel pH, and presystemic or “first-pass” hepatic clearance will, to some extent, influence the amount of drug that is available to the systemic circulation.

A common way to extend interdosing intervals during treatment with drugs that have a relatively short plasma half-life is to formulate them into a sustained-release preparation. These preparations can be particularly affected by changes in bowel pH and other conditions within the gut that influence the amount of drug that is absorbed from the gastrointestinal tract. Drugs can also have altered absorption because of intraluminal binding by other substances, such as milk and antacids. Finally, the physiochemical properties of the drug itself can have an effect on absorption.

Absorption of antiarrhythmic drugs is also dependent upon the solubility of the drug, which is affected by its intrinsic chemical and physical makeup, as well as the composition of the medium. Weak bases are rapidly dissolved in acid medium and, therefore, the use of antacids can slow the absorption of a weakly basic drug by increasing gut pH. In clinical situations, high intestinal pH, caused by such factors as bacterial overgrowth syndrome, can reduce the bioavailability of antiarrhythmic drugs. Thus, for patients with serious arrhythmias, especially those that are controlled by drugs that have a relatively narrow toxic-to-therapeutic ratio, reassessing plasma concentration or clinical efficacy during conditions of altered bowel physiology or pathology is relevant.

Finally, many antiarrhythmic drugs have a food-fast effect; that is, the bioavailability of a drug may be changed several-fold in the presence of food or during fasting. A notable example is oral amiodarone, which is three times more bioavailable after a high-fat meal.²⁷ For such drugs, providing the patient with specific information as to the timing of drug ingestion with relationship to meals is important to maintain a predictable and reproducible plasma concentration over the course of therapy.

Generic antiarrhythmic drugs are approved by demonstration of bioequivalence. Thus, variations in formulation that can occur with generic drugs are permissible as long as there is a clear demonstration that the same amount of the generic drug is absorbed and available to the systemic circulation as the proprietary compound. Regulatory agencies have specified limits in the difference in bioavailability that may be allowed for the approval of new formulations.²⁸

Distribution

An understanding of distribution is key to appreciating both the intended and unintended effects of antiarrhythmic drugs. Following absorption, drug is distributed to various parts of the body, and the pattern of distribution is determined by the amount of blood flow to different tissues (Fig. 87–1). Organs with high blood flow, such as the heart, liver, brain, and kidney, are generally exposed to the drug early, and these organs are generally referred to as the central compartment. However, drugs nearly always redistribute from the central compartment to other tissues or sites of metabolism and elimination. They may distribute to muscle, skin, and adipose tissue, generally in a second phase. These less-perfused organs are considered to be the peripheral compartment. Finally, some drugs may distribute very slowly to tissues and organs that have low blood flow and may be referred to as the deep compartment. When the relative concentrations of drugs in all compartments reach equilibrium, steady state has been reached.

Volume of distribution is the term used to describe the virtual pool into which a drug is administered, and is affected by tissue perfusion and degree of protein binding. Therefore, patient characteristics and disease states may affect the volume of distribution. In congestive heart failure, reduced organ perfusion may decrease the volume of distribution of the central compartment, making more of the drug available to active binding sites in the heart. Consequently, patients with congestive heart failure have increased sensitivity to the electrophysiologic properties of commonly used agents.²⁹

Critically important among the factors that modulate volume of distribution is protein binding, which can be influenced by changes in the concentration of binding proteins, fluctuations in drug concentrations, and interactions with drugs competing for the same protein-binding sites. Most antiarrhythmic drugs are bound to varying extents in plasma to α₁-acid glycoprotein. For example, when dosing lidocaine in a patient with myocardial infarction, potential increases in α₁-acid glycoprotein levels and subsequent increased lidocaine binding would lessen the proportion of unbound drug available for the expected pharmacologic effect.³⁰

Drug Metabolism

The metabolism of drugs in general, as well as of antiarrhythmic drugs, can be divided into two phases. The first phase changes the drug into more polar metabolites via oxidation-reduction reactions. During the second phase, drugs are conjugated to endogenous ligands, such as glucuronide or sulfate. The majority of drug metabolism occurs in the liver, with oxidative metabolism usually occurring via the cytochrome P450 enzyme system. However, the metabolism of rapidly cleared drugs may occur in lung, plasma, vascular endothelium, or even red blood cells.

Knowledge of the relative concentration of active metabolites and their electrophysiologic action is critical to understanding the net pharmacologic effect of an antiarrhythmic drug. An example of an active metabolite is 5-hydroxypropafenone, a metabolite that has similar electrophysiologic effects to those of the parent compound, but with slightly less potency.³¹ The 5-hydroxy metabolite of propafenone possesses little β-adrenergic blocking activity. Thus, the presence of higher concentrations of the metabolite would be associated with less rate slowing in extensive metabolizers compared with a small percentage of individuals who are poor metabolizers of propafenone who manifest a greater β-blocking effect. Similarly, N-acetylprocainamide (NAPA), the principal metabolite of procainamide, has a greater repolarization effect than the parent drug procainamide. NAPA is renally eliminated, and so in a rapid acetylator with renal impairment, a greater effect on QT interval might be expected compared with an individual who has lesser amounts of the metabolite in the circulation.³²

The relative concentration of parent and metabolite in any individual is genetically determined.²⁷ Varying metabolic characteristics of antiarrhythmic agents is a major determinant of the utility of therapeutic drug monitoring, for example, measuring lidocaine or procainamide levels. Genetic polymorphisms have been most extensively described for the oxidative P450 enzyme system. Population studies demonstrate that this enzyme system is expressed in a bimodal pattern, with subjects having either “extensive” or “poor” metabolic capability. The poor metabolizer phenotype is expressed in approximately 10% of the population in whom parent drug plasma concentration is increased, clearance is reduced, and elimination half-life is prolonged. P450 enzyme isoforms have been identified that are responsible for the metabolism of specific agents and now can be identified by genotyping. Careful monitoring of patients during drug initiation to detect differences in response that may be caused by relative concentration of parent and metabolite is critically important for patient safety. As our understanding of pharmacogenetics continues to grow, there may be a role for individually tailored antiarrhythmic drug strategies to achieve optimal drug levels.

CYP2D6 is the enzyme responsible for the metabolism of propafenone, flecainide, acebutolol, metoprolol, and propranolol. Most patients are extensive metabolizers, which means that a large percentage of the parent compound is transformed into a metabolite with activity that is identical to, similar to, or dissimilar from the parent. However, 5% to 10% are poor metabolizers, producing poor clearance with increased drug concentration, for which significant β-blockade can occur with an increased risk of asthma.

CYP3A4 is the most prevalent enzyme in the liver, and plays a role in the metabolism of many antiarrhythmic drugs, including amiodarone, quinidine, lidocaine, and many calcium channel blockers. This enzyme is inhibited by multiple agents, which include cimetidine, erythromycin, fluconazole, and grapefruit juice. Use of these agents causes accumulation of higher concentrations of the parent compound and, thus, an exaggerated electrophysiologic effect.

Metabolism issues are important in predicting the interaction of antiarrhythmic drugs with other agents, including other cardiac and noncardiac drugs that may be metabolized by the same pathways. These drugs may interfere with metabolism either by occupying the enzyme site or by having a direct effect on the activity of the enzyme. The relative affinity of the drug for the enzyme system is predictive, in many cases, of the potency of the drug interaction that might occur with commonly used agents such as digoxin and warfarin.³³

Elimination

Clearance is the term that describes removal of drug from plasma and is defined as the volume of plasma cleared of drug per unit of time. The sum of all individual clearances is called total-body clearance and is the most reliable indicator of the rate of metabolism and elimination of drug. Other methods of quantifying elimination are less satisfactory.

Clearance generally begins with presystemic clearance, which is the metabolism of the drug during its passage through the liver before reaching the systemic circulation, as previously described. A number of drugs, such as lidocaine,³⁴ undergo extensive first-pass clearance, which obviates their oral use. Other drugs with less extensive first-pass clearance may be given at high doses so as to make some of the drug available to the systemic circulation. Examples include propafenone, propranolol, and verapamil.

Half-life is defined as the time required for the plasma concentration to decrease by 50% (Fig. 87–2), and can be altered by changes in both clearance and volume of concentration. Despite its limitations, the concept of half-life can be used to describe the time required for drug elimination. For drugs that have more than one pharmacologic compartment, more than one half-life may be defined. For example, the decrease in plasma concentration after administration of an intravenous bolus of a drug can be divided into its distribution period, when the drug is distributed from the central to the peripheral compartments, and an elimination period, during which time the drug is cleared from the central compartment by metabolism and elimination. Conversely, when a drug is administered by mouth, it is usually absorbed at a rate slower than the rate of distribution of the drug. Therefore, the distribution phase may be masked by the slow absorption of the drug.

As can be seen from Fig. 87–2, the time required to achieve a steady-state plasma concentration during chronic therapy can be estimated from the elimination half-life. After approximately 3.3 half-lives, 90% of the steady-state plasma concentration has been reached during loading or removed during washout. For example, sotalol has an elimination half-life of approximately 12 hours, and therefore takes 36 hours (or 2 to 3 days) to reach near steady state.

For drugs that have a longer half-life, and therefore a longer time to achieve steady state, a loading period may be used to bring plasma concentrations into a desired range more rapidly. Lidocaine is an excellent example of this principle. Using fixed infusion rates without loading, the long elimination half-life of 1.5 to 2 hours in normal subjects would require > 6 hours for lidocaine to achieve a steady-state plasma concentration. In the setting of treatment of patients with severe arrhythmias, this time period is unacceptably long. Therefore, bolus doses are given to fill the central compartment and to replace the amount of drug leaving the plasma through distribution to peripheral compartments.³⁴ Once steady state has been achieved—that is, when there is no more movement of drug from central to peripheral compartments—the drug can be administered as a maintenance infusion that is given at the same rate at which the drug is eliminated.

Amiodarone represents the most complicated example of drug loading to balance distribution and elimination.³⁵ Amiodarone is generally considered to have three compartments, all of which need to be saturated to achieve steady state. Large doses of oral drug are given over several weeks to achieve saturation of the peripheral and deep compartments. However, because the myocardial half-life of the drug is significantly shorter than the half-life of deeper compartments, the drug is given daily to maintain equilibrium in the myocardium.

Knowledge of the elimination half-life is critical for designing proper interdosing intervals for most oral antiarrhythmic drugs. The main considerations in determining how frequently a drug has to be administered are half-life and therapeutic range, defined as the minimum and maximum plasma concentrations that will achieve clinical benefit without exposing patients to toxicity.³⁶ The larger the ratio of maximum to minimum therapeutic effect, the longer may be the intradosing interval, during which time high peak and low trough concentrations will be achieved. Reducing peaks and valleys requires shorter interdosing intervals.

For most drugs, knowledge of renal elimination kinetics is critical in formulating an effective interdosing interval and finding an adequate dose to achieve a therapeutic effect. A notable example of this principle is with dofetilide, which is predominantly excreted by the kidneys. Dofetilide has an elimination half-life of 8 to 10 hours in a patient with normal renal function, but prolongs with decreased creatinine clearance. Therefore, a determination of creatinine clearance is necessary to select an appropriate dose and dosing interval.

One caveat in designing dosing schedules is the problem of active metabolites. Metabolites may have pharmacokinetics that are distinct from the parent.^31,32 For drugs that have metabolites that are active and have longer half-lives than the parent, interdosing intervals might need to be extended to account for the metabolite’s effect. Accumulation of a metabolite with higher than necessary dosing frequency can produce toxicity that may be life threatening.

Finally, drug half-life may be determined not only by the rate, but also by the route of elimination. A prime example is adenosine, which is rapidly taken up and metabolized by erythrocytes and vascular endothelium, and thus eliminated in prompt fashion.³⁷ Drugs with rapid offset of effect frequently are eliminated by routes other than the kidney, or they may be distributed quickly from the central compartment as in the case of ibutilide.³⁸

Drug Interactions

Antiarrhythmic drug interactions are ubiquitous and underappreciated, and therefore present a significant challenge to practicing physicians. Drug interactions may occur for a number of reasons, including inhibition or enhancement of drug metabolism and elimination, displacement of drug from plasma or tissue-binding sites, competition for receptor sites, and additive pharmacodynamic effects.³⁶ Table 87–2 outlines common drug interactions. The P450 enzyme system is responsible for an appreciable number of drug interactions in clinical practice.

Drug interactions resulting from interference with elimination also may occur. For example, digoxin is eliminated using a single pathway utilizing P-glycoprotein. P-glycoprotein activity is inhibited by many drugs, including amiodarone, quinidine, verapamil, and azithromycin.³⁹ Thus, the coadministration of these agents with digoxin can result in digoxin toxicity.

Among the assorted other mechanisms for kinetic interactions is reduced hepatic blood flow by β-adrenergic blockers, which can result in reduction of the clearance of high-extraction drugs such as lidocaine.

Hemodynamic Effects

A number of antiarrhythmic drugs have significant hemodynamic effects that may limit their usefulness under certain clinical situations. It is well known that class I drugs reduce myocardial contractility and may exacerbate congestive heart failure.⁴⁰ Among the sodium channel blockers, class Ic drugs and disopyramide exert the most potent negative inotropic effect; β-adrenergic and calcium channel blockers also are negative inotropic agents because of their inhibitory effect on inward L-type calcium current. Although β-adrenergic blockers, when used in patients with compensated heart failure, reduce symptoms of heart failure and improve survival, their use in patients with decompensated heart failure who need inotropic support of intravenous agents should be avoided. Quinidine also has α-blocking effect that can produce hypotension.

The majority of class III antiarrhythmic drugs are well tolerated hemodynamically in patients with heart failure. Data from clinical trials show that dofetilide and amiodarone do not significantly affect the hemodynamic state of patients with severe left ventricular dysfunction and heart failure.^41,42 However, d,l-sotalol should be used cautiously in patients with significant heart failure because its β-adrenergic blocking effect may exacerbate heart failure.

Class I

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.

Class II

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

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.

Class IV

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

Class Ia Drugs

The common electrophysiologic feature of class Ia drugs is that the drugs block the rapidly activating delayed rectifier potassium current (I_Kr) at relatively lower concentrations than their effect on I_Na. Therefore, they cause QT prolongation that may lead to TdP. At higher doses, they inhibit I_Na, 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.

Quinidine

Electrophysiology

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 I_Kr and I_Na, 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 I_Na, leading to conduction slowing and a decrease in myocardial contractility.

Quinidine also inhibits I_to 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 I_to, cannot be used for unmasking ST-segment elevation in concealed Brugada syndrome.

Pharmacokinetics

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%.

Indications

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 I_to.^12,13,14

Adverse Effects

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

Procainamide

Electrophysiology

Because the concentration gap of procainamide to block I_Kr and I_Na 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 I_to.

Pharmacokinetics

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.

Indications

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.

Adverse Effects

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).

Disopyramide

Electrophysiology

Similar to procainamide, the concentration gap of disopyramide to block I_Kr and I_Na 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 I_to.

Pharmacokinetics

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.

Indications

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.

Adverse Effects

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.

Class Ib Drugs

Electrophysiology

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 I_Kr 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

Pharmacokinetics

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.

Indications

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.

Adverse Effects

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

Pharmacokinetics

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.

Indications

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 (I_Na,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

Adverse Effects

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

Electrophysiology

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

Pharmacokinetics

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.

Indications

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 I_Na 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

Adverse Effects

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 I_Na. 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 I_Na 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 I_Kr at a concentration slightly lower than that at which it blocks I_Na, 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

Pharmacokinetics

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.

Indications

The indications of propafenone are similar to those of flecainide.⁵³

Adverse Effects

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)

Electrophysiology

β-Agonists enhance I_Ca,L and the pacemaker current (I_f). 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

Pharmacokinetics and thus dosing differ significantly among β-blockers. β-Blockers are usually titrated based on resting heart rate.

Indications

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.

Adverse Effects

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.

Class III Drugs

Ibutilide

Electrophysiology

Ibutilide, a methanesulfonamide derivative, blocks the I_Kr 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.

Pharmacokinetics

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.

Indications

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.

Adverse Effects

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.

Sotalol

Electrophysiology

d,l-Sotalol is a racemate of d and l isomers that both exhibit antiarrhythmic actions via blocking I_Kr.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.

Pharmacokinetics

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.

Indications

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.

Adverse Effects

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

Amiodarone

Electrophysiology

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 I_Na and I_Ca,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 I_Kr, I_Ks, I_K1, and I_to. 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.

Pharmacokinetics

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.

Indications

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

Adverse Effects

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

Electrophysiology

Dofetilide is a pure I_Kr 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 T_p-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).

Pharmacokinetics

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.

Indications

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.

Adverse Effects

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

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.

Electrophysiology

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 I_Ca,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.

Pharmacokinetics

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.

Indications

Dronedarone is used for the prevention of recurrent atrial fibrillation and flutter.

Adverse Effects

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

Class IV Drugs

Nondihydropyridine Calcium Channel Blockers

Electrophysiology

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.

Pharmacokinetics

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.

Indications

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.

Adverse Effects

Both agents inhibit I_Ca,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

Electrophysiology

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 (I_KAdo) and inhibits the pacemaker current (I_f) 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.

Pharmacokinetics

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.

Indications

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

Adverse Effects

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

Electrophysiology

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.

Pharmacokinetics

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.

Indications

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.

Adverse Effects

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

Ranolazine is approved for treatment of chronic angina. However, this drug has potent antiarrhythmic activity.⁷⁷ Ranolazine inhibits I_Kr, I_Ks, late I_Na, I_Ca, and I_Na-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

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” (I_f). 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

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 I_Na channel at low heart rates, but increases its I_Na 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.

The Elderly

The elderly are particularly prone to both the adverse effects and overdosing of antiarrhythmic drugs. Elderly patients are more susceptible to common side effects of many antiarrhythmic drugs including bradycardia, orthostatic hypotension, and urinary retention. In addition, several physiologic changes associated with aging that make drug accumulation more likely. These include reduction in lean body mass, decrease in renal function, alterations in hepatic metabolism, and changes in receptor affinity.^89,90 The elderly also have increases in glycoprotein concentrations and reductions in serum albumin concentrations that may alter the ability of drugs to bind to plasma proteins, in effect raising free concentrations. Reduced receptor affinity and stimulation of adenylate cyclase attenuate the effects of catecholamines and may make these patients more susceptible to the depressant effects of β-adrenergic blocking agents. Reduction in the activity of the renin-aldosterone system and arterial wall elasticity make elderly patients more susceptible to the development of orthostatic hypotension.

Age affects the density of ion channels as well as likely alteration of the properties of certain ion channels. This was seen in animal data that that revealed alterations in L-type calcium (I_Ca,L) and outward potassium (I_K) currents from aged canine atrial myocytes.⁸⁸ As a result of these physiologic changes, elderly patients in general should be started on a smaller dose of an antiarrhythmic drug with slow upward dose titration to clinical effect or to tolerance.

Obese Patients

In general, patients with larger body size require higher doses of drugs to achieve a therapeutic plasma concentration. However, drugs may distribute differently in adipose tissue compared with muscle and other tissue. Thus, if adjustment in dose is made only on the basis of the patient’s weight, some drugs will be overdosed.

Underweight Patients

Patients with low lean body mass may require lower doses of certain drugs to achieve a therapeutic plasma concentration, dependent upon the distribution of the drug. For example, digoxin, which distributes significantly into skeletal muscle, should be started at lower doses in this patient population to avoid potential toxicity.

Congestive Heart Failure

The central volume of distribution of an antiarrhythmic drug is generally reduced in congestive heart failure, necessitating reduction in the initial dose.⁹¹ Congestive heart failure also gives rise to derangements of liver and renal blood flow with reduction in clearance of the drug and high extraction ratios. For all of these reasons, as well as altered sensitivity to drug and altered plasma protein binding, drugs should be administered in low dose to patients with congestive heart failure with slow upward dose titration, as in the elderly. Many antiarrhythmic drugs, including the majority of the class I agents, have negative inotropic activity, and therefore should be avoided or used cautiously in the heart failure population. Antiarrhythmic drugs that should be administered with caution or are contraindicated in heart failure and in various other conditions are listed in Table 87–3.

Renal Failure

Drug and metabolites can accumulate in patients with renal failure, depending on the proportion of the drug that is eliminated by the kidney. Drugs such as sotalol and dofetilide, which are predominantly renally eliminated, are particularly important in this regard.⁹² Fortunately, most drugs have other routes of elimination, which can at least partly compensate for reduced elimination because of renal failure. Antiarrhythmic drugs that are almost exclusively cleared via the liver, such as amiodarone and propafenone, can be safely administered to patients with advanced kidney disease, including patients on renal replacement therapy. Specific antiarrhythmic drugs that mandate cautious use or dose reduction are listed in Table 87–3.

Hepatic Disease

Fortunately, until hepatic disease is advanced, hepatic metabolism and elimination of most drugs is not significantly compromised. Short of liver cirrhosis, it can be assumed the drugs will be metabolized and eliminated normally, even in patients who have elevated transaminase and bilirubin concentrations.⁹³ In patients with end-stage liver disease, antiarrhythmic drugs with predominant hepatic clearance should be avoided or dose reduced on initiation. When used in this setting, these agents should be titrated carefully while observing for toxicities, and drug levels should be monitored if available.

Antiarrhythmic drugs have played a central role in the treatment of arrhythmias in the mother as well as the fetus. Increased arrhythmogenesis in pregnancy underscores the importance of the knowledge of safe use and key adverse effects in the various antiarrhythmic drugs that may be utilized in this population. Table 87–4 summarizes the use of antiarrhythmic drugs and their potential adverse effects in pregnancy. As seen in this table, the strong majority of antiarrhythmic drugs are US Food and Drug Administration Category C, meaning that risk to the fetus cannot be ruled out. This is because of the paucity of randomized control trials (animal or human) necessary to demonstrate a higher level of evidence-based safety.

The significant increase of 40% to 50% in intravascular volume may affect doses needed to reach therapeutic levels of concentration and loading doses. Altered absorption characteristics, reduced drug protein binding, and increased renal blood flow also may similarly affect drug blood levels. These changes underscore the importance of closely following drug levels (when possible), as well as monitoring for therapeutic effect and potential toxicities.

Quinidine and procainamide have been safely used for the treatment of maternal and fetal arrhythmias. For pregnant women who develop atrial fibrillation in pregnancy, both quinidine and procainamide can be used to try to pursue pharmacologic cardioversion.⁶² Quinidine may cause thrombocytopenia and eighth nerve damage in the fetus; chronic administration of procainamide may be associated with autoimmune responses such as lupus-like syndrome. There is limited experience with the use of disopyramide, but it can cause uterine contraction and premature labor.

Lidocaine is well tolerated and widely used in pregnancy. Intravenous lidocaine is administrated primarily for the acute management of life-threatening ventricular arrhythmias. Flecainide appears to be a well-tolerated option for maternal arrhythmias, particularly atrial fibrillation, and has evidence of safety in data with its use in treating fetal tachyarrhythmias.⁹⁴ Experience with mexiletine and propafenone in pregnancy is more limited.^95,96 Because propafenone and flecainide have good transplacental passage, both have been used as second-line therapy for sustained fetal supraventricular arrhythmias, particularly in the presence of hydrops fetalis, that are refractory to digoxin.^94,96

β-Adrenergic blockers are primarily used to treat hypertension and thyrotoxicosis in pregnancy. These agents are generally safe for the mother and the fetus. β-Adrenergic blockers are useful in the treatment of supraventricular tachycardia, atrial fibrillation or atrial flutter, idiopathic ventricular tachycardia, and long QT syndrome. Prophylactic treatment with β-adrenergic blockers significantly reduces the risk of cardiac events in patients with the congenital long QT syndrome, particularly in the postpartum period when patients are at the highest risk.⁹⁷

The adverse effects of β-adrenergic blockers include bradycardia, hypoglycemia, fetal apnea, premature labor, and metabolic abnormalities, but these effects occur more frequently in high-risk patients.⁹⁸ Because β-adrenergic blockers may cause intrauterine growth retardation,⁹⁹ the use of β-adrenergic blockers in the first trimester of pregnancy should be avoided. Although some β-adrenergic blockers, such as propranolol, atenolol, labetalol, nadolol, and metoprolol, are excreted in breast milk, significant bradycardia in infants may be seen, although rarely.

There is relatively limited experience with the use of class III antiarrhythmic drugs in pregnancy. Sotalol has been used in the treatment of refractory maternal and fetal supraventricular and ventricular arrhythmia, including efficacy in terminating fetal atrial fibrillation.⁹⁴ Sotalol or flecainide is typically considered for ventricular arrhythmias that fail β-blocker therapy. Ibutilide has also been used safely in case reports for chemical cardioversion of atrial fibrillation, but its use in this setting has not yet been broadly demonstrated.^100,101

Amiodarone should be totally avoided or used with extreme caution for arrhythmias that are refractory to other drugs and are life threatening. Amiodarone causes hypothyroidism or hyperthyroidism, congenital abnormalities, bradycardia, premature labor, low birth weight, and prematurity.^102,103 Amiodarone is excreted in breast milk and can cause hypothyroidism or hyperthyroidism, but not significant bradycardia, in breast-fed infants. Dronedarone is US Food and Drug Administration Category X and is absolutely contraindicated as it has animal data showing teratogenic effects, specifically vascular and skeletal malformations.

Calcium channel blockers, like verapamil and diltiazem, have been used for supraventricular tachycardia and control of the ventricular response to atrial fibrillation or flutter in pregnancy. These agents are also useful in the treatment of selected idiopathic ventricular tachycardias. Calcium channel blockers are considered to be relatively safe, although they have the potential to cause hypotension, heart block, bradycardia, and exacerbation of heart failure in mother and fetus.

Digoxin has a long record of safety for the treatment of supraventricular tachycardia, including AV nodal reentrant tachycardia, and atrial fibrillation or flutter in pregnancy.¹⁰⁴ Because digoxin can cross the placenta, it has been used to treat fetal supraventricular tachycardia. It is often administered in a relatively large dose to the mother to obtain a therapeutic plasma concentration in the fetus because transplacental passage of digoxin may be impaired by some pathologic conditions, such as hydrops fetalis.^96,104 Digoxin is associated with premature labor and low birth weight. Adenosine is used for the acute termination of supraventricular tachycardia and is not associated with adverse effects in the mother or fetus. Fetal bradycardia may occur occasionally, but is usually very brief because of the drug’s short half-life.

Patients with devices may require concomitant drug therapy for a variety of reasons, the most common being to reduce arrhythmia frequency. An antiarrhythmic drug can cause excessive rate slowing that mandates placement of a permanent pacemaker. Drugs can also have an impact on the pacing threshold and the thresholds for arrhythmia termination, which can be seen in Table 87–5. In general, drugs that reduce the sodium current should be expected to raise pacing and defibrillation thresholds, whereas potassium channel blockers reduce the defibrillation threshold and exert little effect on capture threshold. Drugs can change ventricular tachycardia rate and thus the efficiency of detection and termination algorithms.¹⁰⁵ Slowing of ventricular tachycardia may be beneficial in improving hemodynamic stability and decreasing risk of degeneration to ventricular fibrillation, but may also lead to underdetection by the device.

Arrhythmia management is a constantly evolving practice, which requires a comprehensive knowledge of antiarrhythmic drugs, ablation, device implementation and strategies to decrease arrhythmia burden, symptoms, and risk of adverse outcomes. An individualized antiarrhythmic strategy is integral to effective arrhythmia management. Knowledge of antiarrhythmic drug indications, pharmacokinetics, adverse effect profiles, and both contraindications and optimal use in specific patient populations is critically important in guiding safe and effective antiarrhythmic use.