Antiarrhythmic Drugs

Antiarrhythmic Drugs

Aadhavi Sridharan

Noel G. Boyle


Antiarrhythmic drugs are pharmacologic agents that primarily affect specific ion channel activity, thereby altering membrane conductance and ultimately the cardiac action potential. The goal of antiarrhythmic drug therapy is to restore and maintain sinus rhythm and to prevent recurrence of arrhythmias.1 Antiarrhythmic agents were the mainstay of treatment for arrhythmias until the advent of implantable cardioverter defibrillators (ICDs) and catheter ablation in the 1980s. Despite these advances, antiarrhythmic drug therapy still plays a central role in the management of patients with arrhythmias, often in combination with other treatment modalities. A detailed understanding of the underlying mechanism of action, side-effect profile, and potential proarrhythmic effects of these drugs is therefore critical for their safe and appropriate use in clinical practice.2 This chapter first reviews the anatomy of the cardiac electrical conduction system and the cardiac action potential, and then describes the mechanisms of action, side-effect profiles, and proarrhythmic potential of various antiarrhythmic agents.


The electrical impulse of each heartbeat originates in the sinoatrial (SA) node, located in the superior aspect of the right atrium (Figure 58.1). SA nodal cells are specialized pacemaker cells that are able to spontaneously generate rhythmic impulses and typically comprise the natural pacemaker of the heart. This impulse then travels radially to the left atrium as well as inferiorly to reach the atrioventricular (AV) node located in the posteroinferior region of the interatrial septum, near the opening of the coronary sinus. The AV node consists of highly specialized conducting cells that conduct the electrical impulse from the atria to the ventricles and can significantly slow the conduction of rapid electrical impulses as in atrial flutter (AFL) or atrial fibrillation (AF), a property known as decremental conduction. The impulse then reaches the bundle of His at the base of the ventricles and travels rapidly down the right and left bundle branches in the interventricular septum. The left bundle branch further separates into the left anterior and left posterior fascicles. The bundle branches ultimately terminate into numerous Purkinje fibers, which then stimulate small areas of the myocardium to contract. The AV node and His-Purkinje systems are latent pacemakers and may exhibit automaticity if the SA node is suppressed.3,4

This organization of the cardiac electrical conduction system allows for the sequential contraction of the atria followed by the ventricles with each heartbeat. Decremental conduction through the AV node ensures atrial contraction with complete emptying of the atria and occurs before the electrical impulse reaches the ventricles. Rapid conduction of the electrical impulse through the His-Purkinje fibers then allows for brisk and synchronous contraction of the ventricles beginning at the apex of the heart.


Understanding the mechanism of action of antiarrhythmic drugs requires a fundamental knowledge of the cardiac action potential. The cardiac action potential is a brief change in voltage across the cell membrane of myocytes; this is achieved through a complex, coordinated change in permeability of sodium (Na+), potassium (K+), and calcium (Ca2+) ions through different types of ion channels.

The action potential in a typical ventricular myocyte is divided into five phases, named phase 0 through phase 4 (Figures 58.1 and 58.2). During phase 4, also termed the resting phase, there is a higher concentration of Na+ and Ca2+ outside the cell than inside and a higher concentration of K+ inside the cells than outside. During this phase, the membrane is impermeable to Na+ and Ca2+, but there is an abundance of open K+ channels allowing slow leakage of K+ out of the cell, thus maintaining the membrane potential at approximately -90 mV, near the equilibrium potential of K+. When these resting myocytes reach a threshold voltage of approximately -70 mV, they enter phase 0.

The most common stimulus that raises the resting transmembrane potential to the threshold voltage is the depolarization of a nearby myocyte, thus spreading the wave of depolarization across the myocardium one cell at a time. During phase 0, also known as rapid depolarization, there is a transient increase in Na+ conductance through voltage-dependent fast sodium channels and cessation of K+ current. This results in a positive membrane potential closer to the equilibrium potential of Na+. Phase 1 represents an initial, rapid repolarization phase that is caused by a transient outward K+ current through rapidly activating K+ channels. During phase 2, also termed the plateau phase, there is inward Ca2+ current through the
L-type calcium channels that are activated when the membrane potential depolarizes to -40 mV. Inward Ca2+ currents and outward K+ currents are relatively balanced during this plateau phase. Phase 3 is the repolarization phase during which there is cessation of Ca2+ movement and increase in outward K+ current through several (at least six) different potassium channels.3,4,5,6

In pacemaker cells such as in the SA node, the action potential typically consists of three phases (Figure 58.1). During phase 4, there is no true resting membrane potential. Rather there is spontaneous depolarization because of slow, inward Na+ current through “funny” channels and inward Ca2+ current through T-type calcium channels. This is followed by depolarization in phase 0 once the membrane potential reaches approximately -40 to -30 mV; depolarization is primarily because of inward Ca2+ current through L-type calcium channels. Repolarization in phase 3 occurs mainly because of outward, hyperpolarizing K+ currents, which brings the membrane potential back to -60 mV.7 Thus, unlike in non-pacemaker cardiac action potentials, there is no contribution from fast sodium channel in SA nodal cells, resulting in a slower rate of depolarization (ie, slope of phase 0). The cardiac action potential in various other myocardial cells is depicted in Figure 58.1.

Conduction Velocity

The speed of depolarization of a myocyte determines the rate at which its neighboring myocyte is stimulated to depolarize, thereby determining the speed of propagation of the electrical impulse through myocardial tissue. Therefore, the slope of phase 0 determines the conduction velocity of the action potential through the myocardium. Conduction velocity is fastest in the Purkinje system and slowest in the AV node to allow for ventricular filling.4

Refractory Period

Once an action potential is initiated in a myocyte, during the time of phases 0, 1, 2, and most of phase 3, the cell is unable to initiate another action potential; this period of time is termed the refractory period. In other words, the refractory period of an excitable cell refers to the period of time during which it is unable to respond to or propagate a second stimulus. This is due to ion channels that remain inactive until the membrane
potential has fully repolarized and returned to the resting state. The refractory period is thus dependent on the duration of the action potential. Refractory period is a protective mechanism that prevents the occurrence of repeated, compounded action potentials that can lead to poor ventricular filling and ejection.4

Effect of the Autonomic Nervous System

The heart is richly innervated and closely regulated by the autonomic nervous system.8 The SA and AV nodes are directly supplied by both sympathetic and parasympathetic nerve fibers. In contrast, there is much greater sympathetic innervation than parasympathetic innervation in the rest of the cardiac electrical system. Therefore, change in parasympathetic tone most directly affects the SA and AV nodal tissues. Overall, an increase in sympathetic tone leads to enhanced automaticity, faster conduction velocity, and shorter refractory period, whereas increased parasympathetic tone results in the opposite effects.


The most commonly used classification scheme for antiarrhythmic drug therapy was proposed by Singh and Vaughan Williams in 1970.9 This classification groups drugs based on their major mechanism of action (Table 58.1). Class I drugs block sodium channels, thereby slowing conduction velocity; Class II drugs block adrenergic receptors, thereby blunting the effects of the sympathetic nervous system on cardiac electrophysiology; Class III drugs block potassium channels, thereby increasing the refractory period; and Class IV drugs block calcium channels, thereby affecting nodal cells that are depolarized mainly via calcium currents. Figure 58.3 is a schematic that demonstrates the effect of these agents on the cardiac action potential. Critics of this classification system argue that some drugs can affect multiple ion channels, thus having

mixed effects on the action potential, and drugs within the same class can have clinically distinct effects from one another.


Class IA drugs block the rapid sodium channel at high concentrations, resulting in slowing of the conduction velocity, and moderately block potassium channels at lower concentrations, resulting in longer action potential duration and increase in refractory period. Class IA drugs have intermediate kinetics of onset and offset of action; they bind and unbind from sodium channels more slowly than Class IB agents, but more rapidly than Class IC agents. Because they affect both atrial and ventricular tissue, they have the potential to treat both atrial and ventricular arrhythmias. Because of their effect on potassium channels resulting in prolongation of action potential duration and thus refractory period, these drugs have proarrhythmic potential because of QT prolongation, leading to the potential for early afterdepolarizations and risk of developing a polymorphic ventricular tachycardia (VT) known as torsades de pointes. All Class I drugs also exhibit use dependence such that their sodium channel blocking effects are more pronounced at faster heart rates.1,2


Quinidine blocks several channels including the rapid inward sodium channel, the IKr and Ito potassium rectifier channels, and, to a lesser degree, the slow inward calcium channel, the IKs potassium rectifier channel, and the adenosine triphosphate (ATP)-sensitive potassium current. Quinidine is a stereoisomer of the antimalarial drug quinine and is derived from cinchona tree bark.10


After oral administration, 80% to 90% of the drug is absorbed, reaching peak plasma concentration within 3 to 4 hours. It can be given intravenously if infused slowly. Approximately 80% of quinidine in circulation is protein bound, and it has a large volume of distribution. It is primarily eliminated through hepatic metabolism, and elimination half-life is 5 to 8 hours after oral administration.1,2,11

Clinical Use

Quinidine was historically the first medication used to treat both atrial and ventricular arrhythmias and in recent years has found an application in the treatment of Brugada syndrome and short QT syndrome because of its Ito (transient outward potassium channel) blockade properties.11,12 Starting in the 1920s, it was the drug of choice to treat AF, often in conjunction with digoxin, until its proarrhythmic potential was recognized in the 1990s.13 Quinidine may result in torsades de pointes leading to syncope (quinidine syncope) or sudden cardiac death, and because of its significant side-effect profile and drug-drug interactions, its use in clinical practice has markedly declined in recent years.

Adverse Effects of Quinidine

The most common side effects are gastrointestinal, including diarrhea, nausea, vomiting, abdominal pain, and anorexia. Central nervous system (CNS) toxicity (tinnitus, visual disturbances, confusion, delirium, psychosis) and allergic reactions (rash, fever, hemolytic anemia, and rarely anaphylaxis) are not uncommon. Because quinidine is an inhibitor of the cytochrome P450 enzyme system, it can increase blood levels and potentiate the effect of other drugs including warfarin and flecainide.


Procainamide primarily blocks the inactivated state of INa and to a lesser extent also blocks IKr and IK.ATP. The electrophysiologic effects and therapeutic uses of procainamide are similar to those of quinidine.14


Procainamide’s onset of action is immediate with intravenous infusion and approximately 1 hour after oral administration. Approximately 80% of the oral drug is bioavailable. Elimination half-life of procainamide is 3 to 5 hours, with 50% to 60% of the drug excreted in the urine and 10% to 30% undergoing hepatic metabolism. In the liver, procainamide is acetylated to N-acetylprocainamide, an active metabolite with Class III antiarrhythmic properties, which is primarily eliminated by the kidneys with an elimination half-life of 7 to 8 hours (although it can exceed 10 hours if high doses of procainamide are used).14

Clinical Use

It can be used to treat reentrant atrial and ventricular arrhythmias, and its clinical efficacy is similar to that of quinidine. Because it is readily available for rapid intravenous loading, it is commonly used for acute conversion of AF and AFL and terminate or slow incessant VTs.15 It is also the drug of choice for termination of AF in Wolff-Parkinson-White syndrome.16

Adverse Effects

The most common side effects include hypotension with intravenous administration, gastrointestinal effects (nausea, vomiting, and diarrhea), agranulocytosis, and lupus. Procainamide has proarrhythmic effects similar to quinidine.


Disopyramide causes use-dependent block (ie, greater effect at faster rates) of INa, and also blocks of IKr and IK.ATP, with similar electrophysiologic effects to quinidine. Because of its anticholinergic effects, it can increase SA node discharge rate and shorten AV nodal conduction time and refractoriness when the nodes are under cholinergic (vagal) influence.1,2,14

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May 8, 2022 | Posted by in CARDIOLOGY | Comments Off on Antiarrhythmic Drugs
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