Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs

INTRODUCTION — The myocardial action potential refers to the "all or nothing" depolarization followed by repolarization of the cell membrane, which results from a complex interaction of voltage and time dependent ion channels and carriers in the cellular membrane. When abnormalities arise in the normal process of cardiac excitability, patients may develop tachyarrhythmias by a variety of mechanisms.

This topic will review the normal cardiac excitation process and the generation of the myocardial action potential, along with mechanisms of arrhythmia and the classes of antiarrhythmic medications and their impact on cardiac excitability. The treatment of specific tachyarrhythmias is discussed elsewhere. (See "Overview of the acute management of tachyarrhythmias".)

CARDIAC EXCITABILITY — Cardiac excitability refers to the ease with which cardiac cells undergo a series of events characterized by sequential depolarization and repolarization, communication with adjacent cells, and propagation of the electrical activity. The normal heartbeat arises from an organized flow of ionic currents across the cell membrane, through the myoplasm and between cells and the extracellular space [1,2]. Excitable membranes containing specialized ion-specific channels, cell-to-cell connecting proteins, and intracellular components transmit the action potential and lead to excitation-contraction coupling.

Understanding cardiac electrophysiology requires knowing the types and regulation pathways of ion channels, electrogenic exchange transporters, gap junctions, and the proportional contribution of each mechanism. Abnormalities of these elements, both inherited and acquired, can lead to arrhythmia.

●Acquired abnormalities occurring in the setting of cardiac disease such as cardiomyopathy are called electrical remodeling.

●Inherited abnormalities arise from mutations in genes encoding the subunits and associated proteins of these channels, and have been associated with familial arrhythmic syndromes and sudden cardiac death. Examples include the congenital long QT syndrome (mainly sodium and potassium current), the Brugada syndrome (mainly sodium current), and congenital heart block (sodium current). (See "Congenital long QT syndrome: Pathophysiology and genetics" and "Brugada syndrome: Epidemiology and pathogenesis" and "Etiology of atrioventricular block", section on 'Familial disease'.)

Cardiac ion channels and currents — Ions (sodium [Na⁺], potassium [K⁺], chloride [Cl^-], and calcium [Ca²⁺]) flow through cardiac membrane channels with pores formed by proteins, with these ion channels encoded by specific genes [3]. The pore-forming protein is called the alpha subunit, which also contains the voltage-dependent sensors and gates. For many ion channels, one or more secondary regulatory subunit proteins are present (usually named beta, gamma, delta, and so on) in association with the alpha subunit, and many ion channel proteins have subunit isoforms adding to their complexity. The encoding genes, amino acid sequences, and structure-function relationships for many ion channels have been described and are now reasonably well understood (figure 1) [4].

Ion channels are grouped and currents are named in one of three ways: by the ionic charge species to which the channel is permeant, the distinguishing kinetics, or pharmacology (figure 1). For example, the voltage-dependent sodium current (I_Na) flows through the protein NaV1.5 encoded by the gene SCN5A and similarly for other ion channels. The dominant channel types in heart cells are Na⁺ channels (I_Na), L-type and T-type Ca²⁺ channels (I_Ca-L, I_Ca-T), and several K⁺ channels (I_K1, I_to1, I_to2, I_Kr, I_Ks). The sodium-potassium pump and the sodium-calcium exchanger are not considered channels because they require energy to drive ions across the membrane against their gradients, however they do generate currents (figure 1).

Resting membrane potential — The resting cardiac cell membrane potential is normally polarized between -80 and -95 mV, with the cell interior negative relative to the extracellular space. The resting membrane potential is determined by the balance of inward (Na⁺ and Ca²⁺) and outward (K⁺) currents and the corresponding equilibrium potentials of these currents. In turn, the equilibrium potential for a given ion is determined by the concentrations of that ion inside and outside the cell. Using these concentrations, the equilibrium potential is calculated by the Nernst equation. As an example, potassium ion concentrations are higher inside than outside the cell, and the potassium equilibrium potential is between -80 and -95 mV. When potassium channels open, potassium ions flow down their gradient as an outward current, carrying positive ions outside the cell and taking the cell toward more negative potentials.

In the heart, the resting membrane potential is generated by the inward rectifier current (I_K1), which is the predominant open channel at rest. Potassium current flowing through these channels continues until the interior negative potential is at the same magnitude as the equilibrium potential for potassium. Only small amounts of actual potassium flow are required to maintain this potential. The equilibrium potentials for sodium and calcium are positive (approximately +40 mV and approximately +80 mV, respectively) so that when these channels are open, they tend to depolarize the membrane.

Voltage-sensitive sodium, calcium, and potassium channels play only a small role in the resting state since most of these channels are closed [5,6]. The Na-K-ATPase pump maintains the potassium and sodium gradients by pumping potassium into and sodium out of the cells. The Na-Ca exchanger uses the power of the Na gradient to pump Ca out of the cell. These and other pumps maintain the ion channel gradient that is important for both excitability and contraction.

Action potential in fast response tissues — Tissues that depend upon the opening of voltage-sensitive, kinetically rapid (opening in less than a millisecond) sodium channels to initiate depolarization are called fast response tissues [7]. Fast response tissues include the atria, the specialized infranodal conducting system (bundle of His, fascicles and bundle branches, and terminal Purkinje fibers), and the ventricles (figure 2), while the sinoatrial (SA) and atrioventricular (AV) nodes represent slow response tissues. It is important to recognize that accessory AV pathways (ie, bypass tracts) associated with Wolff-Parkinson-White syndrome are derived from the atria and are thus also fast response tissues dependent upon sodium current for depolarization. (See "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis".)

The following is a simplified description of the steps involved in the generation of an action potential in the heart (figure 1 and figure 3 and movie 1) [8]. The particular shape and duration of the individual action potential varies for atria, nodal tissue, specialized conduction tissue, and the ventricles (figure 4), depending upon differences in the density of ion channels in these tissues. The shape and duration of the action potentials also vary in the right and left ventricle, and transmurally across the wall of the heart [9], again depending upon differences in ion channel and current densities.

●Phase 0 – Rapid depolarization (phase 0) occurs when the resting cell is brought to threshold, leading sequentially to activation or opening of voltage-dependent sodium channels, rapid sodium entry into the cells down a favorable concentration gradient, and a cell interior positive potential that can approach +45 mV. The marked depolarization initiates voltage-dependent inactivation of the sodium channels. Calcium channels also open during depolarization, but the inward calcium flux is much slower.

●Phase 1 – Phase 1 repolarization often inscribes a "notch" and is primarily caused by activation of the transient outward potassium currents (I_to) combined with a corresponding rapid decay of the sodium current. The degree of repolarization in phase 1 is dependent on the density of I_to and varies between cardiac chambers and regions within chambers.

●Phase 2 – Following initial repolarization in phase 1, phase 2 represents a plateau that lasts for hundreds of milliseconds and distinguishes the cardiac action potential from nerve and skeletal muscle action potentials, which are significantly shorter. Late inactivating depolarizing calcium and sodium currents are balanced by activating repolarizing potassium currents to maintain the plateau, which is often down-sloping as repolarizing currents begin to dominate.

●Phases 3 and 4 – The final rapid repolarizing phase 3 is driven by the decay of the calcium current and progressive activation of repolarizing potassium currents (I_Kr, I_Ks). Terminal repolarization toward the potassium equilibrium potential is dominated in phase 3 by I_K1, which then maintains the resting membrane potential (phase 4).

During one cycle of depolarization and repolarization, the voltage-dependent channels cycle through three different kinetic or gating states:

●Resting.

●Open, as the channels open during phase 0 depolarization.

●Inactivated, which occurs at positive potentials (end of phase 0) and during sustained depolarization (as during the phase 2 plateau). During recovery in diastole, the channel returns to the resting state.

The resting and inactivated states are different physiologically, even though the channel is effectively nonconducting in both settings. In the resting state, the channels can be opened positive to the threshold potential. In comparison, the inactivated channel cannot be activated until it cycles or "recovers" to the resting state. These different states are important clinically, since, for example, some antiarrhythmic drugs (such as the class I antiarrhythmic drugs) preferentially bind to open and inactivated sodium channels.

Action potential in slow response tissues — The SA and AV nodes represent slow response tissues, which have different properties from the fast response tissues (table 1). Phase 0 depolarization depends on an inward calcium (not sodium) current via L-type calcium channels [10]. These channels are selective for calcium, have a slower conduction velocity than the sodium channels, and take longer to reactivate.

In some cases, as with tissue damage or changes in the extracellular milieu, fast response tissues can be converted to slow response tissues. In this setting, sodium channels become inactivated and depolarization is dependent upon the slow calcium channels.

Impulse propagation — When an action potential forms in a patch of membrane (the source), current flows from this patch to neighboring patches (the sink). Gap junctions are the low resistance structures that allow ions to flow from one cell to another and, if the current flow is sufficient, to cause sequential depolarization from cell to cell. The gap junctions are actually active, opening and closing in response to changes in pH, calcium, and, at times, voltage. In addition to ion flow and gap junction resistance, impulse propagation can also be affected by the orientation of fibers and of the collagen matrix in which the fibers reside.

"Fast" tissues may conduct very slowly (declining from meters/second to millimeters/second) in a number of circumstances, resulting in prolongation of the QRS and QT intervals on the surface electrocardiogram (ECG). These include inactivation of sodium channels induced by hyperkalemia or ischemia-induced acidosis, direct damage to the cells, or the effect of drugs, particularly antiarrhythmic drugs. (See 'Action of antiarrhythmic drugs' below.)

MECHANISMS OF TACHYARRHYTHMIA FORMATION — While the term "arrhythmia" also includes bradyarrhythmias caused by a failure of impulse generation, this section will focus on the cellular and tissue mechanisms of tachyarrhythmias. Three distinct mechanisms underlie tachyarrhythmia induction: enhanced automaticity, reentry, and triggered activity (figure 5).

Enhanced automaticity — Enhanced automaticity refers to abnormal phase 4 diastolic depolarization, and occurs when spontaneous depolarization develops during diastole (figure 5). While this is a normal phenomenon in nodal cells, and with subsidiary pacemakers at slower rates in all myocardial cells, enhanced or abnormal automaticity may lead to tachyarrhythmia. A typical example is automatic (ie, focal) atrial tachycardia. Common automaticity stimulants include excess catecholamine or situations causing hypoxia, acidosis, or ischemic related metabolites. (See "Focal atrial tachycardia" and "Enhanced cardiac automaticity".)

Reentry — Reentry is the most commonly encountered arrhythmia mechanism and refers to any arrhythmia dependent on an electrical circuit within the heart (figure 5). Critical components for reentry include both of the following:

●The presence of fast and slow conduction with varying refractory/recovery periods

●A fixed or functional core about which the circuit moves

Initiation of reentry requires a unidirectional block within the reentrant path, such that one arm of the circuit conducts the approaching electrical wave front and the blocks it in the other arm. Reentry can travel around a fixed or anatomical circuit such as myocardial scar, or a functional circuit such as an area of tissue that is depolarized or refractory and does not support conduction.

A common example of a reentry-based arrhythmia is AV reciprocating tachycardia (AVRT) related to an accessory pathway (ie, bypass tract) as part of the Wolff-Parkinson-White syndrome. In AVRT, the fast conducting limb (for either antegrade or retrograde AVRT) is the accessory pathway, which uses Na⁺ channels to support rapid conduction, while the slow conducting limb is the normal AV node. An example of fixed reentry arrhythmia is ventricular tachycardia with a fixed myocardial scar and variable conduction in the surrounding myocardium.

Interventions to terminate reentrant arrhythmias differ from other mechanisms and are generally geared to modify the critical components of the reentrant circuit. Blocking Na⁺ or Ca²⁺ channels can slow or block conduction, while blocking K⁺ channels prolongs the action potential and therefore increases refractoriness. Another approach is to improve functional properties such as ischemia in an area of functional block that can terminate the arrhythmia. Interventions that electrically interrupt the reentrant loop include delivering a small electrical impulse to depolarize or block a small part of the reentrant loop (ie, anti-tachycardia pacing), delivering a large electrical shock to depolarize most or all the reentrant loop (ie, cardioversion), or ablating tissue critical to the reentrant loop. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".)

Triggered activity — Triggered activity refers to a depolarization that occurs after the initial depolarization wavefront and comes in two forms, either early or late. Secondary depolarizations that occur before the action potential has fully repolarized are early afterdepolarizations (EADs) (figure 5). Those that occur after the action potential has fully repolarized are delayed afterdepolarizations (DADs) (figure 5). Both EADs and DADs depend on the previous action potential to trigger them, hence an afterdepolarization is said to be a triggered arrhythmia. However, it is important to understand that DADs and EADs differ in mechanism.

●EADs – EADs are triggered during prolonged action potentials. A prolonged action potential allows a longer window for reopening of L-type Ca²⁺ channels during phase 2 (or occasionally phase 3) of the action potential. L-type Ca²⁺ current depolarizes the membrane before repolarization, triggering an afterdepolarization. Due to L-type Ca²⁺ channel time and voltage dependence, EADs occur at slow stimulation rates or after a ventricular pause when action potential duration (phase 2) is prolonged and they are suppressed with faster heart rates. EADs are thought to initiate the polymorphic ventricular arrhythmias torsades de pointes (TdP) found in inherited and acquired long QT syndrome (LQTS), for example drug-induced LQTS. A point of distinction to be made here is that triggered activity can initiate TdP, but TdP may be a re-entrant mechanism at the organ level with a functional (spiral reentry) rather than fixed anatomical core. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

●DADs – DADs, which result from intracellular Ca²⁺ overload, are triggered after the action potential is fully repolarized. Under conditions of Ca²⁺ overload, Ca²⁺ taken back up by the sarcoplasmic reticulum is then transiently re-released into the cytoplasm. This in turn causes a transient rise in cytoplasmic Ca²⁺ activating Ca²⁺-dependent depolarizing membrane current mostly through the Na⁺-Ca²⁺ exchanger. The exchange of three Na⁺ for one Ca²⁺ produces a net inward and transient depolarization or a DAD. If the DAD reaches threshold voltage, it can initiate an action potential. Conditions which enhance cellular Ca²⁺ loading, such as rapid heart rates, enhance DAD susceptibility. DADs may be important in myocardial ischemia, digoxin toxicity, and in some inherited arrhythmia syndromes such as catecholaminergic polymorphic ventricular tachycardia. (See "Cardiac arrhythmias due to digoxin toxicity", section on 'Mechanisms of cardiac toxicity' and "Catecholaminergic polymorphic ventricular tachycardia".)

ACTION OF ANTIARRHYTHMIC DRUGS

Classification of antiarrhythmic drugs — The different antiarrhythmic drugs often have several effects on action potential generation and propagation and may also affect the autonomic nervous system. The classification of antiarrhythmic drugs according to the Harrison modification of the Vaughan Williams classification was originally based upon their effects on the action potential, but later modification and enhancements included the molecular targets such as specific ion channels and beta adrenergic receptors [8,11]. The most recent modification (table 2 and table 3) adds additional classes and subclasses to the four traditional classes based on targets, some of which have clinically available drugs (eg, Class 0 pacemaker channel blocker ivabradine), and others that are experimental or theoretical targets (eg, Class VI gap junction blockers) [11]. This scheme differs slightly from a classification endorsed by international societies [4]. Further modifications are to be expected. All these classification schemes assume that individual drugs have a predominant mechanism of action. This distinction remains useful, even though it does not account for the complicated electrophysiologic and autonomic interactions that are present, with some drugs having actions on more than one target.

The modified Vaughan Williams classification has proven surprisingly useful even though it represents an oversimplification of the electrophysiologic events that occur. The classification appears to work because the multiple factors that influence cardiac excitability are sufficiently coordinated to produce predictable outcomes, rather than unpredictably complex behavior [12,13].

●There is an electrophysiologic matrix or substrate of interacting active (ion channels) and passive (lipid bilayer of the cell membrane, myoplasm, and gap junctions) cellular properties that determine normal cardiac excitability.

●The normal substrate is altered by arrhythmogenic influences that affect one or more determinants of excitability. The ensuing proarrhythmic state can result in reentrant, automatic, or triggered arrhythmias. (See "Reentry and the development of cardiac arrhythmias" and "Enhanced cardiac automaticity".)

●The substrate that is deformed by arrhythmogenic factors interacts with antiarrhythmic drugs. Depending upon the substrate encountered, the resulting substrate may be antiarrhythmic, antifibrillatory, or proarrhythmic.

●Certain arrhythmogenic substrates are common, such as those induced by ischemia or infarction. In this setting, a certain effect of a drug becomes predominant and predictable, as with class I activity in ischemia, and a drug classification appears accurate. However, the major drug effect may be quite different if a different proarrhythmic substrate exists. Consider, for example, the differences in digitalis action in hypokalemia and hyperkalemia.

Class 0 — Drugs in the newly proposed Class 0 modulate the pacemaker channel HCN4, affecting the pacemaker current I_f [11]. The blocker ivabradine slows heart rate.

Class I — The class I drugs act by modulating or blocking the sodium channels, thereby inhibiting phase 0 depolarization. They are all at least in part positively charged and presumably interact with specific amino acid residues in the internal pore of the sodium channel. Three different subgroups (table 2 and table 3) have been identified because their mechanism or duration of action is somewhat different due to variable rates of drug binding to and dissociation from the channel receptor [14]:

●The class Ic agents have the slowest binding and dissociation from the binding site.

●The class Ib agents have the most rapid binding and dissociation from the binding site.

●The class Ia agents are intermediate in terms of the speed of binding and dissociation from the binding site.

During faster heart rates, less time exists for the drug to dissociate from the receptor, resulting in an increased number of blocked channels and enhanced blockade. These pharmacologic effects may cause a progressive decrease in impulse conduction velocity and a widening of the QRS complex. This property is known as "use-dependence" and is seen most frequently with the class Ic agents, less frequently with the class Ia drugs, and rarely with the class Ib agents [15].

●Class Ia drugs (quinidine, procainamide, and disopyramide) depress phase 0 (sodium-dependent) depolarization, thereby slowing conduction. They also have moderate potassium channel blocking activity (which tends to slow the rate of repolarization and prolong action potential duration [APD]), and quinidine in particular also blocks potassium current I_To, which is useful for suppressing certain ventricular arrhythmias such as those found in the Brugada syndrome. Class Ia agents also have anticholinergic activity and tend to depress myocardial contractility. At slower heart rates, when use-dependent blockade of the sodium current is not significant, potassium channel blockade may become predominant (reverse use-dependence), leading to prolongation of the APD and QT interval and increased automaticity.

One difference between the drugs is that quinidine and procainamide generally decrease vascular resistance, whereas disopyramide increases vascular resistance. In addition, N-acetyl-procainamide (NAPA), a metabolite of procainamide, has little sodium current blocking activity, while retaining potassium current blocking activity. Thus, NAPA behaves like a class III drug. (See 'Class III' below.)

●The class Ib drugs (lidocaine and mexiletine) have less prominent sodium channel blocking activity at rest, but effectively block the sodium channel in depolarized tissues. They tend to bind in the inactivated state (which is induced by depolarization) and dissociate from the sodium channel more rapidly than other class I drugs. As a result, they are more effective with tachyarrhythmias than with slow arrhythmias.

●Class Ic drugs (flecainide and propafenone) primarily block open sodium channels and slow conduction. They dissociate slowly from the sodium channels during diastole, resulting in increased effect at a more rapid rate (use-dependence). This characteristic is the basis for their antiarrhythmic efficacy, especially against supraventricular arrhythmias. Use-dependence may also contribute to the proarrhythmic activity of these drugs, especially in the diseased myocardium, resulting in incessant ventricular tachycardia.

Flecainide and propafenone also have potassium channel blocking activity and can increase the APD in ventricular myocytes. Propafenone has significant beta blocking activity.

Another recognized target for antiarrhythmic action is the late sodium current, which is enhanced in both acquired and inherited arrhythmias. When enhanced, it lengthens the APD and can create a substrate for arrhythmia by reentry and triggered activity (both early and delayed afterdepolarizations). Some class I drugs such as mexiletine and flecainide and class III drugs such as amiodarone preferentially block the late sodium current. The most selective late sodium current blocking drug is ranolazine, a drug approved for the treatment of chronic angina, but which may have antiarrhythmic activity [16]. This target has been proposed as a new sub-classification, Id [11].

Class II — Class II drugs act by inhibiting sympathetic activity, primarily by causing beta blockade. They may also have a mild inhibitory effect on the sodium channels. Sympathetic stimulation has the following potential proarrhythmic actions [17]:

●An increase in automaticity due to enhancement of phase 4 spontaneous depolarization (see "Enhanced cardiac automaticity").

●An increase in membrane excitability due to shortening in refractoriness (phases 2 and 3 of the action potential).

●An increase in the rate of impulse conduction through the myocardial membrane, resulting from acceleration of phase 0 upstroke velocity or the rate of membrane depolarization.

●An increase in delayed afterpotentials, especially when the cell is calcium loaded, such as in digoxin toxicity.

By blocking catecholamine and sympathetically mediated actions, beta blockers slow the rate of discharge of the sinus and ectopic pacemakers, and increase the effective refractory period of the AV node. They also slow both antegrade and retrograde conduction in anomalous pathways [18].

Carvedilol is a beta-blocker with unique additional properties. In addition to beta- and alpha-adrenergic blockade, carvedilol can also block potassium (KCNH2, formerly HERG), calcium, and sodium currents and modestly prolong APD. However, when administered chronically, carvedilol increases the number of these channels, which is probably a favorable effect in diseased hearts [19].

The most recent classification (table 2 and table 3) expands the definition of class II to include "autonomic inhibitors and activators," with subclass IIa as beta adrenergic blockers such as those mentioned above, IIb as adrenergic activators such as isoproterenol, IIc as muscarinic inhibitors such as atropine, IId as muscarinic activators such as carbachol and digoxin, and IIe as adenosine receptor activators [11]. Adrenergic activators and muscarinic inhibitors augment, and muscarinic activators and adenosine activators decrease, heart rate by actions on the electrophysiology of the sinoatrial (SA) node and AV node. These additional classifications bring drugs that were previously outside the Vaughan Williams classification into the scheme.

Class III — The class III drugs (eg, amiodarone, dronedarone, ibutilide, dofetilide, sotalol, vernakalant) block the potassium channels to inhibit I_Kr, I_Ks, I_K1, and I_KUR, thereby prolonging repolarization, the APD, and the refractory period. The relative potency of these drugs for specific potassium currents may account for atrial selectivity, for example I_KUR is only known to be in the atria [19]. Blockage of ventricular potassium currents is manifested on the surface ECG by prolongation of the QT interval, providing the substrate for torsades de pointes, a polymorphic ventricular tachycardia. Amiodarone and dronedarone are exceptions with very little proarrhythmic activity, perhaps because of a balance of offsetting actions. Additionally, there are more atrial-specific agents such as vernakalant that block primarily I_KUR.

These drugs also have other antiarrhythmic effects:

●Sotalol has beta blocking activity. (See "Clinical uses of sotalol".)

●Amiodarone and dronedarone block sodium channels in depolarized tissues (a Class Ib effect) and also block calcium channels, potassium channels, and adrenergic receptors. Amiodarone also has thyroid effects that dronedarone, an amiodarone derivative without the iodine moiety, lacks. (See "Amiodarone: Clinical uses" and "Clinical uses of dronedarone" and "Amiodarone and thyroid dysfunction".)

●Ibutilide, which is available in intravenous form, is approved for the acute termination of atrial flutter and atrial fibrillation, and it prolongs the QT interval by enhancing the slow, delayed inward sodium current as well as blocking potassium channels during repolarization. (See "Therapeutic use of ibutilide".)

Some of the class III agents, such as sotalol, dofetilide, and ibutilide, exhibit reverse use-dependent effects on repolarization [20]. This pharmacologic property is characterized by a dynamic increase in the repolarization time and the refractory period during slower heart rates. Clinically, this property manifests as an increased QT interval at slower heart rates, which can increase the risk of torsades de pointes [20].

The new classification scheme (table 2 and table 3) adds subclass IIIb and IIIc agents. Subclass IIIb agents (metabolically dependent K⁺ channel openers, eg, pinacidil) may shorten the action potential but do not have antiarrhythmic activity [11]. Subclass IIIc agents (transmitter-dependent K-channel blockers, such as acetylcholine) activate potassium channels, but there are no clinically available drugs in this subclass.

Class IV — The class IV drugs are calcium channel blockers. Verapamil has a more pronounced inhibitory effect on the slow response SA and AV nodes than diltiazem. In comparison, the dihydropyridines, such as nifedipine, have little electrophysiologic effect on the heart. Verapamil and diltiazem can slow the sinus rate (usually in the presence of sinus node dysfunction or beta blockade), increase the refractoriness of and prolong conduction through the AV node, occasionally prolong the PR interval, and depress LV function.

The newer classification scheme (table 2 and table 3) calls this class "Ca handling modulators" and divides it into five subclassifications of targets, of which Class IVa is the classic Vaughan Williams surface channel blockers [11]. The additional classes IVb through IVe for the most part do not yet contain clinically available drugs, but this scheme does serve as a template for further research. An exception to this are the Class I drugs flecainide and propafenone, which qualify as class IVd ryanodine receptor blockers and are active against catecholaminergic polymorphic ventricular tachycardia.

Additional proposed classes include Class V (mechanosensitive channel blockers) and Class VI (gap junction blockers), which have drugs under investigation. Class VII (upstream target modulators) includes angiotensin converting enzyme inhibitors and angiotensin receptor blockers that may have antiarrhythmic action by their effects on cardiac remodeling.

A position paper on antiarrhythmic drugs produced by international societies provides additional detail [4].

SUMMARY AND RECOMMENDATIONS

●Antiarrhythmic drugs target ion channels and receptors in the heart, generally blocking or inhibiting function. (See 'Cardiac excitability' above.)

●Classification of antiarrhythmic drugs is generally done by their predominant action and target (table 2 and table 3). Note that nearly all clinically used drugs act on multiple targets. (See 'Classification of antiarrhythmic drugs' above.)

●The multiple electrophysiologic actions of antiarrhythmic drugs interacting with the variable underlying substrate present in each patient determine whether the clinical effect will be proarrhythmic or antiarrhythmic. (See 'Classification of antiarrhythmic drugs' above.)