CHAPTER 40 Antiarrhythmic Electrophysiology and Pharmacotherapy

Antiarrhythmics of Clinical Relevance in the CCU

CARDIAC ARRHYTHMIAS continue to be a significant cause of morbidity and mortality in the developed world and add to the complexity of management of critically ill patients. Over the past 2 decades treatment strategies have expanded to include other approaches such as catheter ablation and implantable cardiac defibrillators. Although these strategies have demonstrated significant superiority over antiarrhythmics, they have not eliminated the problem of cardiac arrhythmias. Furthermore, these approaches can be difficult to apply to patients in the acute setting. Antiarrhythmic agents continue to be a vital adjunct to these therapeutic approaches.

Despite the important role that antiarrhythmics play to combat cardiac arrhythmias, it has been difficult to overcome the stigma associated with these drugs. This stigma has stemmed from earlier published trials such as the CAST and CAST II trials evaluating class IC antiarrhythmics and the SWORD trial evaluating sotalol in patients with coronary artery disease and left ventricular dysfunction. These trials demonstrated increased mortality, significant side effects, and marginal efficacy.^1,^2,³ The Achilles heel of these agents is their propensity for proarrhythmia that results in more dangerous arrhythmias than the ones they were initially intended to treat. This led to a re-evaluation of the wisdom of using relatively simple agents that took aim at single molecular targets, such as sodium or potassium channels. Subsequently, researchers pursued the development of newer antiarrhythmic agents that target multiple molecules or complex arrhythmogenic pathways, such as amiodarone or d,l-sotalol. There was a renewed interest and emphasis on the use of β-blockers, which do not specifically target ion channels. In addition there has been significant interest in understanding the genetic basis of susceptibility to serious arrhythmias in individuals with genetic syndromes such as long QT and Brugada syndromes.

Despite their potentially serious side effects, antiarrhythmics continue to be a valuable tool when used appropriately and in a targeted manner. The aim of this chapter is to provide a clear and concise overview of the physiologic basis and applicable pharmacology that makes these drugs useful, and to discuss the ones most clinically relevant to the management of the acutely ill patient.

Physiology

Normal cardiac electrical activity is determined by the shape of the cardiac action potential. Antiarrhythmic agents exert both desirable therapeutic effects and undesirable side effects by their capacity to alter the shape of the action potential. These actions are mediated by their ability to affect the ion channels that control it. Therefore, a review of the basic physiology of the cardiac action potential is imperative to understanding the mechanism of action of these drugs.

Over the past 2 decades our knowledge and understanding of cardiac cellular electrophysiology has increased as a result of cutting edge techniques, such as the cloning and sequencing of proteins and ion channels. A detailed description of the many ion channels discovered to date, and their respective roles, is beyond the scope of this chapter. A more fundamental approach to the basic principles that produce the action potential is described.

A simplified model of the His-Purkinje action potential (fast response tissue) is discussed first followed by descriptions of the action potential of the sinoatrial (SA) and atrioventricular (AV) nodes (slow response tissue).

His-Purkinje Action Potential

The His-Purkinje action potential can be conceptually divided into periods of depolarization, repolarization, and resting states. However, the action potential is traditionally divided into five different phases (phases 0-4) to describe the activity of various ion channels that bring about any of these three states (Fig. 40-1, A and B). Phase 4 corresponds to the resting state when the cell is not being stimulated and is ready for subsequent depolarization. Phase 0 corresponds to depolarization of the myocardial cell. It initiates a cascade of events involving the influx and efflux of multiple ions, leading to phases 1-3, manifesting in repolarization and refractoriness.

Figure 40-1 A, Ion channels responsible for the His-Purkinje action potential. This diagram shows the action of the various ion channels responsible for the His-Purkinje action potential over the time it takes for a complete cycle of depolarization and repolarization. B, Ion flux responsible for the His-Purkinje action potential. This diagram shows the influx and efflux of various ions in the His-Purkinje action potential over a single complete cycle of depolarization and repolarization; this corresponds to the action of their respective ion channels seen in A.

Phase 4

The normal resting membrane potential in the ventricular myocardium is between −85 to −95 mV. This membrane potential is determined by the balance of inward sodium (Na⁺) and calcium (Ca²⁺) currents and outward potassium (K⁺) current. The equilibrium potential for a given ion is determined by the concentrations of that ion inside and outside the cell. K⁺ is the principal cation intracellularly, whereas phosphate and conjugate bases of organic acids are the dominant anions. Extracellularly, Na⁺ and chloride (Cl⁻) are the principal cation and anion, respectively. Therefore, when K⁺ channels open, K⁺ ions flow outside the cell along their concentration gradient, leaving the cell with a more negative membrane potential.

The resting membrane potential is generated by the inward rectifier current (I_K1), the predominantly open channel during this phase. The maintenance of this electrical gradient is because of various ion pumps and exchange mechanisms, such as the Na⁺-K⁺ ion exchange pump and the Na⁺-Ca²⁺ exchanger current.

This phase of the action potential is associated with cardiac diastole.

Phase 0 (Depolarization)

Rapid depolarization occurs when the resting cell is brought to threshold causing activation (opening) of fast Na⁺ channels. This results in rapid influx of Na⁺ ions caused by increased cell membrane permeability to Na⁺. The slope of phase 0 represents the maximum rate of cell depolarization (Vmax) and governs the conduction velocity of a cardiac impulse through cardiac cells. This can be altered by drugs such as the class I antiarrhythmics, which retard conduction velocity, and Vmax.

Voltage-gated Na⁺ channels can exist in either the resting, open (phase 0), or inactive state. The response of these Na⁺ channels is dependent on the membrane potential at the time of stimulation. If the membrane potential is at baseline (−95 mV), then all resting Na⁺ channels open simultaneously, resulting in a dramatic influx of Na⁺ ions. If, however, the membrane potential is above baseline (less negative), then some Na⁺ channels may be in the inactive state and unable to open, resulting in a smaller response with less influx of Na⁺ ions (lower Vmax). This has clinical relevance as class I antiarrhythmics prefer binding to inactive Na⁺ channels. Furthermore, this reduced cellular excitability may render cardiac cells prone to variable refractoriness, delayed conduction, and various arrhythmias.

Phase 1 (Early-Rapid Repolarization)

This phase represents the initial stages of cellular repolarization and is caused predominantly by closure of the fast acting Na⁺ channels. However, the net downward deflection of the action potential is also attributable to transient outward flux of K⁺ ions as a result of two K⁺ channels (I_{to, fast} and I_{to, slow}) opening and then closing.

Phase 2 (Plateau)

Although this phase may appear to be a particularly stagnant part of the action potential, it is in fact one of the most complex and dynamic portions. Multiple ions make small contributions resulting in a relatively constant, positive value of the membrane potential. The predominant forces are outwardly directed K⁺ ions and inwardly directed Ca²⁺ ions, which maintain an equal balance. The outward flux of K⁺ through the delayed rectifier K⁺ channel (I_Kur) and through the ADP activated K⁺ channel (I_KATP), is balanced against rapid inflow of Ca²⁺ through L-type Ca²⁺ channels (I_{Ca, L}).

The plateau phase is unique to the cardiac cell and represents an interruption to rapid repolarization, extending the duration of the action potential and therefore the refractoriness of the cardiac cell. The benefit of this is to allow for a single contraction of myocardium to occur before the generation of a subsequent action potential, thus the heart can never be “tetanized,” which would be incompatible with cardiac function.⁴

Phase 3 (Repolarization)

L-Type Ca²⁺ channels are now closed while slow delayed rectifier K⁺ (I_Ks) channels are open and trigger opening of other channels, such as the rapid delayed rectifier K⁺ channel (I_Kr). This results in a net outward flux of positive cations, thereby facilitating cellular repolarization. The I_K1 channel is activated late in phase 3 and continues on to contribute to the resting membrane potential of phase 4.

SA Node and AV Node Action Potential

SA and AV nodal action potentials are very similar with only minor differences between them in phase 0. They are significantly different from fast response tissue’s action potentials previously described. These slow response tissue action potentials are divided into three phases instead of five (Fig. 40-2, A and B). Phase 4 is the spontaneous depolarization (pacemaker potential) phase that triggers the action potential once the membrane potential reaches threshold (between −40 and −30 mV). Phase 0 is the depolarization phase of the action potential. This is followed by phase 3 repolarization. Once the cell is completely repolarized at about −60 mV, the cycle is spontaneously repeated.

Figure 40-2 A, Ion channels responsible for the sinoatrial/atrioventricular (SA/AV) node action potential. This diagram shows the action of the various ion channels responsible for the SA/AV node action potential (slow response tissues) over the time it takes for a complete cycle of depolarization and repolarization. B, Ion flux responsible for the SA/AV node action potential. This diagram shows the influx and efflux of various ions responsible for the SA/AV node action potential (slow response tissues) over a single complete cycle of depolarization and repolarization; this corresponds to the action of their respective ion channels seen in A.

Phase 4—Spontaneous Depolarization (Pacemaker Potential)

The unique firing of pacemaker cells is attributable to their capacity to slowly and spontaneously depolarize. The resting potential of a pacemaker cell (−60mV to −70mV) is caused by ongoing efflux of potassium ions. Potassium permeability decreases with time, contributing to the slow depolarization. Additionally a slow inward flow of sodium, called the “funny current” (I_f) and an inward flow of calcium through T-type calcium channels (ICa _T) all make the cell more positive. When the threshold potential (−40 mV to −50 mV) is reached, the cells enter the depolarization phase.

Phase 0—Depolarization

The predominant ion activity during this phase is dependent on the influx of calcium through L-type calcium channels as opposed to sodium influx in fast response tissues. In fact I_Na channels are largely absent from these cells.

The upstroke (Vmax) and therefore the conduction velocity in a pacemaker cell is significantly slower than in the fast response tissue cells, with the AV node action potential demonstrating a faster Vmax than that of the SA node.⁵

Phase 3—Repolarization

Calcium channels are rapidly inactivated with simultaneous decrease in sodium permeability. This is combined with increased potassium permeability with resultant efflux of potassium, slowly repolarizing the cell once more to its resting potential.

Autonomic Innervation

Both sympathetic and parasympathetic nerve fibers are abundantly found in both the SA and AV nodes; however, parasympathetic nerve fibers are only minimally located in fast response tissue. Therefore, parasympathetic tone fluctuations are notable in the SA and AV nodes with minimal or no effect on fast response tissue.

Increased sympathetic tone results in enhanced automaticity, increased conduction velocity (Vmax), and decreased refractoriness. These effects combine to produce an increased number of action potentials that are propagated faster. Increased parasympathetic (vagal) tone has the opposite effect, with diminished automaticity and conduction velocity but increased refractoriness. These observations have an important impact on clinical arrhythmias and their management.

It is helpful to keep in mind the various roles of ion channels on the different stages of the action potential, in both fast and slow response cells, to achieve an understanding of the potential key effects of antiarrhythmic agents. In addition, the Vaughan-Williams classification of antiarrhythmic drugs is based upon which ion channels they affect.

Classification

This is currently the most widely used classification of antiarrhythmic drugs (Table 40-1). This classification was initially introduced by Vaughan Williams^6,⁷ and was based on the electrophysiologic effects of antiarrhythmics. It was later modified by Harrison⁸ with the recognition that drugs in the same class have different potencies and that the same drug may exert multiple class effects.

Table 40–1 Vaughan-Williams Classification of Antiarrhythmics and Their Mechanism of Action

Class	Mechanism	Drugs
I	Na⁺ channel blockers
A	Slows conduction velocity (Vmax) and prolongs action potential. Results in decreased conductivity and increased refractoriness.	Quinidine, procainamide, disopyramide
B	Minimal effect on conduction velocity (Vmax) and shortens action potential duration. Results in decreased refractoriness.	Lidocaine, mexiletine
C	Significant slowing of conduction velocity (Vmax), minimal effect on action potential duration. Results in decreased conductivity and no change in refractoriness.	Flecainide, propafenone, moricizine
II	β-blockers Decrease sympathetic tone affecting SA and AV nodes	Atenolol, esmolol, propranolol
III	K⁺ channel blockers No effect on conduction velocity with significant increase in action potential duration. Results in no change in conductivity but marked increase in refractoriness.	Amiodarone, sotalol, dofetilide, ibutilide, azimilide
IV	Ca²⁺ channel blockers Affect SA and AV node by direct cell membrane effects	Verapamil, diltiazem (non-dihydropyridine)
V	Other mechanisms Affect SA and AV nodes by increasing vagal tone	Digoxin, adenosine

Amiodarone has effects across all classes, blocking Na⁺ channels in depolarized tissues, but is also capable of affecting Ca²⁺ and K⁺ channels and adrenergic receptors. This makes it an extremely versatile drug capable of affecting a wide variety of arrhythmias. Sotalol has a significant β-blocker effect in addition to its class III action. Ibutilide can also enhance the slow delayed sodium current. Although moricizine has diverse effects across different classes, this drug is not currently used because it has been demonstrated to increase mortality.

Class I Antiarrhythmics and Use Dependence

Class I drugs are all Na⁺ channel blockers with varying potency and are classified based on their effect on the action potential upstroke or Vmax and therefore their ability to alter conduction velocity. They can prolong it, shorten it, or have no net effect (Fig. 40-3). Their different potency is due to variable rates of binding and dissociation from the channel receptor.⁹ Class IC are the most potent Na⁺ channel blockers because they have the slowest binding and dissociation from the receptor; class IA are the least potent (fastest binding and dissociation); and class IB are moderately potent. Faster heart rates allow less time for drug-receptor dissociation, resulting in an increased total number of blocked receptors and more effective antiarrhythmic action. This is known as “use dependence” and is most noted with class IC agents.¹⁰ These effects can result in prolonged conduction velocity and manifest by widening of the QRS complex on the surface electrocardiogram (ECG), especially during tachycardia.

Figure 40-3 Effect of class I antiarrhythmics on the His-Purkinje action potential. All class I antiarrhythmics retard the slope of phase 0 of the action potential resulting in a decrease of Vmax and a decrease in the conduction velocity of the cardiac cell. Class IC agents slow the upstroke of the action potential (Vmax) the most, resulting in prolongation of the action potential. This prolongation causes a marked decrease in conductivity, but has little overall effect on the effective refractory period. Class IC agents do not alter refractoriness significantly. Class IA agents slow the upstroke (Vmax) moderately, prolonging the action potential, decreasing conduction velocity, and increasing refractoriness. Class IB agents have a very small effect on the Vmax, shortening the action potential, which results in an overall decrease in refractoriness.

Class III Antiarrhythmics and Reverse Use Dependence

Class III antiarrhythmic agents extend the plateau phase of the action potential by blocking K⁺ channels. They effectively prolong repolarization and the action potential duration with a resultant increase in refractoriness without a change in conductivity (Fig. 40-4). This manifests as prolongation of the Q–T interval on the surface ECG. These effects are most pronounced during slow heart rates. This is known as “reverse use dependence” and thus, longer Q–T intervals are noted at slower heart rates.¹¹ This provides the potential for dangerous arrhythmias such as torsades de pointes.¹² This is known as proarrhythmia and is one of the most serious, life-threatening side effects associated with antiarrhythmic drug use. Amiodarone, however, appears to be the exception, with proarrhythmia being reported only uncommonly.¹³

Figure 40-4 Lengthening of effective refractory period on class III antiarrhythmics. All class III agents cause a blockade of K⁺ channels. As a result, the rate of outward flux of K⁺ is slowed down during phases 2 and 3, which causes a prolongation of the time it takes a cardiac cell to return to the resting membrane potential. This prolongs the effective refractory period of the cardiac cell, resulting in an increased time before it is ready for the subsequent depolarization.

Class II Antiarrhythmics

These drugs act by competitive inhibition of the β-adrenergic receptor, and largely affect the SA and AV node. Yet they also have mild Na⁺ channel inhibitory effects. There is a preponderance of data demonstrating the antiarrhythmic properties of β-blockers. β-blockers have played an increasingly important role in increasing survival in patients with coronary heart disease and congestive heart failure, along with adjunctive therapy to implantable cardiac defibrillators (ICDs) by decreasing the incidence of sudden cardiac death (SCD). Although not all of the beneficial effects of β-blockers are understood it is likely that they essentially work by reversing or preventing the proarrhythmic actions of sympathetic activity.¹⁴ These include increased automaticity because of enhanced phase 4 depolarization in the SA and AV nodes, increased membrane excitability in phase 2 and 3 of the His-Purkinje action potential, increased Vmax, and increased delayed afterpotentials, which can lead to increased triggered activity type arrhythmias. They are therefore most effective in tissue under intense adrenergic stimulation (e.g., in ischemia) and it is not surprising that their effects are most obvious in patients having acute myocardial infarction and decompensated heart failure.

Class IV

The non-dihydropyridine calcium channel blockers (verapamil and diltiazem) are the only ones that exhibit significant electrophysiologic and antiarrhythmic properties. These are mediated through their ability to block the slow calcium channel. Their antiarrhythmic properties are exerted through two main effects. Their most prominent activity is to block the slow calcium channel in the action potential of the SA and AV node, effectively slowing phase 4 spontaneous depolarization. This results in a variable slowing of the heart rate (similar to β-blocker–induced adrenergic blockade)¹⁵ and slowing conduction through the AV node, manifested by bradycardia and prolongation of the P-R interval on the surface ECG.

The other action is their ability to shorten the plateau phase of the action potential of ventricular myocytes, therefore inhibiting early afterdepolarizations (EADs).¹⁶ EADs are due to fluxes in calcium and appear to occur mostly under conditions that prolong the action potential (e.g., hypoxia, drug induced), giving rise to torsades de pointes. Therefore, calcium channel blockers may play an active role in the prevention of these types of arrhythmias.