Chapter 11 Principles of Electropharmacology

Long before actual medicines were available for arrhythmias, much had been written about the theoretical mechanisms of arrhythmias.^1,² Today, these studies still provide a rational argument for why a certain drug with certain properties should be an effective antiarrhythmic agent. For example, as discussed in Chapter 2, re-entrant excitation involves a circulating excitatory wavefront along a certain path and has a certain conduction velocity (CV) and refractoriness (effective refractory period [ERP]); thus we have the concept that wavelength (λ) = CV × ERP. Depending on path length and the value of λ, the re-entrant circuit will have an excitable gap. Any change in λ would be expected to determine the inducibility and stability of re-entrant excitation. On the basis of this concept, antiarrhythmic drugs are known to affect properties of cardiac excitability (class I and IV drugs) and refractoriness (class III drugs). Class II drugs remain specific for blocking β-adrenergic receptors. Thus what has emerged is a classification of drugs that depends on a drug’s effect on certain ionic channels or receptors of the cardiac cell sarcolemma (Vaughan Williams classification).³ However, as a result of the Cardiac Arrhythmia Suppression Trial (CAST), which was designed to suppress premature ventricular depolarizations, some of these drugs lost favor, particularly for treatment of ventricular arrhythmias.

For arrhythmias caused by abnormal impulse generation, drug effects were determined by using multicellular cardiac preparations that exhibited a certain cellular electrical phenotype, abnormal automaticity, or triggered activity. Most tissues used in these drug screens were from normal hearts, and their effectiveness may or may not extend to tissues of diseased hearts.

Thus most drugs currently used interrupt the direct mediators of electrogenesis, cardiac ion channels, by affecting the channel pore, the channel’s gating mechanism, or both. In 2001, the members of the Sicilian Gambit, while not disposing of the Vaughan Williams drug classification, emphasized the important and emerging role of new drug targets for pharmacological therapy and/or prevention (Figure 11-1).⁴ These suggestions were based on the concept that most hearts that need antiarrhythmic drugs are “remodeled,” which means that drugs are not working at all or not working well because the fundamental nature of the ion channel “pore” or channel gating mechanism has been altered by an underlying disease. A clear example here is the effect of flecainide in patients following myocardial infarction (CAST) and its effect on a re-entrant circuit and the remodeled sodium channels of cells surviving in the infarcted heart.^5,⁶

FIGURE 11-1 Drug targets for pharmacological therapy and intervention.

(From New approaches to antiarrhythmic therapy, part I: Emerging therapeutic applications of the cell biology of cardiac arrhythmias, Circulation 104:2865–2873, 2001.)

Since then, an explosion in knowledge has occurred regarding the fundamental cell biology and biophysics of cardiac ion channels, the mediators activated, the molecular and cellular bases of remodeling of the cardiac cell in acquired heart diseases, the bases of gene-based cardiac arrhythmias, and, last but surely not the least, a wider appreciation of abnormalities of intracellular calcium (Ca²⁺) in arrhythmogenesis. With this new knowledge, new targets for drugs and drug development are being identified.

Biology and Biophysics of Cardiac Ion Channels

From numerous detailed single-cell, voltage-clamp studies, it has become obvious that a very specific heterogeneity in ionic current properties exists, depending on whether the ion channel target is in a ventricular cell (either epicardial or endocardial), a Purkinje cell, or an atrial cell. This has led to the rational development of drugs that target atrial-specific ion channels. For example, since I_Kur, the ultra-rapid delayed rectifier potassium (K⁺) current (encoded by the Kv1.5 gene), is thought to occur only in atrial cells, I_Kur blockers have been used to convert atrial fibrillation (AF). Unlike I_Kr blockers, I_Kur blockers should delay atrial repolarization (a class III effect) without affecting ventricular repolarization. At this time, these agents remain investigational; on further study, many have been found to have a multiple-ion channel–blocking effect. An additional concern is that even complete I_Kur blockade would not lead to sufficient prolongation of atrial repolarization to terminate re-entrant excitation.

Newer antiarrhythmic class III agents have been developed for their marked reverse-use dependence (e.g., nifekalant), for selective I_Ks blockade (e.g., HMR1556), and for blockade of I_to, a major repolarizing K⁺ current that is found in both atrial and ventricular cells (e.g., tedisamil). In addition, several amiodarone derivatives have been developed to produce agents with a similar ion channel–blockade profile as that of amiodarone but with fewer side effects. An example is dronedarone, an amiodarone derivative with no iodine. Like amiodarone, dronedarone blocks multiple K⁺ currents to prolong ventricular action potential duration (APD).

A drug that blocks inward plateau currents would be considered an anti–class III drug in that it should shorten APD. An antianginal drug, ranolazine, is being investigated for its antiarrhythmic properties, since it strongly inhibits the late I_Na current with little or no effect on peak I_Na.⁷ Thus ranolazine would shorten APD rather than reduce excitability in cardiac tissues. More interestingly, this drug, by blocking sodium (Na⁺) influx into the cardiac cell, would be expected to reduce intracellular Na⁺ and therefore would indirectly affect intracellular Ca²⁺ and all its sequelae (see below).

One form of re-entrant excitation is anisotropic re-entry, which was first considered in atrial samples.⁸ In this type of re-entry, conduction in the longitudinal direction is faster than that in the transverse direction. Spach and his colleagues suggested that a component of conduction slowing in the transverse direction in these cardiac tissues was caused by a change in gap junctional conductance. Thus slowing of conduction was brought about by the uncoupling of cells at the level of the gap junctional proteins, for example, connexins 43 and 40 (Cx43 and Cx40). While experiments have clearly shown that gap junctional uncouplers (e.g., heptanol) are, in fact, arrhythmogenic, a preferential effect appears to occur on transverse conduction velocities in various animal models. Thus a corollary would be that in re-entrant circuits in highly remodeled substrates such as those affected by cell uncoupling caused by ischemia, one would expect drugs that enhance gap junctional conductance to be antiarrhythmic. Rotigaptide is now under study as a gap junctional coupler. In experimental arrhythmia models, this drug improves conduction and abolishes lines of block that perpetuate circuits and therefore has been deemed antiarrhythmic. This experimental drug is thought to affect coupling by preventing dephosphorylation of Cx43, a ventricular gap junctional protein, or by maintaining phosphorylation of the protein.