Historical development of the concept of controlling cardiac arrhythmias by lengthening repolarization: particular reference to sotalol.

Abstract Although numerous pathophysiologic states, such as hypocalcemia and hypothyroidism, lengthen repolarization and are associated with a reduced incidence of cardiac fibrillation, the concept of the pharmacologic control of rhythm disorders by prolonging the action potential duration is relatively new. There is now a great deal of interest in the relative merits and applicability of delaying conduction or prolonging refractoriness as ways to prevent arrhythmias. Prolonging the action potential duration in cardiac tissues lengthens the refractory period without affecting conduction, prolongs the cycle length of the tachycardia, and prevents it from deteriorating into fibrilation. Lengthening the action potential duration is also associated with a positive inotropic effect demonstrated most readily in isolated cardiac tissues, an important feature in antiarrhythmic agents intended for use in lifethreatening tachyarrhythmias in patients with reduced ventricular function. This array of properties was first recognized in the β blocker sotalol and formed the basis for a discrete class of antiarrhythmic mechanism—the so-called class III electrophysiologic effect. Such a series of actions was also recognized early in the case of amiodarone, which has a much more complex pharmacologic profile. Clinical studies with sotalol and amiodarone have done much to establish the clinical use of prolonging the action potential duration in controlling a broad spectrum of cardiac arrhythmias. Both amiodarone and sotalol prolong the action potential duration and attenuate adrenergic stimulation, but they do so by fundamentally different mechanisms. The electrophysiologic properties of sotalol represent the combined effects of β blockade and lengthening the action potential duration. Prolonging the action potential duration is not related to β blockade because the dextroisomer of the compound has effects identical to those of the levoisomer at the same drug concentrations. In high concentrations, sotalol inhibits the inward sodium current but does not affect the inward slow calcium current. It prolongs repolarization by inhibiting the delayed rectifier potassium current, with a modest effect on the inward rectifier. After intravenous or oral administration in humans, sotalol stows the heart rate and intranodal conduction and prolongs the refractory period in the atrioventricular node. These effects are due essentially to β blockade and are similar to those produced by most heart rate-reducing β blockers. The class III actions of sotalol are reflected in the prolongation of the monophasic action potential duration accompanied by major increases in the refractory periods in the atria, ventricles, His-Purkinje system, and in the bypass tracts in both the retrograde and anterograde directions. These changes occur independently of β blockade. The available data on the pharmacodynamk and electrophysiotogic properties of sotalol suggest that the drug's action should result in the acute and prophylactic control of a wide variety of supraventricular and ventricular arrhythmias.