Pharmacodynamic, pharmacokinetic and antiarrhythmic properties of d-sotalol, the dextro-isomer of sotalol

Abstract

In recent years, there has been a major shift from the use of antiarrhythmic drugs that act by slowing conduction to those that exert their beneficial actions by lengthening cardiac repolarisation. Such a shift is occurring because sodium channel blockers may increase mortality, especially in patients with structural heart disease, and because drugs such as sotalol and amiodarone are effective, with a potential for decreasing arrhythmic mortality. In this context, the electrophysiological and antiarrhythmic properties of d-sotalol, the dextro-isomer of sotalol, are of major importance. d-Sotalol is essentially devoid of beta-blocking actions and may be considered a pure class III compound. It has been assumed that its clinical efficacy would approximate that of amiodarone and sotalol, but without the complex adverse effect profile of amiodarone and the adverse beta-blocker effects of racemic sotalol. d-Sotalol has pharmacokinetic properties that resemble those of the racemate. It lengthens the QT/QTc interval but does not affect other electrocardiographic (ECG) intervals. It increases the refractory period in the atria, ventricles, bypass tracts and the His-Purkinje system while minimally slowing the heart rate. In preliminary studies, it had a weak suppressant effect on premature ventricular contractions, prevented inducibility of ventricular tachycardia or fibrillation in about 40% of patients, and demonstrated the potential to terminate atrial flutter and fibrillation and maintain stability of sinus rhythm during prophylactic administration. The drug exhibits little or no negative inotropic actions. Thus, it is likely to be better tolerated in patients with congestive heart failure dependent on sympathetic stimulation for compensation. Because it produces less bradycardic effect than the racemate, it is believed that the drug might induce a lower rate of torsade de pointes. The role of d-sotalol in controlling cardiac arrhythmias is being addressed in a number controlled clinical trials. However, one such double-blind, placebo-controlled trial, Survival With Oral d-Sotalol (or SWORD), in survivors of myocardial infarction with depressed ventricular function was recently terminated prematurely because of a strikingly greater all-cause mortality compared with placebo (4.6 versus 2.6%). These preliminary findings, still to be fully analysed and interpreted for clinical significance, nevertheless raise valid concerns regarding the currently popular concept of controlling cardiac arrhythmias by the selective or isolated prolongation of repolarisation ('pure' class III action) as an antiarrhythmic principle.