Concentration dependence of class III and beta-adrenergic blocking effects of sotalol in anesthetized dogs

Abstract

Sotalol is unique among beta-adrenergic blocking drugs in possessing significant class III antiarrhythmic actions. The present study was designed to assess the relative concentration dependence of beta-blocking and class III actions of sotalol and to relate the findings to concentrations achieved during oral sotalol therapy in humans. Measurements were made in anesthetized dogs under control conditions, and then in the presence of a series of stable sotalol plasma concentrations produced by sequential loading and maintenance infusions. Beta-blocking effects of sotalol, determined by attenuation of the chronotropic actions of isoproterenol, were seen at the lowest dose used. Increases in atrial and ventricular refractory periods (observed in dogs with autonomic blockade to exclude beta-receptor-mediated or reflex autonomic effects) required much larger doses of sotalol. Half-maximal beta-blocking effects occurred at an average sotalol concentration of 0.8 +/- 0.3 mg/liter, an order of magnitude lower than the concentrations required for half-maximal effects on atrial (6.9 +/- 1.2 mg/liter, p less than 0.01) and ventricular (6.8 +/- 2.8 mg/liter, p less than 0.05) refractoriness. These results show that substantially higher concentrations are needed for the class III effects of sotalol than for its beta-blocking action. These pharmacodynamic differences need to be considered in evaluating the antiarrhythmic efficacy and mechanisms of this unusual drug.