Concentration-dependent pharmacologic properties of sotalol

Sotalol is a nonselective beta-receptor antagonist that prolongs action potential duration and refractoriness in vitro at higher concentrations than those associated with heart rate slowing. To determine if this additional action can be expressed in humans, 17 patients with chronic stable ventricular premature complexes were studied. Each patient was hospitalized and arrhythmia frequency was quantified during a 48-hour drug-free baseline and during every third day of therapy with increasing incremental sotalol dosages. The dosages were 160, 320, 640 and 960 mg/day, administered in 1 or 2 doses. An index of action potential duration, the rate-corrected QT (QTc), was measured using serial 12-lead electrocardiograms on the third day of each dosage at presumed steady state and the degree of beta-receptor blockade was assessed by the reduction of the maximal exercise-induced heart rate. Of the 17 patients, 11 had an antiarrhythmic response (70 to 100% reduction in VPCs), at a wide range of plasma concentrations (340 to 3,440 ng/ml). The responders to sotalol included 8 patients in whom therapy with conventional beta-receptor antagonists had failed. In the group as a whole, the concentration associated with significant QTc prolongation (2,550 ng/ml) was greater than that associated with 50% reduction of the maximal slowing in heart rate (804 ng/ml). Sotalol was generally well tolerated, but in 1 nonresponder torsades de pointes developed 3 hours after the first 640-mg dose at a plasma sotalol concentration well within the concentration range measured in other patients. Sotalol's repolarization-prolonging actions are seen at higher concentrations than those associated with heart rate slowing and may contribute to its clinical effects.