Action potential prolongation exhibits simple dose-dependence for sotalol, but reverse dose-dependence for quinidine...

Plasma drug concentrations in patients who develop torsade de pointes while receiving quinidine or disopyramide treatment have been reported to be usually in or below the therapeutic range, whereas patients developing the same complication during sotalol treatment usually have drug concentrations well above the therapeutic range. We wished to provide a cellular electrophysiologic rationale for this observation. Standard intracellular microelectrode techniques were used to record action potentials (APs) from canine Purkinje fibers at interstimulus intervals (ISI) of 1,000-6,000 ms, with and without three varying concentrations of quinidine, disopyramide, and sotalol. Cesium chloride 0.5 mM was added to reduce spontaneous diastolic depolarization. We observed a biphasic response in action potential duration (APD) to quinidine and disopyramide. Low concentrations tended to prolong APD, particularly at slower drive rates, whereas this effect tended to reverse as the concentration was increased. In contrast, sotalol produced a consistent, monophasic dose-dependent increase in APD across the therapeutic concentration range and well beyond it. We also observed an apparent increased likelihood of early afterdepolarizations (EADs), with or without triggered activity, at low concentrations of quinidine and disopyramide, with a trend toward reversal as the concentration was increased. We conclude that the biphasic dose response observed for APD with quinidine and disopyramide is due to the opposing effects of these agents on outward potassium and inward sodium currents and may cast some light on the clinical observation noted above. Sotalol on the other hand appears to produce EADs and triggered activity only at high concentrations.