Terfenadine increases the QT interval in isolated guinea pig heart

Torsades de pointes ventricular tachycardia (VT) has been reported in patients taking the nonsedating antihistamine, terfenadine. We performed electrophysiologic studies of 14 isolated guinea pig hearts using the Langendorff technique to assess whether terfenadine exerted actions that could be responsible for inducing the arrhythmia. Twelve hearts were perfused with an oxygenated Tyrode's solution containing a 2-microM preparation of either racemic, R-, or S-terfenadine. QT interval (QT), monophasic action potential duration (APD), and ventricular effective refractory periods (ERP) were measured at a fixed range of cycle lengths (CL). At 400-ms CL, both isomers and racemate prolonged QT and APD by 8% and ERP was increased by 14%. Infusion of vehicle, dimethyl sulfoxide (DMSO), alone in two hearts caused a slight decrease in QT and APD, suggesting that the direct effect of terfenadine on QT may have been underestimated. One-way analysis of variance (ANOVA) showed no statistical difference in effect on QT, APD, or ERP for the three forms of terfenadine (p < 0.05). These results support the conclusion that terfenadine induces torsades de pointes because of direct actions in delaying cardiac repolarization. The lack of stereospecificity in this action indicates that chirally pure formulations are not likely to have greater safety than the racemate.