CONCENTRATION-DEPENDENT CARDIOTOXICITY OF TERODILINE IN PATIENTS TREATED FOR URINARY-INCONTINENCE

Objective-Terodiline, an antimuscarinic and calcium antagonist drug, w as used to treat detrusor instability but was withdrawn in 1991 after provoking serious ventricular arrhythmias associated with increases in the corrected QT interval (QTc). This research was performed to relat e drug induced electrocardiographic changes in asymptomatic recipients to plasma concentrations of the R(+) and S(-) terodiline enantiomers. Setting-Urological and geriatric clinics and wards. Subjects-Asymptom atic patients taking terodiline in stable dose. Methods-Electrocardiog rams (50 mm/s) were collected from patients while they were taking ter odiline and compared with ECGs obtained before or after terodiline. QT interval, heart rate corrected QT interval (QTc), and QT dispersion ( QTd) were measured. Drug induced electrocardiographic changes were rel ated to plasma concentrations of R(+) and S(-) terodiline. Results-Dur ing terodiline treatment mean QTc and QTd were prolonged (491(43) and 84 (35) ms(1/2)) compared with measurements made off therapy (443 (33) and 42 (17) ms(1/2), paired t tests, P < 0.002 and P < 0.01 respectiv ely) in the 12 patients in sinus rhythm. The mean (95% confidence inte rval) drug induced increases were 48 (23 to 74) ms(1/2) for QTc and 42 (13 to 70) ms(1/2) for QTd. These increases correlated with total pla sma terodiline (QTc: r = 0.77, P < 0.006, QTd: r = 0.68, P < 0.025) an d with plasma concentrations of both terodiline enantiomers. Conclusio ns-Terodiline increases QTc and QTd in a concentration dependent manne r. It is not clear whether this is a stereoselective effect and, if so , which enantiomer is responsible. The results suggest that drug induc ed torsade de pointes is a type A (concentration dependent) adverse dr ug reaction.