THERAPY AND PREVENTION Electropharmacology of sotalol in patients with Wolff-Parkinson-White syndrome

The f3-adrenoceptor-blocking and class II1 effects of sotalol were assessed in 1 1 patients with inducible orthodromic reciprocating tachycardia. Serum sotalol concentration, maximum exercise heart rate, and electrophysiologic study data were obtained at control, at the /3-adrenoceptor-blocking dosage (407 149 mg/day, 1.4 0.5 ,ug/m-1), and at the maximum well-tolerated dosage (924 + 337 mg/day, 3.2 ± 1.3 gg/ml). Class III effects (increases in anterograde and retrograde accessory connection effective refractory periods, ventricular effective refractory period, and the QT interval during fixed-rate atrial pacing) were evident at the ,B-adrenoceptor-blocking dosage of sotalol and became more marked at the maximum well-tolerated dosage. For example, the mean anterograde accessory connection effective refractory period was significantly increased over control (272 ± 41 msec) by the ,B-adrenoceptor blocker (324 + 52 msec) and was further significantly increased by the maximum well-tolerated dose (364 37 msec). Similarly, the minimum preexcited RR interval during atrial fibrillation was increased in all patients at each dosage tested. Antiarrhythmic efficacy, defined by the absence of inducible, sustained, orthodromic reciprocating tachycardia and a minimum preexcited RR interval during atrial fibrillation of 300 msec or greater, was achieved in four patients at the /3-adrenoceptor-blocking dosage and in another four patients at the maximum well-tolerated dosage. These eight patients received long-term sotalol therapy and none has had recurrent, sustained reciprocating tachycardia during 15 ± 12 months of follow-up. Therefore, although class III effects of sotalol occur at /3-adrenoceptor-blocking dosages, higher dosages increase class III effects and antiarrhythmic efficacy in the setting of the Wolff-Parkinson-White syndrome. Circulation 76, No. 4, 810-818, 1987. SOTALOL is a newer antiarrhythmic agent with both ,3-adrenoceptor-blocking and class III electrophysiologic activity. 1-6 Although its antiarrhythmic efficacy had been documented for ventricular arrhythmias,7-11 the efficacy and safety of oral sotalol therapy for the supraventricular tachyarrhythmias complicating Wolff-Parkinson-White (WPW) syndrome have not been assessed systematically. The /3-adrenoceptorblocking effects of sotalol should be advantageous in the treatment of the reciprocating tachycardias ofWPW syndrome primarily by slowing conduction and prolonging refractoriness of the atrioventricular (AV) From the Department of Medicine and the Department of Pharmacology and Therapeutics, Foothills General Hospital and the University of Calgary, Calgary, Alberta, Canada. Supported by grants from the Alberta Heart Foundation and the Medical Research Council of Canada. Dr. Mitchell is a Senior Investigator of the Alberta Heart Foundation. Drs. Wyse and Duffare Scholars of the Alberta Heritage Foundation for Medical Research. Address for correspondence: L. Brent Mitchell, M.D., Division of Cardiology, Foothills General Hospital, 1403 29th St. NW, Calgary, Alberta T2N 2T9, Canada. Received June 9, 1986; revision accepted May 22, 1987. 810 node. However, in these patients with accessory AV connections, isolated 3-adrenoceptor blockade may fail to control and may even accelerate the ventricular response rate to atrial fibrillation. 12-15 In distinction to other,-adrenoceptor-blocking agents, the additional class III effects of sotalol should contribute to efficacy in the treatment of the reciprocating tachycardias of WPW syndrome primarily by prolonging refractoriness of the accessory connection. Furthermore, class III activity can also reduce the ventricular response rate to atrial fibrillation. 16 Therefore, a major determinant of the balance between efficacy and safety of sotalol therapy in patients with the WPW syndrome will be the dose ranges over which these two classes of electrophysiologic effects are manifest. The purpose of this study was to determine the dosage range over which the /3-adrenoceptor-blocking and class III electrophysiologic effects of sotalol become manifest and to determine the relative contributions of these effects to the safety and antiarrhythmic efficacy of sotalol in patients with WPW syndrome. CIRCULATION by gest on M ay 1, 2017 http://ciajournals.org/ D ow nladed from THERAPY AND PREVENTION-ARRHYTHMIA