Mexiletine antagonizes effects of sotalol on QT interval duration and its proarrhythmic effects in a canine model of torsade de pointes.
OBJECTIVE
The arrhythmogenic and electrophysiologic properties of sotalol, a class III antiarrhythmic drug, administered alone and in combination with mexiletine, a class I antiarrhythmic drug, were compared in conscious dogs predisposed to torsade de pointes arrhythmias.


BACKGROUND
The utility of sotalol is limited by proarrhythmia related to excessive delays in repolarization. The addition of mexiletine may limit the risk of torsade de pointes because it reduced in vitro the sotalol-induced increase in action potential duration.


METHODS
Two studies were performed in eight hypokalemic dogs (plasma potassium level < or = 3.2 mmol/liter) with chronic atrioventricular block (mean ventricular cycle length, RR 1,100 ms) at 3-day intervals using a crossover protocol. Intravenous sotalol (4.5 + 1.5 mg/kg body weight per h) alone was given for 2 h, or, on another day, an intravenous mexiletine infusion (4.5 + 1.5 mg/kg per h) was begun 30 min before sotalol infusion. Spontaneous ventricular cycle length and QT interval and ventricular effective refractory period at the 1,000-ms pacing cycle length were measured at baseline and 30 min after the onset of each drug infusion. The electrocardiogram (ECG) was continuously monitored for torsade de pointes.


RESULTS
Sotalol plus mexiletine and sotalol alone had a significant (p < or = 0.05) and similar effect on ventricular cycle length (+ 800 +/- 93 vs. + 690 +/- 104 ms [mean +/- SEM]) and ventricular effective refractory period (+ 20 +/- 4 vs. + 25 +/- 4 ms), but sotalol plus mexiletine had a lesser effect on QT interval (+ 20 +/- 6 vs. + 50 +/- 8 ms, p < or = 0.05). Torsade de pointes is less frequent (one of eight dogs vs. six of eight dogs, p = 0.02) with sotalol plus mexiletine than with sotalol alone.


CONCLUSIONS
The coadministration of a class Ib agent can reduce the proarrhythmic potential of a class III drug in experimental animals predisposed to torsade de pointes arrhythmias and further suggests the clinical utility of such a strategy.
Chézalviel-Guilbert
F
F
Laboratoire de Pharmacologie, Faculté de Médecine de Saint Antoine, Paris, France.
Davy
J M
JM
Poirier
J M
JM
Weissenburger
J
J
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects* / Q000379:methods; D004594:Electrophysiology; D008801:Mexiletine / Q000627:therapeutic use*; D013015:Sotalol / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D016171:Torsades de Pointes / Q000188:drug therapy* / Q000503:physiopathology
D008801:Mexiletine; D013015:Sotalol