The cellular electropharmacology of the simultaneous administration of propranolol and mexiletine: a class I and II antiarrhythmic drug combination.
The addition of propranolol to mexiletine may reduce the adverse effects of mexiletine and possibly increase its efficacy. We compared the cellular electrophysiologic effects of this combination with mexiletine and propranolol alone, over concentration ranges of 3.2 to 100 microM mexiletine and 0.80 to 25.0 microM propranolol, using standard microelectrode techniques and a stimulation frequency of 1.5 Hz. Mexiletine and propranolol both depressed the rate of rise of phase 0 (Vmax) with concentration-response curves of similar slope and a relative potency of 8:1, propranolol to mexiletine. Thus, combinations of 8:1 molar ratios of mexiletine to propranolol were assessed. The combination depressed Vmax to the same extent as mexiletine or propranolol alone. Mexiletine, propranolol and the combination all shortened action potential duration (APD) to the same extent. At low concentration mexiletine, propranolol and the combination shortened effective refractory period (ERP). At 25 microM mexiletine, this effect reversed and ERP began lengthening. The effect of the combination paralleled mexiletine while with propranolol alone the reversal did not occur until the highest concentration was reached. Mexiletine prolonged ERP relative to APD, an effect not shared by propranolol and attenuated with the combination (P less than 0.05). We conclude that combining propranolol with mexiletine does not alter any of the cellular electrophysiologic effects of mexiletine except the prolongation of ERP relative to APD. Although this may be an important antiarrhythmic effect, the extent by which in vivo concentrations of propranolol may reduce the clinical antiarrhythmic efficacy of mexiletine is likely to be negligible.
Department of Medicine, University of Toronto, Canada.
N D
ND
Berman
J E
JE
Loukides
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D008297:Male; D008801:Mexiletine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011433:Propranolol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects*
D004338:Drug Combinations; D008801:Mexiletine; D011433:Propranolol