Mexiletine/quinidine combination therapy: electrophysiologic correlates of anti-arrhythmic efficacy.
This article reviews the data which support the use of selected drug combinations to enhance anti-arrhythmic activity. Specifically, we have focused on the mexiletine-quinidine interaction and the relation between anti-arrhythmic efficacy and electrophysiologic effects. In an initial clinical study, we found that combination therapy with mexiletine-quinidine produced enhanced efficacy in suppressing spontaneous ventricular tachycardia with fewer side-effects than high dose monotherapy. This enhanced efficacy has been confirmed in other laboratories. Combination therapy also enhanced suppression of inducible ventricular tachycardia in patients and in animal models. Animal models were used to assess the relation between electrophysiologic effects and anti-arrhythmic efficacy. In the animal studies, combination therapy produced selective prolongation of refractoriness and conduction in the infarct and peri-infarct zones without significant changes in the normal zone. Subsequent studies focused on the relative contribution of sodium channel and potassium channel blocking properties of these drugs to the enhanced activity seen with the combination. Studies using the selective sodium channel blocker tetrodotoxin confirmed that sodium channel blockade was necessary for this interaction. To assess the contribution of prolongation of action potential duration by quinidine to the combined effect we compared the anti-arrhythmic and electrophysiologic effects of the stereoisomers quinidine and quinine given alone and in combination with mexiletine. These experimental data confirm that the property of prolongation of action potential duration by quinidine is essential to the interaction. When comparing quinidine and quinine it is apparent that prolongation of refractoriness in the peri-infarct zone is essential for anti-arrhythmic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Duff
H J
HJ
Department of Medicine, University of Calgary, Faculty of Medicine, Alberta.
Mitchell
L B
LB
Wyse
D G
DG
Gillis
A M
AM
Sheldon
R S
RS
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology; D004359:Drug Therapy, Combination; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008801:Mexiletine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011802:Quinidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology
D015222:Sodium Channels; D008801:Mexiletine; D011802:Quinidine