Tocainide Plus Quinidinefor Treatment of Ventricular Arrhflhmias JEAN T. BARBEY, MD, KATHERINE A. THOMPSON, MD, DEBRA S. ECHT, MD, RAYMOND L. WOOSLEY MD, PhD, and DAN M. RODEN, MD Tocainide and quinidine were administered both as single agents and in combination to 14 patients with chronic ventricular arrhythmias. Therapy with to- cainide was limited by the occurrence of dose-relat- ed adverse reactions in 8 patients, but could be ti- trated to a dose that was well-tolerated in 13 of 14 and effective in 2 of 13. The addition of quinidine gluconate to the tolerated dose of tocainide in- creased the number of patients with arrhythmia sup- pression from 2 to 8. After tocainide washout, quini- dine alone suppressed arrhythmias in only 3 pa- tients. Analysis of electrocardiogram intervals showed that the drugs had additive effects on the coupling interval of the sinus beat to the predomi- nant ectopic beat, but exerted antagonistic effects on the corrected QT interval. These findings suggest that the combination may be clinically useful, exert- ing pharmacologic effects unlike either agent alone. (Am J Cardiol 1g88;81:570-573) A ntiarrhythmic therapy with single agents is fre- quently only moderately effective and can be limited by the occurrence of adverse effects related to plasma concentrati0ns.l Therefore, the strategy of combining drugs to keep doses under those associated with side effects, yet maintain or even increase efficacy, has been advocated. In guinea pig ventricular papil- lary muscle preparations, Hondeghem and Katzung2 showed that the combination of iidocaine and.quini: dine produced supra-additive effects on the V,,, of early extrasystoles but an effect no different from quinidine alone on normal complexes. These data sug- gested that such combinations might suppress closely coupled abnormal beats while exerting little effect on sodium channels of normal beats. In a group of pa- From the Departments of Medicine and Pharmacology, Vander- bilt University School of Medicine, Nashville, Tennessee. This study was supported by grants HL36724, GM31804 and RR095 from the United States Public Health Service, Bethesda, Mary- land, and from Merck, Sharpe and Dohme, West Point, Pennsyl- vania. Dr. Barbey was the recipient of a Research Fellowship Award from the American Heart Association (Tennessee Affili- ate] during the conduct of this work. Manuscript received Sep- tember 4,1987; revised manuscript received and accepted Octo- ber 27,1987. Address for reprints: Dan M. Roden, MD, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232. tients with ventricular arrhythmias, we found that the combination of quinidine and the lidocaine analog mexiletine was more effective and less likely to cause side effects than therapy with either agent alonee3 Tocainide, like mexiletine, is a lidocaine analog which can be used orally. In vitro, it blocks the fast inward sodium current and shortens action potential duration.4 Treatment with tocainide is frequently lim- ited by dose-related neurologic side effects such as tremor or ataxia.5 Although tocainidk and mexiletine produce similar electrophysiologic changes and have comparable side effect profiles, reports from our group and others have suggested that response to 1 lidocaine analog is not predictive of response to the other.6-8 Tocainide is currently prescribed as a racemic mix- ture, Of the 2 stereoisomers, the R(-] form is more potent in suppressing arrhythmias in an animal mod- ‘elg; however, its plasma concentrations are usually lower than those of the S(+) st 7 reoisomer during to- cainide administration in man. O Quinidine also blocks cardiac sodium channels but prolongs the duration of the action potential in most tissuesll As with tocainide therapy, side effects during quinidine are frequent and range from diarrhea to arrhythmia aggravation.12 This study determines if the addition of a low dose of quinidine to tocainide could enhance the efficacy and decrease the toxicity of to- cainide given alone and characterizes the antiarrhyth- mic, pharmacokinetic and electrocardiographic fea- tures of this combination. 570