CardiovascularDrugs and Therapy4: 567-572,1990 © KluwerAcademicPublishers, Boston.Printed in U.S.A.

In-Vitro and In- Vivo Electrophysiologic Effects of Encainide Christian Libersa, Jacques Caron, Ren~ Rouet Department of Pharmacology, Laboratoire de Pharmacologie, Lille, France

Summary. The intracellular electrophysiologic effects of encainide (E) and its main metabolite, O-desmethyl-encainide (ODE), were studied in guinea-pig papillary muscle preparations and related to the in-vivo electrophysiologic effects observed after intravenous (IV) infusion of E in 11 patients undergoing electrophysiologic study (EPS). At equipotent concentrations of E and ODE, frequencydependent reductions in V m ~ studied at pacing rates of 30180 beats/min ranged from -11.5% to -53%, with maximum reductions of -53% and -47%, respectively at the highest frequency. The kinetics of onset of use-dependent Vm~ reduction were slower for ODE than for E at each studied pacing rate. The kinetics of total recovery from use-dependent block were still slower (120 seconds for E and 300 seconds for ODE at a 90 beats/min pacing rate). These in-vitro electrophysiologic data could explain the marked alterations in intraventricular and atrioventricular conduction observed in humans 60 minutes after IV administration of 1 mg/kg of E over a 15-minute period. The QRS, PA, AH, and HV intervals were significantly increased (p < 0.01) and the Wenckebach cycle length was increased by 8% (p < 0.05). Blood pressure, RR, QT, CSNRT, ESACT, ERP, and FRP did not vary significantly. The HV interval was already increased 2 minutes after drug administration, while All was not increased until 15 minutes after drug administration. There was a positive correlation between the increase of the All interval and the blood level of ODE.

Key Words. encainide, O-desmethyl-encainide, electrophysiologic studies, conduction intervals

E a r l y electrophysiologic studies with encainide produced some contradictory results as a consequence of its active metabolites, O-desmethyl-encainide (ODE) and methoxy-O-desmethyl-encainide. To examine the electrophysiologic properties of encainide more closely two electrophysiologic studies (EPS) of encainide and its main metabolite, ODE, were conducted. One of these studies was an in-vivo study in patients with arrhythmias [1] and one was an in-vitro study with guinea-pig papillary muscle preparations using standard microelectrode techniques.

symptoms suggesting cardiac conduction disorders and atrial or ventricular arrhythmias. All antiarrhythmic drugs were discontinued for a period of at least five specific half-lives. Patients were excluded if they had a recent myocardial infarction, uncontrolled right or left ventricular failure, blood pressure disorders, renal or hepatic insufficiency, thyroid dysfunction, or hypersensitivity to local anesthetics. Data obtained before and after intravenous infusion of encainide were analyzed using Student's t test for paired data and regression lines. Electrocardiographic and electrophysiologic data were measured using catheter electrodes positioned under fluoroscopic guidance at various levels in the right atrium and ventricle. As shown in Figure 1, after baseline EPS, encainide at a dose of 1 mg/kg of body weight was infused intravenously over 15 minutes, and a complete EPS was repeated 60 minutes later. At 2, 5, 15, and 30 minutes after the end of drug administration, sinus cycle length, PR, QT, QRS, and intracardiac electrophysiologic intervals, as well as systolic and diastolic blood pressures, were measured and recorded. Blood samples were drawn before and at 2, 5, 15, 30, and 60 minutes after the infusion of encainide for measurement of plasma concentrations of encainide and its main metabolites, ODE, MODE, and NDE.

In- Vivo Study Results Sixty minutes after the end of the infusion, blood pressure was not changed, but three patients complained of malaise and had a transient drop in blood pressure at about the 13th minute. The ECG data revealed that the PR interval was significantly prolonged by more than 20% and the QRS duration by nearly 28%. The prolongation of the corrected QT interval was not statistically significant. The electrophysiologic data

In-Vivo Study P a t i e n t s and methods For the in-vivo study, 11 patients, six males and five females, had a routine E P S for the investigation of

Address for correspondence and reprint requests: Dr. Christian Libersa, Laboratoire de Pharmacologie, Facult6 de M~decine, 1, Place de Verdun, 59045 Lille Cedex, France. 567

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showed that the prolongation of the PR interval was associated with an alteration of the intracardiac conduction with a 38% increase in the HV interval and, to a lesser degree, in the nodal conduction, which can explain the increase of the anterograde atrioventricular Wenckebach cycle length. The remaining EPS data revealed no significant alterations for either sinus node function or for refractoriness at the different levels studied.

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In- Vivo Study Discussion It is worth noting that other investigators who measured the same E P S parameters at the end and only 15 minutes after the end of encainide infusion found no significant change in the AH interval. The increase in the AH interval observed in this study was only significant at 60 minutes after the end of the encainide infusion at the same time that the ODE plasma concentrations reached steady state. Moreover, a positive correlation between the plasma concentrations of ODE and the increase in the AH interval was also observed (Figure 2). This finding points out the necessity for prolonged EPS with compounds such as encainide that have active metabolites.

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These in-vivo data led to the suggestion that encainide and its main metabolites may have synergistic effects, mainly on intraventricular and atrioventricular conduction. This hypothesis, which has also been suggested by others [2], provided the stimulus for a comparative in-vitro study of the electrophysiologic effects of encainide and its main metabolite, ODE.

Electrophysiological Effects of Encainide

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Fig. 3. Schematic representation of the experimental chamberfor the in-vitro study. In- Vitro Study Methods and results The in-vitro study design is shown in Figure 3. Isolated strips of right ventricle tissue from guinea pigs were placed in the experimental chamber and superfused with normally oxygenated Tyrode's solution at a controlled temperature of 37°C. Intracellular recordings using glass microelectrodes permitted the measurement of resting membrane potential, actionpotential amplitude, and the maximal rate of depolarization of the action-potential upstroke, Vmax. The action-potential duration at 30%, 50%, and 90% of repolarization and the effective refractory period, which is a reliable expression of the reactivation of the sodium channel, were then measured. After a 60-minute stabilization period, the preparation was superfused with encainide or ODE at progressively higher concentrations, and the actionpotential parameters were then measured at steady state with a driving rate of 90 beats/min. At the same equimolar concentrations (0.1, 0.3, 1.0, 3.0, and 10.0 ~M), the decrease in resting membrane potential, the action-potential amplitude, and the Vmax, were all greater with ODE than with encainide. The actionpotential duration measured at 30%, 50%, and 90%

repolarization were minimally altered, except at the highest concentrations (10 ~LM), where they were slightly prolonged for encainide as well as for ODE. There was little effect on refractory periods, which only became significant at the highest concentrations. Equipotent concentrations of encainide and ODE were determined by comparing the respective concentration/effect relationships at a driving rate of 90 beats/rain. The concentrations producing a 30% depression of Vmax in this study were found to be 10-6 M for ODE and 10-5 M for encainide, a relative ratio of 1 over 10. These concentrations were then used for the other steps of the study. These other steps consisted of determining and comparing the use and frequency dependency of encainide and ODE. After a period of stabilization, the preparation was superfused with either encainide or ODE and driven at pacing rates of 30-180 beats/rain. The changes occurring in the Vmax were similar, but the rate of achieving the steady state of Vmax depression was two to four times as long for ODE as for encainide, no matter what the driving rates were. The time to steady-state depression of Vmax ranged from 10 to 30 seconds for encainide and from 45 to 80 seconds for ODE. These data are shown in Figure 4.

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Fig. 4. Onset of the use-dependent effects induced by encainide (10 -5 M) and ODE (10 -6 M) for the five tested pacing rates.

The kinetics of recovery from use-dependent effects (offset kinetics) of encainide and ODE were studied in vitro with the guinea-pig preparation, using a stimulus of 90 beats/min for a sufficient duration to reach the steady-state value of Vmax. Each time the steady state was reached, the stimulus was abruptly interrupted and a single extra stimulus was applied at increasingly longer coupling intervals, thus allowing the determination of the time course intervals for which full recovery of Vmax could be obtained. With this procedure, the offset kinetic for ODE (300 seconds) was about three times as long as for encainide (100 seconds). These results suggest that in patients who are extensive metabolizers of encainide, the main metabolite of encainide may contribute to the Class I electrophysiologic effect of the parent drug and most probably has an additive effect, as has been shown in humans by several investigators.

tion, the effective refractory periods, the QRS duration, and intraventricular conduction. More recently, it has been suggested [3-5] that a more accurate characterization of the Class I antiarrhythmic drugs could be achieved by classifying them according to the kinetics of the onset and recovery from use-dependent block of the maximal rate of depolarization. The onset kinetics of mexiletine with the presence of a resting block are shown in Figure 5, and Figure 6 [3] shows the onset kinetics for mexiletine, a fast-onset kinetics agent, compared with the onset kinetics for disopyramide, with intermediate-onset kinetics, and encainide, a slow-onset kinetics drug. These results correspond quite well with the usual classification of the Class I drugs, as shown in Table 1 for some of the well-known IA, IB, and IC antiarrhythmic agents.

Discussion

Encainide is characterized by a marked use-dependent block, a slow onset and offset kinetics, lack of a resting block, and weak alteration of refractory periods. As such, it is a typical slow Class IC antiarrhythmic drug

Glass I antiarrhythmie drugs are usually classified according to their effects on the action-potential dura-

Conclusions

Electrophysiological Effects of Encainide

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Table 1. Classification of some antiarrhythmic drugs based on their onset kinetics Fast-onset kinetic <500 m s • Lidocaine • Mexiletine • Tocainide

Intermediate-onset kinetic • Quinidine • Procainamide • Disopyramide

Slow-onset kinetic > 7 seconds • Encainide • Lorcainide • Flecainide

[6] that will probably find its place among the increasing array of these compounds. Because of its marked effects on conduction, it should be used with caution in patients with preexisting conduction abnormalities.

References 1. Libersa, CC, Lekieffre J P , C a r o n J F , et al. Electrophysiologic effects of encainide and its metabolites in patients. J Cardiovasc Pharmac 1982;7:1077-1082. 2. J a c k m a n WM, Zipes DP, Naccarelli GV, et al. Electrophysiology of oral encainide. Am J Cardiol 1982;49:1270-1278. 3. Campbell TJ. R e s t i n g and r a t e - d e p e n d e n t depression of maxi m u m rate depolarization in guinea pig ventricular action po-

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tential by mexiletine, disopyramide, and encainide. J Cardiovasc Pharmacol 1983;5:291-296.

4. Vaughan-Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 1984;24:129-147. 5. Hondeghem L, Katzung B. Antiarrhythmic agents: The rood-

ulated receptor mechanism of action of sodium and calcium channel-blocking drugs. A n n Rev Pharmacol Toxicol 1984; 24:387-423. 6. Elharrar V, Zipes DP. Electrophysiologic effects of encainide and two metabolites (abstract). Circulation 1981;64 (Suppl IV):272.