Interaction between selected sodium and potassium channel blockers in guinea pig papillary muscle.

Previous studies have reported that enhanced antiarrhythmic effects occur when agents that prolong repolarization are combined with agents that block the sodium channels. The mechanism(s) of this interaction have not been elucidated. In this study, the interactions between the prolongation of action potential duration (APD) by a potassium channel blocker and the reduction in the maximal upstroke velocity of phase 0 of action potential (Vmax) by sodium channel blockers were investigated in guinea pig papillary muscle using conventional microelectrode techniques. Agents that produce selective electrophysiologic effects were chosen, including low concentrations of barium chloride (BaCl2), which selectively blocks the inwardly rectifying potassium current without effects on other repolarizing or depolarizing currents, O-demethyl-encainide (ODME), which blocks the activated sodium channel with slow onset/offset kinetics, and mexiletine, which preferentially blocks the inactivated sodium channel with rapid onset/offset kinetics. Mexiletine (4 x 10(-6) M) decreased Vmax from 195 +/- 29 V/sec at baseline to 180 +/- 26 V/sec (P < .05). Whereas BaCl2 (10(-5) M) prolonged action potential duration, it had no effect on Vmax. However, the addition of BaCl2 to mexiletine synergistically decreased Vmax from 180 +/- 26 V/sec with mexiletine to 166 +/- 18 V/sec (P < .05). ODME (3 x 10(-7) M) decreased Vmax from 179 +/- 17 V/sec at baseline to 133 +/- 15 V/sec (P < .01). However, the addition of BaCl2 to ODME did not produce a further decrease in Vmax as compared with ODME alone. In summary, a synergistic effect on Vmax was observed when BaCl2 and mexiletine were combined.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of food on the bioavailability of encainide.

The bioavailability of drugs that undergo extensive presystemic hepatic metabolism may be increased by concomitant ingestion with food. The effect of food on the bioavailability of encainide, a class IC antiarrhythmic agent, was evaluated in 14 healthy subjects in this randomized crossover study. The subjects received encainide 35 mg every 8 hours for 7 days and were randomized to receive their test dose of encainide with food or after an overnight fast. Encainide area-under-the-concentration versus time curve (AUCs) were detectable in 3 of 14 subjects after fasting and in 7 of 14 after feeding. Although food increased the mean encainide AUC by more than threefold, this increase did not reach statistical significance because of the large number of subjects with indeterminate encainide AUCs. Food did significantly increase the AUC of O-demethyl-encainide (ODE), but not the AUC of methoxy-O-demethyl-encainide (MODE). Despite the increase in ODE AUC, no significant effect on the surface electrocardiogram 2 hours after dose administration could be detected. Food may increase the bioavailability of encainide and one of its active metabolites (ODE). The clinical relevance of this pharmacodynamic effect warrants further evaluation.

Suppression of longitudinal versus transverse conduction by sodium channel block. Effects of sodium bolus.

BACKGROUND: Arrhythmias resulting from treatment with sodium channel-blocking antiarrhythmic drugs have been successfully treated with sodium infusion, although the mechanism underlying this effect is uncertain. METHODS AND RESULTS: In this study, we used a multielectrode array to examine the effects of O-desmethyl encainide (ODE), a potent sodium channel-blocking metabolite of encainide, on conduction in canine ventricle. ODE depressed both longitudinal and transverse conduction velocities in a plasma concentration-related fashion (r = -0.74, -0.60; p less than 0.001). At ODE concentrations less than or equal to 300 ng/ml (n = 34), conduction velocity was depressed to the same extent in the longitudinal (-21.9 +/- 8.4%, SD) and transverse orientations (-22.0 +/- 8.8%). However, at concentrations greater than 300 ng/ml (n = 17), conduction was significantly more impaired longitudinally than transversely (-44.5 +/- 11.7% versus -34.4 +/- 13.7%, p less than 0.02). In 12 animals with high concentrations (mean, 432 +/- 32 ng/ml), a 5-meq/kg bolus of sodium chloride over 1 minute immediately increased conduction velocity; this effect was significantly greater and longer lasting in the longitudinal orientation. In two animals, conduction block in the longitudinal orientation was documented at high plasma ODE and was immediately reversed by sodium bolus. CONCLUSIONS: We conclude that the major effect of sodium in animals with excess sodium channel block is improvement of longitudinal propagation; this effect may underlie the antiarrhythmic action of sodium in the analogous clinical setting.

Intravenous 3-methoxy-O-desmethyl-encainide in reentrant supraventricular tachycardia: a randomized double-blind placebo-controlled trial in patients undergoing EP study.

Encainide is an agent effective in atrioventricular and atrioventricular nodal reentrant tachycardia. The metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide (MODE) are responsible for the clinical effects of encainide in most patients. In this study, intravenous MODE was evaluated in eight patients with reentrant supraventricular tachycardia undergoing electrophysiological testing. After tachycardia was induced at least twice to ensure reproducibility, MODE (30 micrograms/kg/min x 15 min, then 7.5 micrograms/kg/min) or placebo was administered in a double-blind fashion. If tachycardia remained inducible, the infusion was unblinded; in nonresponding subjects who received placebo, MODE was then administered. Placebo was ineffective in 3/3 patients. MODE prevented tachycardia induction in 5/8 patients and increased the tachycardia cycle length from 302 +/- 38 to 413 +/- 67 msec in the other three. At a mean concentration of 774 +/- 229 ng/ml, MODE prolonged PR, AH, HV, QRS, and QT intervals, right ventricular and accessory pathway effective refractory periods, and slowed or blocked antegrade accessory pathway conduction. Changes in intracardiac conduction were rate independent between cycle lengths 400 to 600 msec, while changes in ventricular effective refractory periods were most pronounced at rapid pacing rates. No adverse effects, hemodynamic changes, or conduction disturbances occurred. Thus, MODE can modify or suppress induction of reentrant atrioventricular or atrioventricular nodal tachycardia. The study design used here is well suited for the evaluation of newer antiarrhythmic agents by electrophysiological testing.

Hemodialysis clearance of encainide and metabolites.

The disposition of encainide and metabolites O-desmethylencainide (ODE) and 3-methyl-ODE (MODE) was evaluated in a 31-year-old hemodialysis patient following a 25 mg oral dose during an interdialytic period and a second 25 mg oral dose 48 h later, 2 h before a hemodialysis procedure. The inter- and intradialytic elimination half-lives were not different for encainide and its metabolites ODE and MODE. The hemodialysis clearance of encainide, MODE, and ODE are all less than 10% of the creatinine clearance of the dialyzer. Thus, hemodialysis does not result in clinically significant removal of encainide or its metabolites.

Antiarrhythmic efficacy, clinical electrophysiology, and pharmacokinetics of 3-methoxy-O-desmethyl encainide (MODE) in patients with inducible ventricular tachycardia or fibrillation.

In most patients, the clinical effects of therapy with encainide are mediated by the generation of the active metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide (MODE). Data from in vitro and animal studies have indicated that MODE has electrophysiologic and pharmacokinetic features that make its further evaluation desirable; in earlier studies, we found that MODE suppressed chronic high-frequency nonsustained ventricular arrhythmias at plasma concentrations of 50-160 ng/ml. We now report the clinical electrophysiology, antiarrhythmic activity, and pharmacokinetics of MODE in 17 patients with inducible ventricular tachyarrhythmias (VTs) in whom programmed electrical stimulation was performed before drug administration and after one or two sequences of loading and maintenance infusions of MODE. Because the relation between plasma concentration and effect had been incompletely defined, a dose-titration approach was adopted: available pharmacokinetic data were used to construct loading and maintenance infusion regimens that were predicted to attain low plasma concentrations in initial patients while higher infusion rates were evaluated in subsequent patients. MODE prevented VT induction in three of 17 patients and VT cycle length was increased by greater than or equal to 100 msec in a further seven of 17; most responses to MODE occurred at plasma concentrations greater than 556 ng/ml (greater than 1 SD above mean plasma MODE during encainide therapy). Response to MODE did not predict subsequent response to oral therapy with encainide. MODE increased intracardiac conduction times, QT intervals during atrial and ventricular pacing, and right ventricular effective refractory periods (RVERP); changes in RVERP were most prominent at rapid pacing rates, while changes in intracardiac conduction were rate-independent at cycle lengths between 400 and 600 msec. Plasma MODE concentrations measured during electrophysiology study correlated well with those predicted by the pharmacokinetic simulations (r = 0.91, p less than 0.001). Serial plasma sampling after programmed electrical stimulation indicated a minimum MODE elimination half-life of 8.2 +/- 5.4 hours. Side effects were confined to three instances of asymptomatic conduction system depression in subjects with latent conduction system disturbances. We conclude that MODE slows intracardiac conduction, delays repolarization, and can suppress or substantially modify inducible VT. Moreover, it was only with the adoption of the dose-titration strategy that we were able to safely demonstrate that plasma MODE concentrations higher than those routinely observed during encainide therapy were required to substantially alter cardiac electrophysiology.

Acute electrophysiologic effects of sodium administration in dogs treated with O-desmethyl encainide.

Conduction slowing is the major in vivo effect of sodium channel blocking drugs. Although this action may promote arrhythmia suppression, apparently paradoxical arrhythmia aggravation does occur. The latter outcome is most frequently seen during treatment with the class IC agents such as encainide or flecainide, which are potent depressors of conduction even at usual plasma concentrations and heart rates. Anecdotal reports in patients with such drug toxicity have suggested a beneficial effect of sodium lactate or NaHCO3 administration. The purpose of this study, therefore, was to examine the changes induced by sodium loading on the electrophysiologic properties of the canine ventricle pretreated with a class IC drug. Thirty dogs received loading and maintenance infusions of O-desmethyl encainide (ODE), an encainide metabolite that as a sodium channel blocker is approximately 10 times more potent than the parent drug. Interventions were administered during the maintenance phase when stable plasma ODE concentrations of 448 +/- 68 (SEM) ng/ml were present, and QRS was prolonged from 62 +/- 1 to 89 +/- 2 msec, and HV was prolonged from 28 +/- 1 to 50 +/- 1 msec. NaHCO3 (5 meq/kg during 1 minute) shortened QRS from 92 +/- 6 to 76 +/- 3 msec and shortened HV from 44 +/- 3 to 37 +/- 3 msec within 10 minutes (both p less than 0.01). NaHCO3 also significantly prolonged endocardial monophasic action potential duration from 231 +/- 22 to 272 +/- 33 msec and decreased serum [K+] from 3.8 +/- 0.2 to 3.0 +/- 0.2 meq/l, but it did not alter plasma ODE concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Temperature and voltage dependence of sodium channel blocking and unblocking by O-demethyl encainide in isolated guinea pig myocytes.

O-demethyl encainide (ODE) is a metabolite of encainide with potent antiarrhythmic effects. We studied block of sodium channels by ODE in isolated guinea pig ventricular myocytes, using both direct measurement of whole cell sodium current and Vmax. Specifically, we examined whether block by ODE was use-dependent, whether ODE blocked activated or inactivated channels, and whether ODE's effect depended on membrane potential. At cold temperatures (15-20 degrees C), ODE was a potent blocker of activated cardiac sodium channels, with little or no effect on inactivated channels. At these temperatures, there was no detectable diastolic recovery from block. Repeated depolarizations produced use-dependent unblocking, which increased as the holding potential was made more negative. At warmer temperatures, use-dependent unblocking was increased, the availability curve of sodium channels for use-dependent unblocking was less shifted toward negative potentials, and diastolic recovery from block became detectable, albeit slow (tau approximately 25 s). Our findings demonstrate that electrophysiologic effects of agents such as ODE may be both quantitatively and qualitatively different at cold temperatures than at normal body temperature. One should be cautious about extrapolating electrophysiologic data obtained at cold temperatures to clinical situations.

Pharmacodynamic modeling of antiarrhythmic drug effects--application to 3-methoxy-O-demethyl encainide.

The pharmacodynamic characteristics of 3-methoxy-O-demethyl encainide (MODE) were studied in instrumented, chloralose-anesthetized dogs. The HIS Purkinje conduction times (HV) were utilized to assess drug effect. Two protocols were conducted; the first protocol involved multiple pairs of loading and maintenance infusions to achieve several steady-state plasma drug concentrations. The second protocol involved a single short infusion. The data from both protocols supported a linear concentration-effect relationship for the concentration range studied. The slopes and intercepts were similar for both data sets. The data from the second protocol were also analyzed to assess the temporal aspects of the pharmacodynamics of MODE. Data analysis indicated that there is significant hysteresis in the plasma concentration-effect relationship that is characterized by a first-order rate constant corresponding to a half-life (t1/2) of approximately 10 min. These study results also demonstrated the advantages of single-infusion protocols over multiple-infusion studies for evaluating the concentration-effect relationship of antiarrhythmic drugs.

Differential effects of O-demethyl encainide on induced and spontaneous arrhythmias in the conscious dog.

Encainide is highly effective in suppressing most nonsustained ventricular arrhythmias, but there is evidence that the drug is less effective and may worsen some arrhythmias, particularly in patients with sustained ventricular tachycardia. In most patients it is likely that the major antiarrhythmic effects of encainide are mediated through a potent metabolite, O-demethyl encainide. The effects of infusions of saline solution or O-demethyl encainide on spontaneous ventricular ectopic activity and ventricular fibrillation (VF) threshold were compared in 25 dogs with a mottled myocardial infarct produced by transient coronary occlusion. Plasma levels of the metabolite above 100 ng/ml suppressed (greater than 92%) the spontaneous ventricular ectopic activity that occurred 48 hours after MI, whereas saline solution had no effect. In 15 dogs treated with O-demethyl encainide, the VF threshold decreased an average of 23%, from a baseline level of 23 +/- 8 mA to 18 +/- 9 mA (p less than 0.05). There was a concentration-dependent fall in VF threshold with plasma concentrations of O-demethyl encainide above 150 ng/ml. In 2 dogs with very high plasma concentrations of the metabolite (greater than 1,000 ng/ml), VF was induced by right ventricular pacing alone (S1S1 300 ms). No change in VF threshold was observed in the 8 dogs treated with saline solution, and in each of these dogs VF could be terminated by the countershock protocol. However, in 7 of the 17 dogs treated with O-demethyl encainide, VF could not be terminated by the countershock protocol.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiology of O-demethyl encainide in a canine model of sustained ventricular tachycardia.

The antiarrhythmic agent encainide produces marked suppression of ventricular arrhythmias in most patients. However, in some with sustained ventricular tachycardia, worsening of clinical arrhythmias can occur. Since the effects of this agent are mediated by its O-demethyl metabolite in most patients, we have evaluated the effects of O-demethyl encainide in dogs susceptible to the induction of ventricular tachycardia. Nonsedated animals were studied 3-5 days after 90-min left anterior descending coronary artery occlusions. Electrophysiologic evaluations were carried out at baseline, and then during a series of infusions of O-demethyl encainide that achieved low (58 +/- 5 ng/ml) (mean +/- SE), moderate (190 +/- 16 ng/ml), and high (758 +/- 98 ng/ml) plasma concentrations compared with the range seen in patients (50-300 ng/ml). Ventricular tachycardia induction was unaffected by the drug. Effective refractory period was prolonged in a dose-related fashion at both normal and infarcted epicardial sites. However, local electrogram duration was prolonged only in the infarcted zone. We conclude that O-demethyl encainide exerted no consistent effect on susceptibility to induction of ventricular tachycardia in this study. This agent appears to alter infarcted zone conduction disproportionately.

Electrophysiologic actions of O-demethyl encainide: an active metabolite.

Differences between the electrophysiologic actions of the antiarrhythmic agent encainide have been reported after short-term intravenous and oral administration. Only prolongation of the HV interval and QRS duration have been described immediately after short-term intravenous administration of encainide in dogs and man. However, during oral therapy or more prolonged infusions, prolongation of the AH interval and atrial and ventricular effective refractory periods have also occurred. In most patients receiving encainide therapy, metabolites (O-demethyl encainide and 3-methoxy-O-demethyl encainide) accumulate during prolonged therapy to concentrations greater than those of the parent drug. We compared the electrophysiologic action of O-demethyl encainide with that of saline in anesthetized dogs to determine if this metabolite has pharmacologic activity and whether its electrophysiologic effects could account for the disparities noted between effects of intravenous and oral encainide therapy. An initial pharmacokinetic evaluation allowed design of a series of loading and maintenance infusions that produced plasma concentrations similar to those seen during encainide therapy in man (concentration after first maintenance dose, 149 +/- 27 ng/ml [+/- SE] and after second maintenance dose, 230 +/- 45 ng/ml). Significant increases in atrial effective refractory period and ventricular refractoriness, and prolongation of AH interval and HV conduction time were observed. These effects are similar to those reported after prolonged oral encainide therapy but are substantially different from those seen after short-term infusions of encainide. These findings indicate that the difference between the electrophysiologic actions of intravenous and oral encainide may be due to pharmacologic effects of at least one encainide metabolite, O-demethyl encainide.