Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.

To assess the relative contributions of encainide and its putatively active metabolites, O-demethyl encainide (ODE) and 3 methoxy-O-demethyl encainide (3MODE), to the drug's pharmacologic effects, we compared intravenous infusions and sustained oral therapy in two phenotypically distinct groups of patients, extensive and poor metabolizers of encainide. Unlike poor metabolizers, extensive metabolizers had appreciable quantities of both metabolites detectable in plasma and had fourfold shorter elimination half-lives for encainide. By quantitating electrocardiogram intervals, arrhythmia frequency, and plasma concentrations, we found that, in poor metabolizers, arrhythmia suppression and ventricular complex (QRS) prolongation were correlated positively with encainide concentrations (r greater than or equal to 0.570, P less than 0.014). In these two subjects, antiarrhythmic concentrations of encainide (greater than 265 ng/ml) were at least fivefold higher than those sustained in the six extensive metabolizers during steady state oral therapy. In extensive metabolizers, encainide concentrations were uncorrelated with effects. Arrhythmia suppression and QRS prolongation in extensive metabolizers correlated best with ODE (r greater than or equal to 0.816, P less than 0.001); QTc change correlated positively with both 3MODE and ODE. Arrhythmia suppression paralleled QRS prolongation; the relationship between them appeared similar in both phenotypic groups. In most patients, extensive metabolizers, encainide effects during oral therapy are mediated by metabolites, probably ODE.

Effect of encainide and flecainide on chronic ectopic atrial tachycardia.

In the treatment of chronic ectopic atrial tachycardia, standard antiarrhythmic therapy has been shown to be ineffective in the majority of patients. The intravenous and oral effects of two class IC antiarrhythmic drugs, encainide and flecainide, in five patients with chronic ectopic atrial tachycardia were studied using exercise testing, 24 hour long-term electrocardiography and programmed electrical stimulation. All patients had been treated unsuccessfully with at least four antiarrhythmic drugs. In two patients tachycardia was persistent, and in three patients tachycardia occurred intermittently for more than 12 hours/day. Intravenous encainide and flecainide at doses ranging from 0.3 to 2.0 mg/kg and from 0.5 to 1.5 mg/kg body weight, respectively, terminated atrial ectopic tachycardia in all patients. Oral encainide, 150 to 225 mg/day, completely suppressed ectopic atrial activity in four patients during a mean follow-up period of 8 +/- 3 months. In the remaining patient encainide markedly reduced the number of episodes of tachycardia. In three patients encainide had to be withdrawn because of intolerable side effects. These patients were well controlled with oral flecainide, 200 to 300 mg/day, without side effects. On the basis of these results, the efficacy of encainide and flecainide in the treatment of chronic ectopic atrial tachycardia appears to be not drug-specific but rather a general class IC property.

Events in the Cardiac Arrhythmia Suppression Trial (CAST): mortality in the entire population enrolled.

To test the hypothesis that suppression of ventricular arrhythmias by antiarrhythmic drugs after myocardial infarction improves survival, the Cardiac Arrhythmia Suppression Trial (CAST) was initiated. Suppression was evaluated before randomization during an open label titration period. Patients whose arrhythmias were suppressed were randomized in the main study and those whose arrhythmias were partially suppressed were randomized in a substudy. Overall survival and survival free of arrhythmic death or cardiac arrest were lower [corrected] in patients treated with encainide or flecainide than in patients treated with placebo. However, the death rate in patients randomized to placebo therapy was lower than expected. This report describes the survival experience of all patients enrolled in CAST and compares it with mortality in other studies of patients with ventricular arrhythmias after myocardial infarction. As of April 18, 1989, 2,371 patients had enrolled in CAST and entered prerandomization, open label titration: 1,913 (81%) were randomized to double-blind, placebo-controlled therapy (1,775 patients whose arrhythmias were suppressed and 138 patients whose arrhythmias were partially suppressed during open label titration); and 458 patients (19%) were not randomized because they were still in titration, had died during titration or had withdrawn. Including all patients who enrolled in CAST, the actuarial (Kaplan-Meier) estimate of 1-year mortality was 10.3%. To estimate the "natural" mortality rate of patients enrolled in CAST, an analysis was done that adjusted for deaths that might be attributable to encainide or flecainide treatment either during prerandomization, open label drug titration or after randomization. Because the censoring procedure excluded patients treated with encainide or flecainide after randomization, the mortality estimate will be less than the unadjusted mortality estimate of 10.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Events in the Cardiac Arrhythmia Suppression Trial (CAST): mortality in patients surviving open label titration but not randomized to double-blind therapy.

The patient characteristics and outcomes were studied in the 318 patients who survived open label drug titration in the Cardiac Arrhythmia Suppression Trial (CAST) and who were not randomized to double-blind therapy and in 942 patients, who were randomized to double-blind placebo therapy. The patients randomized to placebo therapy had a lower total mortality or resuscitated cardiac arrest rate (4% vs. 8.5%). However, at baseline, nonrandomized patients were dissimilar from patients randomized to placebo in the following ways: older; lower left ventricular ejection fraction; greater use of digitalis, diuretic drugs and antihypertensive agents; lesser use of beta-adrenoceptor blocking agents and more frequent prior cardiac problems, including runs of ventricular tachycardia and left bundle branch block. A matched comparison that took these inequities into account showed no significant differences in mortality or rate of resuscitation from cardiac arrest between nonrandomized patients and clinically equivalent patients randomized to placebo. Cox regression analysis indicated that two factors significantly increased the hazard ratio for arrhythmic death or resuscitated cardiac arrest in the nonrandomized patients: female gender (4.7, p less than 0.05) and electrocardiographic events (ventricular tachycardia, proarrhythmia, widened QRS complex, heart block, bradycardia) during open label titration (7.0, p less than 0.005). However, some potentially important differences between men and women were not included in the Cox regression model. Of the nonrandomized patients, approximately 70% were not randomized because of lack of suppression of ventricular premature depolarizations or adverse events, or both, and the remaining 30% because of patient or private physician request with no indication of another reason.(ABSTRACT TRUNCATED AT 250 WORDS)

The Cardiac Arrhythmia Suppression Trial: first CAST ... then CAST-II.

The Cardiac Arrhythmia Suppression Trial (CAST) was a study designed to test the hypothesis that suppression of ventricular premature complexes after a myocardial infarction would improve survival. Preliminary results showed that suppression of ventricular premature complexes with encainide and flecainide worsened survival, and the CAST continued as the CAST-II with moricizine compared with its placebo. The protocol for the CAST-II was changed to attempt to enroll patients more likely to experience serious arrhythmias. The enrollment time was narrowed to 4 to 90 days after myocardial infarction; the qualifying ejection fraction was lowered to less than or equal to 0.40; a higher dose of moricizine could be used; early titration itself was double-blind with a placebo, and the definition of disqualifying ventricular tachycardia was changed to allow patients with more serious arrhythmias to be entered into the trial. The Cardiac Arrhythmia Suppression Trial-II was subsequently terminated prematurely because 1) patients treated with moricizine had an excessive cardiac mortality rate during the 1st 2 weeks of exposure to the drug, and 2) there appeared to be little chance of showing a long-term survival benefit from treatment with moricizine. This report outlines the rationale behind the Cardiac Arrhythmia Suppression Trial and the reasons for selection of the drugs used in the CAST and CAST-II.

Comparative study of encainide and quinidine in the treatment of ventricular arrhythmias.

The antiarrhythmic efficacy and safety of oral encainide hydrochloride and quinidine sulfate were compared in a nine center double-blind crossover study in 187 outpatients with benign or potentially lethal ventricular arrhythmias. Patients with at least 30 premature ventricular complexes/h were randomized to receive either encainide, 25 mg four times/day, or quinidine, 200 mg four times/day, for 2 weeks. These doses were continued for another 2 weeks if a 75% or greater reduction in premature ventricular complexes was observed. If this reduction was not seen, encainide was increased to 50 mg four times/day or quinidine to 400 mg four times/day for an additional 2 weeks. Both drugs produced a statistically significant reduction in premature ventricular complex frequency compared with baseline values. Encainide produced a statistically significant greater mean reduction in total premature ventricular complexes than did quinidine during the initial dose phase and after dose adjustment. More patients required dose increases of quinidine (60%) than of encainide (51%). Early discontinuation of treatment resulting in advancement to the next study period occurred in 12 patients taking encainide and 38 patients taking quinidine (p less than 0.05). PR and QRS intervals increased significantly during encainide treatment, as did QTc and JT intervals during quinidine treatment. No adverse reactions resulted from these electrocardiographic changes. Adverse reactions were more common with quinidine than with encainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Predicting mortality after myocardial infarction from the response of RR variability to antiarrhythmic drug therapy.

OBJECTIVES: This study was designed to test the hypothesis that antiarrhythmic drugs that decrease RR variability will predict all-cause mortality during follow-up after myocardial infarction. BACKGROUND: RR variability, a noninvasive indicator of autonomic nervous system activity, predicts death after acute myocardial infarction independently of other risk predictors and changes substantially in response to some drugs. A previous study in patients with chronic heart disease and frequent ventricular premature complexes reported that flecainide decreased vagal modulation of RR intervals but amiodarone did not. The investigators of that study speculated that changes in RR variability during antiarrhythmic drug therapy predict an increased mortality rate during long-term drug treatment. To explore this hypothesis further, we compared the effects of encainide and flecainide, which increase long-term mortality substantially, on RR variability with the effects of placebo and moricizine, which have no significant effect on mortality during long-term treatment of unsustained ventricular arrhythmias after myocardial infarction. METHODS: The 24-h power spectral density was computed from the baseline electrocardiographic recordings and drug evaluation tapes, and six frequency domain measures of RR variability were calculated: ultra-low frequency (< 0.0033 Hz), very low frequency (0.0033 to < 0.04 Hz), low frequency (0.04 to < 0.15 Hz) and high frequency power (0.15 to < 0.40 Hz), plus total power (< 0.40 Hz) and the ratio of low to high frequency power. Changes in power spectral measures were related to drug treatment and to mortality. RESULTS: In the placebo group, values for RR interval and RR variability increased because of recovery from the effects of acute myocardial infarction. Contrasting placebo treatment with all three active antiarrhythmic drug treatments taken together showed that of all the measures of RR variability, only NN50, pNN50 and low frequency power changed significantly during drug treatment (Bonferroni adjusted p value < 0.025); these variables all decreased during drug therapy. Contrasting encainide and flecainide with moricizine, we found that the encainide and flecainide groups taken together showed a larger decrease in dLF than moricizine, but the difference was of borderline significance (Bonferroni adjusted p value < 0.08). Survival was significantly worse in the groups treated with encainide and flecainide than in the groups treated with placebo or moricizine (relative risk > 2.0, adjusted p < 0.05). The antiarrhythmic drug-induced change in measures of RR variability was not a significant predictor of all-cause mortality during a year of follow-up after myocardial infarction. CONCLUSIONS: Encainide, flecainide and moricizine all caused a decrease in RR variability in patients studied approximately 1 month after acute myocardial infarction. Encainide and flecainide caused a significant increase in mortality rates; placebo and moricizine did not. Baseline measurements of RR variability also predicted all-cause mortality after myocardial infarction. The decrease in RR variability produced by the three antiarrhythmic drugs did not predict mortality during follow-up.

Electrophysiologic and clinical effects of oral encainide in paroxysmal atrioventricular node reentrant tachycardia.

The electrophysiologic effects of oral encainide (75 to 150 mg daily) were evaluated in 14 patients (6 male and 8 female, aged 49 +/- 9 years) with atrioventricular (AV) node reentrant tachycardia of the slow-fast type. The patients were studied in control conditions and after 2 to 12 days of treatment. Encainide increased the AH interval from 67 +/- 10 to 82 +/- 23 ms (p less than 0.02). Anterograde Wenckebach cycle length was increased in three patients, reduced in four, unchanged in one; it was not measurable in the remaining patients because tachycardia was induced. Retrograde Wenckebach periodicity increased from 307 +/- 71 to 401 +/- 92 ms (p less than 0.005) in all nine patients in whom it was measurable; complete retrograde block was observed in one patient. At the control study, tachycardia was induced in all patients, with a mean cycle length of 341 +/- 50 ms; after encainide, tachycardia was inducible in only 1 patient, with an increase in cycle length from 270 to 320 ms; in the other patients, tachycardia was not inducible because of a lack of retrograde (11 patients) or anterograde (2 patients) conduction. The mean plasma concentrations of encainide and its metabolites O-demethyl-encainide and 3-methoxy-O-demethyl-encainide measured in 13 patients during the repeat study were 161 +/- 304, 128 +/- 100 and 95 +/- 85 ng/ml, respectively; three poor metabolizers who presented a high concentration of the parent compound were observed in this series. All patients were discharged on encainide at a mean daily dose of 112 +/- 39 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of incessant supraventricular tachycardia by intravenous and oral encainide.

Although uncommon, incessant supraventricular tachycardia (the daily presence of supraventricular tachycardia for more than 50% of the day) is a major therapeutic problem. Using programmed electrical stimulation of the heart, long-term electrocardiographic monitoring and exercise testing, the effect of intravenous and oral encainide for termination and prevention of incessant supraventricular tachycardia was assessed in 11 patients (aged 25 to 58 years). All patients had received 3 to 12 drugs (mean 6) without control of their arrhythmia. Eight patients suffered from incessant supraventricular tachycardia using an accessory pathway in retrograde direction (three with overt Wolff-Parkinson-White syndrome, one with a concealed accessory atrioventricular [AV] pathway of the fast type, three with a concealed accessory AV pathway of the slow type and one with a nodo-ventricular accessory pathway). Three patients had incessant atrial tachycardia, one of whom also had the Wolff-Parkinson-White syndrome. Intravenous encainide (1.5 mg/kg in 15 minutes) terminated incessant supraventricular tachycardia in seven of nine patients. In four of nine patients, supraventricular tachycardia could thereafter still be reinitiated by pacing. Oral encainide (100 to 325 mg/day, mean 180) completely suppressed the incessant supraventricular tachycardia in eight patients in a follow-up period of 5 to 20 months (mean 11). In two patients, episodes of tachycardia were markedly reduced with the administration of encainide in combination with sotalol (one patient) and amiodarone (one patient). Encainide failed to control incessant tachycardia in one patient. Mild central nervous system side effects developed in two patients, but both could continue taking oral encainide. Encainide proved to be a very useful agent to control incessant supraventricular tachycardia resistant to other antiarrhythmic agents.

Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. The Pediatric Electrophysiology Group.

The potential for proarrhythmic responses to the class IC sodium channel-blocking drugs encainide and flecainide has not been well described in young patients. Therefore, data were retrospectively collected from 36 institutions regarding 579 young patients who were administered encainide or flecainide for treatment of supraventricular tachycardias (encainide 86 patients, flecainide 369 patients) or ventricular arrhythmias (encainide 21 patients, flecainide 103 patients) to assess the frequency of proarrhythmia, cardiac arrest and death during therapy (adverse events). The two drugs were similar in regard to efficacy (flecainide 71.4%, encainide 59.8%) and rate of proarrhythmic responses (flecainide 7.4%; encainide 7.5%). However, patients receiving encainide more frequently experienced cardiac arrest (encainide 7.5% vs. flecainide 2.3%, p less than 0.05) or died during treatment (encainide 7.5% vs. flecainide 2.1%, p less than 0.05). Detailed data were provided for 44 patients experiencing one or more adverse events. Patient age, previous drug trials, concomitant therapy and days of inpatient monitoring were similar for patients receiving encainide or flecainide. However, echocardiographic left ventricular shortening before treatment was lower among patients receiving encainide (0.23 +/- 0.09) than among those receiving flecainide (0.34 +/- 0.06, p less than 0.05). Plasma drug concentrations were rarely elevated. Cardiac arrest (12 patients) and deaths (13 patients) occurred predominantly among patients with underlying heart disease, particularly among patients receiving flecainide for supraventricular tachycardia (8.3% vs. 0.3%, p less than 0.001). Fifteen patients with an ostensibly normal heart and normal ventricular function experienced proarrhythmia during treatment for supraventricular tachycardia, but only 3 of the 15 had a cardiac arrest or died. The relatively high incidence of adverse events should be considered when contemplating treatment with encainide or flecainide, particularly among patients with underlying heart disease.

Events in the cardiac arrhythmia suppression trial: baseline predictors of mortality in placebo-treated patients.

Patients randomized to placebo in the encainide and flecainide arms of the Cardiac Arrhythmia Suppression Trial (CAST) have been found to have a relatively low 1-year mortality rate of 3.9% in comparison with previous studies of patients in the postmyocardial infarction period. To determine the comparability of CAST with previous studies, baseline variables were examined in the 743 patients randomized to placebo in the flecainide and encainide arms of CAST. Twenty-three baseline characteristics were correlated with major outcome events: arrhythmic death (16 events), total mortality (26 events) and congestive heart failure (51 events). On multivariate analysis the risk of new or worsening congestive heart failure was significantly associated with diuretic use, diabetes, high New York Heart Association functional class, age, prolonged QRS duration and low ejection fraction. The risk of arrhythmic death or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, history of heart failure, use of digitalis, diabetes and prolonged QRS duration. Total mortality or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, diabetes, ST segment depression, high functional class, prolonged QRS duration and low ejection fraction. The variables at baseline associated with mortality from all causes or arrhythmic death or resuscitated cardiac arrest and heart failure in the CAST placebo-treated patients are similar to those identified in previous postmyocardial infarction studies. Thus, the observation of increased mortality in CAST associated with the administration of encainide and flecainide for suppression of ventricular premature depolarizations is probably applicable to any comparably defined group of patients in the postmyocardial infarction period.

Circadian pattern of arrhythmic death in patients receiving encainide, flecainide or moricizine in the Cardiac Arrhythmia Suppression Trial (CAST).

OBJECTIVES: The purpose of this study was to assess the effect of antiarrhythmic drugs on the timing of arrhythmic death. BACKGROUND: Sudden cardiac death remains a problem of epidemic proportions. Delineating its pathophysiology is an important step in devising preventive measures. Previous studies have shown a circadian pattern of onset of sudden cardiac death. The effect of antiarrhythmic drugs on this pattern has not been systematically studied. METHODS: The Cardiac Arrhythmia Suppression Trial (CAST) was a multicenter double-blind, placebo-controlled study designed to determine whether suppression of ventricular ectopic activity by means of antiarrhythmic drugs (encainide, flecainide or moricizine) after acute myocardial infarction would reduce the incidence of arrhythmic death. RESULTS: The trial was terminated prematurely because of an unexpectedly high mortality rate in the active treatment group. The onset of arrhythmic death in this group (in patients not receiving beta-adrenergic blocking agents) displayed a bimodal variation, with significant peaks in midmorning and late afternoon/early evening. More than half of the symptomatic events were accompanied by anginalike symptoms. Approximately 30% of all events occurred within 2 h of awakening. CONCLUSIONS: Our data suggest the possibility of a complex interaction among antiarrhythmic drugs, sympathetic nervous system activation and acute myocardial ischemia. Planning of future antiarrhythmic drug trials will need to take this information into account.

Relations between heart failure, ejection fraction, arrhythmia suppression and mortality: analysis of the Cardiac Arrhythmia Suppression Trial.

OBJECTIVES: We studied the relations between heart failure, ejection fraction, arrhythmia suppression and mortality. BACKGROUND: Both left ventricular ejection fraction and functional class of heart failure are strongly associated with mortality after acute myocardial infarction. Both are also related to the presence of ventricular arrhythmias and have been identified as factors related to the ability to suppress ventricular arrhythmias. Little has been reported about the relations between these two factors and arrhythmia suppression or mortality. METHODS: Baseline data from the Cardiac Arrhythmia Suppression Trial were used to define several categories of heart failure and to relate both the resulting categories and ejection fraction to arrhythmia suppression and mortality using logistic and survival regression analytic methodologies. RESULTS: Regardless of the prospective baseline definition of heart failure used, the data consistently showed that heart failure was a more powerful predictor of subsequent congestive heart failure events and arrhythmia suppression and was equally powerful in predicting death. However, each variable provided incremental information when included in the prediction model. Heart failure and ejection fraction appeared to be independent predictors of death. Interactions were observed: A low ejection fraction was more predictive of failure of arrhythmia suppression in patients with than without evidence of heart failure before or at baseline; a low ejection fraction was more predictive of subsequent congestive heart failure events in patients without than with evidence of heart failure before or at baseline. CONCLUSIONS: Although heart failure as a prognostic feature appears to be somewhat superior to ejection fraction, both are powerful predictors of arrhythmia suppression and cardiac events in patients with ventricular arrhythmia after myocardial infarction. Each provides incremental prediction.

Treatment of atrioventricular node reentrant tachycardia with encainide: reversal of drug effect with isoproterenol.

To determine the efficacy of encainide in the treatment of atrioventricular (AV) node reentrant tachycardia, Holter electrocardiographic (ECG) monitoring, exercise treadmill testing and programmed electrical stimulation were performed in 16 patients while they were taking no medication and after steady state levels were reached during treatment with encainide (75 to 200 mg/day; mean 117 +/- 47). In addition, to study the possible reversal of drug effects by sympathetic stimulation, AV node conduction and tachycardia induction were reassessed during isoproterenol infusion (1 to 3 micrograms/min), a dose calculated to increase the rest heart rate by 25 +/- 10%. Sustained AV node reentrant tachycardia could be initiated in all 16 patients in the control state, in 2 patients after encainide and in 10 patients during isoproterenol infusion. The shortest mean atrial paced cycle length sustaining 1:1 AV conduction was 358 +/- 57 ms during the control study, which increased to 409 +/- 59 ms with encainide (p less than 0.01 versus control) and decreased to 313 +/- 31 ms during isoproterenol infusion (p less than 0.01 versus control and encainide). The shortest mean ventricular paced cycle length with 1:1 ventriculoatrial conduction was 337 +/- 56 ms in the control study, 551 + 124 ms with encainide infusion (p less than 0.01 versus control) and 354 +/- 72 ms during isoproterenol infusion in the encainide-loaded state (p less than 0.01 versus both control and encainide). During a mean follow-up period of 19 +/- 10 months, significant clinical recurrences occurred in 4 of the 10 patients in whom tachycardia could still be initiated with encainide (with or without isoproterenol).(ABSTRACT TRUNCATED AT 250 WORDS)

Congestive heart failure induced by six of the newer antiarrhythmic drugs.

The incidence of drug-induced congestive heart failure with several newer antiarrhythmic agents including encainide, ethmozine, lorcainide, mexiletine, propafenone and tocainide was determined in a group of 407 patients who underwent 1,133 drug tests. The incidence rate ranged from 0.7% with lorcainide to 4.7% with propafenone. Congestive heart failure was present in 167 patients (41%) who underwent 491 drug trials. Congestive failure was induced in 15 (9%) of these 167 patients and involved 19 (3.9%) of the 491 tests. Left ventricular ejection fraction was 20 +/- 8% in patients who developed congestive failure, in contrast to 39 +/- 19% in those who did not (p less than 0.001). It is concluded that each of the six antiarrhythmic drugs examined has the potential to aggravate congestive heart failure in patients with reduced left ventricular ejection fraction or a history of congestive heart failure, but the incidence rate is low and its occurrence unpredictable.

Comparative study of encainide and disopyramide in chronic ventricular arrhythmias: a double-blind placebo-controlled crossover study.

Ten patients suffering from chronic premature ventricular complexes (greater than 60/h) were treated orally in a double-blind crossover study with encainide (50 mg three times a day) and disopyramide (200 mg three times a day), with five 7 day study periods: survey, placebo, encainide or disopyramide, washout placebo and disopyramide or encainide. At the end of each 7 day period, a 12 lead electrocardiogram, a 48 hour ambulatory electrocardiogram and a treadmill exercise test were performed. Blood levels of encainide and its metabolites and of disopyramide were measured at the end of each treatment (steady state). Drug efficacy was assessed by: 1) more than 80% reduction in the number of premature ventricular complexes per 24 hours, and 2) absence of ventricular tachycardia. Encainide was effective in four patients (complete suppression of premature ventricular complexes) and ineffective in five. One patient who showed a 92% reduction in the number of premature ventricular complexes developed sustained ventricular tachycardia after 24 hours of treatment. Disopyramide was effective in three patients (greater than 80% reduction in the number of premature ventricular complexes) and ineffective in seven patients. With encainide, the percent increase in PR, QRS and QT interval duration was, respectively: 32.7 (p less than 0.001), 30.8 (p less than 0.001) and 10.6% (p less than 0.01). With disopyramide this increase was not significant. Despite the variability of drug blood levels, a relation between blood levels and suppression of premature ventricular complexes on the 48 hour ambulatory electrocardiogram was found with encainide, but not with disopyramide.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential block of cardiac delayed rectifier current by class Ic antiarrhythmic drugs: evidence for open channel block and unblock.

OBJECTIVE: The aim was to compare the effects of the class Ic antiarrhythmic drugs flecainide, encainide, and recainam on the delayed rectifier current, IK. METHODS: Membrane currents were studied using the single suction pipette voltage clamp technique in freshly dissociated cat ventricular myocytes bathed in HEPES buffered physiological saline at 32 degrees C. RESULTS: Flecainide and encainide decreased IK with IC50 values of 2.1 microM and 6 microM, respectively. Recainam (100 microM) reduced IK by only 7 (SEM 3)% after 20-30 min exposure and by 19% after an 80 min exposure (IC50 > 400 microM). None of the compounds blocked the inward rectifier, IK1. Block of IK by flecainide and encainide increased with depolarisation following a voltage dependence similar to that describing channel activation. Flecainide and encainide also slowed the time course of the IK tail currents, consistent with drug dissociating from open channels. CONCLUSIONS: The observed voltage dependence for IK block by flecainide and encainide resembles the interaction reported between these agents and the excitatory sodium channel, ie, depolarisation enhances block while repolarisation leads to removal of block. The results further suggest that the electrophysiological profile of class Ic agents can have a markedly different ionic basis, ie, K+ channel block by flecainide and encainide is balanced by a potent block of sodium channels, while recainam appears to be a weak but relatively specific blocker of sodium channels only. These differences are not readily accommodated by the current Harrison-Vaughan-Williams classification scheme, and suggest the possibility that potentially important drug specific differences can exist within the same antiarrhythmic drug class.

Effect of antiarrhythmic drugs on choline uptake in cardiac cells in culture.

OBJECTIVE: The aim was to examine the effect on choline uptake of various antiarrhythmic drugs: lignocaine, tocainide, encainide, flecainide, propafenone, procainamide, N-acetylprocainamide, bretylium, and amiodarone. METHODS: Cardiac ventricular myocytes from 7 d old chick embryos were exposed in culture to these drugs, at concentrations ranging from 10(-6) to 10(-4) M, for 24 h. Myocyte choline uptake was assessed by the addition of methyl [3H] choline to media. After 120 min, media were removed, the cells were harvested, and intracellular [3H] actively was counted. RESULTS: Lignocaine and tocainide produced a significant (p less than 0.05) dose dependent increase in intracellular [methyl 3H] choline. Encainide produced a small increase and flecainide a small decrease in choline, neither of which was dose dependent. Propafenone significantly (p less than 0.05) altered choline uptake: at 10(-6) M and 10(-5) M choline uptake was increased and at 10(-4) M it was decreased. Amiodarone produced a marked and significant (p less than 0.05) dose dependent reduction in choline uptake. Bretylium, procainamide, and N-acetylprocainamide did not alter myocyte choline. CONCLUSIONS: Choline incorporation into cardiac myocyte is altered by some antiarrhythmic drugs, suggesting this may be part of their antiarrhythmic properties.

Encainide disposition in patients with renal failure.

The antiarrhythmic agent encainide undergoes extensive presystemic biotransformation to form O-desmethylencainide (ODE) and 3-methoxy-ODE (MODE) in subjects who exhibit the extensive metabolizer (EM) phenotype for debrisoquin 4-hydroxylation. These metabolites contribute significantly to the overall antiarrhythmic activity and are extensively excreted in the urine. Therefore, the effects of renal impairment on the disposition of encainide and its metabolites were studied in seven EM patients with renal failure and compared with those in eight healthy normal subjects of the same phenotype. After a single dose of encainide, its systemic and oral clearances were significantly lower and its elimination t1/2 was shorter in patients with renal failure than in healthy volunteers. This shortening was explained by a significant reduction in steady-state volume of distribution in renal failure. After chronic dosing to steady state, quantitatively similar changes were seen. Chronic oral dosing produced 80% higher levels of ODE (the most pharmacodynamically active metabolite) and 167% higher levels of MODE as compared with healthy volunteers. The prolongations in ECG intervals were similar in the two groups despite the higher encainide dose in the normal subjects. In conclusion, patients with renal failure will require lower doses of encainide because of both reduced encainide clearance and increased accumulation of active metabolites.

Metabolite cumulation during long-term oral encainide administration.

Cumulation of encainide and its major metabolites, O-demethylencainide (ODE), 3-methoxy-ODE (MODE), and N-demethylencainide (NDE) was examined in patients with frequent complex ventricular ectopy. After 6 mo on encainide patients were admitted to Stanford University Hospital and the drug was discontinued for 24 hr. During this time blood samples were drawn to characterize the cumulation and disposition of the drug and metabolites. The mean steady-state concentrations of encainide, ODE, and MODE were 56.3, 214.6, and 184.6 ng/ml after doses ranging from 100 to 250 mg/day. The concentration ratios of ODE/encainide and MODE/encainide were 5.02 +/- 2.61 and 5.15 +/- 4.13. NDE was detected in the plasma of only one patient. Elimination half lifes of encainide and ODE were 1.16 +/- 0.5 and 11.41 +/- 9.58 hr. MODE disappeared slowly and at 24 hr the plasma concentration was still 59.8 +/- 39.9% of its mean steady-state concentration. Our data indicate that the metabolites of encainide cumulate in the plasma of patients on long-term oral therapy and must be considered when evaluating its clinical efficacy.