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PubMed1989

Depression of maximum rate of depolarization of guinea-pig ventricular action potentials by metabolites of encainide.

1. Standard microelectrode methods have been used to record action potentials from guinea-pig ventricular myocardium and dog Purkinje fibres, and to study the effects of the two major metabolites of encainide, O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). 2. In concentrations similar to those found in patients during chronic encainide therapy, neither ODE nor MODE produced significant depression of maximum rate of depolarization (Vmax) of action potentials in unstimulated tissue. Repetitive stimulation, however, was associated with depression of Vmax which increased with increasing driving rates (rate-dependent block, RDB). At the fastest rate studied (interstimulus interval = 300 ms) ODE 1 microM depressed Vmax by 47.5 +/- 5.7% and MODE 1 microM, reduced Vmax by 52.2 +/- 12%. 3. The onset and offset kinetics of this rate-dependent block were very slow. Full development of RDB during a train required over 100 action potentials and the time constants of recovery of Vmax from RDB were 86.4 +/- 37 s for ODE and 100.4 +/- 18 s for MODE. The amount of RDB and its rate of onset increased with drug concentration. The recovery time constants were independent of inter-stimulus interval or drug concentration. Both metabolites also produced rate-dependent depression of conduction velocity in canine Purkinje fibres, but no evidence of selective depression of conduction of interpolated premature potentials was seen. 4. Early afterdepolarizations occurred spontaneously in three preparations in the presence of MODE, 1 microM and one preparation in ODE, 1 microM. 5. It is concluded that these metabolites of encainide may play a role in producing both its antiarrhythmic and its proarrhythmic effects.

Action Potentials↗
PubMed1989

Effects of encainide on the function of implanted pacemakers.

The effect of encainide on chronic pacing thresholds was evaluated in 10 patients, age 64-89, who were exposed to weekly increased encainide dosing (25 mg TID, 50 mg TID, 75 mg TID). Median pacing threshold (mujoules) increased modestly at each period compared to placebo and returned rapidly to baseline after discontinuation. (table; see text) No patient experienced a pacing-related clinical event. One patient had a large threshold increase (566%), but no failure to capture on 24-hour ECG, and one patient whose threshold increased minimally had clinically insignificant capture failure, the longest event being 3 beats. No other failure to capture was noted. Thus, encainide, like a number of other antiarrhythmic drugs, appears to affect pacing thresholds. At the highest dose of 225 mg/day (75 mg TID, which exceeds the generally recommended dose of 50 mg TID), but not at lower doses, some patients may experience loss of capture that does not appear related to the change in threshold energy required. Increases in the duration of the paced QRS induced by encainide did not predict increases in threshold. Therefore, when higher doses of encainide are required in patients with pacemakers, clinical observation and ambulatory electrocardiographic monitoring should be carried out.

Aged↗
PubMed1986

Effects of encainide and its metabolites on energy requirements for defibrillation.

Encainide, a class IC antiarrhythmic agent, has been associated with proarrhythmic responses of ventricular tachycardia and fibrillation requiring defibrillation in patients. We examined the short-term effects of intravenous encainide and its two major metabolites, O-demethyl-encainide (ODE) and 3-methoxy-ODE (MODE), on the energy requirements for successful defibrillation in 25 pentobarbital-anesthetized, open-chest dogs. Truncated exponential (60% tilt) defibrillation shocks were administered through right atrial spring and left ventricular epicardial patch electrodes identical to those used in man with the automatic implantable defibrillator. At baseline multiple shocks of varying energy were applied to construct curves of percent successful defibrillation as a function of energy (DF curves) for each animal. Encainide, ODE, or MODE was then infused in loading and maintenance doses to achieve QRS widening of 20% to 50%. Saline was administered to animals serving as controls. Determination of the DF curve was repeated, after which the infusion was discontinued. After 1 hr washout period, an additional DF curve was constructed. The data were analyzed by logistic regression, and the energies required for 50% successful defibrillation (E50) were compared. No significant differences existed between the four groups in body or heart weight, extent of QRS widening, or baseline E50 values. After administration of encainide and ODE, the E50 increased by 129 +/- 43% (p less than .001) and 76 +/- 34% (p less than .005), respectively. Return of E50 toward baseline was observed after the washout periods in both groups (p less than .025), demonstrating the reversibility of the drugs' effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1994

Interaction of baseline characteristics with the hazard of encainide, flecainide, and moricizine therapy in patients with myocardial infarction. A possible explanation for increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST).

BACKGROUND: The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular ectopy with antiarrhythmic drugs after a myocardial infarction reduces the incidence of sudden arrhythmic death. Patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The encainide and flecainide arms of the study were discontinued in 1989 (CAST-I) and the moricizine arm in 1991 (CAST-II) because of excess mortality. To explore the mechanisms of these adverse outcomes, we examined the interaction of baseline characteristics with the hazard of therapy with encainide, flecainide, or moricizine compared with their respective placebos. METHODS AND RESULTS: CAST-I comprised 755 patients assigned to flecainide or encainide and 743 patients assigned to placebo, whereas in CAST-II, 502 patients received moricizine and 491 patients received placebo. Clinical and laboratory baseline variables of patients receiving active drug and those receiving placebo were similar. In CAST-I patients, there was a significant interaction of active therapy with both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest for non-Q-wave myocardial infarction (total mortality hazard ratios, 1.8 versus 7.9 for Q-wave versus non-Q-wave infarction, P = .03). Ventricular premature depolarization (VPD) frequency > or = 50/h and heart rate > or = 74 beats per minute each interacted significantly with total mortality/cardiac arrest only. In the sicker CAST-II patients (ejection fraction < or = 40%), only diuretic use at baseline interacted significantly with moricizine use for both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest (total mortality hazard ratios, 1.9 versus 0.7 for diuretic use versus no use, P = .01). CONCLUSIONS: Although active treatment in CAST-I was associated with greater mortality than placebo with respect to almost all baseline variables, the therapeutic hazard was more than expected in patients with non-Q-wave myocardial infarction and (for total mortality) frequent premature VPDs and higher heart rates, suggesting that the adverse effect of encainide or flecainide therapy is greater when ischemic and electrical instability are present. The relative hazard of therapy with moricizine in the sicker CAST-II population was greater in those using diuretics. Thus, although these drugs have the common ability to suppress ventricular ectopy after myocardial infarction, their detrimental effects on survival may be mediated by different mechanisms in different populations, emphasizing the complex, poorly understood hazards associated with antiarrhythmic drug treatment.

Arrhythmias, Cardiac↗
PubMed1987

Encainide. A review of its pharmacological properties and therapeutic efficacy.

Encainide is an antiarrhythmic drug with class IC activity which has been used in the treatment of life-threatening ventricular arrhythmias, symptomatic ventricular arrhythmias and supraventricular arrhythmias. The antiarrhythmic activity is due to the parent drug and its two principal active metabolites, and in the extensive metabolising phenotype (90% of patients), metabolites are present in plasma at higher concentrations than encainide itself. Encainide produces little haemodynamic change in patients with left ventricular dysfunction and thus has considerable therapeutic potential in view of its efficacy in patients with ventricular tachycardia, premature ventricular complexes and the Wolff-Parkinson-White syndrome. However, this potential is reduced by a tendency for encainide to aggravate arrhythmia in a proportion of patients. At present there is no reliable method of identifying patients at risk for this potentially serious side effect. The most common non-cardiac side effects are dizziness and blurred vision which seldom necessitate withdrawal of treatment. Thus, encainide has proved effective in controlling ventricular tachyarrhythmias including those which have not been controlled by other antiarrhythmic drugs.

Anilides↗
PubMed1989

Adverse hemodynamic and clinical effects of encainide in severe chronic heart failure.

STUDY OBJECTIVE: To evaluate the hemodynamic effects of the antiarrhythmic drug, encainide, in patients with severe chronic heart failure. DESIGN: Unblinded, before-after study. SETTING: Referral center for patients with heart failure. PATIENTS: Thirty patients with severe chronic heart failure and a left ventricular ejection fraction less than 40%. INTERVENTIONS: Invasive hemodynamic measurements were done (using a balloon-tipped thermodilution catheter) before and for 3 hours after a single oral dose of 50 mg of encainide. MEASUREMENTS AND MAIN RESULTS: Ninety to one hundred and twenty minutes after its administration, encainide produced a significant deterioration in cardiac performance, as reflected by a fall in cardiac index from 2.3 to 1.8 L/min.m2 body surface (mean change 0.5 +/- 0.1; P less than 0.001), a fall in stroke work index from 26 to 18 g.m/m2 (mean change 8 +/- 2; P less than 0.001), and an increase in left ventricular filling pressure from 19 to 22 mm Hg (mean change 3 +/- 2; P less than 0.05). These deleterious hemodynamic effects were accompanied by worsening symptoms of heart failure in 8 of the 30 patients. Serum levels of encainide and its metabolites, O-desmethylencainide and 3-methoxy-O-desmethylencainide, were within the therapeutic range in most patients. CONCLUSIONS: Encainide can cause adverse hemodynamic and clinical effects in patients with severe chronic heart failure.

Adult↗
PubMed1984

Effect of encainide and its two major metabolites on cardiac conduction.

The effect of encainide and its two major metabolites, O-demethylated encainide (MJ 9444) and 3-O-methoxy encainide (MJ 14030), on cardiac conduction was studied by recording His bundle potentials in isolated perfused rabbit hearts and Purkinje and muscle conduction in vivo in dog hearts after destruction of the atrioventricular node. Both metabolites are 4 to 15 times more potent than encainide in slowing conduction through the atria, the AV-node and the His-Purkinje system of the rabbit heart. They did not differ from each other in potency but MJ 9444 increased the duration and decreased the height of the ventricular potential whereas MJ 14030 had no effect at doses which caused conduction block. In the dog, encainide (0.8-3.2 mg/kg i.v.) slowed conduction of extrasystoles in both Purkinje and muscle at all coupling intervals, increased the effective refractory period and the functional refractory period of the Purkinje pathway. MJ 9444 (0.05-0.4 mg/kg) speeded Purkinje conduction of early (less than 300 msec) without affecting or while slowing conduction of late (greater than 350 msec) extrasystoles. Higher doses (0.4-1.6 mg/kg) slowed conduction at all intervals. The effective refractory period and the functional refractory period were decreased but in some cases returned to control values at the higher doses. Muscle conduction was slowed at doses of 0.4 mg/kg or more. MJ 14030 (0.05-3.2 mg/kg) had variable effects, behaving like MJ 9444 in three experiments but like the parent compound in two others. Only slowing of conduction was seen with the three drugs when heart rate was changed.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1987

Encainide: its electrophysiologic and antiarrhythmic effects, pharmacokinetics, and safety.

Encainide is a class IC antiarrhythmic agent that has been under clinical investigation for the last decade. Laboratory and clinical studies have demonstrated it to be a potent suppressor of ventricular extrasystoles. It is effective in approximately one-half of patients with malignant ventricular arrhythmias. The preliminary experience in patients with supraventricular arrhythmias indicates that the drug is particularly effective in arrhythmias associated with an accessory pathway. Side effects most commonly include blurred vision, nausea, heart block, and proarrhythmic effects. The hemodynamic effect of oral encainide are insignificant in patients with well-preserved left ventricular function. Despite minimal myocardial depression in patients with left ventricular dysfunction, there is the potential for worsening of heart failure. Encainide has a short half-life of 3 hours, but has 2 active metabolites with longer half-lives. No clinically significant drug interaction has been demonstrated with encainide therapy.

Anilides↗
PubMed1986

Treatment of supraventricular arrhythmias with encainide.

Encainide has been used to treat 230 patients with supraventricular arrhythmias, including patients with reentry supraventricular tachycardia of the atrioventricular reentry (Wolff-Parkinson-White syndrome) and the atrioventricular nodal reentry types associated with atrial fibrillation, paroxysmal supraventricular tachycardia or both, as well as incessant supraventricular tachycardia. The available data are summarized in this review. The short- and long-term response to encainide for preventing recurrence or lessening symptoms was excellent in most cases. There was little arrhythmia aggravation, and side effects, which were mostly central nervous system and visual in nature, did not cause discontinuation of the drug. Anterograde accessory pathway block was clearly an important effect. Whether retrograde block or refractoriness in the accessory pathway is the most important mechanism remains to be resolved. Pediatric patients with tachycardia-related cardiomyopathy responded well to encainide. Oral encainide's absence of effect on blood pressure or myocardial contractility is an added benefit.

Anilides↗
PubMedDate not supplied

Electrophysiologic effects of encainide following acute coronary occlusion in dogs.

Encainide, a benzanilide derivative, is a local anesthetic antiarrhythmic drug. To determine its effects on infarcted and normal tissue in situ, we infused encainide (1.0 mg/kg) for 15 min intravenously followed by 0.01 mg/kg/min for an additional 105 min in 8 adult open-chest, pentobarbital-anesthetized, atrially paced dogs after left anterior descending coronary occlusion. We monitored plasma concentration, blood pressure, and surface electrocardiogram (ECG). We determined conduction intervals from the onset of the QRS in the limb lead ECG to the major deflection of bipolar electrograms recorded in the infarcted and normal zones. We found that the blood pressure did not change significantly. Encainide did significantly prolong the atrial stimulus artifact-to-QRS interval and the QRS duration, as previously reported, and also prolonged intraventricular conduction intervals. In the infarcted zone, the drug prolonged conduction in both subendocardium and subepicardium, and prolongation was of somewhat greater magnitude in this zone than in the normal zone. Encainide prolonged the effective refractory period only in the infarcted zone (19 +/- 5 msec at peak; p less than 0.01). The above electrophysiologic effects may explain in part the previously demonstrated antiarrhythmic properties of this drug.

Anilides↗
PubMedDate not supplied

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.

Anilides↗
PubMed1989

A high-performance liquid chromatographic method for the determination of encainide and its major metabolites in urine and serum using solid-phase extraction.

A high-performance liquid chromatography (HPLC) procedure used to quantitate encainide and two of its active metabolites, O-desmethylencainide (ODE) and 3-methoxy-O-desmethylencainide (MODE), is described. All three compounds were simultaneously extracted from urine and serum using an octyl (C-8) solid-phase extraction column. The compounds were then separated by reverse-phase HPLC on a cyanopropylsilane column using ultraviolet detection at 260 nm. Serum samples were quantified over a concentration range of 25-400 ng/ml and urine over a range of 150-10,000 ng/ml. Total run time for the assay was less than 12 min. Within-day and between-day precision and relative error were less than 10% in serum and less than 13% in urine for all three compounds. The lower limit of quantitation was 10 ng/ml for encainide and ODE and 15 ng/ml for MODE. This HPLC procedure represents a quick and reliable method of measuring encainide and its major metabolites in both urine and serum, making the assay applicable as an aid for therapeutic drug monitoring of patients receiving encainide therapy.

Anilides↗
PubMed1991

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.

Adult↗
PubMed1991

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.

Adult↗
PubMed1981

Clinical pharmacology and antiarrhythmic efficacy of encainide in patients with chronic ventricular arrhythmias.

We determined the pharmacokinetics, efficacy and therapeutic plasma concentration of encainide, a new antiarrhythmic drug that affects His-Purkinje conduction but not ventricular refractoriness. Nine patients with frequent and complex premature ventricular complexes were studied in a 3-day double-blind protocol. Each day, each patient received 75 mg of i.v. or oral encainide or placebo. Frequent blood samples for encainide plasma concentration determination and continuous ambulatory ECGs were obtained. There was a marked intersubject variation in bioavailability (mean 42 +/- 24%, range 7.4-82%), clearance (13.2 +/- 5.6 ml/min/kg, range 3.75-22.1 ml/min/kg) and half-life (3.4 +/- 1.7 hours i.v., 2.5 +/- 0.8 hours oral). Eight of nine patients had more than 90% suppression of premature ventricular complexes for 3-36 hours. Minimal antiarrhythmic plasma concentration was higher (39 +/- 54 ng/ml, range 3.5-170 ng/ml) after i.v. dosing than after oral dosing (14 +/- 16 ng/ml, range 1.5-48 ng/ml), suggesting an active metabolite after oral dosing in many patients. Minimal side effects were seen despite high peak plasma concentrations (range 794-1556 ng/ml i.v., 36-495 ng/ml oral). The minimal ratio of toxic to therapeutic plasma concentration ranged from 4.3-326 (median 23) after oral dosing. Antiarrhythmic action was associated with an 11-44% widening of the QRS complex that was not associated with other adverse effects. We conclude that encainide effectively suppresses ventricular arrhythmias. Despite a variable bioavailability, high clearance and short half-life, its wide ratio of toxic to therapeutic concentration and probable active metabolite permit a long duration of action, which should allow a reasonable dose schedule in most patients during chronic oral dosing.

Aged↗
PubMed1985

[Anti-arrhythmia effect of long-term encainide in chronic ventricular extrasystole].

The long term efficacy and tolerance of encainide were studied in 48 patients with chronic/ventricular extrasystoles (VES) treated for 6 months. Holter monitoring was performed before treatment and at each dose increment (75 mg/day; 150 mg/day and 225 mg/day) during the first week of titration, and then after 1 month and 6 months of treatment. The dose administered in the long-term study corresponded to the minimum effective dose during the titration phase (the dose which reduced the number of VES/24 hours by at least 75%). The average number of VES/hour decreased significantly from 480.6 before treatment to 2.0 at the end of the study. The frequency of episodes of ventricular tachycardia decreased significantly during treatment. The commonest side effects were vertigo, visual disturbances and headaches. Treatment was interrupted because of side-effects or inefficacy in 6 patients. The surface ECG showed significant lengthening of the PR, QRS and QTc periods and encainide appeared to have aggravated the ventricular arrhythmias of 4 patients receiving 200 mg/day. The plasma concentrations of encainide and its two principal metabolites were measured during the titration phase, at 1 month and after 6 months of treatment. 15.6 per cent of patients were slow and 84.4% of patients were rapid metabolizers. The wide individual variations of plasma concentrations and the absence of correlation between the plasma concentrations of encainide and its metabolites and the antiarrhythmic effect suggest that the compound and its metabolites play a role in the antiarrhythmic effect of the drug.

Adolescent↗
PubMed1985

[Anti-arrhythmia and electrophysiological effects of encainide in supraventricular tachycardias].

In order to assess the electrophysiologic effects and anti-arrhythmia effects of encainide after acute IV injection and chronic oral therapy, a group of 10 patients (mean age 54) with recurrent supraventricular tachycardia was studied. Seven patients had more than 2 attacks per month, and supraventricular tachycardia (SVT) resulted in severe symptoms in the three remaining SVT was due to AV nodal re-entry in 6 patients and to concealed accessory pathway in 4. After a control study, SVT was initiated, and encainide (0.75 mg/kg) was infused intravenously in attempt to stop the tachycardia. A second study was achieved. After 4 days of oral therapy (25 or 50 mg T.I.D.) a third study was performed, including SVT initiation attempts. Encainide depressed conduction in all cardiac tissues, and this effect was more evident after oral administration. Antegrade I:I conduction cycle length increased of 13.9% (p less than 0.05), and the same parameter in retrograde conduction increased of 30.03% (p less than 0.05). IV injection interrupted 2 of 10 SVT only. However, after 30 minutes, 5 re-initiated SVT were nonsustained, and mean cycle length increased from 326 +/- 21 to 397 +/- 51 (p less than 0.01). After oral therapy, SVT was initiated in 4 of 10 patients, nonsustained in 3. During long term follow-up (one year or more), no severe adverse effect has been reported. Three patients are still experiencing short events of well-tolerated SVT. Hence, moderate or low doses or oral encainide may safely control recurrent supraventricular tachycardia.

Administration, Oral↗
PubMed1984

Increased incidence of side effects after encainide: a newly developed antiarrhythmic drug.

In a clinical trial the efficacy of encainide, a newly developed class I antiarrhythmic agent, was compared with the well-known mexiletine. Nine patients with different underlying cardiac disease and chronic complex ventricular ectopies (documented by 24-h Holter monitoring, confirmed during the initial placebo period) entered the study. The dosage of encainide was increased from 25 to 75 mg three times daily and the antiarrhythmic effect monitored by repeated 24-h Holter registration and in some patients by treadmill exercise testing. During the clinical followup we noted a high incidence of so-called "minor side effects" (headache, dizziness, blurred vision, tremor, and nausea), which caused us to terminate the study. In all instances adverse effects emerged before ectopic activity was suppressed satisfactorily prohibiting further increment of dosage. These results indicate that encainide cannot be regarded as an antiarrhythmic drug of first choice in routine clinical application.

Adult↗