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PubMed1992

Encainide dosing in patients with severe renal dysfunction: report of a case and literature review.

Dosage of encainide for patients with lethal ventricular arrhythmias is based on pharmacodynamic effects and efficacy of arrhythmia suppression, coupled with metabolizer phenotype and extent of renal and hepatic dysfunction. Decreased clearance in patients with renal dysfunction necessitates a reduction in dosage to avoid toxic and dose-related proarrhythmic effects. This case represents a patient with severe renal dysfunction and sustained ventricular tachycardia who achieved electrophysiologically guided suppression of induced ventricular tachycardia at a steady-state encainide dose of only 25 mg daily, significantly lower than package insert or compendial recommendations for initial dosage in patients with renal insufficiency. Documented "therapeutic" metabolite concentrations correlated to electrophysiologic response. Literature review illustrates the complexity of encainide dosage in such individuals and underscores the need for therapeutic drug monitoring to individualize dosage.

Administration, Oral↗
PubMed1989

The effects of encainide versus diltiazem on the oxidative metabolic pathways of antipyrine.

The effects of diltiazem and encainide on the pharmacokinetics and metabolism of antipyrine were compared in nine healthy male volunteers. Diltiazem 90 mg every 8 hours for 5 days decreased the oral clearance of antipyrine from 2.34 to 1.86 L/hour (p less than 0.05) and increased half-life from 12.7 to 15.9 hours (p less than 0.05). Diltiazem reduced the formation rate constants for 3-hydroxymethylantipyrine by 27% (p less than 0.05) and 4-hydroxyantipyrine by 37% (p less than 0.05). There was also a 21% reduction in the formation rate constant for norantipyrine (0.05 less than p less than 0.10). Encainide 25 mg every 8 hours for 5 days had no apparent effect on the oral clearance or half-life of antipyrine, or on the formation rate constants for metabolites of antipyrine. In contrast to a previously published report in rats, encainide, unlike diltiazem, does not inhibit the oxidative metabolism of antipyrine in humans.

Adult↗
PubMed1990

Efficacy of encainide in supraventricular arrhythmias.

This review summarizes the data from all the studies conducted in the United States and Europe that have evaluated the efficacy of encainide in patients with a variety of supraventricular arrhythmias. Using clinical criteria of efficacy, encainide was found to be effective or partially effective in 77% of patients evaluated by electrophysiologic means. Similar levels of efficacy were observed in patients with AV as well as AV nodal reentry arrhythmias. Patients with other forms of supraventricular arrhythmias in smaller series also experienced comparable degrees of efficacy. Encainide was discontinued because of intolerance by 8% of the patients in these studies: 6% because of side effects and 2% because of proarrhythmia.

Anilides↗
PubMed1982

Acute hemodynamic effects of intravenous encainide in patients with heart disease.

Encainide, a new antiarrhythmic drug, was given intravenously (0.9 mg/kg) to 18 patients over 15 minutes to evaluate the hemodynamic effects. Hemodynamics and drug plasma concentrations were measured during and 30 minutes postdrug infusions. Encainide infusion was associated with a decrease in cardiac index from 2.6 +/- 0.7 to 2.4 +/- 0.7 L/min/m2 (p less than .05), a significant decrease in stroke work index and left ventricular end-diastolic pressure, and with a rise in systemic vascular resistance. There was no change in systemic or pulmonary arterial pressure, left ventricular dp/dt, or pulmonary vascular resistance. The patients were studied 30 to 60 minutes after cardiac angiography. Comparison of hemodynamic values obtained preangiography with those obtained postangiography (before, during, and after drug infusion) strongly suggests that many of the observed effects were due to radiographic contrast media (initial osmotic volume loading and subsequent diuresis). We conclude that if encainide has any significant hemodynamic effects after intravenous use, it is a modest decrease in cardiac output, possibly as a result of decreased left ventricular filling pressure.

Adult↗
PubMed1981

Electrophysiologic evaluation of encainide with use of monophasic action potential recording.

The electrophysiologic effects of encainide in the intact dog heart were evaluated with the use of monophasic action potential and His bundle recordings. Eight mongrel dogs were given 2.7 mg/kg body weight of encainide in two intravenous infusions. Plasma concentration, blood pressure, surface electrocardiogram, atrial and His bundle electrograms, right atrial and ventricular monophasic action potentials and the right atrial and ventricular effective and functional refractory periods were recorded before and 15 to 45 minutes after each infusion. Basic cycle length and A-H, H-V, QRS and Q-Tc intervals were significantly prolonged after administration of the drug. The refractory periods and the monophasic action potential durations were significantly increased in both the atrium and the ventricle although the increases were more pronounced in the atrium. It is concluded that encainide is a class I antiarrhythmic agent with properties very similar to those of quinidine.

Action Potentials↗
PubMed1989

Comparison of twice daily with thrice daily administered encainide for benign or potentially lethal ventricular arrhythmias.

The antiarrhythmic efficacy of encainide administered 2 (group A) or 3 times daily (group B) was evaluated in a randomized, placebo-controlled trial involving 101 patients with benign or potentially malignant ventricular arrhythmias. In group A, encainide was titrated at dosages of 35, 50 and 75 mg twice daily and in group B at dosages of 25, 35 and 50 mg 3 times daily. Drug efficacy, as judged by repeated ambulatory monitoring, was defined as greater than 75% reduction in ventricular premature complexes combined with a greater than 90% abolition of pairs and runs of nonsustained ventricular tachycardia. In group A, 27 of 52 patients (52%) had their arrhythmia suppressed by the drug compared with 34 of 49 (69%) in group B (difference not significant). There was a trend toward better arrhythmia control in group B if a total daily dose of greater than 100 mg was necessary for arrhythmia suppression. Side effects were frequent in both groups (24 vs 28%, difference not significant). Thus, encainide administered twice daily effectively suppresses ventricular arrhythmias in this patient population.

Adult↗
PubMed1987

New antiarrhythmic drugs: tocainide, mexiletine, flecainide, encainide, and amiodarone.

Tocainide, mexiletine, flecainide, encainide, and amiodarone are antiarrhythmic agents that have recently been approved by the Food and Drug Administration for general use in the treatment of ventricular arrhythmias. All five agents are effective in the treatment of patients with ventricular arrhythmias, whereas encainide, flecainide, and amiodarone are also useful in patients with supraventricular arrhythmias and the Wolff-Parkinson-White syndrome (although not yet approved for these indications). Tocainide and mexiletine are similar to lidocaine and are as effective as quinidine in patients with ventricular arrhythmias. Encainide and flecainide are superior to quinidine for the control of ventricular ectopic beats and as effective as quinidine for patients with ventricular tachycardia. Amiodarone is the most effective agent available for treating patients with ventricular tachycardia, but it is also the most toxic antiarrhythmic agent and should be used only when other antiarrhythmic drugs have not been effective or tolerated.

Administration, Oral↗
PubMed1984

The clinical pharmacology of lidocaine congeners--review of encainide, flecainide, lorcainide and tocainide.

Among the newer antiarrhythmic drugs currently being evaluated are the four so-called lidocaine congeners, encainide, flecainide, lorcainide and tocainide. A knowledge of the pharmacokinetic properties of these agents may help to distinguish between them and may also be important for rational patient prescribing. Encainide and lorcainide both undergo predominantly hepatic elimination: both appear to form metabolites which have antiarrhythmic activity of their own and which have longer elimination half-lives than the parent compounds, resulting in accumulation with chronic administration. Flecainide and tocainide are cleared mainly by the kidneys, do not have active metabolites and have long elimination half-lives. All of the drugs have significant antiarrhythmic activity and this is proportionate to the plasma concentration of either the drug alone or combined with the active metabolites. Comparative effectiveness between the drugs has not been established. In general, all four drugs have only minor adverse effects, principally gastrointestinal or neurological, which may disappear with small dose reductions. However, cardiac effects can also occur and rarely pro-arrhythmic effects have been described, particularly with encainide and flecainide. All four drugs are suitable for long-term administration on a twice-daily basis.

Anilides↗
PubMed1992

d-Sotalol has opposite effects from encainide and propafenone on the proportion of episodes of ventricular tachycardia that are sustained in an experimental substrate for reentry.

Conversion of sustained ventricular tachycardia (VT) to nonsustained VT may be a potent mode of antiarrhythmic drug action, whereas a drug's conversion of nonsustained VT to sustained VT could produce serious clinical complications. We tested the effects of two class Ic drugs [encainide (1, 2, and 4 microM) and propafenone (0.1, 0.3, and 0.6 microM)) and a class III drug (d-sotalol (25, 50, and 100 microM)] on the proportion of VT episodes that were sustained (duration greater than 1 min) in an acute in vitro model of reentrant VT in left ventricular (LV) epicardium: a Langendorff-perfused rabbit heart whose LV endocardial and midwall cells have been killed by a selective freezing procedure. Multiple VT episodes were generated by increasing the stimulation rate until self-sustained activity occurred. Some episodes spontaneously terminated in less than 1 min; others lasted longer and were terminated by transient cooling of the heart. Both encainide and propafenone increased the fraction of episodes of sustained VT in all preparations; the increase was significant in 4 of the 5 encainide preparations (p less than 0.02) and 4 of the 5 propafenone preparations (p less than 0.003). d-Sotalol, on the other hand, decreased the fraction of sustained VT in all preparations; the decrease was significant (p less than 0.002) in 4 of the 5 preparations. All 3 drugs increased the basic cycle length of pacing at which VT was induced and the cycle time of the resulting VT. These results of this new assay of drug action may be related to the drugs' different mechanisms of prolonging refractoriness.

Animals↗
PubMed1988

Analysis of encainide and metabolites in plasma and urine by high-performance liquid chromatography.

A high performance liquid chromatography (HPLC) method for the quantification of encainide (4-methoxy-2'-[2-(1-methyl-2-piperidinyl)-ethyl]benzanilide hydrochloride) in plasma and urine has been developed and validated. Encainide and two metabolites, the O-demethyl (ODE) and 3-methoxy-O-demethyl (MODE) congeners of the drug, can be quantified simultaneously in plasma and urine by this procedure. The compounds are extracted from buffered plasma (pH 8.5) using N-butyl chloride containing 5% (vol/vol) isopropyl alcohol. The compounds are then separated on a silica column using ethanol:water:methanesulfonic acid, 500/60/0.2 (vol/vol/vol) as the mobile phase and quantified by measuring their UV absorbance at 254 nm. The lower limit of detection for the analytes was 5 ng/ml in plasma and 25 ng/ml in urine. The method was linear from 5 to 5,000 ng/ml for plasma and 25 to 5,000 ng/ml for urine. The intra-assay precision of the method for encainide, ODE, and MODE in plasma and urine ranged from 2 to 8% RSD depending upon concentration. The inter-assay precision of the method was less than 6% for the three analytes per ml of plasma and urine. Absolute recovery of the analytes from plasma ranged from 82 to 92%, while recoveries from urine ranged from 83 to 99%. The analytes were shown to be stable in frozen plasma and urine for up to 52 weeks.

Anilides↗
PubMed1990

Selective depression of maximum rate of depolarization of guinea-pig ventricular action potentials by amiodarone and lignocaine in simulated ischaemia: comparison with encainide.

1. Standard microelectrode techniques were used to record intracellular action potentials from guinea-pig ventricular myocardium superfused with either control physiological saline (pH 7.5; pO2 500 mmHg; [K+] 5.6 mmol/L) or 'simulated ischaemic' solution (pH 6.4; pO2 90 mmHg; [K+] 11.2 mmol/L). 2. The effects on action potential parameters of therapeutic concentrations of lignocaine, amiodarone and encainide were studied under both conditions. 3. Simulated ischaemia, in the absence of drugs, produced marked reductions in resting potential (-86.6 +/- 2.3 to -64.7 +/- 3.5 mV), maximum rate of depolarization (Vmax; 263 +/- 66 to 106 +/- 36 V/s) and action potential duration (164 +/- 24 to 97 +/- 26 ms). No drug produced any additional effect on resting potential. 4. All three drugs produced enhanced depression of Vmax in ischaemia compared to control conditions (class I effect). This was much more marked for lignocaine and amiodarone (inactivated channel blockers) than for encainide (open channel blocker). 5. In addition the prolongation of action potential duration seen with acute exposure to amiodarone (174 +/- 12 to 192 +/- 17 ms; class III effect) was abolished under simulated ischaemic conditions. 6. It is concluded that lignocaine and amiodarone exert greater selectivity for ischaemic tissue than does encainide and that amiodarone may function primarily as a class I agent under ischaemic conditions.

Action Potentials↗
PubMed1981

Antifibrillatory efficacy of encainide, loracainide and ORG 6001 compared with lignocaine in isolated hearts of rabbits and guinea-pigs.

1 In Langendorff-perfused rabbit hearts, electrical stimulation threshold and ventricular fibrillation threshold (VFT) were measured by applying rectangular impulses of 3 ms duration and increasing current at frequencies of 4 and 20 Hz respectively. 2 Perfusion with lignocaine or one of three new antiarrhythmic drugs, encainide, lorcainide and ORG 6001, produced significant, dose-dependent increases in both thresholds. 3 On a dosage basis, encainide was seven times, lorcainide fourteen times and ORG 6001 twice as potent as lignocaine in raising VFT. 4 In Langendorff-perfused guinea-pig hearts, only lorcainide provided complete protection against ouabain-induced ventricular fibrillation, while 6 of 6, 3 of 6 and 2 of 6 hearts fibrillated in the presence of encainide, lignocaine and ORG 6001 respectively, but with infusion durations significantly higher than control. 5 These results indicate the potential antifibrillatory activity of these new antiarrhythmic agents.

Androstanols↗
PubMed1989

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)

Alkalosis, Respiratory↗
PubMedDate not supplied

[Interactions of quinidine and propranolol with mexiletine, encainide, flecainide and tocainide].

Blood serum quinidine sulphate and propranolol levels have been measured in patients with cardiac arrhythmias treated simultaneously with mexiletine, flecainide, encainide and tocainide. It was found that mexiletine and encainide increase quinidine sulphate serum concentrations. Propranolol serum concentrations have been increased by mexiletine, encainide flecainide, and tocainide. Flecainide ant tocainide have not changed quinidine sulphate serum concentrations.

Adult↗
PubMed1987

Effect of encainide on in vivo drug metabolism in the rat.

The effect of encainide, an investigational antiarrhythmic, on drug metabolism was examined using the model substrate antipyrine. Administration of a single oral dose of encainide hydrochloride 100 mg/kg one hour prior to antipyrine administration resulted in a mean 30% reduction in antipyrine clearance. These data indicate that encainide, like other agents subject to substantial first-pass metabolism, is capable of inhibiting oxidative drug metabolism.

Anilides↗
PubMed1979

Canine electrophysiology of encainide, a new antiarrhythmic drug.

Encainide, a new benzanilide derivative with high potency and a good therapeutic/toxic ratio, was evaluated with the use of standard His bundle recording techniques to determine its effects on the cardiac conduction system in closed chest animals. Twenty mongrel dogs weighing 18 to 29 kg were anesthetized with 4 percent chloralose and classified into groups: group 1, a control group and groups 2, 3, and 4, which were given 0.3, 0.9 and 2.7 mg/kg body weight, respectively, of encainide in an intravenous infusion over a 15 minute period. Plasma concentration, blood pressure, surface electrocardiogram and atrial and His bundle electrograms were recorded before, during and after drug infusion for a total of 120 minutes. Heart rate, A-H and H-V intervals, the QRS complex and Q-Tc interval were measured every 5 minutes during sinus rhythm and with constant atrial pacing. In addition, sinus nodal recovery time and atrial, atrioventricular (A-V) nodal and left ventricular refractory periods were measured before and immediately after infusion and every 30 minutes for 2 hours. Peak plasma concentration averaged 450 ng/ml in group 2, 1,300 ng/ml in group 3 and 4,000 ng/ml in group 4. Blood pressure was not altered at any dose level throughout the study. The QRS complex and H-V interval were significantly prolonged (P less than 0.005) at doses of 0.9 mg/kg and greater. These effects correlated well with plasma concentration. There was no significant change in heart rate, corrected sinus nodal recovery time, A-H interval, Q-Tc interval atrial, A-V nodal or left ventricular refractory period. It is concluded that, unlike other antiarrhythmic agents, encainide prolongs His-Purkinje system conduction without significantly affecting conduction or refractoriness of other parts of the cardiac conduction system in animals.

Anilides↗
PubMed1990

In-vitro and in-vivo electrophysiologic effects of encainide.

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, frequency-dependent reductions in Vmax studied at pacing rates of 30-180 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 Vmax 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 less than 0.01) and the Wenckebach cycle length was increased by 8% (p less than 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 AH was not increased until 15 minutes after drug administration. There was a positive correlation between the increase of the AH interval and the blood level of ODE.

Anilides↗