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PubMed1980

Encainide: a new and potent antiarrhythmic agent.

Encainide is a potent Class I antiarrhythmic drug that prolongs conduction in the His-Purkinje system. It produces only minimal hemodynamic changes in the normal or depressed left ventricle. Studies to date demonstrate excellent effectiveness against ventricular arrhythmia, and in comparative studies with quinidine, encainide was superior in reducing the frequency and complexity of ventricular premature beats in patients late after myocardial infarction.

Anilides↗
PubMed1989

Encainide and flecainide: are they interchangeable?

Encainide and flecainide are two recently released class IC antiarrhythmic agents that have been reported to be highly effective for suppressing all forms of ventricular arrhythmias. Both drugs are potent blockers of the sodium channel and produce marked slowing of conduction within the His-Purkinje system and myocardium. To establish if the response to one agent predicts the response to the other, the antiarrhythmic effect of the two drugs was compared in a group of 18 patients with malignant ventricular arrhythmia. Fourteen patients had sustained ventricular tachycardia and four patients had ventricular fibrillation. The average ejection fraction of this group was 37%. All patients had a high density of spontaneous ventricular arrhythmia and were evaluated noninvasively. Both drugs significantly reduced all forms of spontaneous arrhythmia. By Holter monitoring criteria, the effect of the two drugs was concordant in 61% (p = NS). By exercise criteria, the concordance rate was 50% (p = NS). Overall, 12 patients (67%) responded to encainide and eight (44%) patients responded to flecainide (p = NS). Only 10 of 18 (56%) patients had the same response to both agents (p = NS). There was no significant difference in ejection fraction or in average daily dose of drug between responders and nonresponders. Thus despite their similar electrophysiologic profile, the clinical antiarrhythmic effect of these two agents was different. For the noninvasive management of patients the response to one agent should not be used to predict the response to the other.

Adolescent↗
PubMed1983

Clinical profiles of newer class I antiarrhythmic agents--tocainide, mexiletine, encainide, flecainide and lorcainide.

New class I antiarrhythmic drugs differ in potency, adverse effects and pharmacokinetics. Encainide and flecainide can totally suppress arrhythmias in some patients, but arrhythmia induction can also occur. At effective dose levels, neurologic and gastrointestinal adverse effects are uncommon. Flecainide pharmacokinetics are suitable for oral use but encainide disposition is complex with variable bioavailability and active metabolites that contribute substantially to activity. Lorcainide is also potent, but neurologic adverse effects are common and dose-dependent bioavailability and an active metabolite may complicate long-term oral therapy. Tocainide and mexiletine can suppress arrhythmias in acute myocardial infarction, during convalescence from myocardial infarction and in patients with arrhythmias resistant to other therapy. Dose-related neurologic and gastrointestinal adverse effects are common, but hemodynamic effects are minor and arrhythmia induction is rare. Tocainide disposition is reasonably predictable and stable in patients, but mexiletine disposition is less so because of variation in distribution and clearance. Although all of the newer agents have some disadvantages, their availability should increase the likelihood of success in the high-risk patient.

Administration, Oral↗
PubMed1986

Safety of encainide for the treatment of ventricular arrhythmias.

A data base of 1,245 patients treated for ventricular arrhythmias, most of whom had serious cardiac disease, was reviewed. Only 2.9% of these patients had benign ventricular arrhythmias without structural heart disease. The overall incidence of proarrhythmia in this population was 9.2% (115/1,245), but was as frequent as 16% in patients with a history of cardiomyopathy. The proarrhythmic form was new sustained ventricular tachycardia in 22 patients (1.8%). Only 2 of 71 patients (2.8%) with primary arrhythmia had a proarrhythmic event. The incidence has decreased markedly over the past years as reduced doses and gradual titration have been used. There were 137 deaths in the data base of which 82 were sudden, all in patients with advanced (79) or moderately severe (3) cardiac disease. High initial doses, prior myocardial infarction and congestive heart failure (CHF) were positively associated with sudden cardiac death. There were no deaths among the 71 patients with benign arrhythmias. Death rates were related to the severity of the arrhythmia being treated. Comparisons with published survival curves indicated modest improvement; in no case was survival decreased. Invasive and noninvasive measures of left ventricular function indicated no adverse hemodynamic effects. There was only 1 case of new and 3 cases of worsened CHF probably related to encainide. Only 5 patients discontinued for CHF or related signs and symptoms. The most frequent drug-related noncardiac adverse reactions were dizziness (26%), abnormal or blurred vision (19%), QRS interval prolongation (5%), taste perversion (4%) and tremor (3%). In conclusion, the use of reduced doses and gradual titration of encainide has markedly decreased the incidence of proarrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Safety considerations and dosing guidelines for encainide in supraventricular arrhythmias.

The safety issues relevant to treatment with encainide in patients with supraventricular arrhythmia were reviewed based on 349 patients enrolled in clinical trials in the United States and Europe. Although 20% of patients had a history of congestive heart failure, cardiomegaly, or cardiomyopathy at entry, there was no case of new or worsened heart failure. There were 5 cases (1.4%) of proarrhythmia in adults, reflecting a worsening of the arrhythmia being treated or of a coexisting ventricular arrhythmia. The profile of drug-related adverse effects was comparable to that previously reported, causing discontinuance in 6% of patients. The effects most often seen were dizziness, visual disturbance, headache, nausea and vertigo. Only 1 patient had clinically significant abnormal laboratory values, possibly reflecting hepatocellular injury in conjunction with viral hepatitis. Most responders received a daily dose of 75 to 200 mg/day, generally given in 3 divided doses. Encainide has a very favorable safety profile for use in the treatment of supraventricular arrhythmias.

Adult↗
PubMed1981

Effects of encainide on myocardial contractility of cat papillary muscle.

The action of a new effective antiarrhythmic agent, encainide, was studied with respect to the mechanical performance of isolated cat papillary muscle. Encainide (0.1-10 micrograms/ml) did not alter the performance of cardiac muscle during either the contraction or relaxation phase. By contrast, lidocaine (1-5 micrograms/ml) caused a slight but statistically significant depression of myocardial contractility in terms of the force-velocity-length analysis, while it did not affect load clamp analysis, zero load clamp analysis and load dependence of relaxation.

Anilides↗
PubMed1989

Improved high-performance liquid chromatographic assay for encainide and its metabolites in human body fluids.

Methods reported previously for the determination of encainide and its metabolites in biological fluids have not been extensively described and evaluated. We report an improved high-performance liquid chromatographic assay for the quantification of these compounds in plasma and urine with complete estimation of the accuracy and reproducibility of the analytical method. The major improvements consist of: (1) the use of ethaverine as an appropriate internal standard; (2) the use of the salting-out technique which improves the extraction recovery for the metabolites of encainide and the sensitivity of the assay; and (3) a shift of the ultraviolet absorption wavelength from 254 to 270 nm to increase the selectivity of the detection.

Anilides↗
PubMed1980

Total suppression of ventricular arrhythmias by encainide. Pharmacokinetic and electrocardiographic characteristics.

We studied the antiarrhythmic effect of a range of oral doses of encainide in 11 patients with stable high-frequency ventricular arrhythmias. Total suppression of arrhythmia was documented in 10 patients at a wide range of doses and plasma concentrations, and the suppression was subsequently verified in a placebo-controlled crossover study. Drug elimination was rapid (the half-life was 1.9 to 3.8 hours), but the margin between efficacy and side effects was sufficiently wide for therapy every six to 12 hours to be feasible in all 10 patients, with continuing outpatient treatment at six to 12 months. Marked prolongation of PR (mean, 44 per cent) and QRS (mean, 47 per cent) durations coincided with abolition of arrhythmia, but no evidence that these effects were detrimental was observed in radionuclide ventriculograms, exercise testing, or prolonged monitoring. A single patient whose arrhythmia and electrocardiogram were unchanged during therapy eliminated the drug much more slowly than the others and was the only patient in whom no O-demethyl form could be detected in plasma, suggesting that this metabolite may be active. In this study, encainide was a highly effective, well-tolerated antiarrhythmic agent.

Adult↗
PubMed1989

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.

Anilides↗
PubMed1996

Effects of flecainide, encainide, and clofilium on ventricular refractory period extension by transcardiac shocks.

OBJECTIVE: The mechanisms by which pharmacological agents alter electrical defibrillation are not fully understood. It has been proposed that, in addition to directly stimulating tissue, defibrillation may involve refractory period extension (RPE) produced by the shock. Accordingly, pharmacological agents might modulate defibrillation by altering RPE. This study examined the effect of Class I and Class III antiarrhythmic agents on RPE by transcardiac shocks. METHODS: In four groups of pentobarbital anesthetized dogs, RPE was measured during rapid ventricular pacing before and after administration of either the Class I agents flecainide (n = 7) or encainide (n = 7), the Class III agent clofilium (n = 7), or vehicle (n = 5). Measurements included QRS duration during sinus rhythm and a conduction time, QTC interval and refractory period, and RPE for 4- to 10-V/cm shocks delivered 20-80 ms before the end of the tissue absolute refractory period. For the 6-V/cm shocks, the interval after the shock during which tissue remained refractory (RIAS) was also computed. RESULTS: Drugs affected QRS duration, conduction time, QTC, and refractory period ( without shocks) in accordance with their anticipated Class I and Class III actions. Without drugs, significant RPE was observed in all animals for all shocks delivered 40 ms or less before the end of the refractory period. Clofilium, encainide, and flecainide had a tendency to increase RPE but only clofilium produced a significant increase. For 6-V/cm shocks with different timings, the minimum RIAS was found to be approximately 43 ms, and occurred for shocks given 20-30 ms before the end of the refractory period. CONCLUSIONS: At drug dosages that produced moderate Class III ( approximately equal to 15%) or strong Class I (approximately equal to 35%) effects, only the Class III agent significantly increased RPE and RIAS. Thus, in addition to altering tissue excitability, the effect of antiarrhythmic agents to increase RPE and the minimum RIAS may help explain their influence on defibrillation threshold.

Animals↗
PubMed1989

Previously unreported adverse reaction to encainide.

We describe a patient with recurrent atrial fibrillation who suffered a previously unreported adverse reaction to encainide therapy manifested by fever, chills, diaphoresis and myalgia. The patient had a similar response upon rechallenging with encainide, which resolved on discontinuation of therapy.

Aged↗
PubMed1990

Effects of quinidine, lidocaine and encainide on guinea pig myocardial Na(+)-K(+)-ATPase activity.

The effects of three Class I antiarrhythmic agents, quinidine (Class 1A), lidocaine (Class 1B) and encainide (Class 1C) on the Mg2(+)-dependent, Na+/K+ activated adenosine triphosphatase were compared with those of ouabain in microsomal preparations of the guinea pig heart. Lidocaine and quinidine inhibited the ATP-hydrolysis by the Na(+)-K(+)-ATPase in a concentration-dependent fashion similar to that of ouabain. The concentrations for half maximal inhibition of the enzyme activity were 4.1 +/- 0.7 mM for lidocaine and 0.46 +/- 0.12 mM for quinidine. Encainide exhibited stimulatory tendency at pharmacological concentrations, enhancing the enzyme activity by 2.5% at 1.0 microM and 25% at 1.0 mM. These results show that the Class I antiarrhythmic drugs may influence the Na(+)-K(+)-ATPase activity in different ways.

Adenosine Triphosphate↗
PubMed1984

[Electrophysiological effects of encainide in man].

Encainide is an antiarrhythmic agent under evaluation; it is effective in ventricular and supraventricular arrhythmias. Its electrophysiological effects seem to differ according to the route of administration, oral or intravenous, probably because of the effects of active metabolites. Two electrophysiological studies were carried out in 20 patients, under basal conditions, and after 4 to 10 days oral administration at doses ranging from 75 to 300 mg/day. Encainide depressed intra-atrial conduction (prolongation of the P-A interval from 29,7 +/- 2,2 to 36 +/- 4,5 ms, p less than 0,01), slowed conduction in the atrioventricular mode (prolongation of the A-H interval from 74 +/- 14 to 98 +/- 15 ms, p less than 0,01) and the His-Purkinje system (lengthening of H-V from 50 +/- 3 to 70 +/- 6,2 ms, p less than 0,001). The sinus node function was depressed with lengthening of the corrected sinus node recovery time (297 +/- 64 to 387 +/- 71 ms, p less than 0,01) and of the sinoatrial conduction time (173 +/- 25 to 219 +/- 43, p less than 0,01). The atrial and ventricular refractory periods were significantly longer (245 +/- 16 ms to 273 +/- 10 ms, p less than 0,001, and 237 +/- 12 to 266 +/- 19 ms, p less than 0,01, respectively). This new antiarrhythmic agent therefore seems to act at all levels which suggests that it may have wide ranging antiarrhythmic effects.

Administration, Oral↗
PubMed1984

The use of encainide in atrial fibrillation.

Based on its electrophysiologic characteristics, encainide, a new type 1 antiarrhythmic agent, was selected for a therapeutic trial in a case of refractory paroxysmal atrial fibrillation. This approach represents an attempt to manage the pathophysiologic disturbance of atrial fibrillation by selection of a drug that would be expected to have specific effects on the conduction system.

Anilides↗
PubMed1989

Determination of encainide and its metabolites by high-performance liquid chromatography.

Encainide (ENC) and its metabolites O-demethylencainide (ODE), 3-methoxy-O-demethylencainide (MODE), N-demethylencainide (NDE) and bis-N,O-demethylencainide (NODE) have been measured by two HPLC procedures. The method of Mayol using a mu Porasil column with ethanol-water-methanesulphonic acid as mobile phase was not able to separately measure NODE and NDE in plasma. A new method is described using a mu Bondapak Phenyl column with acetonitrile-phosphate buffer (0.05 M, pH 7.5) that yields satisfactory separation of ENC and its metabolites. NODE was not identified as a metabolite in 23 patients analysed.

Anilides↗
PubMed1994

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.

Aged↗
PubMed1997

Impact of the Food and Drug Administration approval of flecainide and encainide on coronary artery disease mortality: putting "Deadly Medicine" to the test.

In his book Deadly Medicine and on television, Thomas Moore impugns the process of antiarrhythmic drug approval in the 1980s, alleging that the new generation of drugs had flooded the marketplace and had caused deaths in numbers comparable to lives lost during war. To assess these important public health allegations, we evaluated annual coronary artery disease death rates in relation to antiarrhythmic drug sales (2 independent marketing surveys). Predicted mortality rates were modeled using linear regression analysis for 1982 through 1991. Deviations from predicted linearity were sought in relation to rising and falling class IC and overall class I antiarrhythmic drug use. Flecainide came to market in 1986 and encainide in 1987. Combined class IC sales peaked in 1987 and 1988 (maximum market penetration, 20%, first quarter 1989). Results of the Cardiac Arrhythmia Suppression Trial (CAST) were disclosed in April 1989. Overall annual class I antiarrhythmic prescription sales actually fell slightly (-3% to -4%/yr) in the 2 years before CAST and then more abruptly (- 12%) in the year after CAST (1990). Sales of class IC drugs fell dramatically after CAST (by 75%). Coronary death rates (age adjusted) fell in a linear fashion during the decade of 1982 through 1991. No deviation from predicted rates was observed during the introduction, rise, and fall in class IC (and other class I) sales: rates were 126/100,000 in 1985 (before flecainide), 114 and 110 in 1987 and 1988 (maximum sales), and 103 in 1990 (after CAST). Deviations in death rates in the postulated range of 6,000 to 25,000 per year were shown to be excluded easily by the 95% confidence intervals about the predicted rates. Entry of new antiarrhythmic drugs in the 1980s did not lead to overall market expansion and had no adverse impact on coronary artery disease death rates, which fell progressively. Thus, the allegations in Deadly Medicine could not be confirmed.

Anti-Arrhythmia Agents↗
PubMed1992

Encainide overdose in an infant.

Ingestion of as little as a single tablet of encainide resulted in life-threatening ventricular arrhythmias in a child. Insertion of an intraosseous line permitted prompt delivery of medications and fluids. Prehospital care providers must be aware that apparently trivial amounts of some adult dosage forms can be toxic to small children.

Drug Overdose↗