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PubMed1992

Encainide-induced diabetes: analysis of islet cell function.

OBJECTIVE: The purpose of this study was to gain insight into the mechanisms responsible for encainide-induced diabetes. Specifically, we sought to determine if absolute insulinopenia was present or whether encainide-induced diabetes was metabolically more like type II than type I diabetes. RESEARCH DESIGN AND METHODS: Islet function was assessed in a 65 year old white male with encainide-induced diabetes. After 6 months of encainide treatment and 2 months duration of diabetes, C-peptide, glucagon, and glucose levels were measured at baseline and at 30 minute intervals for 120 minutes following an oral mixed meal. These measurements allowed assessment of islet beta and alpha cell function in comparison to control data from our laboratory. RESULTS: In this patient with encainide-induced diabetes, basal and peak C-peptide concentrations were similar to controls although peak C-peptide occurred substantially later than in controls. At peak glucose, the patient's C-peptide/glucose ratio was low indicating relative (but not absolute) insulinopenia. At baseline, glucagon was relatively depressed. Following Sustacal, there was an increase in glucagon of 100% over baseline compared to a mean glucagon rise in controls of only 8%. There was no serological evidence for autoimmune diabetes as islet cell autoantibodies were absent. CONCLUSIONS: Similar to other forms of diabetes, encainide-induced diabetes is a bihormonal disorder. The metabolic pattern was more like type II than type I diabetes with C-peptide secretion in the normal range, yet persistent hyperglycemia that suggests relative insulinopenia and concurrent insulin resistance.

Aged↗

PubMed1987

Encainide hydrochloride and flecainide acetate: two class 1c antiarrhythmic agents.

The chemistry, electrophysiology, pharmacokinetics, clinical use and efficacy, adverse effects, drug interactions, and dosage of encainide hydrochloride and flecainide acetate are reviewed. Encainide and flecainide are class 1c antiarrhythmic agents that slow myocardial conduction and mildly prolong the duration of repolarization. Both agents block anterograde conduction over accessory pathways and prolong the effective refractory period of the accessory pathway. Bioavailability of encainide ranges from 7% to 82%, whereas that of flecainide is 90% to 95%. Encainide is metabolized by the liver to two major active metabolites that are slowly eliminated in the urine. About 23% of flecainide's total body clearance is dependent on renal elimination, and drug excretion is slowed in patients with renal dysfunction, requiring dosage adjustments. Both agents are effective in the suppression and prevention of ventricular arrhythmias, including premature ventricular contractions and sustained and nonsustained ventricular tachycardia. These agents may also be valuable in controlling supraventricular arrhythmias. The most common adverse effects of both agents involve the central nervous system and include dizziness, blurred vision, and headache. The potential for proarrhythmic effects is a concern with these agents. The risk is greater in patients with more severe arrhythmias, poor ventricular function, or high serum concentrations of drug. The usual initial oral dosage of encainide hydrochloride is 25 mg three times a day, with a usual dosage range of 100-200 mg/day. Flecainide acetate should be initiated at 100 mg every 12 hours and may be increased up to 400 mg/day. Encainide and flecainide could become useful therapeutic options in the treatment of a variety of arrhythmias.

Anilides↗

PubMed1985

Effects of encainide on the determinants of cardiac excitability in sheep Purkinje fibers.

Encainide is a benzanilide derivative that is effective against ventricular arrhythmias but, at times, may be arrhythmogenic. The microelectrode technique of intracellular current application and transmembrane voltage recording was used to study the effects of encainide, in a concentration equivalent to a clinically effective antiarrhythmic plasma level, on the determinants of cardiac excitability in sheep Purkinje fibers. A rapid, on-line computerized data analysis system was used to track the alterations in the active and passive membrane properties relevant to excitability in time. Cardiac excitability was defined experimentally in terms of the current required to attain threshold and/or the shift in strength- or change-duration curves. Encainide produced multiphasic changes in cardiac excitability, the final state of excitability depended on the balance between altered passive and active membrane properties. Encainide could enhance excitability by increasing membrane and slope resistance without altering the nonlinearities of the current-voltage relationship despite an actual depression of the sodium system. Encainide could decrease excitability by 1) depressing the sodium system; 2) decreasing membrane resistance without altering the nonlinearities of the subthreshold current-voltage relationship; 3) altering the nonlinearities of the current-voltage relationship; and 4) by a combination of these actions. During washout, excitability could remain altered despite a return of descriptive parameters such as the maximal rate of rise of phase 0, overshoot and action potential duration to normal. The study demonstrated the importance of time-related changes of an antiarrhythmic drug at a constant concentration. The results explain, in part, the antiarrhythmic actions and arrhythmogenic potential of encainide.

Action Potentials↗

PubMed1984

Influence of genetic polymorphism on the metabolism and disposition of encainide in man.

The metabolism of the new, highly effective antiarrhythmic agent, encainide, appears to be polymorphically distributed in a similar fashion to the genetically determined oxidative biotransformation of debrisoquine. Accordingly, the disposition of encainide and known metabolites was investigated after simultaneous acute i.v. (radiolabeled) and single and multiple oral (nonradiolabeled) dosing to two groups of normal subjects characterized as "poor" (PM) and "extensive" (EM) metabolizers of debrisoquine. Pronounced differences in both the plasma concentration/time curves and the 24-hr urinary excretion of encainide and metabolites were observed between the two phenotypes. In the EM group, the oral bioavailability of encainide was only about 25 to 30% because of extensive presystemic (first-pass) metabolism, and no accumulation occurred after multiple oral dosing with 50 mg every 8 hr for 3 days, as the elimination half-life of the drug was about 2.5 hr. The major metabolite formed was O-desmethylencainide which accounted for almost half of the identified urinary metabolites and represented about 10% of the administered dose. This metabolite was present in 5- to 10-fold higher concentrations in the plasma than unchanged drug and accumulated almost 2-fold after multiple oral dosing. 3-Methoxy-O-desmethylencainide also was present at higher concentrations than encainide and accumulated on multiple dosing similarly to O-desmethylencainide. N,O-didesmethylencainide was a minor metabolite only detectable in the urine and N-desmethylencainide was not measurable in either plasma or urine. In contrast, in the PM group, encainide plasma concentrations were 10- to 20-fold higher than in the EMs after both oral and i.v. administration and the elimination half-life was 3- to 4-fold longer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1985

Spectrum of antiarrhythmic response to encainide.

Encainide is effective in suppressing non-life-threatening ventricular arrhythmias; however, inconsistent results have been noted in patients with more serious ventricular arrhythmias. Thirty-seven patients with drug-resistant ventricular arrhythmias were studied. Patients in group I (n = 11) has sustained ventricular tachycardia and those in group II (n = 26) had nonsustained ventricular arrhythmias. In group I, 8 patients had remote myocardial infarction, congestive heart failure and sustained ventricular tachycardia requiring repeated cardioversion (group Ia). None of these patients responded to encainide treatment, but 6 did have an antiarrhythmic response (complete in 3 and only partial in 3) to other investigational antiarrhythmic agents. Three patients in group I, all without ischemic heart disease (group Ib), had an excellent antiarrhythmic response to encainide, as did 21 of 26 patients in group II. In 4 of 5 patients in group II who did not respond, the dosage was limited due to the development of sinus pauses, atrioventricular block or bundle branch block, and in 3 of these 4 patients preexisting conduction disease was evident (PR longer than 0.2 second or QRS longer than 0.12 second). Diplopia occurred while taking the maximal oral dosage in the fifth patient. At 21.5 months of follow-up, 14 of the original 24 patients who responded to encainide continue to receive it; 3 have died (all due to natural progression of left ventricular dysfunction) and encainide was discontinued in 7: in 2 because of syncope, in 2 because of new-onset atrial fibrillation, in 1 patient because of exercise-induced polymorphic ventricular tachycardia, in 1 because of diplopia and in 1 because of skin exanthem.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗

PubMed1986

Basic and clinical cardiac electrophysiology of encainide.

Encainide is a potent sodium channel antagonist. It dissociates slowly from blocked, repolarized channels (time constant of recovery greater than 20 seconds). It markedly slows myocardial and His Purkinje conduction in vitro, in animal models and in humans. In vitro the parent compound and its major metabolites, O-demethyl and 3-methoxy-O-demethyl encainide, have variable effects on action potential duration and refractoriness. In man the parent compound has relatively little effect on refractoriness and QT interval, but its metabolites may increase refractoriness moderately. Encainide has no significant effect on the normal sinoatrial node, and only its metabolites significantly depress atrioventricular nodal conduction and refractoriness. In models of ischemia, all of encainide's actions are more pronounced in ischemic than in normal tissue. Encainide is similar in its basic and clinical electrophysiologic profile to flecainide and lorcainide although its constellation of electrophysiologic properties is unique. It differs from quinidine, procainamide and disopyramide by slowing conduction more and affecting refractoriness less, and by absence of anticholinergic side effects.

Action Potentials↗

PubMed1986

Safety and efficacy of encainide for malignant ventricular arrhythmias.

The antiarrhythmic effect of encainide was evaluated in 140 patients with documented symptomatic ventricular tachycardia or ventricular fibrillation refractory to conventional agents. In 102 patients with reproducible spontaneous arrhythmia, noninvasive methods, including ambulatory monitoring and exercise testing, were used to evaluate drug efficacy, while in the remaining 38 patients electrophysiologic testing was performed. Side effects necessitated drug discontinuation in 10 patients before noninvasive evaluation. Of the remaining 92 patients 44 (48%) responded to encainide. Of the 38 patients who underwent electrophysiologic study, 1 discontinued encainide because of side effects and in 4 patients the spontaneous occurrence of sustained ventricular tachycardia precluded repeat study. Of the remaining 33 patients, 10 (30%) were rendered noninducible with encainide. The drug was more effective in those with a left ventricular ejection fraction greater than 35% (p less than 0.03) and in those presenting with nonsustained ventricular tachycardia. Side effects were reported in 53 of 140 patients (38%) and were primarily nausea, vomiting, headaches and tremors. Aggravation of arrhythmia occurred in 4% of patients with a history of nonsustained arrhythmia and in 25% of those with a history of sustained ventricular tachycardia or ventricular fibrillation. Worsening of arrhythmia was not related to mean dose of drug, mean blood level or electrocardiographic changes; it was more likely to occur in patients with a markedly reduced left ventricular ejection fraction (average 32%) and in those with a history of sustained ventricular tachyarrhythmia (p less than 0.05). Long-term encainide therapy was continued in 48 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

Dosing recommendations for encainide.

The onset of antiarrhythmic action of encainide in patients with ventricular arrhythmias occurred within 3 hours after a single dose of 25 or 50 mg. No significant antiarrhythmic activity was noted after only 10 mg. After 14 days of daily dosing, both the 25- and 50-mg dose levels of encainide administered 3 times/day abolished or decreased ventricular arrhythmias in patients tested over a 24-hour period, whereas the 10-mg dose was ineffective. In 5 well-controlled studies involving 331 patients, encainide produced a dose-related decrease in the absolute number of ventricular arrhythmias as well as an increase in the percentage of responders (greater than 75% decrease in ventricular arrhythmias). Doses of 75 mg/day were required to obtain at least a 50% reduction in ventricular arrhythmias or 50% of patients responding or both. Three-times-a-day dosing was as effective as 4-times-a-day dosing. Further, doses greater than 200 mg/day gave little or no increase in incidence of efficacy. Important side effects were very low using doses of less than or equal to 150 mg/day and increased significantly at greater than or equal to 150 mg/day. It is recommended that encainide be initiated at 25 mg 3 times/day for 4 to 7 days, then carefully titrated upward, as needed, to 35 and 50 mg 3 times/day, respectively, every 4 to 7 days. If needed, 50 mg 4 times/day is an appropriate next dosage. Rapid dose escalation or doses greater than 200 mg are discouraged. Patients with severe life-threatening arrhythmias should receive encainide in a setting with cardiac monitoring and advanced life support systems.

Anilides↗

PubMed1986

Dose-response range of encainide for benign and potentially lethal ventricular arrhythmias.

A multicenter, 2-week, double-blind, placebo-controlled, parallel group study was performed to determine the dose-response relation of encainide administered 3 times daily and to determine its onset of action. To be included in the study, patients with benign or potentially lethal ventricular arrhythmias were required to have an average of at least 30 ventricular premature complexes (VPCs) per hour on 48-hour Holter monitoring after a 48-hour washout period without antiarrhythmic drug treatment. Patients were randomly assigned to receive either placebo or 10, 25 or 50 mg of encainide 3 times daily (tid) for 2 weeks. Of the 125 patients who entered the study, 122 were available for efficacy analysis. Efficacy was determined using 24-hour Holter monitoring on days 1, 7 and 14. There was no difference in frequency of VPCs or of ventricular tachycardia events in the placebo and 10-mg-tid encainide arms. At doses of 25 and 50 mg of tid, encainide was effective in suppressing VPCs and in reducing the number of episodes of ventricular tachycardia. A positive dose-response relation was identified. The onset of effect of encainide was apparent at 3 hours and lasted for 24 hours with tid dosing. No difference in on-therapy conditions were found among the 4 study arms. No patients were discontinued from the study because of electrocardiographic changes. There was no statistically significant change in vital signs or physical examination data. In 1 patient an elevated serum glucose level developed. No symptomatic proarrhythmic events occurred and none required discontinuation of study medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Encainide versus flecainide for chronic atrial and junctional ectopic tachycardia.

For treatment of chronic atrial and junctional ectopic tachycardia, standard antiarrhythmic therapy has been shown to be ineffective in most patients. Both the intravenous efficacy and the oral efficacy of 2 class IC antiarrhythmic drugs, encainide and flecainide, were studied in 16 patients with atrial ectopic tachycardia and in 3 patients with junctional ectopic tachycardia, using exercise testing, 24-hour long-term electrocardiography and programmed electrical stimulation. All patients had been previously treated unsuccessfully with several antiarrhythmic drugs. In 5 patients, tachycardia was persistent; in the remaining patients, it occurred intermittently for more than 12 hours/day. Intravenous encainide, in doses ranging from 0.3 to 2.0 mg/kg body weight, was given to 5 patients with atrial ectopic tachycardia, and it terminated atrial ectopic tachycardia in all patients. Intravenous flecainide was given to 9 patients, and it terminated atrial tachycardia in 4 and slowed the tachycardia rate in 2. It terminated junctional tachycardia in 2 patients and slowed tachycardia rate in 1. During a follow-up period of 10 +/- 5 months, oral encainide, in dosages between 150 and 225 mg/day, completely suppressed atrial ectopic activity in 4 patients. In the remaining patient, encainide reduced the number of tachycardia episodes markedly but had to be withdrawn because of intolerable side effects. During a 12 +/- 11-month (median 6) follow-up, oral flecainide at dosages between 200 and 300 mg/day, completely suppressed ectopic activity in 7 patients and improved symptoms in 5. Only 1 patient failed to respond to oral flecainide. The results of this study indicate that both encainide and flecainide are effective in the treatment of chronic ectopic atrial and junctional tachycardia.

Administration, Oral↗

PubMed1988

Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction: the CAPS.

The National Heart, Lung, and Blood Institute initiated the Cardiac Arrhythmia Pilot Study (CAPS) to evaluate the feasibility of suppressing ventricular arrhythmias after acute myocardial infarction. Ten centers enrolled 502 patients younger than 75 years of age with greater than or equal to 10 ventricular premature complexes (VPC) per hour in a 24-hour electrocardiographic recording and a left ventricular ejection fraction greater than 20%. Patients were enrolled 6 to 60 days after acute myocardial infarction and randomized to 1 of 5 treatment tracks with 2 drugs that included encainide, flecainide, imipramine, moricizine or placebo. During a double-blind drug and dose selection phase, investigators were permitted to change drug or dosage to achieve greater than or equal to 70% suppression in VPC frequency and greater than 90% suppression of runs of VPC with the exception of patients assigned to placebo, who continued receiving it. Patients were followed for a year after randomization. Patients in the 5 treatment arms were similar in age, sex, clinical characteristics, VPC frequency, left ventricular ejection fraction and concomitant drug treatment. As first drugs, encainide and flecainide had higher efficacy rates, 79% and 83%, respectively, than imipramine, 52%, moricizine, 66%, or placebo, 37%. Encainide and flecainide also had high efficacy rates, 68% and 69%, in patients who failed imipramine or moricizine. Encainide, flecainide and moricizine were well tolerated. These 3 drugs had intolerable adverse effect rates of 6% or less, i.e., similar to placebo. More than 70T of the patients who started the follow-up phase on encainide, flecainide or moricizine remained on these drugs to the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗

PubMed1991

Mortality in patients treated with flecainide and encainide for supraventricular arrhythmias.

In a recent clinical trial, the class Ic antiarrhythmic drugs encainide and flecainide were found to be associated with an increased mortality risk in patients with new myocardial infarction and ventricular arrhythmias. The purpose of this study was to assess whether an increased mortality risk also accompanied the use of these drugs to treat patients with supraventricular arrhythmias. Data were obtained from the respective pharmaceutical sponsors on the mortality observed with each drug in United States and foreign protocols enrolling patients with supraventricular arrhythmias. Mortality in the encainide population (343 patients) and the flecainide population (236 patients) was compared with that in a research arrhythmia clinic, the Duke population (154 patients). Nine deaths occurred in the combined encainide-flecainide population and 10 deaths occurred in the Duke population; the follow-up periods averaged 488 days and 1,285 days, respectively. The 6-year survival functions of these 2 populations, estimated by the Kaplan-Meier technique, did not differ significantly (p = 0.62). The hazard ratio for the combined encainide-flecainide population relative to the Duke population was estimated to be 0.6 with a 95% confidence interval of 0.2, 1.7. These descriptive comparisons did not demonstrate any excess mortality when flecainide and encainide were used in patients with supraventricular arrhythmias.

Adult↗

PubMed1982

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.

Administration, Oral↗

PubMed1986

Encainide disposition in patients with chronic cirrhosis.

The antiarrhythmic agent encainide undergoes extensive first-pass hepatic metabolism after oral dosing. The active metabolites O-desmethylencainide and 3-methoxy-O-desmethylencainide are formed in subjects who are extensive metabolizers (EMs), a phenotypic trait that cosegregates with that of debrisoquin. Because of the possibility that drug metabolism is altered by liver dysfunction, the disposition of encainide and its metabolites was studied in six such EMs with cirrhosis and compared with that in eight normal subjects of the same phenotype. Patients with cirrhosis had lower systemic and oral clearances of encainide, resulting in a threefold increase in oral bioavailability. The plasma concentration of encainide was significantly higher among the patients with cirrhosis, whereas the plasma levels of the respective metabolites were comparable with those in normal subjects, resulting in no change in the patient's ECG intervals. Encainide is, therefore, an example of a drug in which cirrhosis causes a three- to fourfold increase in parent drug concentrations. However, because no change occurs in the levels of the pharmacologically active metabolites, dosage adjustment is probably not required in patients with cirrhosis.

Administration, Oral↗

PubMed1989

Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction.

The occurrence of ventricular premature depolarizations in survivors of myocardial infarction is a risk factor for subsequent sudden death, but whether antiarrhythmic therapy reduces the risk is not known. The Cardiac Arrhythmia Suppression Trial (CAST) is evaluating the effect of antiarrhythmic therapy (encainide, flecainide, or moricizine) in patients with asymptomatic or mildly symptomatic ventricular arrhythmia (six or more ventricular premature beats per hour) after myocardial infarction. As of March 30, 1989, 2309 patients had been recruited for the initial drug-titration phase of the study: 1727 (75 percent) had initial suppression of their arrhythmia (as assessed by Holter recording) through the use of one of the three study drugs and had been randomly assigned to receive active drug or placebo. During an average of 10 months of follow-up, the patients treated with active drug had a higher rate of death from arrhythmia than the patients assigned to placebo. Encainide and flecainide accounted for the excess of deaths from arrhythmia and nonfatal cardiac arrests (33 of 730 patients taking encainide or flecainide [4.5 percent]; 9 of 725 taking placebo [1.2 percent]; relative risk, 3.6; 95 percent confidence interval, 1.7 to 8.5). They also accounted for the higher total mortality (56 of 730 [7.7 percent] and 22 of 725 [3.0 percent], respectively; relative risk, 2.5; 95 percent confidence interval, 1.6 to 4.5). Because of these results, the part of the trial involving encainide and flecainide has been discontinued. We conclude that neither encainide nor flecainide should be used in the treatment of patients with asymptomatic or minimally symptomatic ventricular arrhythmia after myocardial infarction, even though these drugs may be effective initially in suppressing ventricular arrhythmia. Whether these results apply to other patients who might be candidates for antiarrhythmic therapy is unknown.

Aged↗

PubMed1987

Flecainide and encainide.

Flecainide and encainide (class IC) are presently under clinical evaluation in Italy. They prolong the duration of the QRS but not the period of ventricular repolarisation: the prolongation of QT is due solely to the prolongation of the Q-J. Flecainide and encainide are extremely powerful and are suitable for the treatment of reciprocating supraventricular paroxysmal tachycardia and of persistent reciprocating tachycardia, the prophylaxis of WPW atrial fibrillation including cases with a short anterograde refractory period of the anomalous pathway and the treatment of ventricular ectopic beats and ventricular tachycardia. Both drugs are probably effective for the treatment of atrial fibrillation. However, in the case of atrial flutter they are of little effect of sinus rhythm cardioversion; on the other hand they significantly prolong the duration of the A-A interval, with variable results on ventricular rate. Flecainide and encainide have 'parodoxical' arrhythmogenic effects, related to administration dosages, severity of the arrhythmia and seriousness of cardiopathy. Encainide shows peculiar pharmacokinetics due to hepatic oxidating metabolisation and to production of metabolites; among these the O-demethylencainide and the 3-methoxy-O-demethylencainide have an antiarrhythmic activity, which is probably more important than the encainide parent and is longer-lasting. There are 'extensive', 'poor' and 'non-metaboliser' subjects. This results in wide pharmacokinetic inter- and intraindividual variability which must be taken into account during clinical treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗

PubMedDate not supplied

Effects of encainide (MJ9067) on the ventricular fibrillation threshold in anesthetized dogs.

The right ventricular epicardial ventricular fibrillation threshold (VFT) was determined during paced supraventricular rhythm using 100 Hz trains of stimuli at 15 min intervals in dogs before and during the intravenous administration of encainide, a new antiarrhythmic drug. With each VFT determination, simultaneous blood samples were obtained for determination of drug concentration. In 6 control dogs, VFT determined every 15 min during a 210 administered as a 90 min intravenous infusion at three successive rates (0.01, 0.02 and 0.04 mg/kg/min) for 30 min each. VFT measured at 5 and 20 min of each infusion increased from a mean control of 11.5 +/- 1.5 (+/-SE) to 20.2 +/- 2.2 mA (p less than 0.01) after 20 min of the third infusion. The maximal effect occurred during the second infusion with plasma concentration of 594 +/- 46 ng/ml and then reached a plateau. In group II (n = 6), encainide was administered in four successive sequences, each one including a bolus loading intravenous dose followed by a 45 min intravenous infusion. VFT measured at 30 and 45 min of each infusion when the encainide plasma concentration was close to a steady state increased significantly (p less than 0.01) after the second infusion from 11.8 +/- 2 to 27.3 +/- 4 mA. Two dogs in group II developed transient complete atrioventricular block at an encainide plasma concentration of greater than 800 ng/ml. These results show that the new antiarrhythmic drug encainide increases the VFT in anesthetized dogs.

Anesthesia↗

PubMedDate not supplied

Resting and rate-dependent depression of maximum rate of depolarisation (Vmax) in guinea pig ventricular action potentials by mexiletine, disopyramide, and encainide.

The influence of stimulation rate on the ability of mexiletine, disopyramide, and encainide to depress the maximum rate of depolarisation (Vmax) of intracellular action potentials has been studied in guinea pig ventricular myocardium, using standard microelectrode techniques. Mexiletine and disopyramide produced modest depression of Vmax even in the absence of stimulation (resting block), while encainide did not. All three drugs produced progressive depression of Vmax as stimulation rate was increased over a wide range of interstimulus intervals (rate-dependent block). This relationship between interstimulus interval (ISI) and depression of Vmax was steepest for mexiletine, least marked for disopyramide, and intermediate for encainide. Mexiletine also exhibited the fastest response to a sudden change of frequency. During a train of stimuli at ISI of 300 ms after a rest period, Vmax fell rapidly, reaching 61% of its final value by the second beat. In response to a similar train of stimuli, disopyramide and encainide produced exponential falls of Vmax with rate constants of -0.113 AP (AP = action potential) and -0.025 AP, respectively. Similar trends were seen in the recovery of cells from this rate-dependent block at the end of a train of stimuli. Time constants for this process for mexiletine, disopyramide, and encainide were 471.2 ms, 12.2 s, and 20.3 s, respectively. It is concluded that the rapid onset of and recovery from rate-dependent block seen with mexiletine may explain its lack of effect on conduction of sinus beats at concentrations that suppress extrasystoles and tachycardias.

Action Potentials↗