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At least 19 recordsLinked to original sources
PubMed1988

Antiarrhythmic activity, electrocardiographic effects and pharmacokinetics of the encainide metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide in man.

Although encainide is an effective antiarrhythmic agent, plasma concentrations and pharmacologic effects are not well correlated. One explanation is the generation of active metabolites: while in most patients (extensive metabolizers; EMs) concentrations of the metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3MODE) are higher than those of encainide, a small subset (poor metabolizers; PMs) lack the ability to extensively biotransform encainide. Considerable data from studies in vitro and animal studies, as well as indirect evidence in patients, indicate that ODE and 3MODE produce the effects seen during long-term encainide therapy in EMs. We now report the initial direct evaluation of the pharmacologic actions of these metabolites of encainide in man. Nine patients with ventricular arrhythmias, seven of the EM phenotype and two of the PM phenotype, were studied. Chronic high-frequency ventricular arrhythmias were suppressed by encainide therapy in seven of nine; monitoring arrhythmia frequency during withdrawal of encainide allowed definition of plasma concentrations of encainide and metabolites associated with arrhythmia suppression. Intravenous infusions of both ODE and 3MODE suppressed chronic ventricular arrhythmias, while infusions of placebo had no effect. ODE clearance was a function of metabolizer phenotype, with higher clearance (mean 914 ml/min; range 554 to 1,314) in EMs than in PMs (434, 298 ml/min); moreover, 3MODE was detected during ODE infusions in all seven EMs but in neither PM. 3MODE clearance was more uniform (mean 289 ml/min in EMs [range 180-410] vs 300 and 78 ml/min in the two PMs) and ODE was not detected in any subject during 3MODE infusion. Encainide itself was not detected after any infusion of ODE or 3MODE. During withdrawal of encainide therapy, ODE plasma concentration at the time of arrhythmia recurrence was 55 +/- 40 ng/ml (mean +/- SD), while ODE by infusion was effective at a concentration of 37 +/- 15 ng/ml. Similarly, plasma concentration of 3MODE at the time of arrhythmia recurrence after withdrawal of chronic encainide was 116 +/- 35 ng/ml and that during 3MODE infusion was 105 +/- 50 ng/ml. While both compounds prolonged QRS duration, ODE was the more potent, increasing QRS by 9.2 +/- 1.6% per 100 ng/ml vs 1.2 +/- 0.5% per 100 ng/ml for 3MODE. On the other hand, 3MODE prolonged the corrected JT interval by 1.9 +/- 0.6% per 100 ng/ml, while ODE shortened it by 2.7 +/- 1.9% per 100 ng/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMedDate not supplied

The effects of encainide and its major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, on experimental cardiac arrhythmias in dogs.

Encainide (E) is a class I antiarrhythmic agent which is metabolised in humans, with the formation in the majority of patients of O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide (MODE). As it has been suggested that these metabolites may contribute to the antiarrhythmic effect of E in humans, we have investigated the effects of E, ODE, and MODE on ventricular arrhythmias produced by ouabain and by coronary artery ligation. In the ouabain model, E restored sinus rhythm (SR) in eight of 13 dogs after a mean dose of 0.81 +/- 0.19 mg/kg (mean +/- SEM). ODE returned SR in five of 10 dogs after 0.30 +/- 0.06 mg/kg, and MODE returned SR in two of nine dogs after doses of 0.40 and 0.68 mg/kg, respectively. For comparison, mexiletine returned SR in six of six dogs after 3.50 +/- 1.02 mg/kg. In conscious dogs with ventricular arrhythmias 24 h after two-stage coronary artery ligation E restored SR in four of four dogs after 2.38 +/- 0.50 mg/kg. ODE restored SR in four of four dogs after 0.63 +/- 0.14 mg/kg, and MODE restored SR in four of four dogs after 1.39 +/- 0.30 mg/kg. Thus, ODE and MODE have antiarrhythmic activity which may contribute to the effects of E in patients with cardiac arrhythmias.

Anilides↗
PubMed1988

Treatment of life-threatening ventricular tachycardia with encainide hydrochloride in patients with left ventricular dysfunction. The Encainide-Ventricular Tachycardia Study Group.

Encainide, a newly released class IC antiarrhythmic agent, was studied in 193 patients with ventricular tachycardia (VT) and depressed left ventricular ejection fraction or important arrhythmia-related symptoms. Therapy was evaluated by 24-hour continuous Holter monitoring if patients had nonsustained VT or by electrophysiologic testing if they had sustained VT. Holter monitoring was used in 99 patients and electrophysiologic testing in 94 patients. At baseline the mean age, percent men, percent with coronary artery disease and mean ejection fraction in the 2 groups was 62 versus 58 years, 76 versus 72%, 62 versus 89%, and 27 versus 30%, respectively. In the Holter monitoring group, 71 of 99 (72%) responded with a significant reduction in VT (35% received 25 mg 3 times day, 47% received 35 mg 3 times a day, 14% received 50 mg 3 times a day and 4% received 50 mg 4 times a day). Adverse cardiac effects in these patients included a 7% incidence of serious proarrhythmic events that were probably related to encainide and a 2% incidence of sick sinus syndrome. In this group no patient developed congestive heart failure that was clearly attributed to encainide. Using electrophysiologic testing, 14 of 94 (15%) had sustained VT rendered noninducible, whereas 18 of 94 (19%) additional patients had partial electrophysiologic response defined as a more tolerable, slower VT. Overall, 32 of 94 (34%) were believed to be effectively treated in this group and were treated with encainide long-term. In the population evaluated by electrophysiologic testing, serious proarrhythmic events occurred in 15 of 94 (16%) and 3% had sinus pauses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Electrophysiological effects of encainide and its metabolites in normal canine Purkinje fibers and Purkinje fibers surviving infarction.

In this study, we assessed the effects of O-demethyl encainide (0.5 microM), the most active metabolite of encainide, and the combination with 3-methoxy-O-demethyl encainide (0.5 microM) and encainide (0.1 microM) on cardiac action potential characteristics in normal canine Purkinje fibers and Purkinje fibers surviving 24 h of myocardial ischemia. O-demethyl encainide decreased Vmax and conduction in normal Purkinje fibers and Purkinje fibers surviving infarction. Further decreases were observed with the combination. Action potential duration at both 50 and 95% repolarization was decreased by O-demethyl encainide. The combination of O-demethyl encainide, 3-methoxy-O-demethyl encainide, and encainide had no further effect. The combination of O-demethyl encainide, 3-methoxy-O-demethyl encainide, and encainide produced a smaller change in effective refractory period than O-demethyl encainide in normal Purkinje fibers and in Purkinje fibers surviving infarction. O-demethyl encainide and the combination shifted the membrane responsiveness curve to more negative potentials in both normal Purkinje fibers and Purkinje fibers surviving infarction. It is apparent from this study that there are differences in the effects of O-demethyl encainide and the combination of O-demethyl encainide, 3-methoxy-O-demethyl encainide, and encainide in normal Purkinje fibers compared with Purkinje fibers surviving infarction. Also, the combination used in this study had different electrophysiological effects than those of O-demethyl encainide alone.

Action Potentials↗
PubMed1986

Drug interaction studies and encainide use in renal and hepatic impairment.

The effect of encainide administration on steady-state plasma digoxin levels was evaluated in 17 patients receiving stable doses of digoxin. A paired t test, comparing plasma digoxin levels (mean +/- standard error) before encainide therapy (1.05 +/- 0.14 ng/ml) and after 2 weeks of encainide, 100 mg/day (1.03 +/- 0.11 ng/ml) or 200 mg/day (1.2 +/- 0.2 ng/ml), indicates no significant (p greater than 0.05) change in digoxin levels. These results were confirmed in a second study of 10 patients with severe congestive heart failure. Also, no difference in efficacy of either drug was observed and changes in dosing of digoxin were not required. Plasma concentrations of encainide and its 2 major metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide, significantly increased by 31.6%, 43.1% and 35.6% after concomitant cimetidine administration in 13 healthy adult men receiving 75 mg/day of encainide. However, a retrospective evaluation of 33 patients receiving both drugs did not reveal any clinically significant interactions. Retrospective evaluation of patients enrolled in clinical studies who received concomitant digoxin (268), antiarrhythmics (118), anticoagulants (78), antidiabetics (40), antipsychotics (23), beta blockers (88), calcium-channel blockers (24) or diuretics (229) did not reveal any clinically significant interactions with encainide. Similarly, in vitro protein binding studies did not reveal any clinically significant interactions with encainide or its major metabolites. Six patients with moderate to severe renal impairment (creatinine clearance 10 to 38 ml/min) received 25 mg of encainide, 3 times/day, for 7 doses. Plasma encainide, ODE and 3-methoxy-O-demethyl concentrations were similar to those observed in normal subjects who had received twice the dose of encainide, and steady-state apparent oral clearance of encainide was reduced by 66% with renal impairment. Based on these data it is recommended that in patients with moderate to severe renal impairment encainide be initiated at one-third the normal dose, or 25 mg once a day. Doses may be elevated in small increments at 1-week intervals if needed for efficacy. The effect of hepatic impairment on the pharmacokinetics of encainide was studied in 7 patients with clinically documented cirrhosis. Compared with normal subjects studied using a similar protocol, the plasma concentrations of encainide were elevated significantly due to a 6-fold decrease in oral clearance. However, since plasma concentrations of the active metabolite ODE were correspondingly lower, specific encainide dosing instructions for patients with hepatic impairment are not indicated.

Adrenergic beta-Antagonists↗
PubMed1988

Encainide-induced hyperglycemia.

Twenty-three patients were treated for at least one month with encainide, a new antiarrhythmic drug. No patient was treated for hyperglycemia prior to encainide therapy. During encainide administration, five episodes of marked hyperglycemia (serum glucose level greater than or equal to 200 mg/dl) developed in four patients. (One patient received encainide twice.) The mean pretreatment glucose level was 190 +/- 69 mg/dl and rose to 397 +/- 163 mg/dl after one month of encainide therapy in patients in whom hyperglycemia developed (p less than 0.025). The glucose level was 111 +/- 27 mg/dl in nonhyperglycemic patients before encainide administration and 108 +/- 22 mg/dl after one month of encainide therapy (p = NS). There was no difference in age or encainide dosage between hyperglycemic and nonhyperglycemic patients. Treatment for hyperglycemia was given during four of the five encainide treatment periods in hyperglycemic patients. Encainide was discontinued in each of the five hyperglycemic episodes; therapeutic requirements for hyperglycemia markedly decreased. Hypoglycemic reactions to insulin occurred in two patients when encainide was stopped. Thus, encainide exacerbates hyperglycemia in some patients. These patients usually have mild hyperglycemia not requiring therapy before administration of encainide but may require insulin while receiving encainide. Treatment requirements for hyperglycemia decrease following withdrawal of encainide. The mechanism of this effect and the consequences of long-term encainide therapy on glucose metabolism are unknown.

Aged↗
PubMed1989

Effect of low dose quinidine on encainide pharmacokinetics and pharmacodynamics. Influence of genetic polymorphism.

Encainide biotransformation to its active metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide cosegregates with the polymorphic oxidation of debrisoquine. Because quinidine has been reported recently to be a potent inhibitor of the enzyme responsible for this polymorphism (cytochrome P450db1), we tested the hypothesis that quinidine would selectively inhibit encainide metabolism and alter its effects in subjects with the extensive metabolism phenotype for debrisoquine oxidation. Seven subjects with the extensive and four subjects with the poor metabolism phenotype received encainide (60 mg p.o. and 4.5 mg of [14C]encainide i.v. administered simultaneously) alone and during chronic treatment with low dose quinidine (50 mg q 6 hr) in a randomized, crossover design. In extensive metabolizers, quinidine decreased encainide systemic clearance from 935 +/- 541 to 190 +/- 77 ml/min and encainide nonrenal clearance from 782 +/- 474 to 95 +/- 32 ml/min (both P less than .02). In this population, quinidine significantly increased encainide elimination half-life from 1.8 +/- 1.2 to 7.7 +/- 2.4 hr and fractional urinary recovery of unchanged encainide from 17.5 +/- 7.6 to 47.4 +/- 7.8% (both P less than .001). The extent to which quinidine altered these indices of encainide disposition was highly correlated with the metabolic ratio for debrisoquine oxidation (r = 0.62-0.95). Moreover, poor metabolism and QRS prolongation during encainide were blunted by addition of quinidine; the extent of quinidine-induced reversal of encainide-related ECG changes was also correlated with debrisoquine ratio (r = 0.91). In contrast, in poor metabolizers, quinidine did not change encainide disposition kinetics and neither encainide alone nor encainide plus quinidine significantly altered electrocardiographic intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Disposition kinetics of encainide and metabolites.

Interpretation of plasma concentration data during encainide therapy is predicated on an understanding of the role of active metabolites during treatment. In over 90% of patients, encainide is rapidly biotransformed to O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3-MODE), which persist in plasma hours after encainide itself is undetectable. This metabolism occurs in the liver, and encainide clearance is sufficiently high that a significant first-pass effect is seen during oral therapy (bioavailability 30 +/- 7%). In these extensive metabolizers, ODE and 3-MODE appear to mediate the arrhythmia suppression and electrocardiographic changes seen during encainide therapy. In less than 10% of patients, a genetic defect prevents expression of the enzyme responsible for the rapid biotransformation of encainide. In this poor metabolizer subset, the systemic clearance of encainide is 10-fold lower than in extensive metabolizers (0.18 +/- .002 vs 1.9 +/- 0.2 liters/min), the first-pass effect is virtually absent (bioavailability 83% to 88%), plasma concentrations are higher and an antiarrhythmic effect may be seen at usual encainide doses. Minimally effective plasma concentrations appear to be 35 ng/ml (ODE), 100 ng/ml (3-MODE) and 300 ng/ml (encainide), making ODE one of the most potent sodium channel blockers yet used in man. The elimination half-life of encainide is 2.3 +/- 0.3 hours in extensive metabolizer patients. Despite this rapid elimination, encainide can be administered every 8 to 12 hours in both extensive and poor metabolizer subsets; this is because of slowly eliminated metabolites in extensive metabolizers and slower elimination of encainide itself (11.3 +/- 0.3 hours) in poor metabolizers.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1986

Qualitative and quantitative comparison of the cardiac effects of encainide and its three major metabolites in the dog.

We have evaluated the electrophysiologic effect of encainide and its three major metabolites, O-demethyl encainide, 3-methoxy-O-demethyl encainide and N-demethyl encainide in an anesthetized dog model. Our results support previous reports that O-demethyl encainide and 3-methoxy-O-demethyl encainide are both more potent than encainide in the depression of conduction. We also have shown that N-demethyl encainide is of about equal potency to encainide. Whereas the major differences between these compounds is primarily one of potency, there are some qualitative differences. Although O-demethyl encainide did not change the ventricular or atrial effective refractory periods significantly, 3-methoxy-O-demethyl encainide and N-demethyl encainide prolonged both. Encainide increased the atrial effective refractory period but did not produce significant changes in the ventricular refractory period. These data support previous suggestions of an important role for these metabolites as modulators of the clinical efficacy of encainide.

Anilides↗
PubMed1988

Clinical pharmacokinetics of encainide.

The disposition kinetics of the new antiarrhythmic agent encainide are a function of the genetic polymorphism which also controls debrisoquin 4-hydroxylation. In the majority of subjects (extensive metabolisers) encainide undergoes extensive first-pass hepatic biotransformation to the active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). The plasma concentrations of these metabolites are higher than those of encainide, and pharmacological effects correlate better with plasma metabolite concentrations than they do with those of encainide itself. In poor metabolisers, who make up to 7% of the population, a first-pass effect is absent, encainide clearance is lower, and plasma encainide concentrations are higher than those in extensive metabolisers. In poor metabolisers, plasma concentrations of active metabolites are low or undetectable, and the effects of encainide therapy can be closely correlated with plasma concentrations of the parent drug. Despite the marked differences in encainide disposition between extensive and poor metabolisers, the dosages which produce pharmacological effects (QRS prolongation and arrhythmia suppression) are similar in both groups. Encainide biotransformation is impaired in hepatic disease, but no major dosage changes are required. On the other hand, excretion of encainide and its metabolites is impaired in individuals with renal disease, and starting dosages should be decreased. The time required to achieve steady-state concentrations of metabolites (in extensive metabolisers) and of encainide itself (in poor metabolisers) is similar (3 to 5 days); therefore, the dosage should be increased no more often than every 3 to 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1991

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

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

Anilides↗
PubMed1987

Hemodynamic and electrophysiologic effects of encainide in patients with bundle branch block.

Electrophysiologic studies were performed in 6 consecutive patients with bundle branch block and organic heart disease. All were studied after intravenous (0.9 mg/kg) encainide and 3 of the 6 after 36-72 hours of oral encainide (50 mg every 6 hours). After intravenous encainide, mean H-Q increased from 51 +/- 20 msec to 58 +/- 25 msec (14% p less than or equal to .05). After oral encainide (3 patients) H-Q increased to 90 +/- 39 msec (56% p less than or equal to .05, compared to baseline). Programmed ventricular stimulation was performed in 5. In 1 patient without spontaneous ventricular tachycardia, tachycardia was non-inducible before and after encainide. Of 5 patients with spontaneous arrhythmia, 3 had ventricular tachycardia induced before and after intravenous encainide at mean cycle lengths of 287 +/- 130 msec and 407 +/- 261 msec, (not significant) respectively, while 1 had ventricular tachycardia induced only after encainide. Four patients began chronic treatment with oral encainide (2 patients with inducible rapid ventricular tachycardia after encainide were excluded). All suffered major adverse outcomes. One died suddenly after an electrophysiology study demonstrated inducible ventricular tachycardia, which occurred only after encainide. One experienced new syncope after baseline H-Q increased 75% after encainide. Two patients developed new sustained atrial tachycardias and 1 patient developed persistent ventricular tachycardia on encainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Pharmacokinetics and metabolism of encainide.

The metabolism of encainide occurs in the liver and is polymorphically distributed according to the same genetic factor that determines the 4-hydroxylation of debrisoquine. Over 90% of patients are extensive metabolizers (EM) in whom the oral bioavailability of encainide is only 30% because of extensive first-pass metabolism. In EMs, elimination t1/2 is about 2.5 hours, with a systemic clearance of 1.8 l/min. The plasma concentrations of the major metabolites O-desmethyl-encainide (ODE) and 3-methoxy-O-desmethyl-encainide (3-MODE) are higher than those of encainide and have antiarrhythmic activity. The remaining patients (less than 10%) are poor metabolizers (PM), in whom the oral bioavailability is near 88% with an elimination t1/2 of 8-11 hours and a systemic clearance of 0.2 l/min. Encainide plasma concentrations are 10- to 20-fold higher than in EMs, but considerably less ODE and no 3-MODE is formed by the PMs. The conversion to the N-desmethyl-encainide (NDE) metabolite seems to be similar in both metabolizer groups, and plasma protein binding of encainide of 70-78% is also similar. During long-term treatment, the antiarrhythmic metabolites of encainide accumulate in the plasma, so that the relationships between the effect and plasma concentration on encainide, ODE, and 3-MODE are not always obvious. Minimally effective plasma concentrations appear to be approximately 300 ng/ml of encainide, 35 ng/ml of ODE, and 100 ng/ml of 3-MODE. Dose adjustment is necessary in patients with decreased kidney function, but not in patients with cirrhosis, in whom the plasma levels of metabolites appear to be comparable to those in normal subjects.

Anilides↗
PubMed1985

Long-term efficacy and safety of oral encainide in the treatment of chronic ventricular ectopic activity: relationship to plasma concentrations--a French multicenter trial.

To establish long-term efficacy and safety of encainide, 48 patients with chronic premature ventricular contractions (PVCs) underwent 6 months of therapy with encainide. Twenty-four-hour ambulatory ECGs were obtained at baseline for each daily dosage of 75 mg, 150 mg, and 225 mg of encainide during the in-hospital titration period and at the end of the first and sixth months during the follow-up period. There was a significant reduction in the median hourly total PVC rates from 480.6 at baseline to 2.0 at the end of the titration period with the highest dosage and to 22.1 at the last visit of the chronic dosing period. Nearly total suppression of PVCs was observed in 56% of patients at the end of the titration period and in 30% at the end of the 6-month follow-up period. The most common side effects were vertigo, vision disturbance, and headache. PR, QRS, and QTc intervals showed consistent significant increases from baseline during the various encainide trial periods. Encainide may have worsened ventricular arrhythmia in four patients who received more than 200 mg of encainide daily. Plasma concentrations of encainide and encainide metabolites showed wide interpatient variation, and no relationship was found between antiarrhythmic efficacy and plasma levels of encainide, O-demethyl-encainide, or 3-methoxy-O-demethyl-encainide.

Adolescent↗
PubMed1986

Encainide for ventricular arrhythmias: placebo-controlled and standard comparison trials.

Efficacy data obtained from the use of encainide in the treatment of patients with benign or potentially lethal ventricular arrhythmias are reviewed. These include an oral dose multicenter titration study involving 111 patients in whom encainide was given from 25 to 75 mg, 4 times/day, which was followed by a 3-center, reduced dose study in which 35 patients received a forced escalation of encainide from 10 to 30 mg, 4 times/day. Frequent Holter monitoring was used to judge efficacy. An 8-center, double-blind, parallel, placebo-controlled outpatient trial was conducted using encainide from 10 to 50 mg, 3 times/day, in 125 patients. This trial defined the lower end of the dose response curve for encainide to be 25 mg, 3 times/day. The data from all these trials show that when properly titrated, encainide is effective in decreasing ventricular premature complex frequency by at least 75% in about 80% of patients. A similar percentage will have abolition of ventricular tachycardia. When encainide was compared with quinidine in a 9-center placebo-controlled crossover study, encainide demonstrated more efficacy at 25 mg, 4 times/day, compared with quinidine at 200 mg, 4 times/day, in all arrhythmia parameters. Encainide was also better tolerated than quinidine and there was no statistically significant difference in the prevalence of asymptomatic proarrhythmia as detected by Holter monitoring between these 2 drugs. Long-term data in 220 patients over 36-month follow-up show continued encainide efficacy. Thus, encainide is a potent, effective class 1C antiarrhythmic agent and it has minimal negative inotropic effects and is well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Genetically determined steady-state interaction between encainide and quinidine in patients with arrhythmias.

A genetically determined pharmacokinetic and pharmacodynamic interaction between quinidine and single doses of encainide in healthy volunteers has previously been described. In subjects with the extensive metabolizer phenotype, quinidine blunted encainide-induced QRS prolongation (a marker of sodium channel block) because it impaired encainide biotransformation to the potent active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide. Therefore, the purpose of this study was to test the hypothesis that quinidine would inhibit sodium channel block (and by inference arrhythmia suppression) during encainide therapy in patients with the extensive metabolizer phenotype. Surprisingly, however, in eight extensive metabolizer patients, the extent of QRS prolongation during chronic encainide therapy was unaltered by quinidine (139 +/- 21 vs. 139 +/- 22 msec) whereas arrhythmia suppression was enhanced (64 +/- 22 to 77 +/- 19%; P = .05). Plasma concentration data demonstrated that although encainide metabolism to ODE was partially impaired by quinidine, subsequent 3-methoxy-O-desmethyl encainide formation from ODE was virtually completely inhibited; thus steady-state plasma ODE remained unchanged whereas plasma encainide increased 10-fold (21 +/- 30 to 240 +/- 118 ng/ml; P less than .05). In contrast, no changes in disposition or in pharmacodynamics were observed in two poor metabolizers. It is concluded that the effect of this drug interaction in patients is determined by differential sensitivities to inhibition by quinidine of encainide O-demethylation and subsequent ODE 3-methoxylation. Evaluation of potential drug interactions should include assessment of possible genetic factors as well as of steady-state effects.

Aged↗
PubMed1989

Encainide.

Encainide is a class IC antiarrhythmic agent having little or no effect on action-potential duration or maximum diastolic potential but decreasing the maximum rate of phase O depolarization as well as increasing atrial and ventricular effective refractory periods. In intact animals or humans, encainide increases the AH, PR, QRS, and H-V intervals while not affecting the sinus node cycle length or JT interval. QT interval increases only by the concomitant increase in the QRS interval. Encainide is metabolized to O-demethyl encainide (ODE) and 3-methoxy-ODE (MODE), both of which are also antiarrhythmics with similar pharmacology to encainide. Encainide and its metabolites have little negative inotropic activity and ancillary pharmacology. Consequently, encainide has little or no effect on hemodynamic variables in patients with either normal or compromised cardiac function. The drug is well tolerated, with side effects being mainly those associated with its local anesthetic activity such as blurred vision and dizziness. Encainide is particularly effective in patients with excessive premature ventricular complexes (PVCs) and less so in patients with sustained ventricular tachycardia (VT). Like all antiarrhythmics, encainide may aggravate or precipitate new arrhythmias (proarrhythmia). The overall incidence of proarrhythmia is about 10%, with less occurring in patients with PVCs and more in those with sustained VT; also, the incidence of proarrhythmia is higher in patients with underlying heart disease. Encainide is also effective for the treatment of supra-ventricular arrhythmias, including atrial fibrillation, PSVT (both PAF as well as reentry of the nodal or W-P-W type), and ectopic atrial tachycardia. Its dosage and role in antiarrhythmic therapy are discussed.

Anilides↗
PubMed1988

Role of adrenergic stimulation by isoproterenol in reversal of effects of encainide in supraventricular tachycardia.

Reversal of the electrophysiologic effects of oral encainide with isoproterenol was evaluated in 16 patients with atrioventricular (AV) nodal reentry (group A) and in another 16 patients with Wolff-Parkinson-White syndrome (group B). Sustained AV nodal reentry was induced in all group A cases before administration of encainide, in 2 cases after oral encainide, and in 12 patients during infusion of isoproterenol. Among group B cases, 14 of 16 had sustained AV reentry during control, 6 of 16 after receiving encainide, and 8 of 16 with addition of isoproterenol. During a mean follow-up of 19 +/- 10 months in group A and 17 +/- 9 months in group B, clinical tachycardia recurred in 8 patients (4 from each group). These 8 patients were among the 20 patients who demonstrated (1) isoproterenol-induced reversibility of encainide-suppressed tachycardia, or (2) acceleration of tachycardia rate slowed by encainide. No recurrences were seen among any of the 12 cases in which isoproterenol failed to reverse the encainide-induced tachycardia suppression. Patients with clinical recurrences were controlled with a variety of means, which included beta blockers in 3 and nonpharmacologic methods in the remaining 5. In patients with AV junctional tachycardia treated with oral encainide, our findings suggest that lack of tachycardia inducibility with isoproterenol predicts freedom from clinical recurrences. Furthermore, addition of a beta blocker to oral encainide may prevent clinical recurrence in some who demonstrate adrenergic reversal of encainide effect.

Administration, Oral↗