Control of ventricular preexcitation and associated arrhythmias by encainide.
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Anilides↗
Biomedical subjects
D M Roden
Publications and source records attributed to D M Roden.
Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide.
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Adult↗
Recurrent ventricular tachycardia in the absence of overt heart disease: clinical characteristics and response to drug therapy.
Eight patients, seven of them women, have been followed up for a mean of 8.1 years (range, three to 18) with the uncommon syndrome of recurrent frequent episodes of ventricular tachycardia in the absence of overt cardiac abnormality. The mean age at diagnosis was 25 years (range, 12 to 44). Serious symptoms were common: five patients had syncope, cardiac arrest, and/or cerebrovascular accidents. Multiple measures to characterize this population, including study of symptoms, response to exercise, degree of prematurity of ventricular ectopic depolarizations, and response to antiarrhythmic drugs, showed little uniformity. An individualized approach to therapy, taking into account age and symptoms as well as frequency of arrhythmia, was used. Excellent control of arrhythmia was eventually achieved in four patients, but only after multiple drug trials (mean 5.3, range two to eight trials per patient) had been ineffective. Prognosis in this syndrome is generally good, but serious complications occur frequently enough that vigorous therapy is justified in selected patients.
Adolescent↗
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↗
Tocainide therapy for refractory ventricular arrhythmias.
Tocainide, a congener of lidocaine, was used to treat symptomatic ventricular arrhythmias in 19 patients resistant to or unable to tolerate conventional agents. In this highly selected group, 15 showed good initial responses to oral therapy. Ventricular tachycardia was suppressed to a greater extent than isolated ventricular ectopic depolarizations at any plasma concentration, and upward dose-ranging showed progressive suppression of both. Arrhythmia responsiveness to lidocaine was found to be an excellent predictor of tocainide response. Of the 15 responders, one died 24 hours after stopping therapy, three died while receiving tocainide, nine stopped because of adverse reactions (five allergic), and two continue on therapy at 1 and 4 years. We conclude that tocainide is an effective agent for the short-term suppression of ventricular arrhythmias, particularly ventricular tachycardia sensitive to lidocaine, but a high incidence of adverse effects limits its application to chronic therapy in many patients.
Adult↗
Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide.
The antiarrhythmic efficacy and pharmacokinetics of N-acetylprocainamide (NAPA), the major metabolite of procainamide, were investigated in 23 patients with chronic, high frequency ventricular ectopic depolarizations. An extensive trial design incorporated the approaches of (1) generation of dose-response relations, (2) randomized crossover, and (3) prolonged electrocardiographic monitoring. Seven patients with reproducible suppression of arrhythmias (70 percent or greater reduction in frequency) were thus identified. The mean plasma concentration of acecainide associated with efficacy was 14.3 micrograms/ml (range 9.4 to 19.5) and with side effects (primarily gastrointestinal) was 22.5 micrograms/ml (10.6 to 37.9). The antiarrhythmic response to procainamide did not predict response to acecainide; this finding implies that estimates of the antiarrhythmic contribution of acecainide concentrations achieved during long-term procainamide therapy are unlikely to be meaningful in a given person. The mean half-life of elimination after a single 500 mg dose of acecainide was 7.5 hours; this had prolonged significantly (p < 0.05) to 10.3 hours after higher dosages. No variable examined (including acetylator phenotype) was found to be a predictor of responsiveness to acecainide. Outpatient therapy (2 to 20 months) was not associated with the development of antinculear antibodies or the lupus syndrome; one patient's procainamide-induced arthritis resolved during therapy. Acecainide, unlike procainamide, is an agent whose pharmacokinetics allow long-term therapy on a practical schedule. It is effective in a subset of patients with ventricular arrhythmias yet appears much less likely to induce the lupus syndrome seen with the parent compound.
Acecainide↗
A prolonged QTc interval. Is it an important effect of antiarrhythmic drugs?
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Adult↗
Electrophysiology of O-demethyl encainide in a canine model of sustained ventricular tachycardia.
The antiarrhythmic agent encainide produces marked suppression of ventricular arrhythmias in most patients. However, in some with sustained ventricular tachycardia, worsening of clinical arrhythmias can occur. Since the effects of this agent are mediated by its O-demethyl metabolite in most patients, we have evaluated the effects of O-demethyl encainide in dogs susceptible to the induction of ventricular tachycardia. Nonsedated animals were studied 3-5 days after 90-min left anterior descending coronary artery occlusions. Electrophysiologic evaluations were carried out at baseline, and then during a series of infusions of O-demethyl encainide that achieved low (58 +/- 5 ng/ml) (mean +/- SE), moderate (190 +/- 16 ng/ml), and high (758 +/- 98 ng/ml) plasma concentrations compared with the range seen in patients (50-300 ng/ml). Ventricular tachycardia induction was unaffected by the drug. Effective refractory period was prolonged in a dose-related fashion at both normal and infarcted epicardial sites. However, local electrogram duration was prolonged only in the infarcted zone. We conclude that O-demethyl encainide exerted no consistent effect on susceptibility to induction of ventricular tachycardia in this study. This agent appears to alter infarcted zone conduction disproportionately.
Anilides↗
The antiarrhythmic activity of meobentine sulfate in man.
Meobentine (sulfate) has antifibrillatory and antiarrhythmic activity in canine models. The antiarrhythmic, pharmacokinetic, and adrenergic neuronal blocking effects of meobentine were assessed in 15 patients with chronic, high-frequency ventricular ectopic depolarizations (VEDs). Eleven of the 15 patients had recurrent nonsustained ventricular tachycardia. The patients were given a series of gradually increasing single doses of meobentine; six received oral meobentine and nine had infusions. The antiarrhythmic efficacy of meobentine was assessed by a comparison of arrhythmia frequency during placebo given on days just prior to meobentine. Oral therapy with meobentine at dosages above 20 mg/kg caused diarrhea, and well-tolerated dosages achieved peak concentrations of 0.69 micrograms/ml (range 0.5-1.0 micrograms/ml). Antiarrhythmic activity was seen in only one patient with oral meobentine. In contrast, intravenous infusions (6.75-34.2 mg/kg) achieved concentrations ranging from 1.3-9.8 micrograms/ml. There was a linear relationship between pseudo-steady-state plasma concentrations and dosage, r = 0.82, p less than 0.01. Antiarrhythmic activity was seen in four of nine patients who received intravenous meobentine over a range of concentrations from 2.5-4.5 micrograms/ml. Four patients developed evidence of adrenergic neuronal blockage (loss of the venous reflex response); two at dosages of 16.2 mg/kg, one at 24.3 mg/kg, and one at 34.2 mg/kg. In one individual (24.3 mg/kg), the adrenergic neuronal blockade was associated with an acute episode of shortness of breath, orthopnea, and cough. With intravenous meobentine, there was a linear relationship between dosage and AUC, and the elimination half-life ranged from 11-27 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Electropharmacologic synergism with mexiletine and quinidine.
We have previously shown that combination therapy with mexiletine and quinidine is more effective and causes fewer side effects than either agent alone in the treatment of patients with serious ventricular arrhythmias. To further assess this enhanced antiarrhythmic effect, the electrophysiologic actions of mexiletine and quinidine alone and in combination were evaluated in isolated perfused rabbit hearts. Dose-response curves were constructed for right ventricular effective refractory period, epicardial monophasic action potential duration, and conduction time (the time from pacing stimulus to the upstroke of the monophasic action potential signals) during constant rate pacing. No significant changes in these parameters were seen in 15 preparations treated with saline over a duration of 1 h (a time equal to the longest experiments). With gradually increasing concentrations of mexiletine (2.3-36 microM) prolongation of conduction time (12 +/- 5 msec, mean +/- SE, p less than 0.05) paralleled change in ventricular refractoriness (20 +/- 5 msec, mean +/- SE, p less than 0.05) but occurred in the absence of any significant change in monophasic action potential duration. With gradually increasing concentrations of quinidine (0.55-34 microM/L) prolongation of ventricular refractoriness (65 +/- 7 msec, mean +/- SE, p less than 0.01) and monophasic action potential duration (65 +/- 7 msec, mean +/- SE, p less than 0.01) occurred in parallel and at concentrations less than those required to prolong conduction time.(ABSTRACT TRUNCATED AT 250 WORDS)
Action Potentials↗
Delayed activation and retrograde propagation in cardiac muscle: implication of virtual electrode effects.
Point cathodal stimulation of cardiac tissue was shown previously to produce both a dog-bone shaped virtual cathode transverse to the muscle fibers and two longitudinal virtual anodes. We hypothesize that virtual anodes can cause a region of delayed activation, separating two regions of early activation caused by the virtual cathode. Using a high-density electrode array in 42 superfused epicardial slices from 14 canine left ventricles, we observed regions of early and delayed activation and different pathways of retrograde propagation corresponding to the earlier patterns. Retrograde propagation was seen from the transversely located early activation area through areas of delayed activation toward the cathode, and from the early activation area toward the cathode directly. These pathways caused a wide dispersion in the direction of retrograde propagation (2 degrees +/- 31 degrees, n = 179, relative to the fast axis of threshold activation; radial velocity: 0.5 +/- 0.2 m/s, n = 95, in 12 slices from 8 hearts with stimuli of 330 micros, 0.8-30 mA). Delayed activations were observed 0 degrees +/- 6 degrees (n = 32) from the axis in 23 maps (at differing stimulation strengths) recorded in 13 slices from 10 hearts. We conclude that point cathodal stimulation induce delayed activation along the fiber axis and retrograde propagation both along and transverse to the axis.
Animals↗