Ventricular Ectopic Depolarizations Research Articles

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 /gm/ml (range 9.4 to 19.5) and with side effects (primarlly gastrointestinal) was 22.5 μg/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 antinuclear 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.

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.

Suppression of chronic ventricular arrhythmias with propranolol.

The antiarrhythmic efficacy of propranolol was evaluated in 32 patients with chronic high frequency ventricular arrhythmias in a placebo-controlled protocol. After a placebo control period, propranolol was begun and the dosage increased sequentially until arrhythmia suppression was achieved, side effects appeared, or a maximum dosage of 960 mg/day was reached. Computerized analysis of ambulatory recordings was used to quantify the arrhythmias. Twenty-four patients had 70--100% arrhythmia suppression at plasma levels ranging from 12--1100 ng/ml (end of dosing interval). Eight patients in this group had frequent episodes of ventricular tachycardia that were totally suppressed at or below the dosage that produced greater than or equal to 70% suppression of ventricular ectopic depolarizations (VEDs). A biphasic dose-response curve was seen in five patients who responded with a decrease in arrhythmia frequency in the lower ranges of dosages but had increased frequency of ectopic rhythms as the dosage was increased above the optimal level. Only one-third of patients responded at doses less than or equal to 160 mg/day. However, with dosages of 200--640 mg/day, an additional 40% responded. Propranolol appears to control ventricular arrhythmias safely and effectively in many patients. The finding that the antiarrhythmic effect in many patients required plasma concentrations greater than those that produce substantial beta-adrenergic blockage raises a question whether blockade of cardiac beta receptors can directly account for all of the antiarrhythmic actions of propranolol.

Antiarrhythmic drug therapy in survivors of prehospital cardiac arrest: comparison of effects on chronic ventricular arrhythmias and recurrent cardiac arrest.

We studied the long-term effects of membrane-active antiarrhythmic agents on chronic ventricular arrhythmias in patients who have survived prehospital cardiac arrest. Among 16 patients treated with a dose-adjusted, plasma level-monitored antiarrhythmic regimen, eight have survived for longer than 12 months and eight have had recurrent cardiac arrests (RCAs). Monthly Holter monitor tapes (HM) recorded during the 4 months before the eight RCAs were compared with monthly HM tapes matched for time of entry and duration of follow-up in the eight patients who did not have RCAs. Transient or persistent complex ventricular ectopic depolarizations (VEDs) have been recorded on 47 of the 63 monthly HM tapes (75%). The difference between VEDs in the RCA patients (mean 153 VEDs/hr, median 19 VEDs/hr) and VEDs in the patients who have not had RCA (mean 122 VEDs/hr, median 8 VEDs/hr) was not significant (p less than 0.2); nor was there a predictable relationship between therapeutic plasma levels of antiarrhythmic agents and the frequency and complexity of chronic asymptomatic VEDs (therapeutic levels--mean 104 VEDs/hr, median 6 VEDs/hr; subtherapeutic levels--mean 184 VEDs/hr, median 21 VEDs/hr). Differences were not significant (p greater than 0.1). In contrast, all eight RCA patients had unstable plasma levels (21 of 31 determinations subtherapeutic) while six of the eight patients who have not had RCA had consistently therapeutic levels (p less than 0.01). Thus, adequate plasma levels of antiarrhythmic agents may protect against RCA, despite failure to suppress VEDs predictably. The apparent dissociation between predictable suppression of chronic VEDs and protection against RCA suggests that clinical effectiveness of these agents may not be best measured by their effect on chronic VEDs.

Suppression of ventricular ectopic depolarizations by tocainide.

In a previous clinical study we demonstrated that tocainide is effective in the suppression of ventricular ectopic depolarizations (VEDs) after single oral doses. This information provided the basis for evaluating this drug's antiarrhythmic efficacy after multiple dose administration according to a loading-maintenance regimen. Twelve patients with stable VEDs were given loading doses of tocainide (400-600 mg) with maintenance doses every 12 hours. Every 48 hours the dose was increased until either arrhythmia suppression to less than 25% of VED frequency during placebo administration or side effects occurred. Computer analysis of 12-hr telemetric ECGs taken 24-36 hr after each dosage increment documented effective suppression (76-95%) in 8 of 12 patients. Those subjects demonstrating suppression were randomly assigned to a cross-over study of placebo or active drug at the dosage found effective in the dose-ranging phase. Dosages for the cross-over stage ranged from 400 to 1100 mg every 12 hours. Comparison of the two five-day periods documented suppression in these patients (mean +/- SE = 83.3 +/- 4%). No serious side effects or undue drug accumulation occurred during the study. The data indicate that tocainide can effectively suppress VEDs for 8-12 hours in many patients and that continuous suppression could be possible on an 8-12 hr dosage regimen.

Evaluation of arrhythmias in the late hospital phase of acute myocardial infarction compared to coronary care unit ectopy.

To evaluate the prevalence and nature of arrhythmias during the entire three-week period in hospital after myocardial infarction, the results of coronary care unit monitoring (initial 3 to 5 days) were compared with continuous 8-hour portable monitoring during the ambulatory phase (second and third weeks) in 83 consecutive survivors. Arrhythmias were detected in 84.3 per cent (70/83) of patients while in the coronary care unit and in 85.5 per cent (71/83) during hospital stay after the coronary care unit. Ventricular ectopic depolarizations were classified as complicated (multifocal, paired, R on T, or five or more a minute) or uncomplicated. Importantly, the high frequency of complicated ventricular extrasystoles and tachycardia persisted during the entire period in hospital (early 34.9% and late 42.5% of all patients). However, only 16.9 per cent (14/83)had these ventricular arrhythmias during both coronary care unit and ward monitoring. Thus, the absence of complicated ventricular ectopic depolarization and ventricular tachycardia in the coronary care unit did not exclude their subsequent occurrence in the majority of the large number of patients with late hospital complicated ventricular ectopy.