Stots B. Reele

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.

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 patients 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.

Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam.

The pharmacokinetics and pharmacodynamics of midazolam and diazepam were compared after intravenous infusions of 0.03 and 0.07 mg/kg midazolam and 0.1 and 0.2 mg/kg diazepam on four separate occasions in 12 healthy male subjects in a randomized four‐way crossover design. The Digit Symbol Substitution Test (DSST) was used as a measure of drug effect. Subjects performed three practice tests before dosing to account for any effects caused by familiarization (“learning curve”) with the testing procedure. Pharmacokinetic and pharmacodynamic data were simultaneously fitted to a semiparametric model. In this model, a pharmacokinetic model related dose to plasma concentrations, a link model related plasma concentrations to the concentration at the effect site, and a pharmacodynamic model related the effect site concentration to the observed effect. The plasma—effect site equilibrium half‐life was approximately 2½ times longer for midazolam than for diazepam, which is in good agreement with previously published data. Based on the estimated effect site concentration at which half of the maximal effect was reached, midazolam had approximately a sixfold greater intrinsic potency than diazepam. This difference in potency was also observed in a previous study that used transformed electroencephalographic (EEG) data to assess pharmacodynamic activity. The findings reported here with a clinically relevant pharmacodynamic marker (DSST) confirm the utility of surrogate drug effect measures such as EEG. This work also shows the feasibility of conducting pharmacokinetic pharmacodynamic analysis during the drug development process.

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.

Pharmacologic reversal of hypotensive effect complicating antiarrhythmic therapy with bretylium.

The value of bretylium for long‐term therapy of arrhythmias is slight because of the almost universal development of orthostatic hypotension induced by adrenergic neuron blockade. Blockade of neurotransmission by bretylium depends on its uptake into adrenergic neurons by the norepinephrine pump. The effects of inhibiting the pump with protriptyline were evaluated in five patients with ventricular tachycardia (VT) resistant to conventional therapy but responsive to bretylium. Adrenergic blockade was assessed by measuring the venous reflex response (VRR) and change in blood pressure on standing. Before bretylium, VRR was present and standing blood pressure was normal. The patients received intravenous bretylium in increasing doses until VT was suppressed, at which time the VRR was blocked and all patients were bedridden due to orthostatic hypotension. The dosage of bretylium was tapered as oral treatment was begun and the dosage gradually increased to maintain VT suppression. Protriptyline was then given orally in slowly increasing doses in an attempt to reverse intolerable orthostatic hypotension. Five to 7 days later the VRR was restored and the blood pressure in the standing position returned toward normal, enabling the patients to become ambulatory. In these patients the antiarrhythmic efficacy of bretylium was not altered by protriptyline and was therefore not dependent on adrenergic neuron blockade. As bretylium was withdrawn and protriptyline continued, recurrence of arrhythmia established that protriptyline did not contribute to bretyliums antiarrhythmic efficacy. These findings do not, however, constitute sufficient evidence to support the routine application of this approach to therapy. Rather, it provides a pharmacologic rationale for more extensive evaluation of the safety and efficacy of the combination. The demonstration of dissociation between the antiarrhythmic and adrenergic effects of bretylium in man suggests that structural modification of the molecule might yield an antiarrhythmic drug free of undesirable effects on the adrenergic nervous system.

Effects of concentration and steric configuration of propranolol on AV conduction and ventricular repolarization in the dog.

Summary To investigate the electrophysiological effects of propranolol in vivo over a wide range of plasma concentrations and to distinguish effects due to β-blockade from those due to a direct membrane action, His bundle electrograms were recorded, and ventricular effective refractory periods (VERP) and monophasic action potential duration (MAP) were measured in anesthetized control dogs and in dogs given three graded infusions of d- or dl- propranolol. Dogs were excluded if the plasma concentrations attained did not fall in predefined ranges of 25–125, 125–700, and 700–3,000 ng/ml. Isoproterenol sensitivity tests were performed to determine the relative β-blocking potency of the isomers at the three concentration ranges. The highest concentration of β-propranolol had approximately the same β-blocking potency as the lowest concentration of dl-propranolol. Mean AH and HV intervals in the His bundle electrogram increased with the concentration of dl-propranolol, and the increase was greater than with β-propranolol (p < 0.03) at the first and second concentration steps but not significantly different at the highest concentrations of d- and dl-propranolol. VERP and MAP increased directly with concentration of d- and dl-propranolol. Although the mean increases of VERP and MAP tended to be greater in the dl-propranolol group, the differences between d- and dl-propranolol were not statistically significant at any concentration. We conclude that prolongations of atrioventricular and His-Purkinje conduction are stereospecific responses and are due to β-blockade. The specific mechanism for the prolongation of ventricular repolarization and refractoriness are effects of propranolol that could not be definitively classified in this study.

Publishing Summary Basis of Approval

Clinical Pharmacology & Therapeutics (1996) 60, 357–357; doi:

Antiarrhythmic effects of the quaternary propranolol analog that does not induce beta-adrenergic blockade

Pranolium chloride (dimethylpropranolol chloride) is a nonbeta blocking quaternary ammonium that has structural similarities to propranolol and bretylium that exerts antiarrhythmic effects in animals. In initial studies, eight patients with chronic ventricular arrhythmias were given gradually increasing intravenous doses of pranolium (up to 3 mg/kg) obtaining plasma concentrations up to 7 μg/ml without change in pulse, blood pressure, or arrhythmia frequency. We therefore evaluated the response to pranolium in seven similar patients at doses up to 10 mg/kg as an infusion of 100 μg/kg/min over 40 to 100 min. At plasma concentrations of 4.7 to 12.2 μg/ml, there was suppression of ventricular ectopic depolarizations (>90%) in three subjects and in two others there was partial suppression (49% and 82%). Arrhythmia frequency was unchanged in two. At plasma concentrations of 4.1 to 17.2 μg/ml four subjects developed nausea (two of these also vomited) and two experienced perioral numbness. There was no change in sinus heart rate, supine or standing blood pressure, venous reflex response (adrenergic reflex venoconstriction), or ECG intervals in any subject. Pranolium appeared to have antiarrhythmic efficacy in five of seven subjects, without evidence of beta‐adrenergic blockade or interference with sympathetic neuron function known to occur with its congeners, propranolol and bretylium. There is a narrow margin between pranolium efficacy and toxicity. It may, however, be a prototype for antiarrhythmic drugs that do not exert undesirable effects on the adrenergic nervous system.