The bioavailability of two slow release preparations of disopyramide has been compared in a randomized cross-over trial of Rythmodan L.A. 250 mg b.d. and Dirytmin Durettes 300 mg b.d., given to 10 healthy volunteers. The plasma concentrations of disopyramide were measured on the 5th day of each treatment period. With both preparations, plasma concentrations were well sustained. The amount absorbed was slightly lower after Rythmodan L.A. than after Dirytmin Durettes, but the fluctuations over a dosing interval were significantly more pronounced for Dirytmin Durettes than for Rythmodan L.A.

Eight healthy male volunteers took a single oral dose of one of the following: Rythmodan (conventionally formulated disopyramide) 150 mg; Rythmodan 250 mg; Rythmodan Retard (controlled-release disopyramide) 250 mg; placebo. The subjects were allocated double-blind to sessions and treatments according to a Latin square design. In each session pupil diameter, heart rate, salivation, and QT interval were measured immediately before and at 1, 2, 3, 4, 6, 8, and 24 h after the drug. QT interval was corrected for heart rate (QT60). Plasma concentrations of total and unbound disopyramide were also determined at each time point. Both formulations of disopyramide reduced salivary output and increased QT60 interval, but there was not significant difference between the effects of the three active treatments. Neither formulation had any effect on pupil diameter or heart rate. The peak plasma concentration of unbound disopyramide was reached 2 h after Rythmodan and 4 h after Rythmodan Retard. The peak plasma concentration of disopyramide was significantly lower after Rythmodan Retard 250 mg than after Rythmodan 250 mg. The plasma concentration of unbound disopyramide was positively correlated with the reduction in salivation and prolongation of the QT60 interval. The reduction in salivation is likely to reflect blockade of muscarinic receptors by disopyramide, whereas the increase in QT60 interval is likely to be related to a direct effect of the drug on the heart. The results of this single-dose study do not indicate that disopyramide in the controlled-release formulation would be better tolerated by patients than conventionally formulated disopyramide.

A multi-centre double-blind randomized study is reported in which the effect on mortality of oral disopyramide (300 mg loading dose, then 100 mg qds) was compared with placebo in 1985 patients entering hospital with suspected acute myocardial infarction. Treatment was commenced with 24 hr of onset of symptoms (mean time to first dose 9 hr) and continued until discharge from hospital or 14 days, whichever came first. Nine-hundred and ninety-five patients were allocated to disopyramide and 990 to placebo. The overall mortality, calculated on an intention-to-treat basis, was 7.2% for the disopyramide and 5.6% for the placebo patients. Among those patients with proven infarction mortality was 9.5% of 687 on disopyramide and 7.4% of 716 on placebo. These differences are not statistically significant. Patients with cardiac failure or hypotension at entry did not fare worse on disopyramide, but those with a conduction defect did. Reinfarction was not significantly influenced by disopyramide. The prophylactic use of disopyramide in patients with suspected acute myocardial infarction does not reduce mortality or the incidence of early reinfarction.

The authors had 75 patients with myocardial infarction under observation. After the 15th day of the disease various disorders of cardiac rhythm and conductivity were revealed in 85% of patients during cardiomonitor surveillance. The most frequent occurrences were ventricular extrasystole (72.5%), sinus bradycardia (40%) and atrial extrasystole (37.5%). Primary ventricular fibrillation was noted in 4 (5.3%) patients two of whom were resuscitated. In 50 patients with myocardial infarction of more than one month duration disorders of cardiac rhythm during physical load were studied (dosed walking under telectrocardiographic control and/or on a treadmill). During dosed waling 28% of patients developed arrhythmia or it was intensified (sinus tachycardia was not taken into account). During a load on a treadmill such changes were encountered in 30% of patients. A favourable effect of treatment with cordarone was produced in most patients with ventricular extrasystole some of whom were resistant to lidocain treatment. A good effect was produced in some patients by means of the pulsnorma or rythmodan. Beta-adrenergic blocking agents as well as cordaron and isoptin were effective in atrial extrasystole and sinus tachycardia. Hyperbaric oxygenation was used in 14 patients with disorders of rhythm. Disappearance of arrhythmia or considerable improvement was registered in 11 patients after treatment consisting of 10-12 procedures.

1 The haemodynamic and electrocardiographic effects of intravenous disopyramide were studied in fifteen patients with acute myocardial infarction. 2 Five minutes after drug injection a rise in heart rate, aortic mean and diastolic pressures and systemic vascular resistence was noted which persisted for at least 30 min. A small increase in pulmonary arterial diastolic pressure (mean = 1.5 mm Hg) occurred at 5 min only and no significant change of cardiac output was found throughout the period of the study (1 h). 3 Surface electrocardiograms revealed transient prolongation of the P-R interval and a sustained increase in the QTc interval. 4 The haemodynamic changes suggest an anticholinergic effect of the drug. There was no definite evidence of a negative inotropic effect in this study, however, these peripheral haemodynamic measurements might not have revealed a modest negative inotropic effect. 5 The electrocardiographic changes are similar to those previously reported in normals and in patients without acute myocardial infarction.

1 Serum, urine and pharmacologic effect (prolongation of the QT interval) kinetics of the antiarrhythmic disopyramide have been investigated in eight volunteers after intravenous administration (2 mg/kg) and oral administration (300 mg) of the two commercially available preparations, Rythmodan (Roussel Laboratories) and Norpace (Searle Laboratories). 2 An open one compartment body model adequately described the kinetics of disopyramide in serum and urine. 3 After intravenous administration, the following average pharmacokinetic parameters were found: biological half-life, 7.8 h; total clearance, 95 ml/min; renal clearance, 54 ml/min; apparent volume of distribution, 60 litres. 4 After oral Rythmodan and Norpace, serum concentration profiles and urinary excretion data revealed significant differences in rates of absorption, times required to achieve peak serum concentrations and biological half-lives. These differences were largely due to the relatively slow absorption characteristics of Norpace. 5 The absence of hysteresis in plots of QT prolongation against disopyramide serum concentration after oral administration indicated that serum and pharmacologic effect kinetics were indistinguishable within a kinetically equivalent compartment. 6 Analysis of both serum and urine data showed that while Norpace had a significantly higher degree of bioavailability (P less than 0.005), the 5--15% difference between the two formulations should not normally be of any clinical significance.