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PubMed1992

[A comparison between amiodarone and disopyramide in a delayed-release formulation in the prevention of recurrences of symptomatic atrial fibrillation].

In order to compare the efficacy in preventing recurrencies of symptomatic atrial fibrillation of amiodarone (A.) and slow release disopyramide (D.RET.), 76 consecutive patients with recent onset atrial fibrillation (1 to 24 hrs.) were enrolled. In 20 (26%) conversion to sinus rhythm was obtained by electrical cardioversion, and in 56 (74%) by oral quinidine loading. Forty-one patients (group A) were assigned at random to treatment with D.RET. (250 mg twice daily) and 35 patients (group B) to amiodarone treatment (1200 mg daily for 10 days, and subsequently 200 mg daily). The two groups were similar as to age, sex and cardiac pathology. Patients were followed as to clinical condition, standard and dynamic ECG after one and three months and every three months subsequently for an average of 13.2 months (group A) and 14.1 months (group B). Six group A patients (14%) were excluded from follow-up on account of side effects which arose during the first week of treatment. Crises of symptomatic atrial fibrillation occurred in 20 patients of group A (57%) and in 11 (32%) group patients; this difference is statistically significant (p less than 0.05). Four (10%) group A patients stopped taking the drug due to side effects of an anticholinergic type, and three (8.5%) patients developed hyperthyroidism during follow-up. The authors therefore come to the conclusion that amiodarone is more effective than slow-release disopyramide in preventing recurrencies of atrial fibrillation; besides untoward side effects are less frequent with amiodarone.

Amiodarone↗
PubMed1991

Pharmacokinetics and optimum dose of disopyramide in patients with chronic renal failure.

The pharmacokinetics and optimum dose for maintenance of disopyramide (DP) which is effective against arrhythmia were studied in patients with chronic renal failure (CRF, n = 10), who had a creatinine clearance (Ccr) less than 30 ml/min. The plasma concentrations (PC) of DP and mono-isopropyl-disopyramide (MDP) an active metabolite of DP, were measured by high performance liquid chromatography. Samples from patients and controls were obtained at 0, 1, 2, 3, 4, 6, 8, 12, 24, 33, and 48 hr after oral administration (OA) of 100 mg DP. The pharmacokinetic parameters were calculated using a two-compartment model. In CRF, the plasma half life (T 1/2) of DP was 5.25 to 22.42 hr (average is 12.45 hr) and that of MDP was 5.09 to 131.66 hr (average is 16.9 hr). In normal controls, the T 1/2 of DP was 6.05 hr, but that of MDP could not be determined the available sensitivity of measurement. T max was 3.11 hr at the total PC of DP and MDP, and C max was 2.48 g/ml on average. In conclusion, the present study revealed that: (1) the PC of a mixture of DP and MDP should rise following OA of DP every 8 or 12 hr in CRF; (2) it is necessary therefore to monitor the accumulation of MDP after rolling OA of DP; and (3) OA of DP every 24 hr can maintain an effective PC.

Administration, Oral↗
PubMed1991

Disopyramide as a negative inotrope in obstructive cardiomyopathy in children.

Two children with left ventricular outflow tract obstruction due to myocardial hypertrophy received oral disopyramide as a negative inotrope. Both showed rapid improvement in clinical signs and by echo Doppler examination. Nearly complete abolition of severe left ventricular outflow tract obstruction was documented in each case. This experience may prompt further application of disopyramide as a therapeutic agent to relieve dynamic muscular subaortic obstruction in children.

Cardiomyopathy, Hypertrophic↗
PubMed1991

[Intake of disopyramide led to diagnosis of insulinoma].

A single dose of 250 mg disopyramide provoked severe hypoglycaemia and confusion in a 75-year-old woman. During subsequent investigation, fasting provoked symptomatic hypoglycaemia (venous blood glucose, 1.6 mumol/1) after 23 hours, plasma concentrations of insulin and C peptide then being 19 micrograms/ml and 0.85 pmol/l, respectively; computerised tomography and ultrasonography of the pancreas n.a.d. However, at laparotomy, a 10 mm diameter insulinoma was detected by intra-operative ultrasonography and palpation. The tumour was removed. To our knowledge, this is the first reported case of an insulinoma being detected due to intake of disopyramide.

Aged↗
PubMed1990

[Effect of amiodarone and disopyramide on the results of electrocardiographic exercise stress testing in patients with coronary disease].

The study was designed to assess the influences of antiarrhythmic therapy on exercise tolerance in patients with coronary artery disease and ventricular arrhythmias. Subjects for this study were subdivided into 3 groups: group I - 46 patients treated with amiodarone 1,200 mg daily during 10 days and 200-600 mg daily within next days, group II - 79 patients receiving disopyramide 300-600 mg daily, group III - 129 patients with combined administration of disopyramide 300-600 mg daily and propranolol 30-240 mg daily. propranolol 30-240 mg daily. Submaximal exercise stress testing was performed in each patient before treatment and after the medication for 4 weeks (group I) and for 2 weeks (groups II, III). The following parameters have been evaluated: maximal archived workload, maximal heart rate blood pressure response, double product (maximal heart rate x maximal systolic blood pressure), reasons for ending the test (target heart rate, typical angina, exhaustion, ST-segment depression greater than or equal to 2 mm, occurrence of ventricular arrhythmia, blood pressure greater than 250/120 mm Hg, significant drop in systolic pressure). Positive result of exercise ECG was defined: horizontal or down-sloping ST-segment depression greater than or equal to 1 mm and/or typical chest pain. The data from the first and second tests were estimated for significance of differences between the mean values with following results: 1) maximal achieved workload, 86 +/- 46 and 103 +/- 49 W (p less than 0.02) in group I; 101 +/- 64 and 106 +/- 50 W (NS) in group II; 107 +/- 55 and 119 +/- 54 W, W (p less than 0.01) in group III.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1990

[In vitro study, in perfused rabbit heart, of interaction between two anti-arrhythmia agents: amiodarone and disopyramide].

The influence of 15 day's amiodarone administration (30 mg/kg/day) on myocardial uptake kinetics and electrocardiographic changes of disopyramide was examined on the isolated perfused rabbit heart (n = 24) under electrical stimulation. Amiodarone significantly reduced myocardial uptake and potentialized the effect of disopyramide on intraventricular conduction.

Amiodarone↗
PubMed1990

Frequency and voltage-dependent effects of mono-N-dealkyldisopyramide, the major metabolite of disopyramide, in canine ventricular tissue.

Mono-N-dealkyldisopyramide (MND), the major metabolite of disopyramide, reaches significant concentrations in patients; however, the contribution of MND to the antiarrhythmic or toxic effects of disopyramide is not known. We assessed the kinetics and magnitude of interaction of MND with the sodium channel in canine ventricular tissue superfused in vitro using Vmax as an index of sodium channel block. At a basic cycle length of 1000 msec, MND (4-32 micrograms/ml) produced a concentration-dependent depression of both Vmax and amplitude of the action potential and accelerated all phases of repolarization in Purkinje fibers. To assess rate-dependent block, Purkinje fibers were stimulated with pulse trains at interstimulus intervals of 400 to 2000 msec. MND produced a concentration- and rate-dependent increase in the magnitude of rate-dependent block. There was also a concentration-dependent increase in the kinetics of onset of block (decrease in rate constant). The rate constant increased with faster stimulation rates. Minimal tonic block occurred at clinically relevant concentrations. Recovery from rate-dependent block followed a single exponential time course with time constants of 5.23 +/- 0.90 and 4.88 +/- 0.94 sec for Vmax and activation time, respectively. There was no shift of the normalized Vmax-membrane potential relationship except at the highest concentration, 32 micrograms/ml. At cycle lengths of 250 to 1000 msec, MND (4 micrograms/ml) shortened all phases of repolarization in Purkinje fibers, the greatest shortening occurring at the longest cycle length. Prolongation of effective refractory period occurred only at rapid heart rates. Both action potential duration and effective refractory period were prolonged in ventricular muscle which was independent of rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1987

The clinical scope of disopyramide seven years after introduction--an overview.

Disopyramide phosphate, seven years after its introduction, has proved to be a useful and effective Type IA oral agent for treatment of ventricular arrhythmias. The experience of these seven years has amplified and more sharply defined the initial efficiency and safety issues related to the use of the agent. This experience now shows that disopyramide is at least as effective as other agents in its class and that it can be used safely in the majority of patients for whom treatment is indicated if therapeutic guidelines are followed. The areas of effectiveness, comparative effectiveness, side effects and toxicity of this agent are summarized and guides to patient selection are presented in this review article.

Anti-Arrhythmia Agents↗
PubMed1979

Liquid chromatographic analysis of disopyramide and its mono-N-dealkylated metabolite.

We describe a rapid, sensitive, and specific "high performance" liquid chromatographic analysis for disopyramide and its mono-N-dealkylated metabolite in serum, urine, and saliva. We used a mu-Bondapak CN column and an acetate buffer mobile phase containing methanol. Retention times for the two compounds and the internal standard, p-chlorodisopyramide, were 3.4, 4.1, and 6.3 min, respectively. The lower limits of sensitivity for drug and metabolite were 50 and 80 micrograms/L, respectively, with maximum coefficients of variation of 4.6 and 12%, respectively. Currently used antiarrhythmic drugs did not interfere with the analysis of disopyramide, and the pharmacokinetics of the drug, obtained from studies of one subject, agree well with reported values.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Pharmacokinetics and steady-state myocardial uptake of disopyramide in the dog.

The pharmacokinetics and steady-state myocardial uptake of the antiarrhythmic drug disopyramide (DP) were determined in dogs after oral or intravenous administration of [14C]disopyramide phosphate. DP was absorbed rapidly and its absolute oral bioavailability was about 70%. Significant dose-dependent kinetics were not apparent after 7.5- to 30-mg/kg po doses. Plasma half-lives of DP were about 2.9 and 1.2 hr after the po and iv doses, respectively. DP and its N-dealkylated metabolites were largely excreted in the urine and their composition was qualitatively similar after the po and iv doses. Marked differences in the protein binding of DP in human and dog plasma were found. In the papillary muscle, ventricular septum, and ventricles of one dog, the steady-state concentrations of DP and its less active mono-N-dealkylated metabolite were about twice those in plasma, whereas in the atria and tricuspid and mitral valves they were similar to those in plasma.

Administration, Oral↗
PubMedDate not supplied

Stereoselective metabolism and pharmacokinetics of disopyramide enantiomers in humans.

Metabolism, pharmacokinetics, and influence of alpha 1-acid glycoprotein (alpha 1-AGP) plasma levels on protein binding of (R)-(-) and (S)-(+)-disopyramide (DP) were compared, in six healthy subjects, at the steady state, after oral administration of 100 mg twice daily. The mean unbound clearance of (R)-(-)-DP and (S)-(+)-DP were 8.59 and 14.9 ml/min/kg, respectively (p = 0.003). The mean unbound renal clearance of (R)-(-)-DP and (S)-(+)-DP were 6.26 and 8.75 ml/min/kg, respectively (p = 0.025). The nonrenal clearance, i.e. hepatic metabolic clearance, of (R)-(-)-DP and (S)-(+)-DP averaged 2.32 and 6.19 ml/min/kg, respectively (p = 0.002). The mean unbound volume of distribution of (R)-(-)- and (S)-(+)-DP were 225 and 381 liters, respectively (p = 0.023). The half-life of (R)-(-)-DP and (S)-(+)-DP averaged 4.17 and 3.91 hr, respectively (p = 0.21). The mean unbound renal clearance of (R)-(-)- and (S)-(+)-mono-N-dealkylated disopyramide (MND) were 3.21 and 7.02 ml/min/kg, respectively (p less than 0.001). The unbound fraction at steady state of (R)-(-)-DP and (S)-(+)-DP averaged 12.5 and 7.5%, respectively (p = 0.002). The unbound fraction at steady state of (R)-(-)-DP and (S)-(+)-MND averaged 62.6 and 60.5%, respectively (p = 0.36). The highest alpha 1-AGP plasma concentration resulted in lower unbound fraction for both DP and MND enantiomers, whereas the lowest alpha 1-AGP plasma concentration resulted in higher unbound fraction for (S)-(+)-DP only.

Adult↗
PubMed1987

Disopyramide-induced hypoglycaemia and increased serum insulin.

A patient treated with disopyramide presented with hypoglycaemia, a raised serum insulin level and died of pneumonia. From these findings and a review of 10 case reports, we propose that disopyramide causes hypoglycaemia by stimulation of insulin release as described for the antimalarial drugs quinine and quinidine.

Aged↗
PubMed1976

[Antiarrhythmic treatment of ventricular ectropic arrhythmies with Disopyramide].

Disopyramide (D.) is a new antiarrhythmic agent, which is not related chemically to any of the known substances. Animal experiments have shown a close similarity to quinidine action. Side effects are mainly due to anticholinergic effects. Pharmacokinetic studies with radioactive labelled D. have demonstrated that 80 per cent are elimated via the kidneys and 15 per cent through the gut. Gastrointestinal reabsorption in 90 per cent. We have studied the antiarrhythmic properties of D. in ventricular ectopic arrhythmias in twenty male patients. There were 13 myocardial infarctions, 5 cardiomyopathies, one severe oartic regurgitation with prosthetic valve replacement, one case with VPB of unknown aetiology. In ten cases the influence of D. on ventricular excitation threshold in implanted pacemakers was studied. The effects were correlated with Disopyramide-plasma levels. D. was effective in suppressing VPB. It was successful in 67 per cent, in 30 per cent the effect was unsatisfactory. Pacemaker-threshold remained unaltered. Side effects included constipation. Two deaths were observed. Their relationship to the adminstration of D. is not definitely proved. Nevertheless should the drug because of its negative inotropic action be employed with caution in cases with congestive heart failure.

Administration, Oral↗
PubMed1976

[The effect of disopyramide phosphate in extrasystole at rest and on exercise (author's transl)].

The antiarrhythmic action of disopyramide phosphate was compared to placebo in a randomized double blind trial at rest and under physical exertion in two groups each of 10 patients with extrasystoles. The exercise was carried out on the bicycle ergometer in a recumbent posture in stages of 25 watts at 2 minutes each without a break to the limit of the individual. The extrasystoles were counted at fixed registration periods. It was shown that the number of extrasystoles in the disopyramide group was significantly lower in comparison to the placebo group (P less than 0.05).

Adult↗
PubMedDate not supplied

Quantitative comparison of the anticholinergic and antiarrhytmic actions of disopyramide and quinidine.

With the purpose of estimating quantitative differences between disopyramide and quinidine two experimental series were designed. In order to establish the atropinic potency of both drugs, pA2 values were determined in rabbits right atria, using acetylcholine as agonist. The capacity to prevent ventricular fibrillation in albino mice subjected to chloroform apnea was also tested using various doses of the drugs. An effective median dose (ED50) to each of the drugs was calculated and the relative antiarrhythmic potency was compared. Disopyramide showed in both experimental series to be a more potent agent than quinidine.

Acetylcholine↗
PubMed1976

[Action of injected disopyramide on ventricular arrhythmias and atrioventricular conduction].

The authors have studied the bathmotropic and dromotropic effects of intravenous injection of 100 mg of disopyramide, the therapeutic dose being 1 to 2 mg/kg. Out of the 28 severe arrhythmias studied, it was the ventricular extrasystoles which benefited most from treatment (79% completely successful, while there was a lesser degree of success in treating the ventricular tachycardias (35% completely successful, 30% partially successful). The negative dromotropic effect of injected disopyramide on sub-nodal conduction was studied by an endocavitary technique in 10 patients presenting with a spontaneous onset of disordered intracardiac conduction; the effects were moderate. With the exception of 4 cases who sustained complications involving rhythm and haemodynamics, the clinical and cardiovascular tolerance of patients to the drug appeared to be satisfactory.

Aged↗
PubMedDate not supplied

Oral tocainide versus disopyramide: a double-blind, randomized, crossover study of outpatients with stable ventricular premature beats.

Oral tocainide and disopyramide were compared in a double-blind, crossover trial in 10 outpatients with stable ventricular premature beats (VPBs). Efficacy was assessed by suppression of VPB activity and reduction of VPB grade during an exercise test and an 18-h Holter recording. An estimate of variance of VPB activity was obtained from two separate placebo periods, and a 95% confidence limit for VPB suppression was calculated. During Holter recording, both drugs produced a significant reduction in VPB frequency and grade (p less than 0.05). During the exercise challenge, tocainide produced a reduction in VPB frequency and grade, but this did not reach statistical significance; VPB frequency was unaltered by disopyramide, but VPB grade was significantly reduced (p less than 0.01).

Adult↗
PubMed1983

Local anesthetic activity and disopyramide toxicity.

In the isolated frog sciatic nerve preparation, IC50 concentrations for nerve block were 0.34 +/- 0.9 mM for lidocaine (LIDO), 0.62 +/- 0.11 mM for procaine, 11.9 +/- 6.1 mM for disopyramide (DIP), and 52.8 +/- 24 mM for MIP (the mono-demethylated metabolite of DIP). In contrast to the LIDO block, DIP-induced nerve block was irreversible. DIP-induced depression of the electrically stimulated rat ventricular strip was completely reversed by washing the drug-free Tyrode's solution. In mice receiving 250 mg/kg DIP, neither convulsions nor death could be prevented by diazepam or other anticonvulsants. These results suggest that DIP has a very weak local anesthetic action which does not contribute significantly to disopyramide toxicity.

Action Potentials↗