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PubMed1982

Comparison of the efficacy of propafenone versus disopyramide for complex premature ventricular contractions. Evaluation with long-term monitoring.

Interpreting the results of this study, propafenone (Rytmonorm), administered orally in a dose of 900 mg daily, was more effective than disopyramide in a dose of 600 mg daily, in the treatment of patients with complex premature ventricular contractions (PVCs). The study was performed in 12 patients, with several Holter ECG monitorings to obtain quantitative data of the effectiveness in the same patient of the new drug propafenone in comparison with disopyramide in a documented effective oral regimen. A quantitative analysis of PVCs was obtained with a computer assisted detection. Clinical effectiveness, considered as 70--80% reduction of total number of PVCs, was obtained in 8/12 patients for propafenone and 6/12 for disopyramide, or as 50% reduction with suppression of all complex PVCs (couplets, repetitive, multiform and bigeminy) was obtained in 11/12 for propafenone and 9/12 for disopyramide.

Adolescent↗
PubMed1981

Relative absorption of disopyramide as determined by liquid chromatography following acute administration of standard capsules and controlled-release tablets.

The absorption of disopyramide has been studied in healthy volunteers following an acute dose of 300 mg in standard capsules (C) and three controlled-release (CR) tablets with different in vitro release rates. Plasma concentrations and the urinary excretion of unchanged compound and its main metabolite, N-deisopropyldisopyramide, were determined simultaneously by using a rapid and sensitive method based on liquid-solid chromatography. The rate of absorption was rapid following C, and maximal concentrations were reached within 1.5-2 h. A CR formulation produced a slower rate of absorption and the rate correlated with the drug in vitro release rate. The maximal concentration of disopyramide was reduced following CR tablets. The extent of absorption was the same following C and two of the CR formulations, whereas the CR composition with the slowest in vitro release rate presented a somewhat reduced extent of absorption. About 70% of the given dose was recovered in urine as disopyramide (50%) and metabolite (20%). The elimination half-life of disopyramide and N-deisopropyldisopyramide was close to 4 and 7 h, respectively.

Absorption↗
PubMed1980

[Therapy of ventricular tachyarrhythmia with disopyramid phosphate].

A controlled multicenter study has been carried out in 46 patients with ventricular tachyarrhythmias to define the antiarrhythmic effect of disopyramide phosphate. Monitoring of cardiac rhythm was performed during the whole study period by ambulatory Holter recording. The daily dose of disopyramide was 600 mg. It was found that disopyramide caused a reduction of at least 80% in the number of premature ventricular beats in 72% of the patients. Episodes of ventricular tachycardia were effectively suppressed in 65% of the patients. In 24 patients there was a reduction in the severity of the observed ventricular arrhythmias of at least one class in the classification of Lown. Analysis of the results showed a relationship between the antiarrhythmic effect and group mean plasma concentration of disopyramide.

Adult↗
PubMedDate not supplied

Disposition kinetics of disopyramide in patients with renal insufficiency.

The pharmacokinetics of an intravenous injection of disopyramide was studied in five normal subjects and six patients with varying degrees of renal impairment. The elimination rate constant (beta) was related to the endogenous creatinine clearance (Clcr). However, a decrease in beta was not observed until the Clcr was reduced below 40 ml min-1. Below 40 ml min-1 a linear relationship existed between beta and Clcr. Similarly, the plasma elimination half-life (t 1/2 beta) showed a significant increase when the Clcr was less than 30 ml min-1. Hence, dosage modification for disopyramide is necessary only when renal function is severely impaired. Overall, the apparent volume of distribution in patients with renal insufficiency was reduced to two-thirds of that in normal subjects. Therefore, in patients with Clcr less than 40 ml min-1 both the loading and maintenance dose of disopyramide should be reduced.

Arrhythmias, Cardiac↗
PubMed1991

Disopyramide analysis using REMEDi: comparison with EMIT and conventional high performance liquid chromatographic methods.

REMEDi (Rapid EMErgency Drug identification; Bio-Rad) is an automated high performance liquid chromatographic (HPLC) system designed to detect, identify and measure a range of basic and neutral drugs in 0.5-1.0 mL of urine or plasma/serum. We have evaluated REMEDi in the analysis of the antiarrhythmic drug disopyramide in patient samples. The specimens were also analysed by a conventional HPLC method, based on solvent extraction and UV detection (254 nm), and by EMIT. There were good correlations between the results obtained with each method (r = 0.91 or greater). REMEDi gave a lower mean result than EMIT [means +/- SD (mg/L): REMEDi 2.64 +/- 1.10, EMIT 3.14 +/- 1.51; t = 4.0, p less than 0.01; n = 25], but there were no other significant differences in mean results. The principal disopyramide metabolite, mono-N-desalkyldisopyramide, did not interfere in any method. Clearly REMEDi can be used for therapeutic drug monitoring of disopyramide provided enough sample is available.

Autoanalysis↗
PubMed1981

Hemodynamic effects of disopyramide at rest and during exercise in normal subjects.

The hemodynamic effects of disopyramide phosphate, 2.0 mg/kg body weight, given intravenously over a period of five minutes were studied at rest and during exercise in ten patients without clinical or angiographic evidence of heart disease. Following disopyramide, the resting cardiac index was lower (4.0 +/- 0.6 vs 4.3 +/- 0.6 liters/min/m2, mean +/- 1 SD,P less than 0.05), while left ventricular end-diastolic pressure (16 +/- 4 vs 11 +/- 4 mm Hg, P less than 0.001), pulmonary arterial (PA) mean pressure (20 +/- 5 vs 17 +/- 5 mm Hg, P less than 0.05), and brachial arterial (BA) mean pressure (105 +/- 8 vs 96 +/- 7 mm Hg, P less than 0.05), were higher than the pre-infusion resting values. During exercise, there was no change in left ventricular end-diastolic pressure while cardiac index rose from 4.0 +/- 0.6 to 6.5 +/- 0.6 liters/min/m2 (P less than 0.001) and left ventricular stroke work index increased from 62 +/- 19 to 84 +/- 22 gm/beat/m2 (P less than 0.001). The normal hemodynamic response during exercise after disopyramide despite the apparent depression of left ventricular function at rest probably reflects the positive inotropic effect of enhanced sympathoadrenergic activity.

Adult↗
PubMed1982

Investigation of digoxin, quinidine, and disopyramide interactions in rats utilizing parotid saliva, blood, and other tissues.

Blood, parotid saliva, heart, liver, and kidney concentrations of digoxin and quinidine were determined in rats chronically treated with digoxin and in nontreated (control) rats after the administration of quinidine (20 mg/kg ip) and disopyramide (10 mg/kg ip). The results indicated that digoxin concentrations increased significantly and proportionally in parotid saliva and plasma after quinidine, but did not increase after disopyramide. With the exception of the liver, which showed an increase in digoxin concentrations, tissue concentrations of digoxin did not differ from control animals. In rats pretreated chronically with digoxin, quinidine concentrations in plasma, parotid saliva, or heart tissue did not differ significantly from control animals, but were significantly lower than controls in liver and kidney tissues. The results presented here lend additional support to the hypothesis that the increase in digoxin plasma concentration following quinidine administration is primarily due to interference with renal excretion and displacement of digoxin by quinidine binding sites. Furthermore, its was demonstrated that disopyramide has little or no effect on plasma digoxin levels in rats.

Animals↗
PubMed1985

Pharmacologically active conformation of disopyramide: evidence from apparent pKa measurements.

We have found evidence that an intramolecular hydrogen bond exists between the amido and pyridine groups of disopyramide in aqueous solutions. This conclusion was reached by a comparison of the pKa values for the basic nitrogen atoms of certain analogues of disopyramide. By comparing the pharmacological actions of disopyramide with those of pheniramine, which lacks an amido group, we have concluded that the constraint on the rotation of the pyridine ring which is imposed by the hydrogen bond is a major determinant of the antiarrhythmic activity. That constraint is, at the same time, a suppressor of the anticholinergic activity. We then concluded that a covalent link would hold the pyridine ring, and the amido group, in the desirable conformation permanently, which would lead to better antiarrhythmic activity and a lower degree of anticholinergic activity. Pharmacological studies on such new molecules are in general agreement with these concepts.

Anti-Arrhythmia Agents↗
PubMed1986

Systolic time intervals in evaluation of the negative inotropic effect after single oral doses of mexiletine and disopyramide.

A placebo-controlled, single blind, crossover study was done to evaluate the inotropic effects of single oral doses of mexiletine and disopyramide assessed by the measurement of Systolic Time Intervals (STI). Each of 8 healthy volunteers received five treatments in random order: 200 and 400 mg mexiletine, 100 and 200 mg disopyramide, and placebo. There was a significant increase in cumulated PEP after 400 mg mexiletine and 200 mg disopyramide. There was no significant change in LVET and QS2. Peak plasma levels were in the lower range of the reputed antiarrythmic levels. Plasma concentration-effect relationships are discussed. Although the study revealed large inter- and intrasubject variability in the measured STIs, it is concluded that a negative inotropic effect was detected despite the low plasma levels of the minor negative inotropic drugs.

Adult↗
PubMed1984

Effect of dose of charcoal on the absorption of disopyramide, indomethacin and trimethoprim by man.

The efficacy of various charcoal-to-drug ratios for the absorption of drugs was studied in 6 healthy volunteers and in vitro at two pHs. Disopyramide 200 mg, indomethacin 50 mg and trimethoprim 200 mg were ingested on an empty stomach with 100 ml water. After 5 min the subjects ingested a charcoal suspension in 300 ml--2.5 g, 10 g, 25 g or 50 g of Norit A, or 10 g of PX-21, or water 300 ml only. Increasing the dose of activated charcoal from 2.5 g to 50 g reduced the gastrointestinal absorption of disopyramide and indomethacin from 30-40% to 3-5%, and that of trimethoprim from 10% to 1% of the respective controls. Disopyramide and trimethoprim were best adsorbed by charcoal in vitro at neutral and indomethacin at acid pH, but saturation of the adsorption capacity was apparent at charcoal-to-drug ratios less than 7.5. Combining the in vitro and in vivo results it can be concluded that the dose of activated charcoal to be given in acute intoxication should be as large as possible, because the drug history is often unknown.

Absorption↗
PubMed1982

The influence of blood collection technique on serum and plasma protein binding of disopyramide.

Serum and plasma disopyramide (D) protein binding was compared after blood was collected from four normal subjects in various Vacutainer tubes. The fraction of disopyramide bound to proteins in control serum and plasma was drug concentration dependent and correlated well with the capacity factor (N) associated with a high affinity protein binding site. D free fraction increased 60% at a postequilibrium concentration of 2 micrograms/ml in plasma following exposure of blood to green-top Vacutainer stoppers due to a 60% reduction in the affinity constant associated with the high affinity protein binding site. Heparin and EDTA had no effect on the plasma protein binding of D. These results suggest a competitive inhibition of disopyramide binding to alpha 1-acid-glycoprotein following contact of blood with rubber Vacutainer stoppers.

Binding Sites↗
PubMed1983

The antiarrhythmic effects of controlled release disopyramide phosphate and long acting propranolol in patients with ventricular arrhythmias.

The antiarrhythmic effect of slow-release disopyramide phosphate (DR) 300 mg twice daily and of long-acting propranolol (PR) 1 X 160 mg daily was compared in a randomized cross-over study in patients with premature ventricular beats (PVB). 12 patients with PVB (Lown Classes II-V) were given: placebo I for 3 days, DR or PR for 7 days, placebo II for 5 days and PR or DR for 7 days. During each study phase Holter-ECG recordings were taken over a period of 24 h. With DR 6 patients showed a positive qualitative effect, improving by at least one Lown class, whereas only 2 patients did so with PR. With DR reduction of PVB greater than 80% occurred in 7 patients, and with PR in 2 patients. In all patients with any reduction in PVB, the median decrease was 85% with DR and 59% with PR. The overall results suggest that the antiarrhythmic effect of disopyramide phosphate in the slow-release preparation is at least satisfactory and comparable to that of disopyramide phosphate in the standard capsule formulation given in the usual and more complicated regime of four divided doses. The antiarrhythmic effect of PR in the recommended dose as given was not convincing.

Adolescent↗
PubMed1988

Effects of disopyramide on repolarisation and intraventricular conduction in man.

Right ventricular repolarisation and refractoriness after therapeutic doses of disopyramide have been studied in 10 patients with coronary artery disease by recording monophasic action potentials (MAP) during programmed stimulation. Using 2 catheters, with the tip of one in the apex and the other in the outflow tract of right ventricle, conduction intervals for propagation of stimuli in the ventricle were also measured. Disopyramide increased the duration of MAP signals at 90% repolarisation (MAP90), the QT-interval and the right ventricular effective refractory period (V-ERP). The ratio refractoriness/action potential duration was slightly increased. Early premature action potentials were more markedly prolonged in relation to steady-state action potentials. The differences between the shortest and longest premature action potentials, however, were not changed significantly. The conduction intervals of the normal and premature paced beats were significantly prolonged. The observed effects of disopyramide on conduction and action potential duration may be of major importance for its effect on termination and slowing ventricular tachycardias. Its influence on the duration of premature action potentials in man is consistent with the results of in vitro studies.

Action Potentials↗
PubMed1981

Efficacy of intravenous disopyramide in acute cardiac arrhythmias.

The efficacy of intravenous disopyramide was studied during 200 episodes of supraventricular and ventricular arrhythmias in 160 patients, mainly presenting with acute myocardial infarction or cardiac failure. Disopyramide 50 mg was administered in a few seconds and any remaining dose within 2 to 5 min. The overall success rate was 80.5%. Intravenous disopyramide was more effective in patients with ventricular arrhythmias (85%) than in those with supraventricular arrhythmias (76%). Dose dependent prolongation of the PR interval, QRS time and the QT interval occurred in 16.32 and 20% of the cases, respectively. The adverse effects were aggravation of the arrhythmias, decrease of blood pressure and anticholinergic activity.

Acute Disease↗
PubMed1980

Comparative bioavailability of disopyramide after multiple dosing with standard capsules and controlled-release tablets.

Plasma concentrations and bioavailability of disopyramide following repeated administration of standard capsules and controlled-release tablets have been compared. Ten patients were randomized into two groups; Group I received disopyramide capsules 150 mg every 6 h for five days. Group II received the same preparations in the reverse order. There was a more rapid rise in disopyramide concentration after the capsules: the maximum of 10.7 +/- 0.6 mumol/l (mean +/- SEM) was reached within 1.8 +/- 0.4 h as compared to 10.6 +/- 0.4 mumol/l within 4.0 +/- 0.3 h after the controlled-release tablets. No significant difference in the fluctuations in individual plasma concentrations during each dose interval at steady state were observed after ordinary capsules compared to controlled-release tablets. The extent of bioavailability was the same. Eight patients reported some side-effects during the capsule period and nine during the controlled-release tablet period.

Aged↗
PubMed1975

Haemodynamic effects of intravenous disopyramide in heart failure.

The haemodynamic effects of disopyramide have been studied in 11 patients with manifest or imminent heart failure. Disopyramide, 2 mg per kg body weight, was given intravenously during right and left heart catheterisation. The cardiac index decreased by an average of 28% (p less than 0.01); mean maximal left and right ventricular end-diastolic pressures were increased by 5.0+/-0.9 mm Hg (p less than 0.01) and 5.0+/-0.6 mm Hg (p less than 0.05), respectively; and left ventricular systolic pressure fell slightly but significantly (p less than 0.05). No significant change in right ventricular systolic pressure was seen. Pulmonary wedge pressure rose on average by 2.7 mm Hg (p less than 0.05). No significant change in heart rate was observed in 5 patients with sinus rhythm. In 6 patients with atrial fibrillation, there was a significant (p less than 0.01) increase in heart rate; the average increase in heart rate for the entire group was 19.6 beats per minute. The maximum effect on all the parameters occurred 7-11 minutes after the injection, and it gradually subsided during the following 10 minutes. It was concluded that disopyramide had a potentially serious myocardial depressant effect.

Adult↗
PubMed1995

"Normal" response of the QT interval and QT dispersion following intravenous injection of the sodium channel blocker disopyramide: methodological aspects.

Measurement of the QT dispersion (the maximal interlead difference) on the surface electrocardiogram has been suggested for assessing the risk for ventricular arrhythmias and for examining drug effects and their proarrhythmic potential. The acute response of QT dispersion was assessed in 10 healthy subjects receiving disopyramide, which is known to delay repolarization and to prolong global measures thereof. The QRS, JT, and QT intervals and their dispersion were assessed at spontaneous rhythm and at atrial pacing at baseline and after an intravenous injection of disopyramide 2 mg/kg over 5 minutes. The short-term (within 30 minutes) and long-term (> or = 2 weeks) variabilities of the QT interval and the QT dispersion, expressed as the coefficient of variation, were also analyzed. At spontaneous rhythm the group average QT interval was between 369 and 375 msec, and the QT dispersion was between 33 and 37 msec; both were relatively stable over time. All subjects responded homogeneously to disopyramide with a significant QT prolongation (p < 0.001), but no consistent response of the QT dispersion was observed. This discrepancy reflects the significant difference in time-dependent variability with a coefficient of variation of spontaneous, paced, and heart rate-corrected QT dispersion between 25% and 42%, 8-42 times greater than the corresponding values of 1-4% for the QT intervals. The individual response of the QT dispersion to drug challenge should therefore be interpreted with caution. Furthermore and as a consequence, QT dispersion is less sensitive for assessing drug effects on ventricular depolarization and repolarization than the QT interval.

Adult↗
PubMed1984

Pharmacokinetic-pharmacodynamic analysis of unbound disopyramide directly measured in serial plasma samples in man.

The pharmacokinetics and pharmacodynamics of the antiarrhythmic drug, disopyramide, were investigated in 12 volunteers who took 300 mg doses of 3 different capsule preparations and an aqueous oral solution of the drug at 1-week intervals. Concentrations of drug unbound to plasma proteins were measured by a sensitive immunoenzyme assay after ultrafiltration of plasma samples taken serially after dosing. QT interval was measured on serial ECG recordings with correction for changes in heart rate. Unbound concentrations of disopyramide were modelled by an open one-compartment pharmacokinetic model with a zero-order absorption rate and a lag time. There was no significant difference in parameter estimates between the four preparations, except for the lag time, which was significantly shorter for the solution preparation. The saturable protein binding of disopyramide was described by a hyperbolic model including a specific binding site and additional nonspecific binding. The pharmacodynamic relationship between unbound drug concentration and QT prolongation was fit by a simple linear model. This fit was better using unbound concentration of the drug than using total concentrations.

Adult↗