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At least 19 recordsLinked to original sources
PubMed1979

Induction of disopyramide N-dealkylation by phenobarbital and disopyramide in rat liver.

An in vitro assay for the determination of the activity of disopyramide-N-dealkylation was developed. This reaction was concluded to be catalyzed by the liver microsomal, cytochrome P-450 centered monooxygenase system. Phenobarbital enhanced the N-dealkylation of disopyramide four fold, and disopyramide itself 1.6 fold, whereas methylcholanthrene was without effect. Disopyramide also increased ethoxycoumarin deethylation 1.6 fold, and had a slight increasing effect on the activity of epoxide hydratase, but did not affect the activities of glutathione S-transferase or UDPglucuronosyltransferase.

Animals↗
PubMed1978

Disopyramide: a review of its pharmacological properties and therapeutic use in treating cardiac arrhythmias.

Disopyramide is a new antiarrhythmic drug with a pharmacological profile of action similar to that of quinidine and procainamide. In a few controlled therapeutic trails and a large number of uncontrolled studies in patients with arrhythmias, often following a myocardial infarction, disopyramide has been relatively effective (more so in ventricular than in atrial arrhythmias) and usually well tolerated. In treating premature atrial and ventricular contractions, the best-studied area of its therapeutic use, disopyramide was superior to a placebo and of similar efficacy to but better tolerated than quinidine; the drop-out rate due to adverse effects of the disopyramide group (10%) being less than one-third that of the quinidine group (36%). In an open ward setting, disopyramide used prophylactically after myocardial infarction appeared to reduce both the incidence of reinfarction and the mortality rate, while in patients treated in coronary care units although the incidence of reinfarction was lower with disopyramide than with a placebo, the mortality rate was not significantly different. Further well-designed trials with adequate numbers of patients are needed before the routine use of disopyramide in infarct patients treated in either setting can be justified. Comparative studies are also required to determine if disopyramide has advantages over other antiarrhythmic agents in this area of use. Side-effects with disopyramide are usually a result of its anticholinergic activity, a dry mouth and difficulty in urination being the most common. Like other antiarrhythmic agents, disopyramide exerts a negative inotropic action on cardiac muscle, and development of acute heart failure has been reported. Development of worsening of heart block and hypotension have also occurred. Disopyramide is largely excreted unchanged and dosage should be reduced in patients with impaired renal function, in accordance with creatinine clearance values.

Arrhythmias, Cardiac↗
PubMed1978

Some effects of disopyramide and its N-dealkylated metabolite on isolated nerve and cardiac muscle.

In animals and man the antidysrhythmic agent disopyramide in primarily metabolised by mono-N-dealkylation. The effects of disopyramide and its N-dealkylated metabolite (MIP) have been investigated using isolated cardiac and nervous tissue, and their effects have been compared with the effects of other antidysrhythmic agents. Disopyramide, d,l-propranolol and quinidine all decreased both maximum driving frequency and developed tension in electrically driven guinea pit atria. MIP and procaine amide also decreased maximum driving frequency, but had a positive intropic effect. MIP was only 4 times less active than disopyramide in decreasing maximum driving frequency. There was no evidence that either disopyramide or MIP possessed beta-adrenoceptor antagonist properties. In superfused rat sciatic nerves, it has been shown that neither disopyramide nor MIP possesses significant local anaesthetic properties. Procaine amide and lignocaine were highly active in this test. The possible contribution of MIP to the actions of disopyramide in vivo is discussed.

Action Potentials↗
PubMed1977

Efficacy of disopyramide phosphate in the treatment of refractory ventricular tachycardia.

The effects of intravenously administered disopyramide phosphate were evaluated in seven patients with refractory ventricular tachycardia. All patients had organic heart disease, including acute infarction (three patients), chronic coronary artery disease (two patients) and cardiomyopathy (two patients). The severity of the heart disease was reflected in the advanced patient age (average 64 years) and the occurrence before disopyramide therapy of cardiac arrest in five patients and congestive heart failure in all seven patients. In five patients, disopyramide was given as a bolus injection, 2 mg/kg body weight, followed by an infusion of 20 to 40 mg/hour. The final two patients received 4 mg/kg divided as a bolus injection and an infusion over 1 hour followed by a 0.4 mg/kg infusion during the next hour. Intravenous administration of disopyramide resulted in more effective electrical stability in all patients and completely eliminated ventricular tachycardia in six. Recurrence of ventricular tachycardia was prevented in six patients with subsequent long-term oral administration of disopyramide. Possible dose-related cardiac pump depression occurred in two patients, but disopyramide was otherwise well tolerated. Therefore, these data document the therapeutic efficacy of disopyramide in the treatment of refractory life-threatening ventricular tachyarrhythmias.

Aged↗
PubMedDate not supplied

Disopyramide plasma and myocardial tissue concentrations as they relate to antiarrhythmic activity.

Antiarrhythmic concentrations of disopyramide in canine plasma and myocardium were determined by gas chromatography. Ventricular tachycardia was incuded in anesthetized dogs by the intravenous administration of ouabain. Disopyramide phosphate was then administered by a two-stage continuous infusion method. A rapid infusion of disopyramide (9.08 mg/kg/hr) was administered for 30 min, followed by a slow infusion (2.18 mg/kg/hr) to maintain steady-state plasma levels of 1.98-2.21, mean +/- SEM = 2.1 +/- 0.02 microgram/ml at the end of 2 hr. Myocardial tissue levels of disopyramide at steady-state plasma levels were four times those of plasma (atrial tissue, 8.91 +/- 0.10; right ventricular free wall, 8.93 +/- 0.13; left ventricular free wall, 9.11 +/- 0.16 microgram/gm wet tissue). The intravenous administration of 80 units crystalline zinc insulin produced both hypokalemia (3.78 +/- 0.22 reduced to 2.36 +/- 0.18 mEq potassium/liter plasma) and a reappearance of ventricular tachycardia despite no change in plasma and myocardial tissue concentrations of disopyramide from those which had been effective in establishing and maintaining sinus rhythm. The observations demonstrate a relationship between plasma and myocardial disopyramide concentrations such that the former can be used in assessing patient therapy. In addition, this study suggests the important of plasma potassium in determining the therapeutic effectiveness of disopyramide.

Animals↗
PubMed1979

The effects of disopyramide phosphate on early post-coronary artery ligation dysrhythmias and on epicardial ST-segment elevation in anaesthetized dogs.

1 The antidysrhythmic, haemodynamic and metabolic effects of intravenously administered disopyramide phosphate (1 to 5 mg/kg) have been studied in greyhounds, anaesthetized with trichloroethylene. 2 In doses of 2.5 and 5.0 mg/kg, disopyramide significantly reduced the ventricular dysrhythmias that occur in the initial 30-min period following acute coronary artery ligation. None of the disopyramide-treated animals developed ventricular fibrillations. 3 The metabolic consequences of coronary artery ligation, assessed by local coronary venous sampling from the ischaemic area, were not modified by disopyramide except that K+ egress was prevented. 4 There was evidence for substantial disopyramide-induced myocardial depression (decreased cardiac output and left ventricular dP/drmax with elevated ventricular filling pressure and pulmonary oedema and shunting) and it is suggested that great care be taken when the drug is administered intravenously in conditions where cardiac function is already compromised. Disopyramide also reduced myocardial blood flow. 5 In chloralose-anaesthetized mongrel dogs, disopyramide (2.5 mg/kg) significantly reduced the ST-segment elevation (assessed from epicardial recordings) that resulted from short (3 min) coronary artery occlusions. This could indicate a reduction in the extent and severity of myocardial injury or simply reflect decreased K+ efflux (since locally administered K+ itself increased ST-segment elevation).

Animals↗
PubMed1979

Adverse hemodynamic effects of intravenous disopyramide compared with quinidine in conscious dogs.

Disopyramide resembles quinidine electrophysiologically, but its effect on left ventricular function has not been clarified. Twelve awake dogs were instrumented for measurement of cardiac output, left ventricular pressure and its maximal first derivative (dP/dt max), and left atrial and aortic pressures. Disopyramide or quinidine at identical, clinically relevant doses (1 and 5 mg/kg i.v.) was infused over 5 minutes at each level. Peak changes after disopyramide 1 mg/kg included increases in heart rate (34%), mean aortic pressure (24%) and systemic vascular resistance (33%), and decreases in stroke volume (16%) and dP/dt max (19%). With disopyramide at 5 mg/kg these changes were of greater magnitude (e.g., dP/dt -- 36%). Quinidine at both doses caused no changes except a 13% decrease in vascular resistance at 5 mg/kg. Heart rate with disopyramide increased after propranolol (1 mg/kg i.v.), was unchanged after atropine (0.1 mg/kg i.v.), and slowed after propranolol and atropine. Phenoxybenzamine (2 mg/kg i.v.) did not prevent the rise in systemic vascular resistance produced by disopyramide. Thus, disopyramide in clinical dosages exerts opposing direct and indirect effects on cardiac pacemakers and, unlike quinidine, is a potent myocardial depressant and vasoconstrictor in the conscious dog.

Animals↗
PubMed1979

Suppression of ventricular arrhythmias with intravenous disopyramide and lidocaine: efficacy comparison in a randomized trial.

Twenty-six patients with clinically significant ventricular arrhythmias were randomly assigned to treatment with either intravenous disopyramide or lidocaine; crossover to the other agent was permitted in nine cases of primary drug failure. In addition, disopyramide was administered nonrandomly to seven patients with ventricular arrhythmias not controlled by lidocaine in standard doses. Arrhythmia control (greater than 50 percent reduction of premature ventricular complexes) was achieved in all 22 trials with disopyramide and in 9 of 13 trails with lidocaine in the random study, whereas clinical efficacy (arrhythmia control with absence of side effects) occurred respectively in 15 of 22, and 8 of 13 trials. In all 11 patients (7 nonrandom, 4 random) whose arrhythmia was not controlled with lidocaine the arrhythmia was controlled with disopyramide. Thus, the clinical efficacy of intravenous disopyramide ran parallel to that of lidocaine in patients with ventricular arrhythmias. Furthermore, intravenous disopyramide was an effective alternative agent for patients with arrhythmia not controlled by lidocaine.

Acute Disease↗
PubMed1978

The electrophysiological effects of disopyramide phosphate on canine ventricular muscle and Purkinje fibers in normal and low potassium.

We studied the effect of lowering the extracellular potassium concentration ([K+]o) on the electrophysiological actions of disopyramide phosphate, a new antiarrhythmic drug. At low [K+]o, therapeutic concentrations of disopyramide phosphate caused significantly less depression of action potential amplitude and maximum upstroke velocity of both Purkinje fiber and ventricular muscle action potentials. The drug shifted the membrane responsiveness curve along the voltage axis to more negative membrane potentials regardless of [K+]o. However, a greater shift occurred when [K+]o was normal. Disopyramide phosphate prolonged both action potential duration and effective refractory period in all fibers but there was consistently greater prolongation of these parameters at low [K+]o. More importantly, disopyramide phosphate altered repolarization time course of action potentials in such a way that action potentials with dissimilar durations throughout the ventricular conducting system became more equal. The drug was less effective in decreasing this disparity in action potential durations throughout the ventricles in the presence of low [K+]o. These modifications of the electrophysiological actions of disopyramide by low [K+]o suggest that a therapeutic concentration of disopyramide might have less of an antiarrhythmic effect in the presence of hypokalemia.

Action Potentials↗
PubMed1979

Electrophysiological effects of disopyramide in patients with bundle branch block.

Electrophysiological studies were performed in 22 patients with intraventricular conduction delay before and after intravenous infusion of disopyramide (Norpace), 2 mg/kg. Mean control maximal sinus node recovery time (1039 +/- 187 msec), atrioventricular nodal conduction time (113 +/- 28 msec), and atrioventricular nodal effective refractory periods (349 +/- 67 msec) did not change significantly after administration of disopyramide (1073 +/- 284 msec, 112 +/- 31 msec, and 342 +/- 42 msec, respectively). Mean spontaneous cycle length (756 +/- 146 msec) decreased significantly 5 minutes after disopyramide (717 +/- 124 msec) (p less than 0.05), but not after 30 minutes (734 +/- 142 msec). A small but statistically significant (p less than 0.05) increase occurred after disopyramide in the mean atrial effective refractory period (259 +/- 51 to 280 +/- 53 msec), ventricular effective refractory period (253 +/- 23 to 275 +/- 33 msec), as well as the relative refractory period of the ventricular specialized conduction system (six patients) 433 +/- 78 to 479 +/- 62 msec). Although mean control infranodal conduction time (67 +/- 35 msec) increased 5 minutes after disopyramide (79 +/- 41 msec) (p less than 0.001) (18%), no spontaneous episodes of second-degree or third-degree atrioventricular block were observed. In six patients with premature ventricular depolarizations (greater than or equal to 1/min), the arrhythmia was totally abolished in four, markedly reduced in one, and remained unchanged in one. Disopyramide resulted in significant prolongation of infranodal conduction time as well as in atrial and ventricular refractoriness, but nevertheless appears to be safe in patients with bundle branch block.

Atrioventricular Node↗
PubMed1979

Electrophysiologic effects of disopyramide phosphate on sinus node function in patients with sinus node dysfunction.

The electrophysiologic effects of intravenously administered disopyramide (2 mg/kg) on three parameters of sinus node function were examined in 16 symptomatic patients with sinus node dysfunction. Based on their ECG data before study, patients were subdivided into group A (n = 8), those with sinus pauses and/or sinoatrial (SA) exit block; and group B (n = 8), those with sinus bradycardia. Disopyramide shortened spontaneous cycle length in 10 of 16 patients and lengthened it in six--markedly so (91%) in one patient. Estimated SA conduction time decreased in seven of 14 patients and increased in seven. Two patients developed second degree SA exit block after disopyramide. Maximum sinus node recovery time was prolonged by disopyramide in 11 of 16 patients and markedly so in four. For the group as a whole there was no significant difference in spontaneous cycle length, maximum sinus node recovery time or estimated SA conduction time. P-wave and QRS durations and H-V intervals were significantly lengthened by disopyramide. Marked depression of the three parameters of sinus node function occurred in three group A patients and in one group B patient who had persistent severe sinus bradycardia. These four patients also had secondary pauses after termination of rapid atrial pacing under control conditions. Disopyramide should be administered cautiously to patients with sinus node dysfunction, particularly those with sinus pauses, SA exit block or secondary pauses.

Adult↗
PubMedDate not supplied

The effects of urine pH and plasma protein binding on the renal clearance of disopyramide.

To ascertain whether the renal clearance of disopyramide (pKa = 8.36) is affected by urine pH, the disposition kinetics of disopyramide were compared during excretion of acidic and alkaline urine following both single dose intravenous (2mg/kg) and oral (5 mg/kg) administration to 4 healthy male volunteers. No significant difference was observed in the plasma concentration-time curve of disopyramide. The mean 72 hour recovery of disopyramide and its N-deisopropyl metabolite (MND) in urine was 55.1 and 20.3% of the dose respectively, with no apparent difference between the two routes of administration or pH of urine. Renal clearance of disopyramide was found to vary with time, which is partly the result of a concentration dependent change in plasma protein binding. The unbound fraction of drug in plasma varied from 0.32 to 0.72 between 0.4 to 4microgram/ml concentration. However, time-dependent change in renal clearance of disopyramide persists even after correction for plasma protein binding.

Administration, Oral↗
PubMed1979

[Clinical and hemodynamic effects of disopyramide phosphate administered i.v. in cardiopathic subjects (author's transl)].

The antiarrhythmic action of disopyramide (1.5 mg/Kg) administered i.v. as a bolus was assessed in 30 patients with ischemic heart disease and different arrhythmias. In 75% of supraventricular parossistic tachycardia and in 75% of parossistic atrial fibrillation, arrhythmia was interrupted within few minutes from drug injection; in 90% with premature ventricular contractions (PVC) and in 100% of ventricular tachycardia, disopyramide was capable to interrupt the arrhythmias. The hemodynamic effects of the same dose of disopyramide were evaluated in other 17 patients, 9 of which in I-II class NYHA and 8 in III-IV class. We used STI's as parameters of cardiac performance. In all patients following the injection of disopyramide, a significant increase of PEP, ICT and PEP/LVET ratio and a significant decrease of LVETc were observed. Thus, the disopyramide impaired cardiac performance and its effect appeared more evident in patients in III-IV class NYHA. In conclusion, disopyramide showed to be effective in interrupting different arrhythmias; however, its depressant action on cardiac performance suggests that caution should be used in patients with severely impaired myocardial function.

Adult↗
PubMedDate not supplied

The renal clearance of disopyramide after bolus intravenous injection.

Following bolus intravenous injection of disopyramide in eight normal volunteers the renal clearance of the drug appeared to fall with time. In the first two hours after injection renal clearance had a mean value of 89.0 ml min-1 and fell to 29.4 ml min-1 between 48 and 72 h. In a separate study disopyramide was given by continuous intravenous (i.v.) infusion for 8 h following a loading dose of the drug. Renal clearance of disopyramide was thus estimated hourly over three narrow serum concentration ranges in a single volunteer. The estimate of renal clearance of the drug over the first hour following the start of these infusions was considerably in excess of values obtained later in the experiments. The change in disopyramide renal clearance following bolus injection is partially time-dependent. There are, however, fallacies in calculating short-term clearance values after bolus drug injection from the venous concentration-time curve and these may partially explain the change in renal clearance of disopyramide with time.

Disopyramide↗
PubMed1979

Electrophysiological effects of disopyramide phosphate during experimental myocardial ischemia.

In order to correlate the antiarrhythmic and electrophysiological effects of disopyramide phosphate during acute myocardial ischemia, we performed experiments in 17 mongrel dogs. Refractory periods obtained by the extrastimulus method and conduction times recorded from local electrograms were determined in potentially ischemic and nonischemic areas prior to, after left anterior descending coronary occlusion, and following intravenous administration of disopyramide phosphate 3 mg./Kg. Control refractory periods were similar in both nonischemic and ischemic areas. Following coronary ligation, a disparity of refractoriness of 28 msec. was induced between these two areas. After disopyramide administration, this disparity was reduced from 28 msec. to 5 msec. (p less than 0.001) after 5 to 15 minutes, and to 15 msec. (p less than 0.01) after 15 to 30 minutes. Coronary ligation prolonged conduction times by 8 msec. (p less than 0.005) in ischemic areas and disopyramide further prolonged conduction in these areas by an additional 9 msec. (p less than 0.001). A minimal and transient prolongation of conduction was present in nonischemic areas. We conclude that the differential effects exerted by disopyramide phosphate in ischemic areas may explain its suppressant action of arrhythmias of ventricular origin.

Animals↗
PubMed1979

Effects of disopyramide on SA nodal pacemaker activity and contractility in the isolated blood-perfused atrium of the dog.

The isolated blood-perfused preparations of canine atrium were suspended in a bath and perfused with arterial blood led from the carotid artery of the heparinized donor dog. Disopyramide caused dose-related negative chronotropic and inotropic effects in a dose range of 30-1000 microgram when injected directly into the cannulated sinus node artery of the isolated atrium. The order of potencies for inducing the negative chronotropic effect in isolated atrium preparations was verapamil greater than propranolol greater than lidocaine = quinidine greater than phenytoin greater than or equal to disopyramide greater than procainamide. On the other hand, the order of potencies for inducing the negative inotropic effect was verapamil = propranolol greater than lidocaine greater than or equal to phenytoin greater than disopyramide greater than procainamide greater than or equal to quinidine. When disopyramide (1 mg/kg or 3 mg/kg) was administered i.v. into the jugular vein of the donor dog, the systemic blood pressure of the donor dog was markedly decreased. However, the tension developed and sinus rate of the isolated atrium were only slightly decreased. Disopyramide produced greater suppression at higher frequencies and slightly depressed the calcium chloride-induced positive inotropic effects.

Animals↗
PubMed1976

Disopyramide: serum level and arrhythmia conversion.

The response of arrhythmias to oral disopyramide in relation to its serum levels has been documented. Disopyramide (100 mg.) was given orally, 6 or 8 hourly, to 16 patients with coronary or hypertensive heart disease who developed acute but stable cardiac arrhythmias (20 episodes) which persisted, despite bed rest and sedation with intravenous diazepam or diamorphine. Blood was taken when arrhythmia conversion was observed and the serum disopyramide levels were estimated by gas chromatography. Over-all control of arrhythmias was achieved in 13 (82 per cent) patients within 24 hours. Disopyramide-serum levels were as follows: effective for atrial arrhythmias, 2.80 to 3.18 mug per milliliter, and 3.27 to 7.48 mug per milliliter for ventricular; mean effective levels for all arrhythmias, 3.69 mug per milliliter; mean ineffective levels, 2.39 mug per milliliter (p less than 0.01). Side effects (prolongation of PR and QTc, fall of diastolic BP, urine retention) were observed with serum levels of 3.61 to 7.48 mug per milliliter (mean, 5.54 mug per milliliter) but they were not troublesome clinically. It is concluded that disopyramide is effective and safe with serum levels ranging from 2.39 to about 3.60 mug per milliliter, and this can be maintained with 100 mg., 8 hourly. The drug, however, should be given with caution to patients with severe myocardial disease or low arterial pressure and in the presence of an abnormal ECG.

Administration, Oral↗