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PubMed1995

Disopyramide stress test: a sensitive and specific tool for predicting impending high degree atrioventricular block in patients with bifascicular block.

OBJECTIVE: To study the value of intravenous disopyramide as part of an invasive electrophysiological study in predicting impending high degree atrioventricular block in patients with bifascicular block. DESIGN: An invasive electrophysiological study was performed in the basal state and after the infusion of disopyramide (2 mg/kg body weight). The progression to high degree atrioventricular block was assessed by bradycardia-detecting pacemakers or repeated 12-lead electrocardiogram recordings, or both. PATIENTS: 73 patients with bifascicular block were included, of whom 25 had a history of unexplained syncope. The remaining 48 patients had no arrhythmia related symptoms and were included as controls. All patients had an ejection fraction of > 35%. RESULTS: After a mean follow up of 23 months, seven patients in the syncope group and three in the non-syncope group had a documented high degree atrioventricular block or pacemaker-detected bradycardia of < or = 30 beats/min for > or = 6 s. The sensitivity of the disopyramide test was 71% and the specificity 98%. The corresponding figures for an abnormal electrophysiological study in the basal state were 14% and 91%, respectively. CONCLUSIONS: The sensitivity of an invasive electrophysiological study in patients with bifascicular block and syncope can be markedly increased by the use of intravenous disopyramide. A positive test is a highly specific finding and warrants pacemaker implantation.

Adolescent↗
PubMed1998

Relation between bradycardia dependent long QT syndrome and QT prolongation by disopyramide in humans.

BACKGROUND: Recent molecular biological investigations have identified abnormal genes in familial forms of long QT syndrome, but in bradycardia dependent acquired long QT syndrome, no such genetic abnormality has yet been identified. OBJECTIVE: To investigate the relation between the responses of QT interval to pacing change and to disopyramide. METHODS: This study included 13 patients with bradyarrhythmia who had undergone pacemaker implantation. The patients were divided into two groups: group I (n = 8), patients with QT prolongation (QT interval > or = 500 ms) during bradycardia; group II (n = 5), patients without QT prolongation (QT interval < 500 ms) during bradycardia. The responses of QT interval caused by the change of pacing rate were determined and compared with the changes of the QT interval after disopyramide administration. RESULTS: The QT interval in group I was significantly longer than that in group II when the pacing rate was decreased from 110 to 50 beats/min: mean (SD) 451 (16) v 416 (17) ms at 90 beats/min (p = 0.0033), and 490 (19) v 432 (18) ms at 70 beats/min (p = 0.0002), respectively. The QT interval was prolonged significantly by disopyramide in both groups, but the change was more pronounced in group I than in group II: 78 (33) v 35 (10) ms (p < 0.05). CONCLUSIONS: This study suggests that the patients showing bradycardia dependent QT prolongation are also more markedly affected by disopyramide and that abnormal potassium channel may be the underlying mechanism.

Adult↗
PubMed1980

Some cardiovascular problems with disopyramide.

Five patients with apparent adverse cardiovascular effects of disopyramide are reveiwed. Attention is drawn to the following problems. (1) A vagolytic effect may produce a sinus tachycardia with wide QRS complexes due to aberrant conduction or intraventricular block superficially resembling a ventricular tachycardia, or may allow increased transmission of an atrial tachycardia or atrial flutter to the ventricles by improving atrio-ventricular conduction. (2) Although the vagolytic effect is helpful in increasing sinus rate in patients with sinus node disease, disopyramide may lead to bradycardia and asytolic cardiac arrest, and should not be used without a demand pacemaker. (3) Dangerous ventricular arrhythmias may be provoked in susceptible subjects, as with quinidine. (4) Rapid intravenous injection may produce transient toxic effects before the drug is distributed. The rate of injection as a loading dose for prophylaxis should be slower (2 mg/kg in 15 min) than for the urgent conversion of a resistent tachycardia (2 mg/kg in 5 min). Although disopyramide seems less toxic than quinidine, caution is advised, as over-enthusiastic application of disopyramide, particularly with rapid intravenous injection, might tend to bring a useful new agent into disrepute.

Adult↗
PubMed1992

Effect of propranolol and disopyramide on left ventricular function at rest and during exercise in hypertrophic cardiomyopathy.

In 19 patients with hypertrophic cardiomyopathy (15 males, 4 females, mean age 49.2 +/- 10.8 years) left ventricular function was studied with radionuclide ventriculography at rest and during exercise in a crossover design without intervention and after disopyramide and propranolol treatment. 15 of the 19 patients had a resting or latent intraventricular gradient of more than 30 mm Hg. Left ventricular function at rest and during exercise was evaluated before medication, 90 min after oral administration of 200 mg disopyramide or 160 mg propranolol and after 3 weeks of oral therapy with disopyramide 200 mg 2 times a day or propranolol 80 mg 4 times a day. After long-term treatment with disopyramide, resting ejection fraction decreased from 72 +/- 12 to 69 +/- 14% (p less than 0.01) and peak ejection rate (PER) decreased from 3.46 +/- 135 to 3.24 +/- 65 end-diastolic volume (EDV).s-1 (p less than 0.01). Peak filling rate (PFR) at rest decreased from 3.01 +/- 0.8 to 2.77 +/- 0.63 EDV.s-1 (p less than 0.05). Time to peak filling rate (TPFR) at rest and during exercise after acute and chronic therapy did not change compared to control values. Acute and long-term administration of propranolol lead to a significant reduction in heart rate at rest and during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1983

The direct electrophysiologic effects of disopyramide phosphate in the transplanted human heart.

To evaluate the direct electrophysiologic effects of i.v. disopyramide phosphate and to differentiate these effects from its autonomically mediated actions, we administered the drug (2 mg/kg over 5 minutes) during electrophysiologic study to eight cardiac transplant recipients who had documented functional cardiac denervation. After disopyramide, the cycle length of the denervated donor right atrium increased from 626 +/- 129 to 716 +/- 148 msec (mean +/- SD, p less than 0.001), whereas that of the innervated recipient atrium decreased from 846 +/- 195 to 659 +/- 99 msec (p less than 0.02). There were small increases in both the sinus node recovery time (1128 +/- 616 to 1198 +/- 592 msec, p less than 0.05) and corrected sinus node recovery time (440 +/- 418 to 489 +/- 409 msec, p less than 0.02) of the donor atrium, whereas the recovery times of the recipient atrium shortened (sinus node recovery time, 1298 +/- 218 to 1218 +/- 196 msec; corrected sinus node recovery time, 464 +/- 108 to 410 +/- 115 msec). Disopyramide markedly prolonged all conduction intervals. The PA interval increased from 47 +/- 16 to 54 +/- 17 msec (p less than 0.01), the AH interval from 55 +/- 12 to 78 +/- 12 msec (p less than 0.001), the HV interval from 38 +/- 9 to 58 +/- 13 msec (p less than 0.001), the QRS duration from 93 +/- 18 to 129 +/- 34 msec (p less than 0.001) and the QT interval from 339 +/- 23 to 403 +/- 39 msec (p less than 0.001). There was no significant change in the effective refractory period of the atrium, ventricular or atrioventricular node. The functional refractory period of the atrioventricular node increased from 369 +/- 34 to 395 +/- 31 msec (p less than 0.001). The electrophysiologic effects of disopyramide in the denervated heart are markedly depressant. In the innervated normal heart, the majority of these effects are counteracted by the drug's autonomically mediated anticholinergic actions.

Adult↗
PubMed1991

Two components of use-dependent block of Na+ current by disopyramide and lidocaine in guinea pig ventricular myocytes.

We studied the kinetics of the use-dependent block of the Na+ current (INa) by disopyramide and lidocaine. INa was recorded from isolated guinea pig ventricular myocytes by using the whole-cell patch-clamp technique. The use-dependent block of INa by disopyramide with 20- and 200-msec depolarizing pulses developed in two exponential functions. The degree of the use-dependent block and the amplitude of the fast (Af) and slow (As) components with the short (20-msec) pulse protocol were comparable to those with the long (200-msec) pulse protocol. When pH was raised from 7.3 to 8.0, disopyramide increased Af without a change in As. At pH 6.5, INa block developed with a single exponential function revealing only the slow component. The fast and slow components of INa block by disopyramide could be explained by binding of the uncharged and charged forms, respectively, to the activated state of the channel. Development of INa block by lidocaine also was expressed by two exponentials at all pulse durations (5-200 msec). As pulse durations were prolonged or holding potentials were depolarized, the degree of the use-dependent block and Af increased. When pH was lowered to 6.5, the short pulse produced only the slow component, whereas the long pulse caused two exponentials with decreased Af and increased As. Internal application of QX-314, a permanently charged lidocaine analogue, produced a single exponential block of INa with a very slow onset rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

The use of disopyramide in resistant cardiac arrhythmias due to acute ischaemic heart disease.

Disopyramide, a new anti-arrhythmic drug, has been assessed in twenty-one episodes of cardiac arrhythmia secondary to acute ischaemic heart disease which failed to respond to more conventional suppressive therapy with lignocaine and other standard drugs. The intravenous administration of 100 mg of disopyramide resulted in suppression of two out of seven episodes of supraventricular arrhythmia, and eleven out of fourteen episodes of ventricular arrhythmias. Successful suppression correlated with blood levels of disopyramide in most cases of ventricular arrhythmias but not in the supraventricular arrhythmias. There were no adverse effects on blood pressure or cardiac function. There were minimal effects on conduction in the electrocardiogram. It is concluded that disopyramide, which probably acts by direct depression of myocardial irritability, is a useful new anti-arrhythmic drug in acute myocardial infarction, especially in those patients with ventricular arrhythmias resistant to more conventional anti-arrhythmic therapy.

Acute Disease↗
PubMedDate not supplied

Clinical significance of the negative inotropic effect of disopyramide.

This study determined the extent of the negative inotropic effect of either 200 mg standard release disopyramide given three times daily or 250 mg sustained release disopyramide given twice daily in 10 patients with normal and 10 with abnormal ventricular function. Assessment, by measurement of ejection fraction using 99mTc radionuclide ventriculography, was made 3 h after the first dose and again after 7 days' treatment, both at rest and after exercise. A similar reduction in ejection fraction occurred at rest and after exercise. Patients with an abnormal left ventricular function showed a greater decrease in ejection fraction compared with patients with normal left ventricular function, both at rest and after exercise. The extent of this reduction appeared to be correlated with the extent of left ventricular dysfunction. In no cases were these decreases statistically or clinically significant. No significant changes in heart volume occurred in any patient and none showed impaired clinical status. Plasma concentrations of disopyramide were also similar for both types of disopyramide in both groups of patients on days 1 and 7.

Adult↗
PubMed2005

Influence of hypothyroidism induced by thiamazole on the toxic interaction between propranolol and disopyramide in chick embryos.

The effect of the hypothyroidism induced by thiamazole on toxic interactions between propranolol and disopyramide were studied in chick embryos. Fertilized eggs of White Leghorns were incubated and investigated. 1.2 mg/0.2 ml/egg of thiamazole was injected into the albumen of fertilized eggs on the 9th day of incubation. The control group was given 0.2 ml/egg of physiological saline in the same manner. Propranolol at 0.1 mg/egg and disopyramide at 0.3 mg/egg were injected into the air sac of fertilized eggs on the 16th day of incubation. Electrocardiograms were recorded 0 to 60 min after the injection. After the injection of propranolol and disopyramide into the thiamazole treated eggs, the heart rate was significantly decreased compared with the thiamazole untreated eggs. These findings indicate that hypothyroidism induced by thiamazole has a marked influence on the toxic interaction between propranolol and disopyramide in chick embryos.

Animals↗
PubMed1980

Electrophysiological effects of a new antiarrhythmic agent, lorcainide, on the isolated cardiac muscle fiber as compared with disopyramide.

Electrophysiological effects of a new antiarrhythmic agent, lorcainide, were studied in the isolated guinea pig ventricular myocardium and were compared with those of disopyramide; some of the experiments were also made by using the canine ventricular myocardium. Both lorcainide and disopyramide selectively depressed the maximum rate of rise of the action potential with little effect on the resting and overshooting potential. The action potential duration tended to be shortened slightly, and the prolongation of the refractory period produced by these agents was only slight. Both agents did not produce the substantial modification of the slow response produced by isoproterenol in the depolarized muscle at the concentrations enough to depress the maximum rate of rise of the action potential. Both agents also produced the marked depression of the rate of the action potential of the canine ventricular muscle, and the conduction velocity measured in the canine false tendon was markedly decreased by both agents. It was concluded that both lorcainide and disopyramide are typical Class I agents according to the classification proposed by Vaughan Williams and that lorcainide is about 10 times (at least 3 times) more potent than disopyramide in this respect.

Action Potentials↗
PubMed2002

Effects of disopyramide and mexiletine on the terminal repolarization process of the in situ heart assessed using the halothane-anesthetized in vivo canine model.

This study was designed to assess the effects of typical class I drugs on the terminal repolarization process of the in situ heart, which is a useful marker of the potential of drug-induced long QT syndrome. Disopyramide (0.3 and 3.0 mg/kg per 10 min, n = 6) or mexiletine (0.3 and 3.0 mg/kg per 30s, n = 6) was intravenously administered to halothane-anesthetized beagle dogs under the monitoring of multiple cardiovascular parameters. Antiarrhythmic concentrations were obtained with the high dose of each drug. The low dose of disopyramide or mexiletine hardly affected any of the electrophysiological parameters assessed. The high dose of disopyramide prolonged the monophasic action potential duration (MAP90) and effective refractory period (ERP) to a similar extent, thus displacing the terminal repolarization period backward, which might provide a potential proarrhythmic substrate, particularly at a slow heart rate. On the other hand, the high dose of mexiletine shortened the MAP90, but prolonged the ERP, resulting in the disappearance of the terminal repolarization period, which could prevent premature excitation with its associated conduction slowing. These electrophysiological effects of disopyramide and mexiletine on the terminal repolarization phase may at least in part explain their clinically described antiarrhythmic and proarrhythmic properties.

Action Potentials↗
PubMed1991

Coupling interval-related effects of class I antiarrhythmic drugs, mexiletine, cibenzoline and disopyramide, on ventricular activation in canine myocardial infarction.

Time-dependent inhibition of sodium channels by class I antiarrhythmic drugs has been observed in isolated cardiac muscles or cells. We examined coupling interval-related effects of class I antiarrhythmic drugs, mexiletine, cibenzoline and disopyramide, on ventricular activation in canine infarcted myocardium. A ventricular stimulation with various coupling intervals was applied to the right ventricle, and activation delays (time intervals between the initiation of a deflection and the final rapid deflection of a bipolar electrocardiogram) of infarcted and normal zones were measured. The premature stimulation produced a delayed activation and in some animals, caused reentrant beats. Mexiletine (3 and 10 mg/kg), cibenzoline (1 and 4 mg/kg) and disopyramide (1 and 4 mg/kg) further enhanced or blocked the delayed activation. The effects of these drugs were more marked at shorter coupling intervals, although cibenzoline and disopyramide showed significant effects also at long coupling intervals. The effect of these drugs on the activation in the normal zone was less than that in the infarcted zone. In conclusion, mexiletine, cibenzoline and disopyramide showed a coupling interval-related depression of delayed activation in infarcted myocardium, which may be a reflection of their time-dependent inhibition of sodium channels.

Animals↗
PubMed1981

Cardiovascular collapse associated with disopyramide therapy.

Five patients with severe left ventricular failure, renal insufficiency, and recurrent ventricular tachycardia had cardiovascular collapse and died eight hours to 23 days after initiation of the usual doses of disopyramide. Three patients had recent myocardial infarction (12 to 33 days), and one had severe congestive cardiomyopathy. ECG changes antedated appearance of cardiovascular collapse and consisted of lengthening of the QRS (0.10 plus or minus 0.02 to 0.22 plus or minus 0.09; P less than 0.025) and the QTc duration (0.44 plus or minus 0.04 to 0.56 plus or minus 0.09; P less than 0.05). Sinus bradycardia or varying degrees of atrioventricular block or both occurred in all patients. Terminal disopyramide blood concentration (4.9 and 8.1 micrograms/ml) were available in two patients. A syndrome of progressive lengthening of ventricular depolarization and repolarization terminating in cardiovascular collapse and death associated with disopyramide is described. In addition, a high incidence of sinus bradycardia, atrioventricular conduction disturbances, or both was also noted. Disopyramide is contraindicated in patients with severe heart failure and renal insufficiency. Progressive widening of the QRS complex or the QT interval may presage appearance of severe myocardial dysfunction.

Administration, Oral↗
PubMed1988

[Antiarrhythmic agent caused marked hypoglycemia in a patient receiving hemodialysis: relation with disopyramide and verapamil].

A 70-year-old man with a 5-year history of hemodialysis was admitted to Keio University Hospital due to severe constipation on March 27, 1986. He recognized constipation and abdominal distention one month before admission, and his general condition became gradually worse. After the admission, a barium enema revealed obstruction at the upper portion of the ascending colon. A righ colectomy was successfully performed on April 8. Before the operation he showed frequent premature ventricular beats on his ECGs, but after the operation atrial fibrillation with rapid ventricular responses appeared. The arrhythmia was normalized with the intravenous administration of verapamil and disopyramide and oral administration of those drugs was continued. A few weeks later he was found to be drowsy occasionally. His fasting plasma glucose was revealed to be 29 mg/dl. After the discontinuation of the antiarrhythmic agents his plasma glucose level returned to normal. To see what role disopyramide might play in this hypoglycemic phenomenon, oral glucose tolerance tests were done before and during the administration of disopyramide. The examination revealed stimulation of insulin secretion by disopyramide.

Aged↗
PubMed1988

Effects of procainamide and disopyramide on long chain acyl carnitine and long chain acyl CoA concentrations in the ischemic heart.

Though the efficacies of procainamide and disopyramide in treating arrhythmias are well established, their precise mechanisms of antiarrhythmic action remain unclear. Arrhythmias which occur during acute myocardial ischemia can be explained partly on a metabolic basis. The accumulation of intermediates subsequent to impaired beta-oxidation of free fatty acids has been suggested as a cause of serious arrhythmias. The purpose of this study was to investigate changes in free carnitine, long chain acyl carnitine and long chain acyl CoA concentrations in the ischemic canine heart following the administration of procainamide and disopyramide. The coronary artery was occluded for 40 min and myocardial samples were prepared from both nonischemic and ischemic areas. Procainamide and disopyramide prevented the accumulation of long chain acyl carnitine and long chain acyl CoA in the ischemic myocardium. The results showed that procainamide and disopyramide had beneficial effects on fatty acid metabolism. It was suggested that one of the antiarrhythmic mechanisms of these drugs might be the prevention of the accumulation of fatty acyl derivatives in the ischemic myocardium.

Acyl Coenzyme A↗
PubMed1992

Mexiletine and disopyramide suppress ventricular premature contractions (VPC) irrespective of the relationship between the VPC and the underlying heart rate.

The effects of mexiletine (300 mg/day, 24 patients) and disopyramide (300 mg/day, 20 patients) on ventricular premature contractions (VPCs) were studied using a 24-hour ambulatory electrocardiogram. The VPC frequency was evaluated as a function of the underlying heart rate (HR). The VPC-HR correlation was classified into 2 major types, depending on whether the frequency of the VPC increased with the increased HR (positive type) or not (nonpositive type). The effects of the drugs were assessed based on the VPC-HR correlation and on the percent reduction of the VPC frequency. Mexiletine and disopyramide significantly decreased the frequency of the VPCs of both the positive and nonpositive types. Each drug was assumed to be effective when the percent reduction of the VPC frequency exceeded 70%. Mexiletine (300 mg/day) was 58.5% effective in positive type patients and 33.3% effective in nonpositive type patients, with a total efficacy of 45.8%. Disopyramide was effective in 50% of total cases with 44.4% in positive type patients and 54.5% in nonpositive type patients. However, the efficacy of these drugs on the 2 different types of VPCs was the same statistically. The findings strikingly contrasted those obtained with diltiazem and atenolol, which predominantly suppressed VPCs of the positive type which share similar characteristics with a triggered activity in vitro. We conclude that the mode of action of class I antiarrhythmics on the VPCs differs from that of class II or IV antiarrhythmics, as viewed from the VPC-HR relationship, and that the difference probably comes from the different arrhythmogenesis for positive and nonpositive types of VPCs, in addition to the different electrophysiological actions of mexiletine and disopyramide.

Cardiac Complexes, Premature↗
PubMed1993

Effects of pilsicainide on the atrial fibrillation threshold in guinea pig atria. A comparative study with disopyramide, lidocaine and flecainide.

The effects of pilsicainide, a new class Ic antiarrhythmic agent, on the atrial fibrillation threshold (AFT), the atrial effective refractory period (ERP), and the interatrial conduction time (ACT) in Langendorff-perfused guinea pig hearts were investigated. These effects were compared with those of disopyramide, lidocaine and flecainide. Whole guinea pig heart was perfused with Tyrode's solution containing acetylcholine (3 x 10(-7) M). Three indices were measured before and after the administration of the test drugs using right atrial extrastimulus and high frequency stimulation. Pilsicainide, disopyramide and flecainide (> or = 10(-6) M) all significantly increased the AFT. Both pilsicainide and flecainide (> or = 3 x 10(-6) M) significantly prolonged the ERP, but this prolongation was less pronounced than that observed with disopyramide. The ACT was significantly prolonged with pilsicainide (> or = 10(-6) M), and this prolongation was greater than that observed with disopyramide but less than that with flecainide. Lidocaine had no effects on any of the indices measured. In conclusion, pilsicainide had a preventive effect on the atrial fibrillation induced by a combination of acetylcholine and high frequency stimulation in guinea pig hearts, by increasing the atrial ERP and slowing the interatrial conduction. These effects may explain, in part, the clinical effectiveness of this drug on paroxysmal atrial fibrillation.

Animals↗
PubMed1984

Circadian phase dependent pharmacokinetics of disopyramide in mice.

The focus of the reported work is investigation of disopyramide chronopharmacokinetics in the mouse. Different groups of male NMRI mice maintained under controlled environmental conditions (LD: 0600-1800) received a single intraperitoneal injection of disopyramide (30 mg per kg of body weight) at one of four different fixed time points of a 24-h period, i.e. 1000, 1600, 2200 or 0400. Blood samples were taken 0.5, 1, 2, 3, 4 and 6 hr after drug administration and total and free plasma levels of disopyramide were measured by an immunoenzymatic method. Our data showed statistically significant circadian rhythms in the following pharmacokinetic parameters: highest volume of distribution = 3.91 +/- 0.21 l kg-1 at 2200 (circadian amplitude, half the peak-to-trough difference relative to the 24-hr mean multiplied by 100, is 34%); highest area under concentration curves = 16.06 +/- 1.03 micrograms ml-1 hr-1 at 0400 (circadian amplitude = 43%) and highest clearance = 3.04 +/- 0.19 l hr-1 kg-1 at 2200 (circadian amplitude = 21%). Protein binding of the drug was shown to be circadian time dependent. Alpha and beta phase elimination half-lives were not found to be significantly circadian phase-dependent. Thus circadian changes in disopyramide clearance may represent circadian changes in the drug's volume of distribution.

Absorption↗