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PubMed2001

Species difference in stereoselective involvement of CYP3A in the mono-N-dealkylation of disopyramide.

1. To determine which CYP isoenzyme is involved in the N-dealkylation of disopyramide (DP) metabolism in human and dog, and to determine the stereoselectivity of DP metabolism with human CYP and dog CYP isoenzymes, the following in vitro metabolism studies of DP were conducted: correlation between human CYP isoenzyme activities and DP metabolism with human liver microsomes; inhibition of DP metabolism in human and dog liver microsomes with chemical inhibitors of CYP isoenzymes; inhibition of DP metabolism in human microsomes with human CYP antibodies; inhibition of DP metabolism in dog liver microsomes with human and dog CYP antibodies; metabolism of DP with human (CYP3A4) and dog (CYP3A12) cDNA-expressed isoenzymes; determination of Km and Vmax of DP enantiomers by using cDNA-expressed CYP3A4 and CYP3A12. 2. In human liver microsomes, the formation of the mono-N-dealkylated disopyramide (MNDP) metabolite was best correlated with CYP3A4 activities. DP metabolism was substantially inhibited by ketoconazole, troleandomycin (TA) and human CYP3A4 antibody. DP was metabolized by cDNA-expressed CYP3A isoenzymes. In dog liver microsomes, DP metabolism was inhibited by ketoconazole, TA and dog anti-CYP3A12. DP was also metabolized by cDNA-expressed CYP3A12. 3. CYP3A4 and CYP3A12 are the principal isoenzymes involved in DP metabolism in human and dog respectively. There was no stereoselectivity in N-dealkylation of DP by human CYP3A4. However, there was notable stereoselectivity in the N-dealkylation by dog CYP3A12.

Amino Acid Sequence↗
PubMed1991

Antiarrhythmic drugs preferentially produce conduction block at the area of slow conduction in the re-entrant circuit of canine atrial flutter: comparative study of disopyramide, flecainide, and E-4031.

STUDY OBJECTIVE: The aim was to test whether antiarrhythmic drugs preferentially suppressed conduction in the area of slow conduction in the re-entrant circuit. DESIGN: Intravenous disopyramide [n = 8, plasma concentrations: 1.4 (SEM 0.2) micrograms.ml-1], flecainide [n = 8, 0.6(0.1) micrograms.ml-1], and E-4031, a new class III antiarrhythmic drug [n = 8, 5.6(1.0) ng.ml-1], were investigated for their effects on atrial flutter due to re-entry in dogs with intercaval crush. In three dogs, detailed atrial activation sequence during atrial flutter was determined with a hand held bipolar electrode and an epicardial isochronal map was drawn. EXPERIMENTAL MATERIAL: 24 anaesthetised adult mongrel dogs were used. MEASUREMENTS AND MAIN RESULTS: There was an area of slow conduction during atrial flutter in the low right atrium. Atrial flutter was terminated in all dogs except for one treated with flecainide. In 92% of the dogs, conduction block occurred in the low right atrium in which the area of slow conduction was located. Increase in local conduction time was greater in the area of slow conduction than other parts of the atria (percent ratio to the increase in cycle length of atrial flutter: 63% with disopyramide, 52% with flecainide, and 99% with E-4031). CONCLUSION: These data suggested antiarrhythmic drugs preferentially suppressed conduction at the area of slow conduction in the re-entrant circuit leading to termination of atrial flutter in this canine model, irrespective of electrophysiological effects of antiarrhythmic drugs.

Animals↗
PubMedDate not supplied

Disopyramide fatality: case report and GC/FID analysis.

This case involves massive ingestion of disopyramide by a 19-year-old male, found dead, not having had the benefit of medical intervention. Quantitation of the drug was accomplished by gas chromatography using a flame ionization detector (GC/FID). Identification of the compound was done by thin layer chromatography (TLC) and ultraviolet spectrophotometry (UVS). The blood concentration of disopyramide was 15 times the usual therapeutic level and was easily detected by FID.

Adult↗
PubMed1983

Hypoglycemic coma due to disopyramide toxicity.

Disopyramide (Norpace) is a widely used, generally well tolerated antiarrhythmic agent. We have described an 82-year-old patient with non-insulin-dependent diabetes mellitus and renal insufficiency who had hypoglycemic coma and obstructive uropathy due to disopyramide therapy.

Aged↗
PubMed1982

Plasma disopyramide concentrations following a 300-mg oral loading dose in acute myocardial infarction.

Plasma disopyramide concentrations were measured in 19 patients with suspected myocardial infarction (MI) following an oral loading dose of 300 mg. Infarction was confirmed in 17 patients. In 10 patients blood samples were collected frequently over a period of 6 h, and in the remaining nine, blood samples were collected for 60 h whilst they were receiving a maintenance dose of 100 mg six hourly. There was a wide variation in the absorption of the drug, and only 8 patients achieved plasma concentrations in the range 2-4 mg/L within one hour of ingestion; 8 of the patients on maintenance therapy were within this range 24 h following the start of therapy. Although only 2 noninfarct patients were observed, they achieved the highest plasma disopyramide concentrations--above the therapeutic range--within 1 h of receiving the loading dose. Narcotic analgesia was associated with poor absorption of the drug, but this does not exclude severity of infarction or vomiting after the loading dose from contributing to the wide variation in plasma concentrations in the early stages following the loading dose. It is concluded that this regime is unsuitable for prophylactic use in acute MI.

Adult↗
PubMed1976

Hemodynamic and electrocardiographic effects of disopyramide in patients with ventricular arrhythmia.

Antiarrhythmic and hemodynamic effects of i.v. disopyramide phosphate (1.7 mg/kg b.wt. over 2 min) have been studied in nine patients, several in various degrees of cardiac decompensation, with sinus rhythm and persistent ventricular ectopic beats (VEBs). In one case with primary cardiomyopathy, with greater than 30 VEBs/min, disopyramide (DE) abolished the arrhythmia for 30 min, but precipitated brief dysponea. Other side-effects were tolerable and mainly attributable to anticholinergic effects of the drug. DE either abolished or significantly reduced the arrhythmia in all cases. For 30 min, only one patient showed VEBs, and in three patients no VEBs were seen for three hours. Changes in cardiac output and pulmonary artery (PAP) and central aortic pressures were measured in eight patients. Negative inotropic effects were indicated in seven by an increased diastolic PAP/stroke volume ratio and in seven by a decreased central aortic (dp/dt)max. Patients with high control values for diastolic PAP showed marked reductions in cardiac output, stroke volume and stroke work. In predicting myocardial depressant effects of DE, the control values for diastolic PAP seemed to be superior to central venous pressure, cardiac index and systolic time intervals. Mean arterial pressure measured 5 and 10 min after drug administration showed no significant change, indicating that vasoconstrictor reflexes were well preserved, and a pressure level significantly above the control value was reached from the 20th min. It is concluded that DE is potent in suppressing VEBs but exerts negative inotropic effects that may be of clinical importance. The optimal antiarrhythmic dose is probably lower than that used in the present study.

Arrhythmias, Cardiac↗
PubMed1989

Impairment of the antagonism of vecuronium-induced paralysis and intra-operative disopyramide administration.

A 63-year-old male was admitted to hospital for a cholecystectomy, vagotomy and gastro-enterostomy. Muscle paralysis was induced with 70 micrograms/kg vecuronium, followed by increments of 20 micrograms/kg when the initial twitch height returned to 25% of control. The patient received 3 doses of 10 mg disopyramide intravenously, on account of supraventricular ectopic beats, followed by an infusion of 25 mg/hour. Paralysis was reversed using 0.75 mg atropine and 2.5 mg neostigmine once the twitch height had returned spontaneously to 25% of its initial value. Fifteen minutes later, twitch height had returned to control value and the train-of-four was above 85%, but the responses to tetanic stimulation at 100 Hz and 50 Hz remained severely depressed (10% and 45%, respectively). The patient's trachea was extubated after 20 minutes, but residual fade was still observed. This impairment of neuromuscular transmission, detected only with high frequency stimulation, was present with a measured concomitant plasma level of disopyramide of 5.1 micrograms/ml.

Atropine↗
PubMed1979

The effect of intravenous disopyramide phosphate on recurrent paroxysmal tachycardias.

1 Reccurent paroxysmal atrial, atrioventricular and ventricular tachycardias in 50 patients without acute coronary insufficiency, heart failure or metabolic abnormlity were treated with disopyramide phosphate in a dose of 2 mg/kg body weight infused over 5 min. 2 Conversion to sinus rhythm within 10 min of the completed infusion occurred in 10 of 14 (71%) patients with paroxysmal 'lone' atrial fibrillation, 3 of 7 (43%) patients with paroxysmal atrial flutter, 6 of 9 (67%) patients with paroxysmal atrial tachycardia, 5 of 9 (56%) patients with paroxysmal atrioventricular tachycardia associated with the Wolff-Parkinson-White syndrome and 8 of 11 (73%) patients with paroxysmal ventricular tachycardia. 3 Side effects: significant systemic hypotension in 3, high grade AV block in 1, an increased ventricular response producing symptoms in 4, post conversion asystole in 1 land sinus bradycardia in 2. 4 The anti-arrhythmic effect and arrhythmogenic side effects may be related to both the direct membrane stabilizing effect and the anticholinergic effect of disopyramide.

Atrial Fibrillation↗
PubMed1980

Quantitative analysis of the disopyramide concentration-effect relationship.

1. A combined pharmacokinetic-pharmacodynamic model has been used to analyse the relationship between QT prolongation and changes in plasma concentration which occurred after disopyramide was given intravenously and orally to eight healthy subjects. 2. The pharmacokinetic models appropriate to intravenous and oral disopyramide have been extended by an 'effect compartment' which has no influence on the predetermined mass of drug in the body. 3. The model incorporates an adjustment for lag of effect behind any rapid changes in plasma concentration such as occur in the early distributive phase following intravenous administration. This permits calculation of the proportionality constant relating plasma concentration to effect. 4. Irrespective of the route of administration the mean (+/- s.d.) prolongation of the QT interval was 14.5 +/- 6.5 ms/micrograms ml-1. 5. There was no evidence that metabolite produced during first pass after oral administration made any significant contribution to effect. 6. This modelling technique should be applicable to the study of the concentration-effect relationship of a number of other drugs, both in health and in disease.

Administration, Oral↗
PubMed1982

Disopyramide pharmacokinetics during recovery from myocardial infarction.

1 Previous pharmacokinetics studies of disopyramide in patients with ischaemic heart disease include unexplained reports of poor bioavailability and extremely long elimination half-lives which undermine accepted dosage recommendations. 2 Disopyramide pharmacokinetics were investigated after intravenous and oral administration to nine such patients. 3 Mean elimination half-life (6.82 h) and bioavailability (79.8%) were consistent with findings from a previous study in young healthy volunteers. 4 Volume of distribution was reduced by 25%: the mean +/- s.d. value was 0.61 +/- 0.17 l/kg. Total body clearance was significantly reduced: the mean +/- s.d. value was 1.02 +/- 0.16 ml min-1 kg-1. 5 These figures indicate that, in this patient group, if renal function is not significantly impaired, a standard loading dose of 2 mg/kg should be followed by the appropriate maintenance dose administered three or four times daily.

Adult↗
PubMed1991

Stereoselective pharmacokinetics of disopyramide and interaction with cimetidine.

The pharmacokinetics of each of the enantiomers of disopyramide were examined after i.v. bolus administration of 150 mg racemic drug in a randomized cross-over study before and after the administration of cimetidine 400 mg twice daily orally. Clearance and volume of distribution (Vz) of total drug were significantly (P less than 0.001) higher for the R-(-) enantiomer than the S-(+) enantiomer (7.9 vs 4.6 l h-1 and 89 vs 50 l, respectively), whereas no significant difference in half-life could be demonstrated. The clearance of free drug was significantly (P less than 0.05) higher for the S-(+) enantiomer than that of the R-(-) enantiomer (34.6 +/- 5.4 l h-1 vs 27.2 +/- 5.6 l h-1), whereas no significant enantioselective difference in unbound volumes of distribution (258 +/- 38 l vs 226 +/- 42 l) could be demonstrated. Coadministration of cimetidine did not alter the pharmacokinetics of disopyramide. A significant concentration- or time-related decrease in the renal clearance of each of the enantiomers measured with respect to total drug in serum was observed, whereas renal clearances of the free enantiomers were similar.

Adult↗
PubMed1982

Comparison of a high pressure liquid chromatographic analysis and an enzyme immunoassay technique for quantitation of disopyramide in serum or plasma.

High pressure liquid chromatographic (HPLC) and enzyme immunoassay (Emit) methods for measuring disopyramide concentrations in plasma and serum were compared. The precision of both methods was satisfactory, with all coefficients of variation in the range 1.3--6.5%. Quantitation was comparable, with a correlation coefficient of 0.991 (n = 96). There was no interference in either method from lignocaine, digoxin, propranolol, procainamide or N-monodealkylated disopyramide. HPLC was superior in terms of lower cost, the ability to quantitate metabolite concentrations, lack of interference by lipaemia or haemolysis and slightly better within-run precision. However, Emit was considered the method of choice for routine therapeutic drug monitoring because of its relative simplicity and speed of performance.

Antibody Specificity↗
PubMed1980

Disopyramide induced atypical ventricular tachycardia.

A patient presenting with atypical ventricular tachycardia due to oral disopyramide given in normal doses over a period of four months is described. This arrhythmia was preceded by marked prolongation of the QTc. It is suggested that patients receiving treatment with oral disopyramide should be closely monitored for symptoms of ventricular tachyarrhythmias, particularly in the face of a prolonged QTc.

Administration, Oral↗
PubMed1983

Effect of disopyramide on isolated aortic ring of the rat.

Disopyramide produces a contraction of the isolated aortic ring of the rat which is graded, develops slowly, and has a time course similar to the tonic phase of the noradrenaline response. This effect is not modified by alpha-adrenoceptor blockade (yohimbine) but is completely abolished by a Ca2+ antagonist (verapamil) or by removal of Ca2+ from the bathing solution. These results indicate that, in the rat aorta, disopyramide has a vasoconstrictor effect dependent on Ca2+ influx across the vascular smooth muscle membrane.

Adrenergic alpha-Antagonists↗
PubMed1975

Effects of disopyramide on electrophysiological properties of specialized conduction system in man and on accessory atrioventricular pathway in Wolff-Parkinson-White syndrome.

Seven patients with normal specialized conduction system and three patients with the Wolff-Parkinson-White (WPW) syndrome were studied using programmed stimulation of the heart before and after the administration of intravenous disopyramide. The principal effect of this drug was to prolong the effective refractory period of the atria and ventricles, and to prolong the effective refractory period of the anomalous pathway in the WPW syndrome. In addition, it prolonged the conduction time in the anomalous pathway in the WPW syndrome. These findings suggest that disopyramide would be a useful and safe drug in the management of certain atrial and ventricular arrhythmias and in the management of the Wolff-Parkinson-White syndrome with atrial fibrillation.

Adolescent↗
PubMed1979

Haemodynamic effects of disopyramide in patients after open-heart surgery.

Disopyramide phosphate was administered intravenously in a dose of 1.2 mg/kg body weight over one minute to nine patients after open-heart surgery and coronary artery bypass grafting. The haemodynamic changes were studied during and for 30 minutes after drug administration. Heart rate was unchanged throughout the study. During infusion the only significant changes were an increase in systemic blood pressure and systolic impedance signifying a direct increase in peripheral arterial resistance. Systemic blood pressure remained significantly higher for 10 minutes and systolic impedance for 30 minutes. Immediately after infusion max. dPower/dT, a measure of ventricular contractility, was significantly depressed for 15 minutes. Both cardiac output and aortic flow were significantly depressed for 30 minutes. DPTI/TTI, an estimate of subendocardial supply/demand ratio, showed an insignificant increase throughout the study. This study shows that intravenous disopyramide starts acting within 45 seconds of the start of infusion, directly increases peripheral arterial resistance, has a breif negative inotropic action, and does not reduce subendocardial blood flow.

Adult↗
PubMed1980

Response of atrial flutter to overdrive atrial pacing and intravenous disopyramide phosphate, singly and in combination.

Ten patients who suffered spontaneous paroxysms of atrial flutter were investigated by electrophysiological techniques. Two had overt Wolff-Parkinson-White syndrome; three Lown-Ganong-Levine syndrome; and one a concealed accessory atrioventricular connection. Atrial flutter was initiated, at study, by right atrial pacing and electrograms from the right atrium and coronary sinus were observed for at least five minutes to ensure stable flutter in both atria. Atrial flutter was terminated by 2.5 s or 5 s bursts of atrial pacing at rates 10, 50, or 100 beats/min faster than the intrinsic flutter rate in only two patients. Atrial flutter, which was reinitiated in two patients, was then treated with intravenous disopyramide phosphate, 2 mg/kg body weight, infused over five minutes. In all 10 patients the atrial rate slowed from a mean of 310 +/- 39 beats/min to 217 +/- 27 beats/min and atrial flutter terminated in one case. Though the mean ventricular rate fell from 161 +/- 52 beats/min to 156 +/- 45 beats/min the atrioventricular conduction ratio fell from 2.17 +/- 0.86 to 1.55 +/- 0.59 and four patients were left with symptomatically significant increases of ventricular rate. In seven of nine patients overdrive atrial pacing, repeated after disopryamide, resulted in the conversion of atrial flutter to sinus rhythm. In this study, overdrive atrial pacing and intravenous disopyramide, singly and in combination, terminated atrial flutter in nine of the 10 patients and it is suggested that this method may provide an effective alternative to direct current cardioversion.

Adult↗
PubMed1985

Intravenous sotalol for the treatment of atrial fibrillation and flutter after cardiopulmonary bypass. Comparison with disopyramide and digoxin in a randomised trial.

The efficacy of sotalol in treating acute atrial fibrillation and flutter after open heart surgery was compared with that of a digoxin/disopyramide combination. Forty adult patients with postoperative atrial arrhythmias were randomised into either group 1 (sotalol 1 mg/kg bolus intravenously plus 0.2 mg/kg intravenously over 12 hours) or group 2 (digoxin 0.75 mg intravenously, then two hours later disopyramide 2 mg/kg intravenous bolus and 0.4 mg/kg/h intravenously for 10 hours). In each group, 17 out of 20 patients reverted to sinus or junctional rhythm within 12 hours. The time to reversion in group 1 was significantly shorter than in group 2. Systolic blood pressure fell by greater than or equal to 20 mm Hg or to less than or equal to 90 mm Hg during drug administration in 17 out of 20 patients in group 1 (sotalol withdrawn in two) and in none out of 20 in group 2. Two patients in group 1 developed transient bradycardia (sotalol withdrawn in one). None of 17 patients in group 1 and two of 17 in group 2 relapsed temporarily into atrial fibrillation during the 12 hours of intravenous treatment. On continued oral treatment, one late relapse occurred in group 1 and five in group 2, and five patients in group 2 had disopyramide withdrawn because of anticholinergic side effects (acute urinary retention in four). Sotalol was as effective as the digoxin/disopyramide combination and acted significantly faster. Sensitivity to beta blockade in these patients may be related to high plasma catecholamine concentrations known to occur after cardiopulmonary bypass.

Atrial Fibrillation↗