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PubMed1985

Disopyramide pharmacokinetics in patients with acute myocardial infarction.

To study the effects of acute myocardial infarction on the pharmacokinetics of disopyramide a single oral dose of disopyramide base (200 mg) was administered to 6 patients with myocardial infarction both in the acute (Study I) and recovery (Study II) phases. An intravenous tracer dose of 14C-disopyramide (2.5 micrograms/0.3 mg) was given simultaneously with the oral dose. On the basis of the intravenous tracer data, the volume of distribution, binding to plasma proteins, total plasma clearance, renal clearance and elimination half-life of disopyramide and mono-N-dealkyl disopyramide were the same in Studies I and II. The peak serum concentrations of disopyramide after oral dosing in Studies I and II were 2.6 +/- 1.2 (SEM) and 6.4 +/- 1.9 microgram/ml, respectively (p less than 0.05), the peak times 3.29 +/- 1.22 and 1.21 +/- 0.39 h (N.S.) and the AUCINF 38.0 +/- 7.7 and 60.7 +/- 9.9 micrograms . h . ml-1 (p less than 0.05). The recovery of disopyramide in urine over 3 days averaged 46% and 47% of dose, and that of mono-N-dealkyl disopyramide 22% and 16% of the dose, respectively. Thus, the gastrointestinal absorption of disopyramide was disturbed, resulting in low plasma concentrations after oral dosing, whereas the elimination of disopyramide was unaltered in the acute phase of myocardial infarction.

Administration, Oral↗
PubMed1993

A placebo-controlled trial of intravenous and oral disopyramide for prevention of neurally mediated syncope induced by head-up tilt.

OBJECTIVES: A double-blind randomized trial was designed to determine the efficacy of intravenous and oral disopyramide phosphate in preventing neurally mediated syncope induced by a head-up tilt test. BACKGROUND: Neurally mediated syncope is a frequent cause of syncope and may be induced by head-up tilt testing. Recent uncontrolled trials have suggested that disopyramide may be an effective therapy in patients with neurally mediated syncope. METHODS: Twenty-two consecutive patients with recurrent neurally mediated syncope and two or more successive positive head-up tilt test responses were randomly allocated to receive either intravenous disopyramide or placebo. Head-up tilt testing at 60 degrees was performed for 15 min. If presyncope or syncope was not provoked, isoproterenol infusion was started at a rate of 1 microgram/min and the rate gradually increased until a 25% increase in heart rate was achieved. Eleven patients were subsequently randomized in crossover fashion to receive oral disopyramide (800 mg/day) or placebo during 1 week. The primary end point was prevention of syncope or presyncope provoked by head-up tilt testing. RESULTS: Head-up tilt test results were positive for syncope in 12 (75%) of 16 patients receiving intravenous placebo and in 12 (60%) of 20 patients receiving disopyramide (p = 0.55 Fisher exact test, 95% confidence interval [CI] -14% to 40%). In the intravenous phase, complete crossover was achieved in 15 patients. Head-up tilt test results during this phase were positive in 13 patients (87%) receiving placebo and in 12 patients (80%) receiving disopyramide (p = 0.50 Fisher exact test, 95% CI -19% to 32%) and were positive in all patients receiving their initially randomized drug or placebo. In the oral phase, head-up tilt results were positive in only two patients (18%) assigned to placebo and in three patients (27%) receiving disopyramide (p = 0.54 Fisher exact test, 95% CI -42% to 24%). A mean follow-up time of 29 +/- 8 months was obtained in 21 of the 22 patients. Syncope recurred in 3 (27%) of the 11 patients receiving disopyramide and 3 (30%) of the 10 patients not treated pharmacologically (p > 0.05). CONCLUSIONS: Intravenous disopyramide was ineffective for the prevention of neurally mediated syncope provoked by head-up tilt testing. No significant effect was observed after oral therapy with disopyramide. There was a striking decrease in the incidence of positive tilt test results over time regardless of intervention, thus discouraging the use of head-up tilt as the single method of assessing therapeutic efficacy. Recurrence of syncope after the investigative protocol was infrequent over long-term follow-up regardless of treatment group.

Administration, Oral↗
PubMed1992

Effects of a combination of disopyramide and mexiletine on the anterograde accessory pathway conduction in patients with Wolff-Parkinson-White syndrome.

In order to evaluate the electrophysiological effects of the combined administration of disopyramide and mexiletine on anterograde accessory pathway conduction, we studied 11 patients with Wolff-Parkinson-White (WPW) syndrome. Disopyramide was first infused intravenously at 1 mg kg-1 for 5 min followed by a continuous infusion at 0.025 mg kg-1 min-1. After the infusion rate of disopyramide was decreased to 0.004 mg kg-1 min-1 to maintain a lower serum concentration, mexiletine was infused at 2 mg kg-1 for 5 min followed by a continuous infusion at 0.008 mg kg-1 min-1 (protocol 1). The shortest atrial paced cycle length with 1:1 anterograde accessory pathway conduction (shortest CL with 1:1) and the anterograde effective refractory period of the accessory pathway (ERP) were measured: (1) before drug administration, (2) after disopyramide was given alone, and (3) after disopyramide and mexiletine were combined at lower concentrations. The same protocol was repeated with the order of drug administration reversed (mexiletine followed by disopyramide) in all patients (protocol 2). Both disopyramide and mexiletine lengthened the shortest CL with 1:1 and the ERP to the same degree. The combination of disopyramide and mexiletine at lower concentrations further lengthened the shortest CL with 1:1. It was longer than with disopyramide (protocol 1) or mexiletine (protocol 2) alone [protocol 1: 412 +/- 169 ms (combination) vs 356 +/- 117 ms (disopyramide); P less than 0.05, protocol 2: 409 +/- 166 ms (combination) vs 355 +/- 119 ms (mexiletine); P less than 0.01].(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Stereoselective effects of disopyramide enantiomers in humans.

The effects of 100 mg of (S+)- and R(-)-disopyramide infused over 20 min on systolic time intervals and the QT interval were compared in five healthy volunteers. S(+)-disopyramide maximally prolonged the QTI (QT corrected for heart rate) by 10% (p less than 0.05); R(-)-disopyramide had no effect on QTI. R(-)-disopyramide maximally prolonged the preejection period and shortened the left ventricular ejection time corrected for heart rate (PEPI and LVETI), and increased the ratio of PEP/LVET by 32, 6, and 52%, respectively; S(+)-disopyramide maximally increased PEPI and PEP/LVET 15 and 20%, respectively (p less than 0.05), and had no effect on LVETI. These data suggest that the electrophysiologic effects of disopyramide enantiomers are different, and that S(+)-disopyramide has a less negative inotropic effect than R(-)-disopyramide. Changes in response were fitted to a pharmacokinetic-pharmacodynamic model, which estimated that 72% of the negative inotropic effects associated with racemic disopyramide may be avoided by using S(+)-disopyramide.

Adult↗
PubMed1987

Comparison of propafenone and disopyramide in the treatment of ventricular premature complexes: a randomized double blind crossover placebo controlled trial.

To determine the efficacy of the newer antiarrhythmic drug propafenone and to compare it to disopyramide, sixteen patients--11 men and 5 women--participated in a randomized double-blind crossover placebo-controlled trial using 150 mg quid of propafenone or disopyramide. Twenty-four hour ECG's were performed at the end of the placebo period and each 2 weeks of drug therapy. Droupouts (2) because of adverse effects were not included in analysis. On placebo there were 485 +/- 535 (mean +/- SD) ventricular premature complexes (VPC's)/hour. Propafenone significantly (p = 0.010) reduced VPC's to a slightly smaller amount 182 +/- 298/hour. There was no significant difference between propafenone and disopyramide in suppressing VPC's, however, analysis of the circadian rhythm of VPC's showed a greater reduction in VPC's from 1600 to 2400 hour after propafenone compared to disopyramide using this dose regimen. Using a criterion of efficacy of greater than 80% reduction in VPC's, 8/14 patients had a good suppression with propafenone, 3 patients responded only to propafenone, 4 patients only to disopyramide, 5 patients to both and 2 patients to neither. Using a criterion of efficacy of greater than 65% reduction in VPC's 11/14 patients had good suppression with propafenone or disopyramide, 3 patients responded only to propafenone and 4 patients only to disopyramide. Side effects were more common with disopyramide. Two patients dropped out after disopyramide because of gastrointestinal symptoms. Side effects were found in 11/14 remaining patients on disopyramide, but in 6/14 on propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗
PubMed1987

The pharmacokinetic and pharmacodynamic effects of varying the free fraction of disopyramide.

We have evaluated the influence of several factors on the binding of disopyramide to protein in human serum using a new ultrafiltration system and the enzyme multiplied immunoassay technique (EMIT) for disopyramide immunoassay. From these studies and those of other investigators, we conclude that the most significant in vivo factors influencing disopyramide binding in human serum are total disopyramide concentration, the concentration of alpha 1-acid glycoprotein, and the concentration of mono-N-dealkyldisopyramide. Significant variation in binding occurs in patients whose total disopyramide concentration is within the therapeutic range. The proportion of free disopyramide ranged from 16% to 54% in the sera of 50 cardiac patients whose total disopyramide concentration ranged from 0.5 to 5.8 mcg/ml. Since there is so much variation in the proportion of disopyramide that is free, and since it is the unbound form of the drug that is pharmacologically active, it is likely in patients whose arrhythmia responds to disopyramide therapy that unbound drug concentration will be a better indicator of drug efficacy and toxicity than will be total drug concentration. To test this hypothesis, we are investigating the relationship between steady state total and unbound disopyramide plasma levels in patients with supraventricular or ventricular arrhythmias, and pharmacologic response as determined by standard intracardiac electrophysiologic studies.

Blood Proteins↗
PubMed1985

Factors affecting the binding of disopyramide to serum proteins.

We investigated the influence of the following factors on the binding of disopyramide to serum proteins: method of drug quantification [enzyme immunoassay (EMIT) compared with liquid chromatography (HPLC)], separation technique (ultrafiltration vs equilibrium dialysis), temperature, pH, and total concentration of disopyramide. EMIT and HPLC measurements of disopyramide in ultrafiltrates prepared from 50 sera agreed well: EMIT = 1.046 HPLC + 0.042, (r = 0.928, SEE = 0.04 mg/L). Free disopyramide concentrations in ultrafiltrates of dialyzed sera were similar to those measured in the corresponding dialysates by the EMIT method for 30 patients' sera: ultrafiltrate of serum retentate = 1.053 dialysate + 0.042. Concentrations of free [14C]disopyramide were little affected by temperature. The concentration of free disopyramide decreased as the pH was increased from 7.0 to 7.8. The concentration of free disopyramide, as determined by ultrafiltration, is strongly and directly related to total drug concentration. In the sera of 50 cardiac patients receiving chronic therapy with disopyramide and with total disopyramide concentrations of 0.5 to 5.8 mg/L, the proportion of free disopyramide ranged from 16 to 54%.

Blood Proteins↗
PubMed1996

Propafenone versus disopyramide for maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation: a randomized, double-blind study. PRODIS Study Group.

Safety and efficacy of propafenone and disopyramide for long-term maintenance of sinus rhythm after electrical cardioversion was studied in 56 patients with chronic atrial fibrillation (median arrhythmia duration, 5 months). After cardioversion, patients were randomly assigned to receive double-blind propafenone 300 mg tid (25 patients) or disopyramide 250 mg tid (31 patients). Downward dose adjustment was allowed in case of intolerable side effects. The endpoints were arrhythmia recurrence; and side effects not amenable to dose reduction. For patients randomized to propafenone (mean dose, 878 +/- 65 mg/day), 66% [95% confidence interval [(CI) 46-85%] and 55% (95% CI, 34-76%) remained in sinus rhythm at 3 and 6 months, respectively (Kaplan-Meier method). Similar figures were found with disopyramide (mean dose, 704 +/- 81 mg/day): 71% (95% CI, 54-87%) and 67% (95% CI, 50-84%) at 3 and 6 months, respectively (p = NS). In the patients with a relapse of atrial fibrillation, the ventricular rate while still using the prophylactic agents did not increase significantly compared with precardioversion. However, one patient on disopyramide had an excessively high relapse heart rate (170 vs. 100 beats/min). Side effects were more frequent on disopyramide. Side effects necessitating drug discontinuation occurred in 12 patients: 4 patients (16%) on propafenone and 8 (26%) on disopyramide. Severe adverse effects occurred in two patients, who developed heart failure while on disopyramide. There were no proarrhythmic events or deaths. Thus, propafenone and disopyramide are equally effective for maintaining sinus rhythm after cardioversion of atrial fibrillation. Propafenone is, however, better tolerated than disopyramide, which may cause heart failure.

Aged↗
PubMed1986

Kinetics of disopyramide in decreased hepatic function.

The elimination kinetics of disopyramide was studied in 9 patients with decreased hepatic function (DHF) due to histologically verified cirrhosis of the liver, and in 11 patients with ischaemic heart disease (IHD). Disopyramide 100 and 150 mg was given intravenously as a bolus to the patients with IHD and DHF, respectively, followed by a continuous infusion of disopyramide 0.3 (DHF group) and 0.4 mg X min-1 (IHD group) until steady-state was achieved. A significant (p less than 0.001) positive correlation between the percentage unbound and total serum concentration of disopyramide was demonstrated in both groups. The percentage of unbound disopyramide at a total serum concentration of 5.9 mumol X l-1 was 45.5% and 19.4% in the DHF and IHD groups, respectively. A negative correlation (r = -0,751, p less than 0.05, and r = -0.827, p less than 0.01 in the IHD and DHF patients, respectively) between the free fraction of disopyramide and alpha 1-acid glycoprotein was observed. The serum concentration of alpha 1-acid glycoprotein, the major binding protein of disopyramide, was significantly lower in the patients with DHF. The clearance of unbound disopyramide and its total volume of distribution and half-life were significantly lower in the DHF patients. No difference in total elimination clearance could be demonstrated. The clinical implication of the present findings appear to be that the dosage of disopyramide should be reduced by 25% when it is given intravenously to patients with decreased hepatic function.

Adult↗
PubMed1985

Comparison of propafenone and disopyramide for treatment of chronic ventricular arrhythmias: placebo-controlled, double-blind, randomized crossover study.

In a double blind, placebo-controlled study, the efficacy of propafenone, a new antiarrhythmic drug was compared to that of disopyramide. Sixteen patients with frequent and complex premature ventricular contractions (PVCs) were studied by serial 24-hour ambulatory monitoring, while they were receiving propafenone, 300 mg, and disopyramide, 200 mg, both every 8 hours. A reduction in the mean frequency of PVCs per hour, in comparison to the placebo period, from 574 +/- 535 to 100 +/- 130, was observed after propafenone (p less than 0.005) and from 629 +/- 455 to 231 +/- 280 after disopyramide (p less than 0.008). A greater than 70% reduction in PVCs in comparison to placebo was observed in 11 of 14 after propafenone and 9 of 15 after disopyramide (NS). A greater than or equal to 90% reduction in PVCs was observed in 9 of 16 with propafenone and in 4 of 15 with disopyramide (p less than 0.05). The suppression of complex PVCs (repetitive, polymorphic, or more than 5/min with bigeminism) was observed in 11 of 14 after propafenone and in 9 of 14 after disopyramide. The abolition of nonsustained ventricular tachycardia was observed in 6 of 6 and 3 of 5, respectively, after propafenone and disopyramide (p less than 0.05). A lower incidence of side effects, 4 of 16 vs 8 of 16, was observed during propafenone than during disopyramide treatment. We conclude that propafenone, in a dose of 900 mg daily, is more effective than disopyramide, in a dose of 600 mg daily, in the treatment of frequent and complex PVCs and nonsustained ventricular tachycardias. Propafenone also showed a lower incidence of side effects.

Adult↗
PubMed1995

Inhibition of ATP-sensitive K+ channels of mouse skeletal muscle by disopyramide.

Single ATP-sensitive K+ channels (KATP channels) were studied in inside-out membrane patches excised from mouse skeletal muscle. The class Ia antiarrhythmic, disopyramide (5-100 microM), applied to the cytoplasmic membrane surface inhibited KATP channels at -40 and +40 mV. Channel inhibition by disopyramide started slowly and reached an almost stationary level within 1 min. Recovery from channel inhibition by disopyramide was incomplete. At pH 7.4, the disopyramide concentrations producing 50% channel inhibition were 8.1 microM at -40 mV and 7.1 microM at +40 mV. The Hill coefficients of the concentration-response curves were close to unity at both potentials. Raising the internal pH from 7.4 to 8.0 had no significant effect on the actions of disopyramide, but lowering the pH to 6.5 greatly potentiated the inhibition of KATP channels by the antiarrhythmic. Thus the open probabilities of KATP channels at -40 mV and in the presence of disopyramide (20 microM) were smaller by a factor of 18 at pH 6.5 than at pH 7.4. The results suggest that disopyramide interacts with KATP channels through the lipid phase of the membrane and that lowering the intracellular pH increases the affinity of KATP channels to disopyramide. Thus disopyramide at therapeutic concentrations (6-15 microM) affects muscular KATP channels, in particular at reduced intracellular pH values that occur under ischaemic conditions and during fatiguing exercise.

Adenosine Triphosphate↗
PubMed1992

Interactions with the cardiac cholinergic system: effects of disopyramide and its mono-N-dealkylated metabolite.

The cardiac vagolytic effects of disopyramide and its mono-N-dealkylated metabolite (MND), and their interactions with the cardiac cholinergic system, were assessed using in vivo and in vitro experiments. In chloralose anesthetized dogs, disopyramide phosphate (0.25 mg/kg/min) and MND at equimolar dose (0.173 mg/kg/min) reduced vagal bradycardia. As indicated by the ED80, MND exhibits a vagolytic activity 1.5-2 times less potent than disopyramide. Concomitantly, increases in heart rate and mean blood pressure were observed with disopyramide, whereas with MND only a rise in mean blood pressure occurred. In conscious dogs, where vagal tone is fully expressed, disopyramide and MND increased heart rate and, interestingly, prevented any atropine-induced additional tachycardia, though heart rate was relatively low. Binding studies on rat heart membranes yielded Ki values 2-2.5 times higher for MND than for disopyramide, and demonstrated that neither disopyramide nor MND binding modified the cardiac muscarinic receptor sites. Taken together, these results show that disopyramide exhibits a more potent cardiac vagolytic action than MND, very likely linked to a greater ability to bind to cardiac muscarinic receptors. They also show that disopyramide and MND are very potent in preventing atropine-induced "excess tachycardia", very likely by inhibiting the ionic pacemaker current(s) involved in its genesis.

Animals↗
PubMed1991

Evaluation of disopyramide and mexiletine used alone and in combination for ventricular arrhythmias in patients with and without overt heart disease.

The efficacies and side effects of disopyramide and mexiletine used alone and in combination were assessed in 29 patients with chronic ventricular arrhythmias. In combination therapy, one half or two thirds of the conventional doses of each drug were administered. Each patient underwent Holter electrocardiographic monitoring during 4 different periods: baseline, disopyramide alone, mexiletine alone and combination of the two drugs. The mean baseline number of ventricular premature complex per hour was 783 +/- 521 (mean +/- SD), which was significantly reduced with all three therapies. Disopyramide alone significantly reduced the ventricular premature complex frequency in patients with organic heart disease (P less than 0.05), but did not significantly reduce the ventricular premature complex frequency in patients with no apparent heart disease. In contrast, mexiletine alone significantly decreased the ventricular premature complex frequency in no apparent heart disease patients (P less than 0.05), but did not significantly reduce the ventricular premature complex frequency in organic heart disease patients. With disopyramide alone, patients having a significant reduction in ventricular premature complexes (greater than or equal to 83% reduction in ventricular premature complexes) or elimination of ventricular tachycardias tended to be more frequently found in organic heart disease than in no apparent heart disease. The opposite was observed with mexiletine alone. QTc interval with disopyramide alone was significantly prolonged, and the prematurity index of ventricular premature complexes was significantly lowered as compared to mexiletine alone or combination therapy (P less than 0.01 for disopyramide versus mexiletine; P less than 0.05 for disopyramide versus combination therapy). During combination therapy, no patients withdrew from the study due to side effects. However, 3 patients receiving single drug therapy withdrew from the study due to severe side effects. Consequently, disopyramide is suggested to be more effective on ventricular premature complexes in organic heart disease than in no apparent heart disease patients, whereas the opposite was true for mexiletine. A combination of disopyramide and mexiletine in smaller doses may provide almost the same or enhanced antiarrhythmic effects, no aggravation of electrocardiographical parameters and less incidence of side effects when compared to the conventional dose of each drug alone.

Administration, Oral↗
PubMed2000

Inhibition of isolated rat and human detrusor muscle contraction by disopyramide.

1. The aim of this study was to investigate the effect of in vitro and in vivo disopyramide treatment on human and rat isolated detrusor muscle contractile response. Muscle strips were suspended in an organ bath chamber containing Kreb's solution at 37 degrees C aerated with 95% oxygen and 5% carbon dioxide. 2. Disopyramide antagonized significantly the contractile response of isolated human detrusor muscle to carbachol stimulation, shifting the concentration-response curve to the right in a parallel manner. The pA2 for competitive inhibition was estimated to be 6.4 with a slope of 0.64 for disopyramide. 3. Rat detrusor muscle contractile response to electrical field stimulation (EFS) was inhibited by 28% (P < 0.01) after in vitro administration of disopyramide (7.5 x 10(-6) M). Disopyramide had no effect on the atropine-resistant component of the response to EFS or on spontaneous contractions of isolated rat detrusor muscle strips. The concentration-response curve to carbachol was competitively antagonized by disopyramide with a pA2 of 6.3 and a Schild curve a slope of 0.85. 4. Disopyramide (7.5 x 10(-6) M) had no effect on rat detrusor contractile response to low concentrations of KCl but at high concentrations contraction was reduced significantly by 16% (P < 0.01). 5. In vivo treatment of rats with disopyramide for 8 days or with a single dose had a significant inhibitory effect on the contractile response of detrusor muscle strips. 6. In conclusion, disopyramide had a significant anticholinergic effect on isolated human and rat detrusor muscle contraction.

Aged↗
PubMed1982

Disopyramide and its N-monodesalkyl metabolite in breast milk.

The plasma and breast milk were sampled from a woman who was breastfeeding whilst taking disopyramide (200 mg three times daily). Paired samples taken on the fifth to eighth day of treatment showed that disopyramide was present in breast milk in a similar concentration to plasma (mean +/- s.d. milk; plasma ratio 0.9 +/- 0.17). The estimated dose likely to be ingested by an infant is less than 2 mg kg-1 day-1. The active N-monodesalkyl metabolite of disopyramide (NMD) although present in plasma in much smaller concentrations than the parent compound, was excreted in breast milk (mean +/- s.d. milk: plasma ratio 5.6 +/2.9) in concentrations similar to those of disopyramide. The pharmacological and toxicological properties of the disopyramide metabolite need to be considered when assessing likely effects on the infant. No adverse effects were noted in the infant in this case. Maternal plasma and breast milk were sampled again along with infant plasma after 28 days. Disopyramide and NMD were undetectable in the infant's serum. No evidence was found to indicate that the concentrations of disopyramide or NMD in breast milk might be sufficient to pose a definite risk to the infant. Whenever disopyramide is prescribed in a breast feeding mother, close observation of the baby and measurement of both disopyramide and its active metabolite NMD in breast milk or infant plasma is recommended, pending further investigation.

Adult↗
PubMed1989

Disopyramide-induced hypoglycemia: case report and review of the literature.

Disopyramide is a group I antiarrhythmic drug which is mainly used for the treatment of ventricular and supraventricular rhythm disturbances. Commonest side effects result from disopyramide's anticholinergic activity. Other side effects such as hypoglycemia have been reported less frequently. We report one observation of disopyramide induced hypoglycemia, and a review of the literature is presented. Including our observation, 14 cases (9 men and 5 women, aged from 41 to 88) have so far been reported. Doses of disopyramide ranged from 200 to 1,200 mg per day, administered from one day to one year. Symptomatology was mainly neurologic (12 patients) and two patients were clinically asymptomatic. The outcome was favorable in all but the 2 patients who died with persistent hypoglycemia after a single dose of 250 mg in one patient and after 400 mg daily during 4 days in the other (without stopping the drug). Renal function was markedly impaired in 9 patients, two of these patients being on a long term dialysis therapy. Blood levels of disopyramide were measured in 7 patients and ranged from 1 to 11.4 ng/ml. In five patients it was in the normal range (1-4 ng/ml). Three patients were rechallenged for disopyramide: hypoglycemia occurred in all, without clinical symptoms in two of them. The main risk factors of disopyramide induced hypoglycemia are a preexisting chronic renal failure, advanced age, and malnutrition. In these patients normally non toxic disopyramide blood levels, as defined in normal subjects, seem to be inappropriately high. We suggest that in patients at risk, disopyramide blood levels should be maintained at the lower range of therapeutic level.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1982

The cellular electrophysiologic mechanism of the dual actions of disopyramide on rabbit sinus node function.

To determine the contribution of disopyramide's suggested opposing direct depressant and indirect acceleratory actions on sinus node function, we studied the effects of disopyramide, 1 x 10(-7) to 1 x 10(-4) M, on isolated rabbit sinus node preparations using standard microelectrode techniques. Transmembrane potentials were recorded simultaneously from the sinus node and adjoining crista terminalis area. Disopyramide, as much as 1 x 10(-5) M, had no effects on the sinus cycle length. At a concentration of 1 x 10(-4) M, sinus cycle length was significantly prolonged due to prolongation of the sinus nodal action potential duration. During cholinergic blockade with atropine, 1 x 10(-6) M, disopyramide, 1 x 10(-7) to 1 x 10(-4) M, significantly prolonged sinus cycle length as a result of a prolongation of the sinus nodal action potential duration and a decrease of the slope of phase 4 depolarization. During cholinergic stimulation with carbamyl choline, 1 x 10(-9) M, disopyramide, 1 x 10(-7) to 1 x 10(-6) M, tended to reverse carbamyl choline-induced prolongation of the sinus cycle length (NS). This acceleratory action of disopyramide was caused by a significant increase of the slope of phase 4 depolarization. Disopyramide, 1 x 10(-7) to 1 x 10(-4) M, had no significant effects on corrected sinus node recovery time or on sinoatrial conduction time under any conditions studied. We conclude that disopyramide has a direct depressant action on normal sinus node cells at the upper therapeutic and toxic levels, which is enhanced during cholinergic blockade, and that disopyramide's acceleratory action appears only at much lower concentrations and only during cholinergic stimulation.

Action Potentials↗
PubMed1983

Plasma levels of disopyramide after administration of conventional capsules and sustained-release tablets.

A study was carried out in 33 patients with myocardial infarction and complicating arrhythmias to compare plasma levels of disopyramide attained after administration of conventional capsules or sustained-release tablets. On Day 1, 29 patients started treatment wtih 600 mg disopyramide in 3 divided doses of conventional capsules. In 18, disopyramide plasma concentrations of 3 mg/l or more were achieved within 300 minutes after the first dose. On the second day, patients were allocated at random to receive treatment double-blind for 11 days with 500 mg disopyramide daily given either as conventional capsules (17 patients) or as sustained-release tablets (16 patients). Plasma concentrations were measured just before and 3 hours after the morning dose. Mean maximum and minimum concentrations in the conventional capsule group were 4.4 mg/l and 2.8 mg/l, respectively, compared to 4.3 mg/l and 3.0 mg/l, respectively, in the sustained-release tablet group. For the next 30 days all patients continued treatment with sustained-release tablets. Mean disopyramide plasma concentration measured 15 to 18 hours after the last dose was 2.8 mg/l. Myocardial function was estimated during and 1 week after discontinuing disopyramide treatment. The mean fractional fibre shortening (echocardiography) during treatment was 23% less than that 1 week after discontinuation. The mean PEP/LVET (systolic time interval recording) was 7% higher during treatment compared with 1 week after discontinuation. In 4 cases, mean ejection fraction, measured by scintigraphic methods, during treatment was 10% less than 1 week after discontinuation. Anti-arrhythmic effect was investigated by continuous monitoring in the first 12 days and by Holter monitoring during the 30-day ambulant period and 1 week after discontinuing disopyramide. A significant reappearance of warning arrhythmias could be detected after discontinuing disopyramide sustained-release tablets. No anti-arrhythmic effect was detected in 4 patients. Six patients had to be withdrawn because of side-effects. It is concluded that disopyramide sustained-release tablets 500 mg per day in 2 divided doses gives therapeutic plasma concentrations of 3 mg/l comparable with conventional capsules. A myocardial depressive effect is noted of about 10%.

Adult↗