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PubMed1988

Oral disopyramide therapy for obstructive hypertrophic cardiomyopathy.

Seven patients with obstructive hypertrophic cardiomyopathy (HC) were treated with oral disopyramide. Left ventricular outflow tract gradients were estimated using either Doppler or M-mode echocardiography. Gradients were measured before treatment, after acute and chronic dosing, after washout and after rechallenge. Disopyramide serum levels were measured at the time of echocardiography. With the first dose, mean outflow gradient decreased from 64 to 14 mm Hg (p less than 0.0001). This decrease in gradient was still present after long-term oral treatment 23 days later, with a mean gradient of 13 mm Hg (p less than 0.001). After withdrawal from the drug, gradient returned to the pretreatment value, 79 mm Hg. After rechallenge, the gradient once again declined to 30 mm Hg (p less than 0.001). High disopyramide serum levels correlated with lower outflow tract gradients, r = -0.77 (p less than 0.0001). Even at low therapeutic drug levels, there was a 49% reduction in outflow tract gradient. Four patients were symptomatically improved and have been maintained on disopyramide for greater than 1 year. In symptomatic patients, disopyramide acutely decreases obstruction and also provides sustained pharmacologic control of obstruction. Disopyramide should be considered as a good alternative to treatment with adrenergic blockers, calcium antagonists or surgery.

Aged↗
PubMed1981

Effects of disopyramide on transmembrane action potentials in guinea-pig papillary muscles.

The effects of disopyramide on the transmembrane action potential in guinea-pig papillary muscles were studied with special reference to the dependence of the effects on the external concentrations of K+ ([K+]0), stimulation rates, and diastolic intervals. Disopyramide, 2 micrometer, prolonged the 90% action potential duration (ADP90) without changing the maximum rate of phase 0 depolarization (Vmax) (class 3 action), whereas disopyramide, 20 micrometer, reduced Vmax, (class 1 action). The class 3 action was prominent in 2.7 and 5.4 mM [K+]0, at 0.25--1 Hz, and so was the class 1 action in 8.1 mM [K+]0, at 2--5 Hz. Disopyramide, 20 micrometer, enhanced the rate-dependent reduction in Vmax only in 8.1 mM [K+]0. Neither concentration of disopyramide altered the recovery kinetics of APD90 in the premature responses in three [K+]0, but slowed that of Vmax only in 8.1 mM [K+]0. These results indicate that the manifestation of class 3 action of disopyramide is favored with low concentrations of the drug, low [K+]0, and low stimulation rates, whereas the reverse is true in the class of the class 1 action.

Action Potentials↗
PubMed1987

Interaction of disopyramide enantiomers for sites on plasma protein.

The binding of disopyramide enantiomers to donor plasma to which had been added human alpha-1 acid glycoprotein (AAG) was characterized alone and in the presence of the opposite enantiomer. At pre-dialysis concentrations of 10(-5) M, S(+)-disopyramide increased the percent of R(-)-disopyramide free (unbound) 2.6-fold from 11 to 30%. At similar pre-dialysis concentrations, R(-)-disopyramide increased the percent of S(+)-disopyramide free 2-fold from 4.1 to 9.0%. Differences in the binding of one enantiomer due to the presence of the other were due to apparent changes in association constant; no changes in capacity to bind the enantiomers were observed. It is concluded that the enantiomers of disopyramide compete with each other for one site on AAG.

Blood Proteins↗
PubMed2000

Comparative actions of cibenzoline and disopyramide on I(Kr) and I(Ks) currents in rat sino-atrial nodal cells.

Modulation by class Ia antiarrhythmic drugs, cibenzoline and disopyramide, of the pacemaking activity and the underlying ionic currents in rat sino-atrial nodal cells was investigated using current-clamp and whole-cell patch-clamp techniques. Both drugs depressed the spontaneous activity and often caused sinus arrest. The negative chronotropic effect was significant at 10 microM cibenzoline and 30 microM disopyramide. The L-type Ca(2+) current (I(Ca)) and the hyperpolarization-activated inward current decreased by 69.7+/-3.2% and by 45.8+/-3.0% at 30 microM cibenzoline and by 51. 2+/-3.3% and by 48.3+/-2.7% at 100 microM disopyramide, respectively. The delayed rectifier K(+) current, which is composed of rapidly and slowly activated currents (I(Kr) and I(Ks)), also decreased. The IC(50) values of I(Kr) for cibenzoline and disopyramide were 8.8+/-1. 1 and 25.1+/-2.3 microM, respectively. In the presence of 5 microM E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonylaminobenzoyl) piperidine), the IC(50) values of I(Ks) for cibenzoline and disopyramide were 12.3+/-1.8 and 81.1+/-2.3 microM, respectively. The I(Ks) was completely blocked by 30 microM 293B (trans-6-cyano-4-(N-ethylsulphonyl-N-methtamino)-3-hydroxy-2 , 2-dimethyl-chromane). These results indicate that the ionic currents are more sensitive to cibenzoline than disopyramide in rat sino-atrial nodal cells, and that I(Ca) and I(Kr) make major contributions to pacemaking activity.

Action Potentials↗
PubMed1982

Electrophysiologic effects of disopyramide studied in a hypoxic canine Purkinje fiber model.

Under normal (95% + 5% CO2) and hypoxic (95% N2 + 5% CO2) perfusions, electrophysiologic effects of disopyramide phosphate (5 microgram/ml) on canine Purkinje fibers were studied using microelectrode techniques. In the presence of normal oxygenation, disopyramide decreased the action potential amplitude and maximal rate of phase 0 depolarization, and lowered the level of plateau. The action potential duration at 80% of repolarization was prolonged in fibers initially having shorter durations, whereas it was shortened in fibers with longer durations, making the repolarization process more uniform. Addition of disopyramide under hypoxia similarly decreased the amplitude and upstroke velocity of action potential, and tended to reverse hypoxia-induced shortening of the refractory period. The maximal diastolic potential was altered by neither hypoxia nor disopyramide alone, but was significantly decreased by the combination of these two factors. Disopyramide prolonged the effective refractory period more than the action potential duration. From these results, antiarrhythmic effects of disopyramide under hypoxia appear to depend on (1) depressed conduction and resultant conversion of unidirectional block to bidirectional block abolishing reentry, and (2) decreased vulnerability due to decreased inhomogeneity of repolarization. Usefulness of this experimental model in studying electrophysiologic action of antiarrhythmic agents in ischemic hearts is also suggested.

Animals↗
PubMed1987

Disopyramide-pyridostigmine interaction: selective reversal of anticholinergic symptoms with preservation of antiarrhythmic effect.

This double-blind, randomized, placebo crossover study was used to evaluate the effects of a cholinesterase inhibitor--slow-release pyridostigmine (180 mg orally every 12 hours)--on the anticholinergic and antiarrhythmic properties of disopyramide. Quantitative side effects questionnaire scores were used to guide disopyramide administration in 20 men with ventricular tachycardia. Disopyramide was given to each patient both with placebo and with active pyridostigmine. The maximal administered dose for each regimen was used in conjunction with corresponding questionnaire scores to calculate an index or estimate of the maximal tolerable dose of disopyramide. Additional evaluations performed at baseline and at each maximal administered dose regimen included tear and saliva quantitation, 24 hour electrocardiogram (ECG), exercise testing and programmed ventricular stimulation. Results showed that the maximal administered dose of disopyramide was greater with active pyridostigmine than with placebo: 295 +/- 75 versus 245 +/- 100 mg every 6 hours (p less than 0.05). The calculated maximal tolerable dose was substantially greater in the presence of pyridostigmine: 355 +/- 90 versus 260 +/- 115 mg every 6 hours (p less than 0.001). Maximal side effects questionnaire scores also reflected decreased anticholinergic activity in the presence of pyridostigmine compared with placebo: 101.9 +/- 2.2 versus 104.6 +/- 2.8, respectively (p less than 0.005). Baseline tear and saliva production was significantly reduced during disopyramide therapy, but was restored toward normal by the addition of pyridostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1999

Disopyramide decreases the fasting serum glucose level in man.

The effect of disopyramide, a class Ia antiarrhythmic drug, on the serum glucose level was evaluated in 6 consecutive in-patients. A 19-hour starvation test was repeated with oral administration of sustained-release disopyramide (150 mg) 0 and 12 hours after starting the test. Serum glucose levels during the starvation test decreased with disopyramide administration from a mean value of 96.5 +/- 1.8 to 85.9 +/- 1.4 mg/dl (24 samples, p < 0.05). The average reduction of the serum glucose level by disopyramide in each patient was 9.7 +/- 2.2 mg/dl. The decrease in the serum glucose level was not related to the serum concentration of disopyramide or serum creatinine levels. The decrease in the serum glucose level was larger in older patients (r = 0.75) and in light patients under 45 kg. These results suggested that disopyramide reduced the fasting serum glucose levels even in normal ranges as a common side effect of the drug, and that not only the occurrence of severe hypoglycemia but also the decrease in glucose levels were influenced by multiple factors including age and body weight.

Age Factors↗
PubMedDate not supplied

Electrophysiology of the enantiomers of disopyramide in dogs.

The antiarrhythmic agent disopyramide comprises two enantiomers. In the present study, we examined the effects of the individual enantiomers on in vivo electrophysiology in anesthetized, closed-chest dogs. Six dogs received d-disopyramide, seven received l-disopyramide, and three dogs served as controls. Electrophysiologic measurements were performed at a series of geometrically increasing steady-state plasma concentrations of d- or l-disopyramide. Concentration-response curves were constructed for each electrophysiologic parameter, and the slopes of the regression lines of response versus plasma concentration were compared between enantiomers. Electrophysiologic parameters in the control dogs did not significantly change with time. However, stereoselective electrophysiologic effects were observed, with l-disopyramide being more potent than d-dispopyramide in prolonging sinus cycle length, Wenckebach cycle length, and atrioventricular nodal refractoriness (p less than 0.05). These findings are consistent with the established increased anticholinergic activity of the d-enantiomer which appeared to offset its local anesthetic or sodium channel inhibiting properties. Interrelationships between the autonomic nervous system and the cardiac electrophysiologic effects of disopyramide may be important in its antiarrhythmic effects.

Anesthesia↗
PubMedDate not supplied

Effects of CM7857, a derivative of disopyramide, on electrophysiologic properties of canine Purkinje fibers and inotropic properties of canine ventricular muscle.

Effects of CM7857 on electrophysiologic properties in canine Purkinje fibers and inotropic effects in canine ventricular muscle were studied. As CM7857 is a derivative of disopyramide phosphate, the effects of CM7857 (5 mg/L, 1.5 X 10(-5) M) were compared with those of disopyramide phosphate (5 mg/L, 1.4 X 10(-5) M). CM7857 significantly lowered the maximum rate of rise of phase 0 (Vmax) from 351.5 +/- 50.6 V/s (mean +/- SE, n = 5) to 283.6 +/- 33.0 V/s, and conduction velocity from 2.68 +/- 0.56 m/s to 1.70 +/- 0.28 m/s. The automaticity of Purkinje fibers was depressed by CM7857 as the result of reduction in the slope of phase 4. These effects were comparable to those of disopyramide. A marked difference between CM7857 and disopyramide was observed in the effect on action potential duration. APD90 was significantly shortened from 327.4 +/- 14.8 ms (n = 8) to 279.9 +/- 12.9 ms by CM7857, whereas disopyramide did not show any significant changes in APD90. As the CM7857-induced shortening of APD disappeared in low [Na+]o or low [K+]o concentration, it may be attributed to the lowering effect of "window current," a steady-state sodium current, maintaining action potential plateau. Effective refractory period (ERP) did not show any significant change. An acetylstrophanthidin-induced oscillatory afterpotential was significantly depressed by disopyramide, but not by CM7857. Isotonic contraction and isometric contraction of the right ventricular trabecullae were depressed by both drugs.

Action Potentials↗
PubMed1990

Comparison of anticholinergic effects of cibenzoline, disopyramide, and atropine.

The anticholinergic effects of cibenzoline, disopyramide, and atropine were compared on experimental models. Using inhibition of specific binding of 3H-quinuclidinyl benzylate (3H-QNB) in rat heart and cerebral cortex, Ki values were 15.8 +/- 1.6, 12 +/- 3.5, and 0.013 +/- 0.001 microM, respectively, for heart membranes and 31.6 +/- 1.5, 7.8 +/- 1.3, and 0.006 +/- 0.001 microM, respectively, for cerebral cortex membranes. In isolated guinea pig ileum, disopyramide was about 15 times more anticholinergic than cibenzoline but about 900 times less so than atropine. In anesthetized dogs, the three drugs administered by intravenous bolus reduced bradycardia caused by vagal stimulation. The effect of cibenzoline at 7 mg/kg i.v. (double the antiarrhythmic dose) was approximately the same as that of disopyramide at 2.5 mg/kg (half the antiarrhythmic dose). The drugs were infused for 1 h at 0.17 mg/kg/h for atropine, 11.6 mg/kg/h for disopyramide, and 5.5 mg/kg/h for cibenzoline. The maximal inhibition of the vagal stimulation was 98, 95, and 52%, respectively, for the three drugs. In nonanesthetized dogs, inhibition of the vagal-tone-induced tachycardia reached 33 +/- 4, 134 +/- 20, and 206 +/- 19% for cibenzoline, disopyramide and atropine, respectively. These results show cibenzoline to exert less potent anticholinergic effects than disopyramide.

Animals↗
PubMed1994

Quinidine but not disopyramide prolongs cardiac Purkinje fiber action potentials after a pause.

Prolongation of the cardiac action potential (AP), leading eventually to early afterdepolarizations (EADs), is believed to underlie drug-induced long QT syndromes and torsade de pointes. Episodes of torsade de pointes frequently occur after a prolonged pause. We studied the effects of quinidine and disopyramide on AP duration (APD) in canine cardiac Purkinje fibers after pauses of 2,000-10,000 ms. Standard intracellular microelectrode techniques were used to record APs from canine Purkinje fibers at an interstimulus interval (ISI) of 1,000 ms. Pauses of 2,000-10,000 ms were introduced into the basic drive cycle in the presence and absence of subtherapeutic and therapeutic concentrations of quinidine and disopyramide. We observed a biphasic response in APD to quinidine and disopyramide at ISI = 1,000 ms. Quinidine but not disopyramide produced a marked dose- and time-dependent additional prolongation of APD immediately after the pauses. This effect was highly statistically significant. We conclude that disopyramide and quinidine have qualitatively different effects on APD after a pause and that this observation may cast some light on the apparently greater frequency of torsade de pointes occurring with quinidine than with disopyramide. Possible mechanisms include differential drug effects on outward potassium or inward sodium channels.

Action Potentials↗
PubMed1984

Serum drug concentrations and adverse effects in cardiac patients after administration of a new controlled-release disopyramide preparation.

Despite widespread marketing of a controlled-released preparation of disopyramide phosphate (Norpace-CR, G. D. Searle), literature demonstrating its efficacy in maintaining uniform serum drug levels over a 12-h dosing interval is derived from only normal healthy volunteers. Twenty patients with cardiac arrhythmias (ages 37-80 years) were administered 400-800 mg/24 h (5.1-10.5 mg/kg/day) of controlled-release disopyramide in two equally divided doses on a q. 12 h. schedule. After achievement of steady-state equilibrium drug concentration, disopyramide levels were determined by high-pressure liquid chromatography on sera obtained from blood samples drawn 2, 7, and 11 h after an oral dose. Mean maximal and minimal disopyramide serum concentrations were 3.2 +/- 1.0 and 2.5 +/- 0.9 microgram/ml, respectively. Adverse drug effects occurred in nine (45%) subjects, necessitating discontinuation of the preparation in five patients (25%). These data demonstrate that in a population of patients with cardiac arrhythmias q. 12 h. dosing with a controlled-release disopyramide phosphate preparation is associated with an acceptable variation between maximal and minimal serum disopyramide concentrations, and is tolerated by the majority of subjects. The preparation should, therefore, offer greater patient convenience and compliance without sacrificing antiarrhythmic efficacy.

Administration, Oral↗
PubMed1985

Determination of free disopyramide plasma concentrations using ultrafiltration and enzyme multiplied immunoassay.

Disopyramide is an antiarrhythmic drug that exhibits nonlinear binding to plasma proteins. As a result, the total body clearance increases with increasing total drug plasma concentration. A rapid and sensitive method for the determination of free (unbound) disopyramide plasma concentrations is described. The procedure employs an ultrafiltration system (Centrifree), which can be used for basic drugs, along with an enzyme multiplied immunoassay system (EMIT) for the measurement of free disopyramide concentrations in plasma water filtrate. The EMIT method was adapted to permit measurement of disopyramide in plasma over a concentration range of 0.02-1.2 micrograms/ml. Plasma storage at -20 degrees C, filtration volume, or the presence of buffer and mono-N-dealkylated metabolite in plasma did not affect the binding determinations. There was no loss of drug during the filtration process. A good correspondence was found between the EMIT assay and a high performance liquid chromatography method, when applied to plasma samples obtained from a human subject who had ingested disopyramide. Furthermore, the extent of protein binding determined by the ultrafiltration system and by equilibrium dialysis were in good agreement. The binding of disopyramide in fortified human plasma decreased from 64 to 52% over a total drug concentration range of 1-5 micrograms/ml.

Blood Proteins↗
PubMed1990

Antiarrhythmic activity and unbound concentrations of disopyramide enantiomers in patients.

Six patients with reproducible inducible atrial flutter randomly received, in double-blinded fashion, 77 mg of S(+)-disopyramide and R(-)-disopyramide over 20 min by intravenous infusion on two occasions separated by at least 24 h. The S(+) enantiomer prevented the inducibility of atrial flutter in five of the six patients; atrial flutter was inducible following R(-) enantiomer administration in all six patients (p less than 0.05). The mean (+/- SD) antiarrhythmic unbound serum concentration range of S(+)-disopyramide was 0.55 +/- 0.31-0.90 +/- 0.81 mg/L. The binding of disopyramide was stereoselective: the mean unbound fractions of S(+)- and R(-)-disopyramide were 0.207 +/- 0.119 and 0.338 +/- 0.214 (p less than 0.05). Binding of the individual enantiomers in some patients was markedly concentration dependent. The data suggest that the antiarrhythmic activity associated with racemic disopyramide resides in the S(+) enantiomer.

Anti-Arrhythmia Agents↗
PubMed1983

Prolonged variability in plasma protein binding of disopyramide after acute myocardial infarction.

1 Disopyramide plasma binding was determined in vitro in plasma from 20 patients with acute myocardial infarction (aged 35-79 years) and in 20 age and sex matched healthy subjects. Plasma samples were collected on days 1, 5 and 12 after infarction and when the patient returned to the outpatient clinic. 2 In healthy subjects there was a significant negative correlation between disopyramide free fraction and plasma alpha 1-acid glycoprotein (AAG) concentration. A similar correlation was observed in the patients with myocardial infarction, however this correlation was dependent on time elapsed after infarction. Disopyramide free fraction did not correlate with albumin concentration in either group. 3 Mean plasma AAG concentrations were increased by 63% within 5 days after infarction and had returned to initial levels some months later (73.5 +/- 7.8 days). On each of the four sampling days, a two to four fold individual variability in plasma AAG concentrations was observed. 4 Maximum increases in disopyramide plasma binding were shown on days 5 and 12 after infarction. These increases were dependent on both drug and AAG concentrations. Increases in fraction bound were greater at the higher drug concentrations. Within the usual therapeutic plasma range for disopyramide (2 to 5 mg/l), the mean increases in fraction bound, compared to day 1 data, varied from 22 to 45% respectively. 5 Sequential alteration in AAG concentration after infarction indicates that disopyramide plasma binding may not reach a steady state until some months after infarction. Prediction of the time to achieve this steady state would be difficult due to inter- and intra-patient variability in binding.

Adult↗
PubMed1985

The influence of age and smoking on the elimination of disopyramide.

The influences of smoking and age on the elimination kinetics of disopyramide were studied in 27 subjects. Total elimination clearance of disopyramide was measured after an infusion to steady state. The total elimination clearance was significantly (P less than 0.05) decreased in elderly non-smoking patients compared with young non-smoking subjects (1.54 +/- 0.33 vs 2.12 +/- 0.67 ml kg-1 min-1) (mean +/- s.d.). Smoking more than 20 cigarettes per day significantly (P less than 0.05) increased total elimination clearance in elderly (2.02 +/- 0.35 vs 1.54 +/- 0.33 ml kg-1 min-1), while no significant induction by tobacco was observed in young healthy persons. Serum concentrations of alpha 1-acid glycoprotein, the major binding protein of disopyramide, were significantly higher (P less than 0.001) in the elderly patients. However, the volume of distribution (V) was significantly (P less than 0.001) greater in the elderly patients (2.44 +/- 0.64 vs 1.16 +/- 0.15 1 kg-1). Steady-state serum concentrations of the free drug were significantly (P less than 0.01) lower in the young volunteers (0.75 +/- 0.13 micrograms ml-1) than in the elderly (0.90 +/- 0.10 micrograms ml-1). The half-life of disopyramide was significantly shorter (P less than 0.01) in the young volunteers than in the elderly patients. No difference was observed in the relationship between the serum concentration of disopyramide and its main dealkylated metabolite in the groups studied. The results indicate that it might be advisable to reduce the dosage of disopyramide by approximately 30% in elderly non-smokers compared with young subjects.

Adult↗
PubMed1981

Disopyramide anticholinergic action.

The effect of disopyramide on cholinergic transmission has been studied using the frog isolated abdominis rectus preparation and the guinea pig isolated vas deferens hypogastric nerve preparation. Disopyramide (2 X 10(-5) mol litre-1) reduced the response of the abdominis rectus to carbachol (1.36 X 10(-6)--4.8 X 10(-5) mol litre-1). Furthermore, disopyramide (1 X 10(-6)--3 X 10(-4) mol litre-1) produced a concentration-dependent reduction in the response to carbachol (5.46 X 10(-6) mol litre-1). The response to potassium chloride (3.34 X 10(-2) mol litre-1) was unaltered by disopyramide (1 X 10(-6)--3 X 10(-4) mol litre-1). Disopyramide produced a dose-related ganglionic blockade at concentrations greater than 2 X 10(-5) mol litre-1. Complete blockade to ganglionic transmission occurred at 3 X 10(-4) mol litre-1 disopyramide.

Abdominal Muscles↗
PubMed1986

Comparison of the parasympatholytic activity of ACC-9358 and disopyramide.

ACC-9358 (N-[(3,5-di(pyrrolidinylmethyl)-4-hydroxy)benzoyl]aniline) is a newly developed analogue of changrolin, an antiarrhythmic agent used in the Peoples Republic of China. Since changrolin and other antiarrhythmic agents exert parasympatholytic activity which may limit their clinical usefulness, it was of interest to examine the parasympatholytic effects of ACC-9358. For comparative purposes we also studied the parasympatholytic activity of disopyramide. In guinea-pig isolated ileal strips, disopyramide, 3-30 microM, and ACC-9358, 100-300 microM, competitively antagonized carbachol-induced contractions with pA2 values of 5.78 and 4.17, respectively. In guinea-pig isolated right atria, disopyramide 3-30 microM, competitively antagonized methacholine-induced slowing of spontaneous beating with a pA2 value of 5.99 whereas ACC-9358, 3-300 microM, produced no significant muscarinic blockade in this preparation. Disopyramide (1.9-15 mg kg-1, i.v.), but not ACC-9358 (7.5-1.5 mg kg-1, i.v.), significantly increased rat pupil diameter in vivo. Disopyramide and ACC-9358 blocked vagal-induced reductions in heart rate in dogs anaesthetized with pentobarbitone. ED50 values were approximately 0.65 and 11.25 mg kg-1, respectively. We conclude that ACC-9358 possesses significantly less parasympatholytic activity than disopyramide.

Animals↗