Simultaneous high-performance liquid chromatographic assay for quinidine, disopyramide and the mono-N-dealkylated metabolite of disopyramide.
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Arrhythmias, Cardiac↗
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Fluorescence photometric determination of disopyramide and mono-N-dealkylated disopyramide in plasma after separation by thin-layer chromatography.
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Chromatography, Thin Layer↗
Effect of disopyramide on potassium currents in rabbit ventricular myocytes.
The effects of disopyramide (1-30 microM) on the 4-aminopyridine sensitive transient outward current (I(to)), on the rapid component of the delayed rectifier potassium current (I(Kr)) and on the inward rectifier potassium current (I(kl)) were studied in single rabbit ventricular myocytes at 35 degrees C by applying the whole-cell configuration of the patch clamp technique. Disopyramide significantly decreased the amplitude of I(to) (from 1510 +/- 122 pA at control to 1015 +/- 21 pA after 30 microM disopyramide at +50 mV; n = 5). This effect was not voltage- or use-dependent. Disopyramide (10 microM) influenced neither the recovery from inactivation of I(to) nor the steady-state inactivation curve. The drug dose dependently decreased the time constant of the fast component of the decay of I(to) (tau(f) = 6.41 +/- 0.25 ms, n = 24 for control; and 2.20 +/- 0.38 ms, n = 5 after 30 microM disopyramide at +50 mV). The fractional block caused by 30 microM disopyramide as a function of time was well fitted by a single exponential function with time constant of 1.48 +/- 0.18 ms (n = 5), most likely reflecting the binding kinetics of the drug to the open channel. The offset kinetics of the drug was estimated by using a double-pulse protocol and its time constant was 3.9 +/- 0.5 ms. Disopyramide (30 microM) did not influence significantly the onset of inactivation measured at -20 mV. The estimated EC50 value for the I(to) block by disopyramide was 14.1 microM. Our results are consistent with an open-channel block of I(to) by disopyramide, however, a weak, drug-induced increase of the rate of inactivation and a moderate tonic block cannot be excluded. The amplitude of the outward tail current attributed to I(Kr) was depressed dose dependently by disopyramide (after clamping the cells back to the holding potential from +30 mV, 139.5 +/- 10.9 pA for control, and 30.7 +/- 3.2 pA in the presence of 10 microM disopyramide; n = 11). The estimated EC50 was 1.8 microM. I(to) is thus less sensitive to disopyramide than I(Kr). I(kl) was not influenced significantly by disopyramide, even when applied in the highest tested concentration (30 microM). It is concluded that in rabbit ventricular myocytes disopyramide blocks not only I(Kr), but also I(to), both of which may play an important role in the well established repolarization lengthening and antiarrhythmic effects of the drug.
Animals↗
Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy.
OBJECTIVES: In this study we assessed the long-term efficacy and safety of disopyramide for patients with obstructive hypertrophic cardiomyopathy (HCM). BACKGROUND: It has been reported that disopyramide may reduce left ventricular outflow gradient and improve symptoms in patients with HCM. However, long-term efficacy and safety of disopyramide has not been shown in a large cohort. METHODS: Clinical and echocardiographic data were evaluated in 118 obstructive HCM patients treated with disopyramide at 4 HCM treatment centers. Mortality in the disopyramide-treated patients was compared with 373 obstructive HCM patients not treated with disopyramide. RESULTS: Patients were followed with disopyramide for 3.1 +/- 2.6 years; dose 432 +/- 181 mg/day (97% also received beta-blockers). Seventy-eight patients (66%) were maintained with disopyramide without the necessity for major non-pharmacologic intervention with surgical myectomy, alcohol ablation, or pacing; outflow gradient at rest decreased from 75 +/- 33 to 40 +/- 32 mm Hg (p < 0.0001) and mean New York Heart Association functional class from 2.3 +/- 0.7 to 1.7 +/- 0.6 (p < 0.0001). Forty other patients (34%) could not be satisfactorily managed with disopyramide and required major invasive interventions because of inadequate symptom and gradient control or vagolytic side effects. All-cause annual cardiac death rate between disopyramide and non-disopyramide-treated patients did not differ significantly, 1.4% versus 2.6%/year (p = 0.07). There was also no difference in sudden death rate, 1.0%/year versus 1.8%/year (p = 0.08). CONCLUSIONS: Two-thirds of obstructed HCM patients treated with disopyramide could be managed medically with amelioration of symptoms and about 50% reduction in subaortic gradient over >/=3 years. Disopyramide therapy does not appear to be proarrhythmic in HCM and should be considered before proceeding to surgical myectomy or alternate strategies.
Administration, Oral↗
Bioavailability assessment of disopyramide using pharmacokinetic-pharmacodynamic (PK-PD) modeling in the rat.
The relationship between the serum concentration and the pharmacological effect of disopyramide was investigated quantitatively to estimate the extent of its oral bioavailability (EBA(p.o.) and to evaluate the drug interaction with miconazole, a CYP3A4 inhibitor. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was used to describe the relationship between the serum concentrations and changes in QT interval (pharmacological data) of disopyramide after intra-vascular infusion for 15 min (i.v. short-term infusion) to rats. A two-compartment model was applied to the pharmacokinetics of disopyramide. The pharmacological data after short-term infusion were well explained using a PK-PD link model. To validate the present PK-PD model. disopyramide was administered intra-vascularly in separate experiments, and the doses were predicted only from the pharmacological data. The model predicted doses were identical to the actual doses, regardless of the dosing rates. This result indicates that the PK-PD model used in the present study is appropriate, and that the relationship between the serum concentrations and changes in QT intervals is independent of the dosing (input) rate. When miconazole was co-administered orally 1 h before disopyramide infusion, the serum disopyramide concentrations were significantly higher than that following disopyramide alone. The raised serum concentrations under miconazole co-administration were well explained by nonlinear elimination clearance. The pharmacological effects of disopyramide under miconazole co-administration, were also greater than those following disopyramide alone. The results of the PK-PD analysis indicated that the enhanced pharmacological response under miconazole co-administration was simply caused by a pharmacokinetic change. The EBA(p.o.) values estimated from the pharmacological effects predicted the observed values reasonably well. In conclusion, we demonstrated following: (1) the pharmacological effect after intra-vascular administration of disopyramide is related quantitatively to the serum concentrations using a PK-PD model; (2) miconazole affects only the elimination clearance of disopyramide to enhance the pharmacological effect; (3) the EBA of disopyramide can estimated reasonably only well from the pharmacological data using the PK-PD model; (4) there is no dosing-rate-dependent or dosing-route-dependent pharmacological effect of disopyramide.
Algorithms↗
Effects of intravenous and oral disopyramide on paroxysmal atrioventricular nodal tachycardia.
The effect of intravenous and oral disopyramide on the mechanisms of the arrhythmia were studied in 11 patients with the common type of atrioventricular (AV) nodal paroxysmal reentrant tachycardia. Programmed electric stimulation of the heart was used to initiate and terminate tachycardia and to evaluate the effect of disopyramide on mode of initiation and termination of tachycardia. Disopyramide was given intravenously to all patients during tachycardia. This resulted in termination of tachycardia, by block in the anterograde slow pathway in 1 and in the retrograde fast pathway in 3 patients. In all 4 patients, reinitiation of tachycardia was no longer possible. In these 4 patients, oral disopyramide prevented spontaneous and pacing-induced AV nodal tachycardia. In 4 of the remaining 7 patients in whom tachycardia was not terminated by intravenous disopyramide, reinitiation of the arrhythmia during programmed stimulation was prevented by the drug. In these 4 patients, oral disopyramide was also effective in preventing spontaneous occurrence of tachycardia. In 3 patients, tachycardia was not terminated and its reinitiation was not prevented by intravenous disopyramide. Only 1 of these 3 patients received disopyramide by mouth, and it failed to prevent reinitiation and spontaneous tachycardia. In conclusion, disopyramide is an effective drug in patients with AV nodal paroxysmal reentrant tachycardia. A good correlation was found between intravenous and oral effect of disopyramide on the mechanisms of the arrhythmia. The study of the effect of intravenous disopyramide predicted the outcome of oral disopyramide therapy.
Administration, Oral↗
Combination of disopyramide and mexiletine for better tolerance and additive effects for treatment of ventricular arrhythmias.
The efficacy and tolerance of disopyramide and mexiletine used alone and in combination were studied in 21 patients with frequent (greater than or equal to 30/h) ventricular premature complexes. Ambulatory electrocardiographic monitoring was performed at baseline and during therapy with disopyramide alone, mexiletine alone and a combination of disopyramide and mexiletine. During single drug therapy, the dose of disopyramide was 602 +/- 152 mg/day and that of mexiletine was 738 +/- 144 mg/day. During combination therapy with smaller doses of disopyramide (524 +/- 134 mg/day) and mexiletine (652 +/- 146 mg/day), no patient had side effects. At baseline before therapy, the mean number of ventricular premature complexes per hour, was 608 +/- 757, of couplets per hour was 22.4 +/- 45.8 and of episodes of nonsustained ventricular tachycardia/24 h was 219.7 +/- 758.2. The mean number of ventricular premature complexes per hour was reduced to 156 +/- 217 with disopyramide alone, 188 +/- 298 with mexiletine alone and 76 +/- 144 with combination therapy (p less than 0.05 for combination therapy versus disopyramide or mexiletine alone; p = NS for disopyramide versus mexiletine). Individually, an effective regimen (greater than 83% reduction in ventricular premature complexes and abolition of nonsustained ventricular tachycardia) was found in 5 (24%) of 21 patients during therapy with disopyramide alone, in 3 (14%) receiving mexiletine alone and in 13 (62%) receiving combination therapy (p less than 0.05 for combination therapy versus disopyramide or mexiletine; p = NS for disopyramide versus mexiletine). Thus, the antiarrhythmic effects of disopyramide and mexiletine are additive.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effects of cisapride on gastrointestinal motor activity and gastric emptying of disopyramide.
The effects of cisapride on the gastrointestinal contractile activity and pharmacokinetics of disopyramide were determined in beagle dogs and patients with arrhythmia. In the animal experiments, the gastric motor index was significantly decreased by i.v. administration of disopyramide in a dose-dependent fashion. The peak decrease of the motor index was observed within 5 min after i.v. injection of disopyramide; the motor index then recovered gradually to the level present prior to drug administration. I.v. administration of cisapride (0.5 mg/kg) markedly increased gastrointestinal contractile activity following the decrease induced by disopyramide pretreatment (5 mg/kg, i.v.). In the clinical studies, the gastric emptying test was performed using the acetaminophen method. A significant correlation between plasma concentrations of disopyramide and gastric emptying time has been found (p < 0.001). The combination of disopyramide (100 mg t.i.d.) and cisapride (2.5 mg t.i.d.) significantly increased gastric emptying compared with that induced by disopyramide alone. The peak plasma concentration of disopyramide in association with cisapride oral administration was significantly higher, and the apparent absorption rate constant and lag time of disopyramide were about 2-fold higher and 2-fold shorter, respectively, than for disopyramide alone. Cisapride, acting as a cholinergic agonist, may counteract the anticholinergic effect of disopyramide on gastric motility. As a factor influencing drug absorption, gastric emptying is of importance, as it determines the rate of drug delivery to the small intestine. Therefore, the oral administration of disopyramide with cisapride may be useful for patients with delayed gastric emptying.
Administration, Oral↗
Effect of disopyramide on systolic and early diastolic time intervals in patients with hypertrophic cardiomyopathy.
The present study clarified the effect of disopyramide on left-ventricular function in patients with hypertrophic cardiomyopathy (5 obstructive type: HOCM, 21 non-obstructive type: HNCM). The systolic and early diastolic time intervals were assessed 3 hours after a single oral administration of 100-mg disopyramide. The following parameters were evaluated at rest and after administration of disopyramide: 1) left-ventricular ejection time index (LVETI), 2) pre-ejection period index (PEPI), 3) the interval from aortic component of the second heart sound to mitral valve opening (IIA-MVO), and 4) the interval from MVO to O point of apexcardiogram (MVO-O). LVETI in HNCM did not change after disopyramide but that in HOCM was significantly shortened (P less than .05). PEPI in both HOCM and HNCM was significantly prolonged after administration of disopyramide. IIA-MVO time in both HOCM and HNCM was not influenced by disopyramide. MVO-O time in both HOCM and HNCM was significantly shortened after disopyramide. These results suggest that 1) shortening of LVETI in HOCM after disopyramide seemed to be due to the decrease in pressure gradient, 2) PEPI prolongation after disopyramide reflected the decrease in myocardial contractility, and 3) shortening of MVO-O time after disopyramide indicated the improvement of left-ventricular filling. The authors conclude that disopyramide may be an important new therapeutic agent in the treatment of patients with hypertrophic cardiomyopathy.
Adult↗
The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide.
Disopyramide exhibits saturable binding to plasma proteins in the therapeutic plasma concentration range. Because of this property, controversy exists in the literature regarding the pharmacokinetic properties of the drug. The purposes of this study were to reassess the pharmacokinetic properties of disopyramide in humans, taking into consideration both total and unbound concentrations and to use disopyramide as a model compound to study the effect of drug binding on the renal clearance of both total and unbound drug. A single intravenous dose of disopyramide (1.5 mg/kg) was administered to eight normal volunteers. Blood and urine samples were collected for 36 h. Total concentrations of disopyramide in plasma and urine were determined by high pressure liquid chromatography. Binding of disopyramide to plasma proteins was determined by equilibrium dialysis. In all subjects the binding of disopyramide to plasma proteins was saturable, but there were considerable differences in binding between subjects. The volume of distribution, total body clearance, and renal clearances of both total and unbound drug were calculated. Because only the total body clearance and renal clearance of unbound compound are not dependent upon unbound fraction (alpha), these are the only parameters which can be reported without qualification as to the concentration. The mean +/-DS total body clearance of unbound drug in the eight subjects was 5.40 +/- 2.80 ml/min/kg. About 50% of this was due to renal elimination. A statistically significant negative correlation of the renal clearance of total disopyramide with time was observed in seven of eight subjects, whereas a significant correlation between the renal clearance of unbound disopyramide and time was observed in only one subject. This suggests that the renal clearance of unbound disopyramide is independent of alpha, while the renal clearance of total disopyramide is dependent upon alpha.
Adult↗
Disopyramide: evaluation of electrophysiologic effects and clinical efficacy in patients with sustained ventricular tachycardia or ventricular fibrillation.
The efficacy of disopyramide in the management of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) was evaluated in 50 patients by programmed ventricular stimulation: 38 patients had coronary artery disease (16 with left ventricular aneurysm), 8 had other cardiac diseases, and 4 had no apparent heart disease. Disopyramide was administered orally for 72 hours (dosage 400 to 1,600 mg/day), resulting in a plasma level of 3.6 +/- 1.2 micrograms/ml (mean +/- standard deviation [SD]). Disopyramide prevented induction of sustained ventricular tachyarrhythmias in 17 patients (34%) and failed to prevent induction in 33 patients (66%). Plasma levels were not significantly different regardless of response to disopyramide. The VT cycle length in patients responding to disopyramide was shorter than in nonresponding patients (225 +/- 51 ms versus 281 +/- 70 ms, p = 0.005). Disopyramide increased VT cycle length in those patients in whom it was ineffective (failed to prevent induction) from 281 +/- 70 ms to 347 +/- 64 ms (p less than 0.001). Ventricular refractory periods, QRS, and QTc durations significantly increased after disopyramide administration. Of the 17 patients in whom tachyarrhythmias were noninducible on disopyramide, 11 were discharged on disopyramide and followed up for 19 +/- 9 months; 9 of them remained free of VT. Heart failure developed in 2 of these patients. One other patient in whom disopyramide was ineffective had irreversible heart failure and died. It is concluded that disopyramide (1) prevents induction of ventricular tachyarrhythmias in one third of patients studied and remains clinically effective in approximately 80%, (2) is more frequently effective in rapid tachycardias, (3) prolongs the VT cycle length when ineffective, and (4) may produce marked hemodynamic embarrassment in patients with significant left ventricular dysfunction.
Adult↗
Immediate- versus controlled-release disopyramide: importance of saturable binding.
OBJECTIVE: To examine the effects of saturable plasma binding on the pharmacokinetics of immediate-release (IR) and controlled-release (CR) disopyramide. BACKGROUND: Saturable binding causes a lack of correspondence between the pharmacokinetics of total and unbound plasma disopyramide. Levels of total drug may therefore be insensitive to important differences between formulations. METHODS: Patients receiving long-term disopyramide underwent serial blood sampling during withdrawal of equivalent doses of IR and CR disopyramide, and during accumulation of IR disopyramide. Plasma disopyramide was measured by enzyme-multiplied immunoassay technique, protein binding by ultrafiltration, and alpha 1-acid glycoprotein by radial immunodiffusion. Pharmacologic effect was assessed by use of high-speed ECGs. Values for plasma area under the concentration-time curve and elimination half-life were determined from the log-plasma concentration data; rate of plasma drug accumulation was determined by nonlinear modeling. RESULTS: Saturable plasma binding was evident in all patients. Comparison of total to unbound drug showed that peak-to-trough ratios during steady state were smaller (1.45 versus 2.39; p < 0.001), elimination half-life was longer (12.1 versus 4.5 hours; p < 0.001), and the time to achieve 50% of steady-state levels during drug accumulation was shorter (8.1 versus 4.3 hours; p < 0.05). Comparison of IR and CR disopyramide showed that unbound drug levels for CR disopyramide revealed lower peak plasma concentrations (0.75 versus 0.96 micrograms/ml) and peak-to-trough ratios (1.83 versus 2.31; p < 0.001). Trough plasma concentrations were similar. Fluctuations in ECG intervals during usual dosing were observed only with IR disopyramide. CONCLUSIONS: Because of saturable plasma binding, total plasma concentrations underestimate fluctuations in unbound disopyramide during usual dosing and are insensitive to significant differences between IR and CR formulations. CR disopyramide provides less interdose variation in free drug levels and more constant pharmacologic effects.
Aged↗
Electrophysiologic effects of disopyramide phosphate in patients with Wolff-Parkinson-White syndrome.
We evaluated the electrophysiologic effects of disopyramide phosphate in 12 patients with the Wolff-Parkinson-White syndrome. Electrophysiologic studies were performed during a control period and after administering i.v. disopyramide (four bolus doses of 9.5 mg/kg over 40 minutes superimposed on a continuous infusion at 1.0 mg/kg/hour). All patients were then restudied after 3 days on oral medication in doses of 800-1200 mg/day. In all patients we tried to induce reciprocating tachycardia and atrial fibrillation. The cycle length during reciprocating tachycardia was not changed by i.v. disopyramide, but increased after oral disopyramide, from 331 +/- 53 (+/- SD) to 370 +/- 68 msec (p less than 0.01). This increase occurred predominantly as a result of prolongation of retrograde conduction time in the accessory pathway. Despite prolonging cycle length during reciprocating tachycardia, disopyramide did not prevent its induction. The shortest and mean RR intervals during atrial fibrillation were used to assess antegrade refractoriness of the accessory pathway. Intravenous disopyramide prolonged the shortest RR from 169 +/- 18 to 226 +/- 24 msec (p less than 0.0001) and the mean RR from 255 +/- 58 to 329 +/- 62 msec (p less than 0.005). Oral disopyramide prolonged the shortest RR interval from 169 +/- 18 to 248 +/- 36 msec (p less than 0.0001) and the mean RR from 255 +/- 58 to 360 +/- 93 msec (p less than 0.001). After oral disopyramide, the episodes of atrial fibrillation were shorter and self-terminating. No acute hemodynamic side effects were observed, but five patients developed gastrointestinal or anticholinergic side effects on oral disopyramide. Seven patients elected to have surgical interruption of their accessory pathways and five have been successfully treated with oral disopyramide for 14-33 months. Disopyramide appears to have beneficial electrophysiologic effects in patients with Wolff-Parkinson-White syndrome. Prolongation of refractoriness in the accessory pathway markedly slows the ventricular response during atrial fibrillation and therefore prevents the development of life-threatening arrhythmias.
Administration, Oral↗
Anticholinergic effects of disopyramide and quinidine on guinea pig myocardium. Mediation by direct muscarinic receptor blockade.
We studied the interaction of disopyramide, quinidine, and procainamide with cardiac muscarinic receptors. In electrophysiological experiments, the effects of disopyramide, quinidine, procainamide, and atropine were determined on spontaneously depolarizing guinea pig right atria (GPRA) both in the presence and absence of pharmacologically induced (physostigmine) cholinergic stimulation. All four agents demonstrated a concentration-dependent antagonism of the negative chronotropic effects of physostigmine. The order of anticholinergic potency was atropine greater than disopyramide greater than quinidine greater than procainamide. The ability of disopyramide to antagonize the physostigmine induced slowing was stereoselective, (+)disopyramide greater than (-)disopyramide. In contrast, the ability of quinidine to antagonize the negative chronotropic effects of physostigmine was non-stereoselective, quinidine = quinine. In parallel experiments, we studied the ability of disopyramide, quinidine, procainamide, and atropine to compete with the radiolabeled muscarinic receptor antagonist [3H] quinuclidinyl benzilate ([3H]QNB) for binding to muscarinic receptors in crude homogenates of GPRA and membrane vesicles from canine ventricular myocardium. All four agents inhibited [3H]QNB binding to muscarinic receptors. The order of anticholinergic potency determined by the receptor binding studies was identical to that determined by the physiological studies. The interaction of disopyramide with muscarinic receptors was stereoselective, (+)disopyramide > (-)disopyramide. Quinidine was only slightly more potent than quinine in inhibiting [3H]QNB binding to muscarinic receptors. Interaction of antiarrhythmic drugs with muscarinic receptors satisfied criteria for a competitive interaction. The data from this study localize the anticholinergic effects of disopyramide and quinidine to the muscarinic receptor.
Animals↗
Disopyramide: a review of its pharmacological properties and therapeutic use in treating cardiac arrhythmias.
Disopyramide is a new antiarrhythmic drug with a pharmacological profile of action similar to that of quinidine and procainamide. In a few controlled therapeutic trails and a large number of uncontrolled studies in patients with arrhythmias, often following a myocardial infarction, disopyramide has been relatively effective (more so in ventricular than in atrial arrhythmias) and usually well tolerated. In treating premature atrial and ventricular contractions, the best-studied area of its therapeutic use, disopyramide was superior to a placebo and of similar efficacy to but better tolerated than quinidine; the drop-out rate due to adverse effects of the disopyramide group (10%) being less than one-third that of the quinidine group (36%). In an open ward setting, disopyramide used prophylactically after myocardial infarction appeared to reduce both the incidence of reinfarction and the mortality rate, while in patients treated in coronary care units although the incidence of reinfarction was lower with disopyramide than with a placebo, the mortality rate was not significantly different. Further well-designed trials with adequate numbers of patients are needed before the routine use of disopyramide in infarct patients treated in either setting can be justified. Comparative studies are also required to determine if disopyramide has advantages over other antiarrhythmic agents in this area of use. Side-effects with disopyramide are usually a result of its anticholinergic activity, a dry mouth and difficulty in urination being the most common. Like other antiarrhythmic agents, disopyramide exerts a negative inotropic action on cardiac muscle, and development of acute heart failure has been reported. Development of worsening of heart block and hypotension have also occurred. Disopyramide is largely excreted unchanged and dosage should be reduced in patients with impaired renal function, in accordance with creatinine clearance values.
Arrhythmias, Cardiac↗
Effect of phenytoin on serum disopyramide concentrations.
The effects of phenytoin on serum disopyramide concentrations in 10 volunteers were studied. Leading to the study was the case of a 59-year-old man who received phenytoin and disopyramide and who required unusually high doses of disopyramide and an unusually high serum concentration of this drug to control his ventricular tachycardia. Ten healthy men 23-36 years of age each received a single oral dose of disopyramide phosphate 300 mg. Periodic blood samples were obtained for 24 hours after the dose. On day 2, the subjects began a 13-day course of oral phenytoin sodium 300 mg/day, and on day 14 each again received a single oral dose of disopyramide, after which blood samples were obtained. Serum disopyramide concentrations were determined by enzyme-mediated immunoassay and gas chromatography and serum phenytoin concentrations by fluorescence polarization immunoassay. Pharmacokinetic values before and after phenytoin administration were calculated. The mean area under the serum concentration-time curve for disopyramide and the disopyramide half-life and elimination rate constant were significantly different before and after phenytoin treatment. The maximum serum disopyramide concentrations were not significantly different. After phenytoin therapy, subjective complaints of anticholinergic effects increased in number and severity. An interaction between disopyramide and phenytoin appears to exist and to be caused by an increase in the hepatic metabolism of disopyramide.(ABSTRACT TRUNCATED AT 250 WORDS)
Disopyramide↗
A comparison of the anticholinergic effects of two formulations of disopyramide in healthy volunteers.
Eight healthy male volunteers took a single oral dose of one of the following: Rythmodan (conventionally formulated disopyramide) 150 mg; Rythmodan 250 mg; Rythmodan Retard (controlled-release disopyramide) 250 mg; placebo. The subjects were allocated double-blind to sessions and treatments according to a Latin square design. In each session pupil diameter, heart rate, salivation, and QT interval were measured immediately before and at 1, 2, 3, 4, 6, 8, and 24 h after the drug. QT interval was corrected for heart rate (QT60). Plasma concentrations of total and unbound disopyramide were also determined at each time point. Both formulations of disopyramide reduced salivary output and increased QT60 interval, but there was not significant difference between the effects of the three active treatments. Neither formulation had any effect on pupil diameter or heart rate. The peak plasma concentration of unbound disopyramide was reached 2 h after Rythmodan and 4 h after Rythmodan Retard. The peak plasma concentration of disopyramide was significantly lower after Rythmodan Retard 250 mg than after Rythmodan 250 mg. The plasma concentration of unbound disopyramide was positively correlated with the reduction in salivation and prolongation of the QT60 interval. The reduction in salivation is likely to reflect blockade of muscarinic receptors by disopyramide, whereas the increase in QT60 interval is likely to be related to a direct effect of the drug on the heart. The results of this single-dose study do not indicate that disopyramide in the controlled-release formulation would be better tolerated by patients than conventionally formulated disopyramide.
Administration, Oral↗
Enantioselective steady-state kinetics of unbound disopyramide and its dealkylated metabolite in man.
Disopyramide is provided as a racemic mixture of R and S enantiomers, which have different pharmacodynamic and pharmacokinetic characteristics. Five volunteers were given racemic disopyramide 100 mg and 200 mg t.d.s. in a cross-over design. Plasma and urine concentrations of disopyramide and its active metabolite monodesisopropyl-disopyramide (MND) were determined at steady state by an enantioselective HPLC method. Unbound drug in plasma was measured after ultrafiltration. There was enantioselective clearance of unbound disopyramide (0.39 l.h-1.kg-1 for R-disopyramide and 0.58 l.h-1.kg-1 for S-disopyramide after 100 mg t.d.s.). The enantioselectivity was due to differences in the metabolism of disopyramide to MND and in further non-renal clearance, and the renal clearance of disopyramide was not enantioselective. The in vivo protein binding of disopyramide, which was saturable for both enantiomers, was also enantioselective. The difference in binding of the two enantiomers was explained by a difference in apparent binding capacity rather than in apparent binding affinity. The renal clearance of S-MND was significantly higher than R-MND (0.29 and 0.19 l.h-1.kg-1, respectively, after 100 mg t.d.s.). The renal clearance of MND also showed a tendency to saturation at higher concentrations.
Adult↗