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PubMed1984

Effect of concentration-dependent binding to plasma proteins on the pharmacokinetics and pharmacodynamics of disopyramide.

Disopyramide exhibits concentration-dependent binding to plasma proteins at therapeutic plasma concentrations. This paper reviews the effect of this type of binding on both the pharmacokinetic and pharmacodynamic properties of the drug. For a drug with capacity-limited, binding-sensitive elimination like disopyramide, concentration-dependent binding to plasma proteins produces a non-linear relationship between dosing rate and total plasma concentrations of the drug. However, when dosing rate is related to unbound concentrations of drug, the relationship is linear. Renal clearance of total disopyramide has been found to depend on the unbound fraction whereas renal clearance of unbound drug may be dependent upon time after drug administration as well as route of drug administration. However, due to some potential methodological problems, these data need verification. The concentration-dependent binding of disopyramide to plasma proteins, with its resultant effects on clearance and distribution, produces a concave curvature in the log unbound concentration versus time curves and a log-linear decline in total plasma concentration versus time after intravenous administration of the drug. Several pharmacological studies suggest that the unbound drug is active in terms of producing both desirable and undesirable effects. Hence, monitoring unbound concentrations of disopyramide seems more rational for clinical purposes. The few studies that have been carried out examining the optical isomers of disopyramide have suggested that both the pharmacokinetic and pharmacodynamic properties of the drug are stereoselective. Recent data reveal stereoselective binding to plasma proteins in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Mechanism of transient outward K(+) channel block by disopyramide.

The block of the transient outward K(+) current (I(to)) by disopyramide was studied in isolated rat right ventricular myocytes using whole cell patch-clamp techniques. Disopyramide at a concentration of 10 to 1000 microM reduced peak I(to) and accelerated the apparent rate of current inactivation. The onset of block was assessed using a double pulse protocol with steps from -70 to +50 mV. As the duration of the first (conditioning) pulse was increased from 1 to 50 ms, block was increased. Further prolongation of the conditioning pulse resulted in relief of block, which was nearly complete with a 1-s conditioning pulse. In the absence of drug, the recovery from inactivation of I(to) at -70 mV was fast and best fit with a single exponential function having a time constant of 33 +/- 13 ms. In contrast, in the presence of 100 microM disopyramide, recovery from apparent inactivation was biexponential with time constants of 35 +/- 13 ms and 7.16 +/- 1.5 s. The time course of the slow component was used to estimate recovery of channels from block by disopyramide. Recovery from block was voltage-dependent, suggesting that disopyramide was trapped by the open channel. Taken together, these results suggest that disopyramide rapidly blocks channels in the open state and that unblock occurs from the inactivated state.

Algorithms↗
PubMedDate not supplied

Stability-indicating methods for the determination of disopyramide phosphate.

Four methods were developed for the determination of intact disopyramide phosphate in the presence of its degradation product. In the first and second methods, third-derivative spectrophotometry and first derivative of the ratio spectra were used. For the third-derivative spectrophotometric method, the peak amplitude was measured at 272 nm, while for the derivative ratio spectrophotometric method, disopyramide phosphate was determined by measuring the peak amplitude at 248 and 273 nm. Both methods were used for the determination of disopyramide phosphate in the concentration range 12.5-87.5 microg/mL, with corresponding mean recovery 100.8 +/- 0.7% for the first method and 99.9 +/- 0.7% and 99.6 +/- 0.7% for the second method at 248 and 273 nm, respectively. In the third method, an ion selective electrode (ISE) was fabricated using phosphotungstic acid as an anionic exchanger, PVC as the polymer matrix, and dibutylsebacate as a plasticizer. The ISE was used for the determination of disopyramide phosphate in pure powder form in the concentration range 10(-2)-10(-5) M. The slope was found to be 58.5 (mV/decade), and the average recovery was 99.9 +/- 1.6%. The fourth method depended on the quantitative densitometric determination of the drug in concentration range of 0.25-2.5 microg/spot using silica gel 60 F245 plates and ethyl acetate-chloroform-ammonium hydroxide (85 + 10 + 5, v/v/v) as the mobile phase, with corresponding mean accuracy of 100.3 +/- 1.1%. The 4 proposed methods were found to be specific for disopyramide phosphate in presence of up to 80% of its degradation product for the spectrophotometric methods, 90% of its degradation for the densitometric method, and 40% for the ISE method. The 4 proposed procedures were successfully applied for the determination of disopyramide phosphate in Norpace capsules. Statistical comparison between the results obtained by these methods and the official method of the drug was done, and no significant differences were found.

Anti-Arrhythmia Agents↗
PubMed1990

[Effects of verapamil and disopyramide phosphate on the termination, reinduction and long-term prevention of paroxysmal supraventricular tachycardia].

The efficacy of verapamil and disopyramide phosphate for the termination and prevention of paroxysmal supraventricular tachycardia (PSVT) were studied electrophysiologically in 32 patients with inducible sustained PSVT (17 patients received verapamil, 15 patients received disopyramide). Twelve patients had atrioventricular nodal tachycardia, 7 had concealed and 13 had overt Wolff-Parkinson-White syndrome. Intravenous verapamil (0.15 mg/kg) terminated the sustained PSVT in 15 of the 17 patients (88%) by production of AV block in 13 patients, VA block in one, and a ventricular premature beat in one. PSVT could not be induced in any of these 15 patients after they had received verapamil. In the remaining 2 patients, PSVT could not be terminated by the use of verapamil, but the cycle lengths of PSVT were lengthened. Long-term oral dosages of verapamil of 120-240 mg/day were administered in 13 of the 17 patients. All patients except two, whose PSVT was unable to be effected by intravenous verapamil, were well controlled: PSVT disappeared in 7 patients and decreased in 4. Intravenous disopyramide (1.5 mg/kg) terminated induced PSVT in 10 of the 15 patients (67%) by production of VA block. Although PSVT could not be reinitiated in 5 of these 10 patients, non-sustained PSVT was induced in 2 and sustained PSVT was induced in 3 after having received disopyramide. PSVT was induced in all of the 5 patients who failed to respond to disopyramide. The cycle lengths of PSVT after administration of disopyramide remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1989

Gastrointestinal dialysis of disopyramide in healthy subjects.

The effect of oral activated charcoal on the clearance of disopyramide was investigated in six healthy subjects. Oral administration of multiple doses of activated charcoal at 4, 6, 8 and 12 h after ingestion of the drug reduced the serum levels of both disopyramide and its main metabolite, mono-N-dealkyldisopyramide (MND). The mean serum level of disopyramide at 24 h after oral administration of the drug was significantly decreased from 0.22 in the control to 0.091 micrograms/ml by multiple doses of activated charcoal. The serum half-life and AUC0-infinity were decreased to 67% and 81%, respectively, and the apparent total body clearance was increased to 122% as compared with the control treatment. The apparent volume of distribution was not significantly different between both treatments. The cumulative amounts of urinary excretion of both disopyramide and MND with activated charcoal treatment were decreased as compared with those in the control treatment. Mean residence time (MRT) of disopyramide obtained from the serum data decreased from 7.8 (control) to 6.9 h (charcoal treatment) and the values were approximately consistent with those obtained from the urinary data. These results indicate that oral administration of activated charcoal would enhance the clearance of disopyramide in acute drug poisoning even after the drug has been absorbed into the systemic circulation from the g.i. tract.

Adult↗
PubMed1987

Tolerability and antiarrhythmic efficacy of disopyramide compared to lignocaine in selected patients with suspected acute myocardial infarction.

In a randomized open study with intravenous lignocaine and disopyramide in patients with suspected acute myocardial infarction and ventricular premature contractions the occurrence of cardiac events, adverse reactions, withdrawals and arrhythmias were compared. Of the total 68 patients included in the study, 33 were randomized to disopyramide and 35 to lignocaine treatment. The treatment was given for 24 hours or until withdrawal due to occurrence of serious cardiac events or side-effects possibly related to the drugs. Sustained ventricular tachycardia occurred in one patient in each treatment group. 15 per cent of the patients treated with disopyramide and 14 per cent of the patients treated with lignocaine were withdrawn because of adverse reactions. Withdrawals due to depressed left ventricular function and sinoatrial and atrioventricular conduction disturbances were not different in the two treatment groups. However, more patients treated with lignocaine had supraventricular arrhythmias compared to disopyramide. Significantly more patients treated with disopyramide obtained complete abolition of premature ventricular contractions on Holter recordings compared to lignocaine treatment (P less than 0.001). The results indicate that disopyramide and lignocaine can be used alternatively in the treatment of ventricular arrhythmias in patients with suspected acute myocardial infarction.

Adrenergic beta-Antagonists↗
PubMed1987

Long-term use of controlled-release disopyramide in patients with severe ventricular arrhythmias.

Controlled-release (CR) disopyramide phosphate has been available for the past four years for the management of patients with ventricular arrhythmias. The advantages of this preparation over the earlier form have for most patients been striking. Improved patient compliance as regards dosing, ease in stabilizing blood levels of disopyramide, and effective antiarrhythmic control has been a significant factor in physician satisfaction with this preparation. Studies have demonstrated that effective blood levels are obtained with the 12-hour dosing schedule for controlled-release disopyramide phosphate in both normal volunteers and in patients with cardiac arrhythmias. Concern over the safety of disopyramide in patients with significant underlying heart disease, and especially in patients with a history of congestive heart failure, has been reported in a number of publications. No clinical observations are available in which patients with intractable ventricular arrhythmias have been managed with controlled-release disopyramide phosphate in addition to other appropriate therapy for their cardiac condition. Fifteen patients with significant left ventricular dysfunction were followed for an average of 20.6 months while receiving controlled-release disopyramide phosphate, and control of ventricular arrhythmias was achieved without worsening of left ventricular function.

Adult↗
PubMed1979

[Clinical and hemodynamic effects of disopyramide phosphate administered i.v. in cardiopathic subjects (author's transl)].

The antiarrhythmic action of disopyramide (1.5 mg/Kg) administered i.v. as a bolus was assessed in 30 patients with ischemic heart disease and different arrhythmias. In 75% of supraventricular parossistic tachycardia and in 75% of parossistic atrial fibrillation, arrhythmia was interrupted within few minutes from drug injection; in 90% with premature ventricular contractions (PVC) and in 100% of ventricular tachycardia, disopyramide was capable to interrupt the arrhythmias. The hemodynamic effects of the same dose of disopyramide were evaluated in other 17 patients, 9 of which in I-II class NYHA and 8 in III-IV class. We used STI's as parameters of cardiac performance. In all patients following the injection of disopyramide, a significant increase of PEP, ICT and PEP/LVET ratio and a significant decrease of LVETc were observed. Thus, the disopyramide impaired cardiac performance and its effect appeared more evident in patients in III-IV class NYHA. In conclusion, disopyramide showed to be effective in interrupting different arrhythmias; however, its depressant action on cardiac performance suggests that caution should be used in patients with severely impaired myocardial function.

Adult↗
PubMed1983

Comparison of electrocardiographic response and disposition of R- and S-disopyramide in the rabbit.

Both R- and S-disopyramide prolong the QRS interval of the electrocardiogram in the rabbit. R-disopyramide is more potent than S-disopyramide at high concentrations (greater than 6 micrograms/ml), but shows similar potency at low concentrations (less than 6 micrograms/ml). R-disopyramide shows an estimated intermediate hepatic extraction ratio with a plasma clearance of 31.0 +/- 3.2 ml/min/kg that is only to a small degree concentration-dependent. S-disopyramide plasma clearance, on the other hand, is highly concentration-dependent, with a value larger than 50 ml/min/kg at concentrations below 4 micrograms/ml, that decreases to a value of approximately 30 ml/min/kg at 16 micrograms/ml. No differences in the binding of R- and S-disopyramide to rabbit serum or rabbit serum spiked with human alpha 1-acid glycoprotein were found.

Animals↗
PubMed1982

The pharmacokinetics of disopyramide in patients with acute myocardial infarction.

The effects of acute myocardial infarction on the pharmacokinetics of disopyramide were studied. Disopyramide (200 mg) was given orally to nine patients with left-sided cardiac failure due to acute myocardial infarction within 24 h after the onset (phase I). In seven patients the study was repeated 7-14 days later at discharge from the hospital (phase II). Serum concentrations and the 24-h area under the serum concentration-time curve of disopyramide were significantly lower during phase I than during phase II (p less than 0.05 and p less than 0.001, respectively). The peak serum concentrations and the 24-h area under the pulmonary capillary wedge pressure (less than 0.05) in phase I. Rates of absorption and elimination of disopyramide were similar during both phases. Renal clearance of disopyramide showed concentrations and the decrease of 24-h area under the serum concentration-time curve are most probably due to decreased gastrointestinal absorption and are related to the degree of left ventricular failure. Thus, the dosage of oral disopyramide obviously needs to be increased in these patients to achieve therapeutic concentrations in the acute phase.

Adult↗
PubMed1981

Concentration-dependence of disopyramide binding to plasma protein and its influence on kinetics and dynamics.

Disopyramide binds to two independent sites on protein in human plasma. The first binding site located on alpha-1-acid glycoprotein has an association and a capacity constant of 1.0 x 10(6) M-1 and 3.5 x 10(-6) M, respectively, and accounts for the majority of disopyramide binding. The second site is probably located on albumin and accounts for 5 to 10% of the binding. The bound fraction of disopyramide was concentration-dependent at drug concentrations reported to be therapeutic. After administration of 100, 150, 200 and 300 mg doses of disopyramide (Norpace) to each of four human volunteers, the area under the free (unbound) disopyramide serum-concentration time curve averaged 2.32, 3.33, 5.21 and 8.24 mg/l. hr, respectively, and was directly proportional to dose. The elimination half-lives based on free and total drug concentrations averaged 4.36 and 6.51 hr, respectively (P less than .001), and were dose-independent. The peak response (change in pre-ejection period) and area under the response time curves were better related to free than to total serum concentrations of disopyramide.

Binding Sites↗
PubMed1993

[Effects of propafenone on the parameters of body surface electrocardiogram in comparison with those of disopyramide].

The purpose of this study is to investigate the clinical effects of propafenone on the QT(QTc), QRS, PQ and RR interval of body surface electrocardiogram (ECG) in comparison with the effects of disopyramide. In 10 patients (5 with paroxysmal atrial fibrillation and 5 with ventricular premature complex: ages 48-77), after 4 days' observation without any cardioactive drugs, disopyramide (300mg/day) was administered orally for 7 days. After discontinuing the administration of disopyramide, 4 more days were allowed to wash out the drug, and propafenone (450mg/day) was administered orally for 7 days. 12-lead ECG was taken twice before the administration of disopyramide (Pre-1 and -2), on the 1st, 3rd, 5th and 7th days after the administration of disopyramide. Then it was also taken on the day before the beginning of propafenone administration and on the 1st, 3rd, 5th and 7th days after the administration of propafenone. The corrected QT (QTc = QT/square root of RR), QRS, PQ and RR intervals in lead II or V2 of each ECG were measured as the mean value of 5 consecutive sinus beats. The control values of QTc, QRS, PQ and RR intervals were calculated as the mean values of Pre-1 and -2, and the other values were expressed as the % ratio to the control values. Propafenone hardly altered the QTc interval but prolonged QRS interval after the 5th day of administration (110 +/- 12%, p < 0.05), while disopyramide significantly prolonged the QTc interval after the 3rd day of administration (109 +/- 5%, p < 0.001) without affecting the QRS interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMedDate not supplied

The renal clearance of disopyramide after bolus intravenous injection.

Following bolus intravenous injection of disopyramide in eight normal volunteers the renal clearance of the drug appeared to fall with time. In the first two hours after injection renal clearance had a mean value of 89.0 ml min-1 and fell to 29.4 ml min-1 between 48 and 72 h. In a separate study disopyramide was given by continuous intravenous (i.v.) infusion for 8 h following a loading dose of the drug. Renal clearance of disopyramide was thus estimated hourly over three narrow serum concentration ranges in a single volunteer. The estimate of renal clearance of the drug over the first hour following the start of these infusions was considerably in excess of values obtained later in the experiments. The change in disopyramide renal clearance following bolus injection is partially time-dependent. There are, however, fallacies in calculating short-term clearance values after bolus drug injection from the venous concentration-time curve and these may partially explain the change in renal clearance of disopyramide with time.

Disopyramide↗
PubMedDate not supplied

Acute oral antiarrhythmic testing with disopyramide.

Acute antiarrhythmic drug testing with disopyramide was accomplished in 25 patients with frequent ventricular premature depolarization (VPD). Systolic time intervals (STI) were used to assess left ventricular performance. Eighteen patients responded after a loading oral dose of 300 mg disopyramide with 80% or greater reduction in VPD and abolition of advanced grades. Mean onset of drug action was 93 min and the mean plasma level at 2 h was 3.4 microgram /ml. During maintenance therapy 2 of the 18 patients had a relapse, In 2 others, initially protected, VPD recurred during both exercise and psychological stress testing. STI showed increments in pre-ejection period (PEP) and in PEP/ejection time ratio at peak concentrations of plasma disopyramide. Acute tests repeated with placebo in a single-blind fashion in responding patients failed to significantly reduce VPD frequency or grade. Side effects consisted of anticholinergic actions of disopyramide. In 3 patients aggravation of heart failure compelled discontinuation of disopyramide which then remitted.

Acute Disease↗
PubMed1988

Stereoselective gastrointestinal clearance of disopyramide in rabbits treated with activated charcoal.

The ability of activated charcoal to enhance the drug elimination of two enantiomers, R- and S-disopyramide, was compared in rabbits. Orally administered activated charcoal significantly decreased the area under the serum concentration curve of R-disopyramide, whereas the same treatment had no effect on that of S-disopyramide. The difference could be explained by the difference in the hepatic extraction ratio of two enantiomers in rabbits. S-Disopyramide is a drug of high hepatic extraction ratio in rabbits and R-disopyramide is of intermediate hepatic extraction ratio. Equations were derived to illustrate the influence of the hepatic extraction ratio on the apparent gastrointestinal clearance. A higher hepatic extraction ratio decreases the apparent gastrointestinal clearance of a drug. This phenomenon may explain some unsuccessful experiments of gastrointestinal dialysis. When considering the use of activated charcoal to enhance systemic drug elimination, the hepatic extraction ratio of the drug should be included.

Animals↗
PubMed1991

Efficacy of disopyramide and mexiletine used alone or in combination in the treatment of ventricular premature beats.

The efficacy of oral disopyramide and mexiletine used alone or in combination was studied in 75 patients with frequent ventricular premature beats (VPBs). The efficacy was evaluated with 24-hour ambulatory ECG and greater than or equal to 75% reduction in the number of VPBs was defined as effective. When disopyramide or mexiletine were ineffective or not tolerated, the alternative drug was administered and the efficacy was again evaluated. If the single administration of neither drug was effective, the combination of disopyramide and mexiletine was then given. Either disopyramide or mexiletine was effective in 48 patients, and neither drug was effective in 19 patients. In 19 patients unresponsive to both drugs, combination therapy was effective in six patients (32%). Both drugs caused side effects or one drug caused side effects and another drug was ineffective in eight patients. In five out of those patients, we attempted combined therapy with a reduced dosage of those drugs that caused side effects. This therapy was effective in two patients without intolerable side effects. Thus, when the single use of neither disopyramide nor mexiletine single-drug therapy is effective, it is worthwhile to try combination therapy. Also, combination therapy with a reduced dosage of the drugs that caused side effects might be the therapy of choice in patients who have developed dose-dependent side effects.

Adult↗
PubMed1983

Effect of ethanol intake on disopyramide elimination by healthy volunteers.

The effect of ethanol intake on disopyramide elimination was examined in an open crossover study in six healthy volunteers. No effect of ethanol on the elimination half-life or total body clearance of disopyramide was found, although it did decrease the percentage of mono-N-dealkylated disopyramide excreted in the urine (p less than 0.05) as well as the relative metabolic clearance of disopyramide (p less than 0.05). The renal clearance of disopyramide was increased by 19 +/- 16% (p less than 0.05) in subjects in whom ethanol caused a diuresis.

Adult↗
PubMed1982

The influence of protein binding on disopyramide clearance.

Individual disopyramide clearance is not constant and previous studies have suggested that this may be time and/or concentration dependent. Steady state disopyramide concentrations were achieved in six volunteer subjects at each of three infusion rates. Drug analysis was by HPLC and protein binding was determined by ultrafiltration. The disopyramide free fraction was concentration dependent and marked interindividual variability was observed. Disopyramide clearance was independent of time but dependent on total plasma concentration. This can be completely explained by non-linear protein binding since free disopyramide clearance was observed to be independent of free concentration.

Adult↗