Summary
Synopsis
Disopyramide1 is a widely used class IA antiarrhythmic drug with a pharmacological profile of action similar to that of quinidine and procainamide. Over the past 10 years disopyramide has demonstrated its efficacy in ventricular and atrial arrhythmias. In therapeutic trials, usually involving small numbers of patients, the efficacy of disopyramide was comparable with that of mexiletine, perhexiline, tocainide, propafenone or prajmalium. Recent comparisons with quinidine have confirmed the similar efficacy and better tolerability of disopyramide. The suggestion from initial studies that disopyramide may be less effective than amiodarone or flecainide requires further investigation. In addition, studies have failed to demonstrate that the early administration of disopyramide after acute myocardial infarction decreases important arrhythmias or early mortality. Thus, disopyramide is now well established as an effective antiarrhythmic drug in ventricular and supraventricular arrhythmias although its role in therapy relative to that of recently introduced antiarrhythmic agents is not clear.
Pharmacodynamic Studies
Disopyramide has electrophysiological and haemodynamic effects in man which are qualitatively similar to those of quinidine and procainamide. Single intravenous doses of 1 to 2 mg/kg in patients with heart disease increased the effective and functional refractory periods of the atria and ventricles (usually by about 10 to 15%) in most patients, increased the His-Purkinje conduction time interval (especially in patients with underlying distal conduction system defects), and reduced the sinus node recovery time after atrial pacing. Electrocardiographic changes are similar to those seen with quinidine, but appear to be less pronounced. Thus, in most studies the QRS complex has been slightly widened and the QTc interval prolonged.
In patients with sinoatrial node dysfunction (sick sinus syndrome) the effects of disopyramide appear to be variable, but further deterioration in sinoatrial function may occur. In the Wolff-Parkinson-White syndrome, intravenous disopyramide increased the conduction time and refractory periods of the accessory pathway in most cases, producing temporary antegrade and/or retrograde block in a few patients. In a small number of patients with implanted pacemakers, oral disopyramide 300 to 1200mg daily did not affect the pacemaker stimulation threshold.
Haemodynamic studies showed a negative inotropic effect after intravenous injection of 1.5 to 2 mg/kg over 2 to 5 minutes in patients with heart disease or recent myocardial infarction, resulting in about a 15% reduction in cardiac output. This effect was particularly evident in patients with impaired left ventricular function. A negative inotropic effect also occurred in healthy subjects given disopyramide 2 mg/kg intravenously or 450 to 800mg daily. A lesser effect was produced by therapeutically equivalent doses of mexiletine or lignocaine (lidocaine). Combined intravenous administration with a β-blocker results in a greater reduction in cardiac output, but there was no additive effect on left ventricular function when disopyramide and β-blockers were both given orally. Studies on the extent of myocardial depression in patients with heart disease during oral administration have not been reported. Effects on heart rate and blood pressure have been variable and usually slight although a small increase in nocturnal heart rate may occur. Hypotension, which has been reported in a few patients during therapeutic trials, did not occur after 1 to 2 mg/kg intravenously during haemodynamic studies in patients with heart disease or arrhythmias. A marked increase in heart rate has been reported in a few patients with atrial fibrillation after 2 mg/kg intravenously.
Pharmacokinetic Studies
Oral administration of disopyramide as the phosphate salt or free base results in rapid and essentially complete absorption. The relative systemic availability of the 2 oral forms has varied between studies but appears to be about 70 to 85% compared with intravenous administration. Although the incomplete systemic availability of oral disopyramide has been attributed to the non-linear renal clearance with time, studies with unbound drug suggest a ‘first-pass’ effect of around 15%.
Peak plasma concentrations which are 3 to 4 mg/L after an oral dose of 300mg and 4 mg/L after intravenous injection of 1.5 to 2 mg/kg occur at 2 hours and 5 minutes, respectively. Peak plasma concentrations are lower in patients with acute myocardial infarction than in non-infarct patients and during the first 24 hours after infarction than during the period 7 to 14 days later. However, it is reported that bioavailability in patients with myocardial infarction is not significantly different from that in healthy subjects. At steady-state, mean maximum and minimum plasma concentrations have been similar with controlled release and conventional capsules and tablets. There was less intersubject variability in absorption when controlled release capsules were compared with conventional capsules, but not when controlled release tablets and conventional capsules were compared. Peak plasma concentrations occurred later after controlled release than conventional preparations, but bioavailability did not differ significantly. Therapeutic mean plasma concentrations of 3 to 5 mg/L were readily attained and maintained for 12 hours when an intravenous bolus of disopyramide 100mg was followed immediately by a controlled release tablet of disopyramide 250mg.
There are few data regarding the distribution of disopyramide in humans. Studies in lactating women reported a mean milk: plasma ratio of unchanged disopyramide of 0.5: 0.9 although the N-dealkylated metabolite appeared to accumulate in breast milk. Nevertheless, after 28 days of breast feeding the metabolite was not detectable in the plasma of the suckling infant. The volume of distribution of total drug varies according to dose, but that of the unbound fraction is not concentration dependent. However, the steady-state volume of distribution is lower in patients with congestive heart failure or myocardial infarction than in healthy subjects. The extent of protein binding of disopyramide is concentration dependent, the unbound fraction increasing with rising plasma concentrations. Disopyramide and its main metabolite are bound mostly to α1-acid glycoprotein,and increased concentrations of this protein are associated with increased binding.
The main metabolite of disopyramide is mono-N-dealkylated disopyramide which possesses antiarrhythmic activity, although the contribution of this metabolite to the antiarrhythmic or toxic effects of disopyramide is not known. The metabolism of disopyramide is increased by concomitant administration of phenytoin or rifampicin (rifampin).
About 50 to 60% of an administered dose is excreted unchanged, mainly in the urine. Total clearance of disopyramide is concentration dependent, but that of the unbound fraction is not. Total clearance of unbound disopyramide was similar in healthy subjects and patients with congestive heart failure although it appears to be higher during the first 48 hours after acute myocardial infarction than later, and is decreased in patients with renal impairment.
The elimination half-life after intravenous administration was longer in patients with renal myocardial infarction (7.0 to 11.8 hours) or severe renal dysfunction (8.3 to 43 hours), the value increasing with decreasing creatinine clearance, than in healthy subjects (4.4 to 8.2 hours). Suitably designed studies correlating plasma concentrations of disopyramide with clinical effects are few, but it appears that a plasma concentration of about 3 to 5 or 6 mg/L represents the likely desirable therapeutic range.
Therapeutic Trials
Over the past 10 years disopyramide has become widely used in the treatment of ventricular and atrial arrhythmias. It has been better studied in ventricular than in atrial arrhythmias. In patients with ventricular premature contractions, the best studied area of its therapeutic use, oral disopyramide 300 to 600mg daily was similar in efficacy to mexiletine 400 to 1000mg daily or perhexiline 400mg daily. In most such studies, efficacy has been based on the decrease in premature beats or complexes during a single 24-hour period of continuous ambulatory monitoring. Under these conditions, the proportion of patients who responded to disopyramide was generally 40 to 60%.
In small numbers of patients with ventricular arrhythmias of Lown’s grade II to V, disopyramide 600mg daily was comparable in efficacy with atenolol 200mg, tocainide 1800mg, propafenone 900mg or prajmalium 80mg. In one of the few studies involving large numbers of patients, disopyramide 600mg was of equal efficacy to quinidine 1300mg daily. Disopyramide 600mg daily was more effective than quinidine 500 to 750mg daily, but less efficacious than flecainide 400mg, dihydroquinidine 900mg or ethmozine 800mg. At the lower dosage of 400mg daily, disopyramide was less effective than amiodarone 400 to 600mg in controlling ventricular premature complexes. In some studies disopyramide appeared to be particularly effective in reducing the frequency of ectopic beats, but the patient numbers were generally too small to permit valid comparisons of relative efficacy against specific types of ventricular arrhythmias.
Disopyramide has been either compared with or used in combination with mexiletine in patients with ventricular tachycardia or fibrillation. In general, combined therapy has been more effective than that with either drug alone and elicited a response rate of 60 to 75%. As might be expected, disopyramide treatment was associated with a poor response rate in patients who had previously failed to respond to a variety of other antiarrhythmic drugs. Results of a few studies suggest that patients whose ventricular tachyarrhythmias are controlled by intravenous disopyramide can be successfully maintained during oral administration of the drug.
In patients with supraventricular ectopic beats, disopyramide was of similar efficacy to quinidine, as it was in maintaining sinus rhythm in patients who had undergone cardioversion. Intravenous disopyramide was more effective than intravenous digoxin given in controlling persistent atrial tachyarrhythmias after open heart surgery. When given after digoxin, intravenous disopyramide was similar in efficacy to intravenous sotolol in patients with atrial arrhythmias after cardiac surgery, although the time to reversion was shorter with sotolol. Flexible doses of amiodarone produced asymptomatic status more frequently than disopyramide in patients aged over 65 years, but there was no difference in the percentage of patients in whom sinus rhythm was maintained.
Several studies have examined the efficacy of disopyramide in decreasing arrhythmias and mortality in patients with acute myocardial infarction admitted to a hospital coronary care unit. Early treatment (6 to 9 hours after infarct) with disopyramide failed to reduce mortality relative to placebo. Since ventricular fibrillation occurred infrequently, no reduction in its incidence could be demonstrated.
Side Effects
At usual therapeutic dosages disopyramide has been well tolerated in most patients. The most common adverse effects of disopyramide are related to its anticholinergic activity, dryness of the mouth and difficulty in urination occurring frequently (40%, and 10 to 20% of patients, respectively), and urinary retention has been reported in several patients. Electrocardiographic changes similar to those seen with other antiarrhythmic drugs may occur, and myocardial depression and development of acute heart failure has been reported usually in patients with pre-existing left ventricular dysfunction. Thus, disopyramide should only be used in such patients under certain conditions (see below). Development of heart block or worsening of pre-existing heart block have occurred in a few patients (and may be of particular importance in patients with pre-existing distal conduction system defects), as has hypotension. Infrequent, though important, side effects include hypoglycaemia, which occurred mostly in elderly, malnourished patients with renal impairment, atypical ventricular tachycardia with prolonged QTc intervals and intrahepatic cholestasis. Isolated adverse effects include acute psychosis, photosensitisation, allergic reactions, peripheral paraesthesia, peripheral neuropathy and impotence.
Drug Interactions
Concomitant intravenous administration of disopyramide and acebutolol results in a larger than expected negative inotropic effect, while phenytoin and rifampicin markedly decrease mean plasma concentrations of concomitantly administered disopyramide.
Dosage and Administration
The dosage of disopyramide should be individualised for each patient on the basis of response and tolerance. The recommended dose of disopyramide is 600mg daily, administered in 4 divided doses with a maximum of 800mg daily. An initial loading dose of 300mg should be followed by 100mg or 150mg 6-hourly, according to manufacturers’ recommendations. Some patients have tolerated much higher doses (up to 1600mg daily). If such treatment is considered warranted, therapy should be instituted in hospital and followed by continuous close monitoring. Patients with low bodyweight, or those with moderate renal insufficiency, hepatic insufficiency, or possible cardiac decompensation, should receive 200mg initially followed by 100mg 6-hourly. In patients with cardiomyopathy a loading dose should not be given. In severe renal impairment (creatinine clearance less than 40 ml/min), the recommended dose is 100mg every 12 or 24 hours for creatinine clearances of 40 to 30, 30 to 15, or less than 15 ml/min, respectively.
If intravenous administration is considered necessary, a bolus injection of 2 mg/kg (but not exceeding 150mg) may be given over 5 to 10 minutes. If conversion to sinus rhythm occurs during administration, the injection should be stopped. In patients who cannot take oral medication or in severe arrhythmias being treated in a coronary care unit, the initial intravenous bolus may be followed by a maintenance infusion of 20 to 30 mg/h up to a maximum of 800mg daily.
Disopyramide should not be used in patients with cardiogenic shock or pre-existing second or third degree heart block without a pacemaker. Use in first degree heart block requires careful evaluation of benefits versus risks. In poorly compensated or uncompensated heart failure, disopyramide should only be used if the condition is due to or made worse by an arrhythmia, and then only after appropriate measures (e.g. digitalisation) have been instituted. Patients with atrial tachyarrhythmias should also be digitalised before receiving disopyramide. Use in conduction abnormalities such as the sick sinus syndrome or bundle branch block may result in further deterioration of cardiac function. When anticholinergic effects could complicate an existing condition (e.g. glaucoma, prostatic hypertrophy), the use of disopyramide should be accompanied by other therapeutic measures.
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References
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Various sections of the manuscript reviewed by: J. Caplin, Cardiothoracic Centre, Southampton General Hospital, Shirley, Southampton, England; A.S. Iskandrian, Presbyterian-University of Pennsylvania Medical Centre, Philadelphia, Pennsylvania, USA; J. Lekieffre, Service de Cardiologie A, Hôpital Cardiologique, Lille, France; R.G. Wilcox, Department of Medicine, University Hospital, Queen’s Medical Centre, Nottingham, England.
‘Durbis’, ‘Ritnodar’, ‘Ritmoforine’, ‘Rythmodan’, ‘Rythmodul’ (Roussel); ‘Dirythmin’, ‘Norpace’ (Astra); ‘Norpace’ (Searle).
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Brogden, R.N., Todd, P.A. Disopyramide. Drugs 34, 151–187 (1987). https://doi.org/10.2165/00003495-198734020-00001
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DOI: https://doi.org/10.2165/00003495-198734020-00001