Disopyramide - Antiarrhythmic Cardiovascular Poison

Disopyramide

Disopyramide is a quinidine-like class IA antiarrhy-thmic, cardiac depressant drug. It has negative inotropic and anticho-linergic properties, and is effective in the treatment of various supraventricular and ventricular arrhythmias. It depresses myocardial excitability and conduction velocity.

Uses

·      Maintenance of sinus rhythm in patients with atrial flutter or fibrillation.

·      Prevention of recurrence of ventricular tachycardia or fibril-lation.

·      Treatment of neurally mediated hypotension

Toxicokinetics

Disopyramide is 85% bioavailable. Protein binding varies with drug concentration (decreasing as concentration increases) from 5 to 65%, averaging 40%. The kidney excretes 40 to 60% of the drug, while the liver metabolises the parent compound and its metabolite mono-N- dealkylated disopyramide. The latter is responsible for most of the anti-cholinergic effects of the drug. The major route of excretion occurs predominately via the urine with about 50% excreted unchanged, approximately 20% excreted as the N-dealkylated metabolite, and 10% as other metabolites. The half-life of disopyramide is 6 to 8 hours, and that of its principal metabo-lite 3 to 4 hours.

Adverse Effects

Hypotension, dry mouth, blurred vision, angle-closure glau-coma, vomiting, diarrhoea, colic, difficulty in micturition. Rarely, blood dyscrasias and psychosis. Therapeutic doses have occasionally been associated with cholestatic jaundice with elevated serum liver enzyme levels. Laboratory values generally return to normal following discontinuance of the drug, but may remain elevated for several months. 

Drug Interactions

Reduced efficacy with phenytoin. Potentiates some of the effects of beta blockers, verapamil, digitalis, and amiodarone. Because of the serious risk of potentiating arrhythmias, disop-yramide must not be combined with any other antiarrhythmics.

Clinical (Toxic) Features

·      Usual adult dosage is 400 to 800 mg per day in divided doses. The toxic dose is said to be 1.5 grams. Therapeutic plasma range is reported to be 2 to 6 mcg/ml.

·      In overdose, cardiovascular and anti-muscarinic effects are pronounced.

o     Similar cardiovascular toxicities occur as with quinidine and procainamide: depression of atrial, atrioventricular and ventricular conduction, arrhythmias, hypotension, heart failure, syncope, cinchonism, paraesthesia, and coma; but anticholinergic effects are more pronounced, and heart failure is more frequent. Syncope is usually related to transient torsade de pointes ventricular tachy-cardia.

o     Hypotension occurs from alpha receptor blockade and depressed myocardial contractility.

o     ECG manifestations, in addition to the aforementioned arrhythmias, include significant QRS and QT interval prolongation, PR prolongation, ST depression, and T inversion.

·      Early loss of consciousness with subsequent respiratory arrest, tachy- or bradyarrhythmias and cardiac arrest is characteristic of severe disopyramide overdoses.

·      Pulmonary oedema, probably secondary to compromised cardiac function, may occur.

Treatment

·              Obtain serial ECGs and institute continuous cardiac monitoring following overdoses. ECG should be monitored for cardiac arrhythmias, including torsade de pointes, QRS widening, QT prolongation, and AV dissociation.

·              Monitor oxygen saturation and respiratory function in all disopyramide overdose cases. Severe overdoses may result in respiratory failure.

·              Activated charcoal is beneficial.

·              Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalaemia, hypocalcaemia, and hypo-magnesaemia).

·              Lignocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Sotalol is an alternative for stable monomorphic ventricular tachycardia. Amiodarone and sotalol should be used with caution (since disopyramide prolongs the QT interval and/or causes torsades de pointes). Unstable rhythms require cardioversion. Atropine may be used when severe bradycardia is present and PVCs are thought to represent an escape complex.

·              Do not use procainamide or quinidine. Bretylium has not been studied for these overdoses, but its alpha blocking properties may cause severe hypotension and cardio-vascular collapse when combined with the negative inotropism of disopyramide.

·              Treatment of ventricular tachycardia (especially torsades de pointes variant) may require DC cardioversion, over-drive pacing, isoproterenol infusion to decrease temporal dispersion of refractoriness, and/or sodium bicarbonate IV bolus therapy.

·              High doses of calcium chloride (0.5 grams every 5 minutes upto a maximum of 3 grams) in combination with conventional supportive measures and cardiopulmo-nary resuscitation are quite effective in reversing some of the cardiac effects.

·              For hypotension: infuse 10 to 20 ml/kg of isotonic fluid and place in Trendelenburg position. If hypotension persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy.

·              Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases. Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FiO₂ is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 ml/kg) is preferred if ARDS develops.

·              Forced diuresis is potentially dangerous, has not been shown to increase disopyramide excretion or improve outcome after overdose, and is not recommended. Attempt to maintain normal urine output, since 40 to 70 percent is excreted unchanged in the urine irrespective of pH.

·              Haemodialysis or haemoperfusion is effective in enhancing the elimination of the drug. The former is preferable.