Clinical pharmacokinetics of disopyramide

Disopyramide is an antiarrhythmic agent with proven efficacy in the management of atrial and ventricular arrhythmias. The drug is well absorbed and undergoes virtually no first-pass metabolism. Peak concentrations are achieved approximately 0.5 to 3.0 hours after a dose. Absorption is reduced and slightly slowed in patients with acute myocardial infarction. Disopyramide is excreted as unchanged drug (two-thirds) or as the metabolite mono-N-desisopropyldisopyramide, with elimination via both renal and biliary routes. Elimination half-life is approximately 7 hours in normal subjects and patients, but is prolonged in patients with renal insufficiency (creatinine clearance less than 60 ml/min). Disopyramide exhibits complex protein binding. It is bound to alpha 1-acid glycoprotein (AAG), an acute phase reactant, and binds in a concentration-dependent (saturable) manner. The unbound fraction is reduced in the presence of elevated concentrations of AAG, as are found in acute myocardial infarction and in some chronic haemodialysis patients and renal transplant recipients. Free disopyramide concentrations are low relative to total concentration in these patients. Because the pharmacological effects of disopyramide are determined by unbound drug, changes in the unbound fraction could make total disopyramide concentrations misleading as a guide to therapy. Changes in protein binding do not, however, alter free disopyramide or metabolite concentrations, both of which are dependent only on dosage and intrinsic clearance. Free drug concentration measurement could potentially improve therapeutic monitoring, but is as yet of unproven clinical value. Disopyramide is cleared more rapidly in children than in adults, and therefore children require higher dosages to attain therapeutic concentrations.