Clinical pharmacokinetics of N-acetylprocainamide

Abstract

Since N-acetylprocainamide was identified in the urine of patients receiving procainamide, this compound has been studied both as a metabolite of procainamide and as a separate antiarrhythmic agent. N-acetylprocainamide absorption following oral administration is more than 8-% complete. 59 to 89% of N-acetylprocainamide is excreted unchanged in the urine in subjects with normal renal function. Deacetylation of N-acetylprocainamide to procainamide is a minor route of N-acetylprocainamide elimination. The half-life of N-acetylprocainamide in patients with normal renal function has been reported to vary between 4.3 and 15.1 hours. Total body clearance (mean +/- SD) of N-acetylprocainamide in patients with normal renal function has been reported to range from 2.08 +/- 0.36 ml/min/kg to 3.28 +/- 0.52 ml/min/kg. There is a linear relationship between N-acetylprocainamide clearance and creatinine clearance. The half-life of N-acetylprocainamide in functionally anephric patients may be as long as 42 hours; however, it can be effectively cleared from plasma by haemodialysis. N-acetylprocainamide is 10% protein-bound. There is an age-related decline in N-acetylprocainamide clearance, mostly due to the decrease in creatinine clearance that occurs with ageing. In the neonate, the half-life of acetylprocainamide is prolonged. Several therapeutic trials carried out to assess the effectiveness of N-acetylprocainamide in suppressing chronic ventricular premature beats have now been reported. If there is a therapeutic response to N-acetylprocainamide it will probably occur at a plasma concentration between 15 and 25 micrograms/ml. A high degree of overlap has been reported between the concentration range associated with arrhythmic suppression and the range of concentrations where intolerable side effects begin to occur. No severe cardiac toxicity has been reported with oral therapy despite plasma concentrations as high as 40 micrograms/ml. However, hypotension has been reported in association with a rapid intravenous bolus of N-acetylprocainamide. A maximum intravenous infusion rate of 50 mg/min has been recommended. N-acetylprocainamide in patients receiving procainamide; however, N-acetylprocainamide concentrations remain below the therapeutic range in patients with normal renal function. In patients with renal failure receiving procainamide, N-acetylprocainamide concentrations rise dramatically. The dose of N-acetylprocainamide must be adjusted in patients with renal insufficiency, and it should be used more cautiously in the very old and very young. N-acetylprocainamide plasma concentration monitoring would be valuable clinically in patients with renal insufficiency receiving either N-acetylprocainamide or procainamide, and in the very young and the aged.