Little information is available currently regarding the time course of myocardial accumulation and the onset of the electrophysiologic effects of antiarrhythmic drugs in humans. The myocardial uptake and pharmacodynamics of the antiarrhythmic drug, procainamide, were studied during i.v. infusion in nine patients with ventricular tachycardia undergoing electrophysiologic study. Myocardial procainamide uptake was determined by serial measurements of arterial-coronary sinus drug concentration differences and measurement of coronary sinus blood flow during a 50-min procainamide infusion. The myocardial uptake of procainamide was 10 +/- 4% (mean +/- S.D.) of the total dose at 50 min. Coronary sinus procainamide concentrations equilibrated with arterial concentrations within 30 min of the start of the infusion. However, peripheral venous procainamide concentrations did not reach equilibrium with the arterial compartment during the 50-min drug infusion. Changes in the QRS duration, ventricular conduction time, QTc and ventricular refractory periods correlated in a linear fashion with changes in the plasma procainamide concentrations. The slopes of the arterial and coronary sinus concentration-effect relationships were similar and significantly greater than the slopes of the peripheral venous concentration-effect relationships (P < .05). Thus, procainamide equilibrates rapidly, but not instantaneously, in the myocardium. Short-term electrophysiologic effects correlate best with the arterial and coronary sinus drug concentrations. During this period, venous procainamide concentrations do not accurately reflect the myocardial concentration, effects or the eventual steady-state relationships.