The effect of quinidine and its metabolites on the electrocardiogram and systolic time intervals: concentration--effect relationships

Abstract

1 A combined pharmacokinetic and pharmacodynamic model has been used to analyze the relationship between electrocardiographic (ECG) and systolic time intervals (STI) and changes in plasma concentration of quinidine after oral and i.v. doses in ten normal subjects. 2 The major effects of quinidine were on cardiac repolarization. Contrary to previous descriptions, we found no important change in the U wave, but the T wave was split into two peaks. The amplitude of these two peaks (T and T') was reduced, and the QT' peak and QT intervals were prolonged. The QT peak interval and systolic intervals did not change appreciably. There were small increases in the PQ and QRS intervals. 3 The effect of quinidine on the QT interval could be explained by a linear pharmacodynamic model. The equilibration between plasma and effect site had a half-time of 8 min. The slope of the pharmacodynamic model was 20.3 ms . mg 1(-1) after i.v. dosing and 33.5 ms . mg 1(-1) after oral dosing. 4 The difference in effect model slopes suggests pharmacologically active metabolites of quinidine are formed during absorption from the gut. 5 The total effect of a single oral dose of quinidine appears to be the same as the same dose given intravenously, even though only 70% of the oral dose reaches the systemic circulation as quinidine.