Differential effects of digoxin at comparable concentrations in tissues of fetal and adult sheep

Electrocardiogram (ECG) electrodes and carotid arterial and superior vena caval (SVC) catheters were placed in eight nonpregnant ewes and 11 fetuses (109-129 days gestation) to measure heart rate, arterial presssure, P-R interval, left ventricular pre-ejection period (PEP), and left ventricular ejection time (LVET), before and after digoxin infusion into the SVC. After the ewes were killed, the steady state concentration of digoxin in plasma was related to the concentration in midbrain and left ventricular free wall. Although concentrations of digoxin in tissue differed between fetuses and ewes, tissue-plasma ratios were similar; the myocardial-plasma ratio was 87 for fetuses and 90 for ewes and the midbrain-plasma ratios were 6.4 and 5.3, respectively. In spite of these similarities, physiological and toxic effects differed at comparable plasma concentrations. Reduction in PEP/LVET ratio was greater in ewes than fetuses, and P-R interval prolongation was linearly related to digoxin concentration in fetuses but uncommon at plasma concentrations below 2 ng/ml in ewes. Arrhythmias occurred in six ewes, but in only one fetus, even though the mean steady state concentration of digoxin in plasma was 4.5 ng/ml in the fetuses and 2.3 ng/ml in the ewes. Atropine had little effect on digoxin-induced P-R interrval prolongation, and isoproterenol produced no tachyarrhythmias in the fetuses. Age-related differences in inotropic and arrhythmogenic effects of digoxin exist exist and are related to differences in drug response rather than drug kinetics; this provides experimental support for the different dosage responses.