The physiologic response to the chronic administration of digoxin was studied in 12 adult and 13 newborn sheep. Vascular pressures, cardiac output, isovolumic contraction phase indexes and systolic time intervals were measured before and after 2 weeks of digoxin therapy. Physiologic measurements were correlated with drug levels in plasma and myocardium. Resting myocardial function in newborns exceeded that in ewes. In ewes, the heart rate decreased from 98 to 74 beats/min, the preejection period (PEP) decreased from 76 to 57 msec, the ratio of PEP to left ventricular ejection time (LVET) decreased from 0.323 to 0.223 and dP/dt max increased from 2415 to 3460 mm Hg . sec-1 as plasma concentrations of digoxin increased to a mean of 1.8 ng/ml. Although the final steady-state plasma concentration of digoxin in newborn lambs averaged 1.7 ng/ml, cardiac output, PEP, PEP/LVET and dP/dt max did not change significantly from baseline values. These studies suggest that developmental differences in the physiologic response to digoxin are due either to a limited capacity for improvement in myocardial contractility shortly after birth or to an age-related difference in the effect of digoxin on myocardial tissue.

The pharmacokinetics of digoxin were determined in 12 ewes and 13 newborn sheep after bolus drug administration and under steady state drug conditions. After death, tissue distribution of digoxin was determined and normalized to plasma drug concentrations at steady state. Volume of distribution and total drug clearance were lower at steady state than the comparable variables calculated from bolus drug administration. No significant difference between ewes and newborns was shown for drug distribution half-life (0.72 vs. 0.76 hr), drug elimination half-life (15.2 vs. 13.7), or renal drug clearance (0.86 vs. 0.89 liters/kg/hr). Total drug clearance as well as the area derived and steady state volumes of distribution were higher in newborns than in ewes. Digoxin secretion into the urine was limited in newborns, as evidenced by a lower renal digoxin clearance to creatinine clearance ratio in newborns than in ewes (371 vs. 600%). The plasma concentration of digoxin at steady state correlated well with myocardial drug concentrations. Drug distribution was similar in both age groups; however, the tissue to plasma digoxin ratio in kidney was higher in newborns than in ewes (mean 469 vs. 263, respectively). Although age-related differences in drug clearance and distribution volume existed, intersubject variation was substantial, and the demonstrated variations were not large enough to account for the high doses of digoxin used to treat congestive heart failure in immature subjects.