Penicillins, for example, are cleared by preterm infants at 17% of the adult rate based on comparable surface area and 34% of the adult rate when adjusted for body weight. The dosage of ampicillin for a neonate less than 7 days old is 50–100 mg/kg/d in two doses at 12-hour intervals. The dosage for a neonate over 7 days old is 100–200 mg/kg/d in three doses at 8-hour intervals. A decreased rate of renal elimination in the neonate has also been observed with aminoglycoside antibiotics (kanamycin, gentamicin, neomycin, and streptomycin). The dosage of gentamicin for a neonate less than 7 days old is 5 mg/kg/d in two doses at 12-hour intervals. The dosage for a neonate over 7 days old is 7.5 mg/ kg/d in three doses at 8-hour intervals. Total body clearance of digoxin is directly dependent upon adequate renal function, and accumulation of digoxin can occur when glomerular filtration is decreased. Since renal function in a sick infant may not improve at the predicted rate during the first weeks and months of life, appropriate adjustments in dosage and dosing schedules may be very difficult. In this situation, adjustments are best made on the basis of plasma drug concentrations determined at intervals throughout the course of therapy.
Although great focus is naturally concentrated on the neonate, it is important to remember that toddlers may have shorter elimination half-lives of drugs than older children and adults, due probably to increased renal elimination and metabolism. For example, the dose per kilogram of digoxin is much higher in toddlers than in adults. The mechanisms for these developmental changes are still poorly understood.
Special Pharmacodynamic Features in the Neonate
The appropriate use of drugs has made possible the survival of neonates with severe abnormalities who would otherwise die within days or weeks after birth. For example, administration of indomethacin (see Chapter 36) causes the rapid closure of a patent ductus arteriosus, which would otherwise require surgical closure in an infant with a normal heart. Infusion of prostaglandin E1, on the other hand, causes the ductus to remain open, which can be lifesaving in an infant with transposition of the great vessels or tetralogy of Fallot (see Chapter 18). An unexpected effect of such infusion has been described when the drug caused antral hyperplasia with gastric outlet obstruction as a clinical manifestation in 6 of 74 infants who received it. This phenomenon appears to be dose-dependent. Neonates are also more sensitive to the central depressant effects of opioids than are older children and adults, necessitating extra caution when they are exposed to some narcotics (eg, codeine) through breast milk.
At birth, the function of drug transporters may be very low; for example, P-glycoprotein, which pumps morphine from the blood-brain barrier back to the systemic circulation. Low-level function of P-glycoprotein at birth can explain why neonates are substantially more sensitive than older children to the central nervous system depressant effects of morphine.