Neonates renal drug elimination

It is important to appreciate that these tubular transport mechanisms are not as well developed in the neonate as in the adult. In addition, their functional capacity may be diminished in the elderly. Thus, compounds normally eliminated by tubular secretion will be excreted more slowly in the very young and in the older adult. This age dependence of the rate of renal drug secretion may have important therapeutic implications and must be considered by the physician who prescribes drugs for these age groups. 

Age-related alteration of renal function is a very important factor in selecting the dose regimen. Renal function in newborns is incompletely developed. Neonatal renal plasma flow and glomerular filtration rates (normalized for body surface) are only 30-40% of those of adults. The half-life of penicillin G is 3.2 h in newborns (up to 6 days of age) and 1.4 h in infants (14 days of age or older), whereas in older children and adults, it is about 0.5 h. The mean half-life of gentamicin is about 5h in newborns under 1 week of age and about 3 h in infants 1-4 weeks of age. The half-life of gentamicin in older infants and adults is approximately 2 h. Thus, drugs that depend on renal excretion as the principal mode of elimination would be expected to have a longer residence time in infants. 

Host factors can help to ensure selection of the most appropriate antimicrobial agent. Age is an important factor in antimicrobial selection. With regard to dose and interval, renal and hepatic function varies with age. Populations with diminished renal function include neonates and the elderly. Hepatic function in the neonate is not fully developed, and drugs that are metabolized or eliminated by this route may produce adverse effects. For example, sulfonamides and ceftriaxone may compete with bilirubin for binding sites and may result in hyperbilirubinemia and kernicterus. Gastric acidity also depends on... 

Chloramphenicol is inactivated in the liver by glu-curonosyltransferase and is rapidly excreted (80-90% of dose) in the urine. About 5 to 10% of the administered drug is excreted unchanged. Renal elimination is by tubular secretion and glomerular filtration. Other degradation pathways are known to exist and may account for some of the toxicity seen in neonates and children. 

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. 

Most infants are slow acetylators and may accumulate toxic levels of those drugs that are metabolized by this second phase of metabolism route. Renal perfusion and glomerular filtration rates (GFR) vary for the premature, 2-4 ml min-1 for neonates, 25 ml min-1 and by 1-1.5 years old, 125 ml min-1, which is equivalent to adult clearance rates (Arant, 1978). The potential toxic implication of renal metabolites and elimination of unchanged drug in the very young are obvious (Stewart and Hampton, 1987). 

Metabolism in pediatric patients can be quite different from adults. In the very young infant, drug uptake by the liver is decreased due to reduced transport proteins. The biliary excretion of antibiotics with dual routes of elimination suggests that hepatic transport maturation is even slower than glomerular filtration or renal transport maturation. Overall, mixed function oxidases are present at 30-50% of adult activity, while individual enzymes may be less than 5% of adult activity. In particular, isoenzymes of CYP 2C9 and 1A2 have greatly reduced activity in neonates however, there is a rapid increase in 2C9 activity in the first weeks of life. After birth. Phase I and II enzymes have a programmed order of expression, which is different for each isoenzyme. Some isoenzymes increase in days, others over weeks, and stUI others over months. 

Renal elimination of drugs also is reduced in the neonatal period. Neonates at term have markedly reduced GFR (2-A mL/min/1.73 m ), and prematurity reduces renal function even further. As a result, neonatal dosing regimens for a number of drugs (e.g., aminoglycosides) must be... 

Hepatic metabolism to the inactive glucuronide is the major route of elimination. This metabolite and chloramphenicol are excreted in the urine. Patients with impaired liver function have decreased metabolic clearance, and dose should be decreased. About 50% of chloramphenicol is bound to plasma proteins this is reduced in cirrhotic patients and in neonates. Half-life is not altered significantly by renal insufficiency or hemodialysis, and dose adjustment usually is not required. However, if the dose of chloramphenicol has been reduced because of cirrhosis, clearance by hemodialysis may be significant. Drug administration after hemodialysis minimizes this effect. Variabihty in the metabolism and pharmacokinetics of chloramphenicol in neonates, infants, and children necessitates monitoring of plasma drug levels. 

Dose regimens of renally eliminated drugs in neonates are generally based on postconceptional or postmenstrual age as a measure of renal maturation, and postnatal age, to take into account the adaptive changes that occur after birth. However, these should be regarded as initial doses and dose frequency and should be adjusted according to response. 

---