This decreased protein binding could be due to qualitative and quantitative differences in neonatal plasma protein and also to exogenous and endogenous substrates in the plasma. Decreased protein binding may alter pharmacologic responses and drug clearance but is seldom considered in older children. The increased sensitivity of newborns to certain drugs, eg, theophylline, has been attributed in part to decreased protein binding, resulting in more available drug at the receptor site and leading to a more intense pharmacologic effect. Thus, adverse reactions may occur at much lower plasma drug concentrations, considered safe in adults. These processes tend to be very slow in the newborn, increase progressively during the first few months of life, and exceed adult rates by the first few years of life.
Drug elimination slows during adolescence and probably attains adult rates by late puberty.
Changes in drug metabolism and disposition as a function of age are extremely variable and depend also on the substrate or drug. Most drugs, including phenytoin, barbiturates, analgesics, and cardiac glycosides, have plasma half-lives two to three times longer in newborns than in adults. Metabolism and drug elimination show marked interpatient variability and vulnerability to pathophysiologic states. These observations have resulted in modified dosages for infants and children. The principles are illustrated in Fig.