If small body size is not the major reason for heightened drug sensitivity in infants, what is? The increased sensitivity of infants is due largely to the immature state of five pharmacokinetic processes: (1) drug absorption, (2) protein binding of drugs, (3) exclusion of drugs from the central nervous system (CNS) by the blood-brain barrier, (4) hepatic drug metabolism, and (5) renal drug excretion.
Gastrointestinal physiology in the infant is very different from that in the adult. As a result, drug absorption may be enhanced or impeded, depending on the physicochemical properties of the drug involved.
Gastric emptying time is both prolonged and irregular in early infancy, and then gradually reaches adult values by 6 to 8 months. For drugs that are absorbed primarily from the stomach, delayed gastric emptying enhances absorption. On the other hand, for drugs that are absorbed primarily from the intestine, absorption is delayed. Because gastric emptying time is irregular, the precise effect on absorption is not predictable.
Gastric acidity is very low 24 hours after birth and does not reach adult values for 2 years. Because of low acidity, absorption of acid-labile drugs is increased.
Drug absorption after intramuscular injection in the neonate is slow and erratic. Delayed absorption is due in part to low blood flow through muscle during the first days of postnatal life. By early infancy, absorption of intramuscular drugs becomes more rapid than in neonates and adults.
Drug absorption through the skin is more rapid and complete in infants than in older children and adults. The stratum corneum of the infant’s skin is very thin, and blood flow to the skin is greater in infants than in older patients. Because of this enhanced absorption, infants are at increased risk for toxicity from topical drugs.
Binding of drugs to albumin and other plasma proteins is limited in the infant because (1) the amount of serum albumin is relatively low and (2) endogenous compounds (e.g., fatty acids, bilirubin) compete with drugs for available binding sites. Consequently, drugs that ordinarily undergo extensive protein binding in adults undergo much less binding in infants. As a result, the concentration of free levels of such drugs is relatively high in the infant, thereby intensifying effects. To ensure that effects are not too intense, dosages in infants should be reduced. Protein-binding capacity reaches adult values within 10 to 12 months.
The blood-brain barrier is not fully developed at birth. As a result, drugs and other chemicals have relatively easy access to the CNS, making the infant especially sensitive to drugs that affect CNS function. Accordingly, all medicines employed for their CNS effects (e.g., morphine, phenobarbital) should be given in reduced dosage. Dosage should also be reduced for drugs used for actions outside the CNS if those drugs are capable of producing CNS toxicity as a side effect.
The drug-metabolizing capacity of newborns is low. As a result, neonates are especially sensitive to drugs that are eliminated primarily by hepatic metabolism. When these drugs are used, dosages must be reduced. The capacity of the liver to metabolize many drugs increases rapidly about 1 month after birth and approaches adult levels a few months later. Complete maturation of the liver develops by 1 year.