The Liver
At term, the functional maturity of the liver is somewhat incomplete.
Most enzyme systems for drug metabolism are developed but not yet induced (stimulated)
by the drugs that they metabolize. As an infant grows, the ability to metabolize
medications increases rapidly for two reasons: (1) hepatic blood flow increases
and more drug is delivered to the liver, and (2) the enzyme systems
Figure 60-4
The glomerular filtration rate is markedly impaired at
birth but develops rapidly during the first year of life. The ability of the kidney
to handle large amounts of solutes and water is also limited during the first several
months of life. These developmental changes have significant implications for drug
excretion and fluid therapy, particularly during the first 4 weeks of life. Maturation
of renal function may be delayed in sick neonates. (Data from McCrory WW:
Developmental Nephrology. Cambridge, MA, Harvard University Press, 1972.)
develop and are induced.[25]
[26]
[27]
[28]
The cytochrome
P450 system is responsible for phase I drug metabolism of lipophilic compounds.
This system reaches approximately 50% of adult values at birth, thus suggesting an
overall reduced capacity for drug metabolism, for example, caffeine. However, this
generalization does not hold true for all lipophilic medications, and the ability
of the neonate to metabolize specific drugs is dependent on individual drug-specific
cytochromes (CYP1, CYP2, and CYP3 enzyme subfamilies).[29]
[30]
[31]
[32]
[33]
Phase II reactions involve conjugation, which
makes the drug more water soluble to facilitate renal excretion.[33]
[34]
[35]
These
reactions are often impaired in neonates, and jaundice (decreased bilirubin breakdown)
results, as well as long drug half-lives, such as those for morphine and benzodiazepines.
[25]
[36]
Some
of
these reactions do not achieve adult activity until after 1 year of age.[31]
[35]
A premature infant's liver has minimal glycogen stores and is
unable to handle large protein loads. This difference accounts for the tendency
to hypoglycemia and acidemia and for the failure to gain weight when the diet contains
too much protein. Additionally, plasma levels of albumin and other proteins necessary
for binding of drugs are lower in term newborns (and are even lower in premature
infants) than in older infants. This condition has clinical implications regarding
neonatal coagulopathy (e.g., the need for vitamin K at birth), as well as for drug
binding and pharmacodynamics; the lower the albumin value, the less protein binding
and the greater the levels of free drug.[37]
[38]
In addition, drug binding to albumin may be altered in the presence of hyperbilirubinemia
for some medications in the neonatal period.[37]
