The pediatric patient responds to medications differently than the adult patient for a number of reasons.
These differences in body composition have important implications regarding drug effect, loading dose, interval of dosing and drug metabolism. For example, if one is giving a medication that is highly water soluble and therefore rapidly redistributed in this large water compartment, then one might have to give a higher initial dose on a mg/kg basis compared with older patients. A good example of this would be succinylcholine and many antibiotics.
Another difference between infants and older children is maturity of hepatic function. Certainly, newborns are capable of conjugating and glucuronidating most medications but the rate of metabolism is generally delayed compared to the older child or adult. The half-life of thiopental is approximately 18 hours in a term newborn, about 7 hours in a child 4 to 10 years of age and 10 hours in the adult. Thus in addition to having less fat for the thiopental to redistribute into there is a markedly prolonged beta elimination phase due to immaturity of hepatic metabolism. Another factor is alterations in hepatic blood flow and therefore alterations in drug delivery to the liver where it can be metabolized. Any procedure that results in increased intra abdominal pressure such as an omphalocele or gastroschisis repair will decrease hepatic blood flow and also markedly delay drug metabolism. In some neonates with these surgical problems, a single dose of fentanyl has been demonstrated to maintain constant plasma values for as long as 16 hours.
In the preterm infant, the glomerular filtration rate in ml’s/minute/1.73 meters squared surface area is only about 25, in the term infant it is about 35, by two weeks of age it is doubled to approximately 60, by 6 months of age it is 80 ml/minute/1.73 meters squared surface area and at 1 year of age it is roughly equivalent to that of the adult. This is the reason why drugs that are rapidly excreted through the kidneys, such as antibiotics, are given at less frequent intervals in the premature compared to the term newborn and at less frequent intervals in the term newborn compared to the older child.
These differences can then alter the amount of drug that is protein bound which in turn affects the amount of free drug available to cross a biologic membrane. Less protein or less albumen results in higher free drug levels.
Another issue regarding pharmacodynamic differences is the central nervous system and the maturity of the blood brain barrier. For medications with high fat solubility, the blood brain barrier does not make a significant different but it will make a difference for medications that have a low fat solubility since it is fat solubility that determines a drugs ability to cross cell membranes. If one looks at the fat solubility of the synthetic opioid fentanyl compared to morphine, one would find that fentanyl is so fat soluble (nearly 2,000,000 times > morphine!) that there virtually is no blood brain barrier effect. Whereas with morphine, which has a low fat solubility, a proportionally higher amount of morphine would cross into the brain of a newborn compared to an older patient simply because of this difference in fat solubility. This same effect is also very marked for the benzodiazepines. A number of studies have shown that the peak pharmacodynamic effects of benzodiazepines are directly proportional to their fat solubility. Thus the peak EEG effect of diazepam isnearly three times faster than that of midazolam. A common misconception is the reverse, i.e., because midazolam is shorter acting it must enter the CNS more apidly (see Figure 7).
The figure below (Figure 8) illustrates the overall interactions between maturation of excretory mechanisms, alterations in body composition and their effects upon drug clearance and beta elimination half-life for sufentanil.
Transdermal drug delivery
In general, we can say that infants are different from children and children are different from adults. There tends to be a lower ability to excrete drugs in infants because of the differences in glomerular filtration and hepatic function and there are also differences in the way drugs are redistributed within the body, all of which will affect the patient’s ability to eliminate the drug. As the child matures, the ability to excrete and metabolize improves resulting in a shortened half-life of most medications. As we become older, particularly as we become octogenarians, our ability to excrete drugs becomes almost like that of a neonate.