Drug therapy in pediatric patients

Patients who are very young or very old respond differently to drugs than do the rest of the population. Most differences are quantitative. Specifically, patients in both age groups are more sensitive to drugs than other patients, and they show greater individual variation. Drug sensitivity in the very young results largely from organ system immaturity. Drug sensitivity in the elderly results largely from organ system degeneration. Because of heightened drug sensitivity, patients in both age groups are at increased risk of adverse drug reactions. In this chapter we discuss the physiologic factors that underlie heightened drug sensitivity in pediatric patients, as well as ways to promote safe and effective drug use. Drug therapy in geriatric patients is discussed in Chapter 11.

Pediatrics covers all patients up to the age of 16. Because of ongoing growth and development, pediatric patients in different age groups present different therapeutic challenges. Traditionally, the pediatric population is subdivided into six groups:

• Premature infants (less than 36 weeks’ gestational age)

• Full-term infants (36 to 40 weeks’ gestational age)

• Neonates (first 4 postnatal weeks)

• Infants (weeks 5 to 52 postnatal)

• Children (1 to 12 years)

• Adolescents (12 to 16 years)

Not surprisingly, as young patients grow older, they become more like adults physiologically, and hence more like adults with regard to drug therapy. Conversely, the very young—those less than 1 year old, and especially those less than 1 month old—are very different from adults. If drug therapy in these patients is to be safe and effective, we must account for these differences.

Pediatric drug therapy is made even more difficult by insufficient drug information: Fully two-thirds of drugs used in pediatrics have never been tested in children. As a result, we lack reliable information on dosing, pharmacokinetics, and effects, both therapeutic and adverse. Is this lack of knowledge causing adverse events and even death? Possibly, but no one knows. Is it preventing optimal treatment? Probably, but again, we just don’t know. To help expand our knowledge, Congress enacted two important laws: the Best Pharmaceuticals for Children Act, passed in 2002, and the Pediatric Research Equity Act of 2003. Both are designed to promote drug research in children. What we have learned so far underscores both the state of our ignorance and the need for much more work. For example, of the drugs studied to date:

• About 20% were ineffective in children, even though they were effective in adults.

• About 30% caused unanticipated side effects, some of them potentially lethal.

• About 20% required dosages different from those that had been extrapolated from dosages used in adults.

As more studies are done, the huge gaps in our knowledge will shrink. In the meantime, we must still treat children with drugs—even though we lack the information needed to prescribe rationally. Hence, similar to drug therapy during pregnancy, prescribers must try to balance benefits versus risks, without knowing with precision what the benefits and risks really are.

Pharmacokinetics: neonates and infants

As we discussed in Chapter 4, pharmacokinetic factors determine the concentration of a drug at its sites of action, and hence determine the intensity and duration of responses. If drug levels are elevated, responses will be more intense. If drug elimination is delayed, responses will be prolonged. Because the organ systems that regulate drug levels are not fully developed in the very young, these patients are at risk of both possibilities: drug effects that are unusually intense and prolonged. By accounting for pharmacokinetic differences in the very young, we can increase the chances that drug therapy will be both effective and safe.

Figure 10–1 illustrates how drug levels differ between infants and adults following administration of equivalent doses (ie, doses adjusted for body weight). When a drug is administered intravenously (Fig. 10–1A), levels decline more slowly in the infant than in the adult. As a result, drug levels in the infant remain above the minimum effective concentration (MEC) longer than in the adult, thereby causing effects to be prolonged. When a drug is administered subcutaneously (Fig. 10–1B), not only do levels in the infant remain above the MEC longer than in the adult, but these levels also rise higher, causing effects to be more intense as well as prolonged. From these illustrations, it is clear that adjustment of dosage for infants on the basis of body size alone is not sufficient to achieve safe results.