Pediatric Drug Therapy

Absorption

Absorption is the process in which a drug is transported from the site of administration (i.e., the GI tract for oral administration) to the systemic circulation. Children have unique differences that may lead to changes in drug absorption. Figure 171.1 illustrates many of the key factors that account for pharmacokinetic differences between children and adults. For example, young children have higher gastric pH levels, which affects the bioavailability of acid-labile drugs (such as penicillins) to be absorbed in the stomach. They have decreased gastric emptying times, which prolongs exposure to medications before they pass the pylorus and may impact time to achieve peak concentrations. Variations in the intestinal tract also result in pharmacokinetic differences. The activity of drug-metabolizing enzymes on the intestinal border vary as development occurs, and differences in gut flora can impact drug absorption in young infants. One commonality between children and adults is that drug absorption is often impaired in the setting of critical illness.

Absorption of drugs via a non-oral route can also vary significantly in children compared to adults. The topical route can result in increased absorption in children due to their relatively larger body surface area and increased skin vascularity. Additionally, children’s skin contains more water and has a thinner stratum corneum. These factors make children more prone to increased absorption and risk for systemic toxicity from dermally applied drugs. Children have less muscle mass with associated weaker muscle contraction and reduced muscle blood flow. This can result in erratic absorption of intramuscular medications in young children. Absorption of rectally administered medications also varies widely, depending on the age of the child and chemistry of the drug involved. However, this route can be used for medications when children are unable to tolerate or are refusing oral administration, such as for acetaminophen and diazepam. The ability to administer medications via the pulmonary route is particularly desirable in pediatric populations, given the high prevalence of respiratory conditions, such as asthma. At the same time, younger children may be less able to coordinate the use of a metered-dose inhaler to deliver these medications properly; parental assistance and adjunct devices such as spacers maximize efficacy by minimizing drug deposition in the oropharynx. There has been increasing experience in the use of intranasal preparation of analgesic, sedative, and anxiolytic medications in children. Medications that can be used intranasally include fentanyl, ketamine, dexmedetomidine, and midazolam. This relatively noninvasive route of administration provides rapid absorption and clinical effect for circumstances requiring immediate pain control or sedation.

Distribution

Drug distribution is the movement of the drug after entering systemic circulation to the tissues of the body. Drug distribution can be impacted by circulation, proteins, extracellular fluid, and body composition. The specific drug composition can also impact drug distribution greatly. Distribution can differ significantly in children, which has important clinical implications. Neonates and infants have higher total body water and larger volumes of distribution and extracellular fluid; therefore, dosing of medications such as aminoglycosides will differ in this age group, and drug concentrations should be closely monitored. The larger volume of distribution (Vd) may impact hydrophilic drugs and result in larger weight-based doses to achieve sufficient systemic concentrations. Free drug concentrations are also affected by relatively lower concentrations of plasma proteins (albumin, glycoprotein, globulins, etc.) in infants and young children. A consideration specific to neonates is the displacement of bilirubin from protein-binding sites by drugs such as ceftriaxone, which can lead to kernicterus. Consequently, these medications should be avoided until the blood-brain barrier matures. Table 171.1 presents examples of other commonly used medications in the practice of emergency medicine that carry pediatric-specific toxicities as a result of pharmacokinetic and other idiopathic differences.

Body composition can impact drug pharmacokinetics. Childhood obesity has reached epidemic proportions in the United States and worldwide, and significant knowledge gaps have led to a lack of guidance on how medications should be dosed in an obese pediatric patient. Drugs should be cautiously administered in this patient population, especially for high-risk medications such as opioid analgesics and sedatives. Additionally, childhood obesity has resulted in more children being placed on medications, more commonly used in adults, for chronic conditions, such as anti-hypertensives and diabetes medications. Because these medications have been traditionally prescribed for adults, there are few guidelines and a significant paucity of safety and efficacy data in children, which can predispose them to adverse drug events.

Metabolism

Drugs are metabolized through various organs—most commonly the liver, but also in the kidneys and gastrointestinal mucosa. Phase 1 metabolism often involves oxidation or hydrolysis (often by cytochrome P450 enzymes [CYP]), whereas phase 2 metabolism includes conjugation reactions such as glucuronidation and sulfation. Drug metabolism in neonates and infants can be diminished because of immature drug-metabolizing enzymes ( Box 171.1 ). An example of toxicity due to differences in drug-metabolizing enzymes is the neonatal gasping syndrome. Benzyl alcohol, a common preservative for parenteral medications, is metabolized to benzoic acid, which is detoxified by glycine conjugation. Glycine conjugation is decreased in neonates and therefore benzoic acid accumulates when they are given drugs containing benzyl alcohol, leading to metabolic acidosis, respiratory distress, and cardiovascular collapse. As children approach adolescence, drug metabolism is generally the same as in adults.