Introduction

Medication pharmacodynamic and pharmacokinetic characteristics vary based on age-related effects, especially in neonatal and pediatric populations. (Age-related differences in neonatal versus adult populations are discussed later.) Four main principles are involved in medication dosing strategies, effectiveness, and adverse event risk:

1.Absorption—how the medication gets into the body and blood stream.

2.Distribution—where the medication goes after it is in the body and blood stream.

3.Metabolism—what happens to medication inside the body.

4.Elimination—how the parent medication and metabolites leave the body.

Absorption

To reach systemic circulation, medications administered extravascularly undergo absorption. All patient populations, neonatal and adult, have barriers limiting absorption including medication-related properties and physiologic-related patient characteristics. The differences between patient populations are the extent of medication absorption and the rate of absorption. Extravascular absorption is required for medications administered enterally, intramuscularly (IM), percutaneously, and rectally.

Gastrointestinal Absorption

Gastric pH decreases to a pH of 1 to 3 from a neutral pH at birth during the first 48 hours of life. Over the first week of life, gastric pH again neutralizes. Gastric pH gradually decreases over the first 2 years of life to adult pH.^1–3 More neutral gastric pH may contribute to increased bioavailability of acid-labile medications, such as penicillin,⁴ and decreased bioavailability of weak bases, such as phenytoin,⁵ in preterm and term neonates. Prolonged gastric emptying and decreased intestinal motility reduce the rate of both active and passive medication absorption in neonates. A nonlinear relationship independent of small bowel pH and brush border metabolism exists between age and rate of medication absorption where absorption rate increases with patient age.⁶ Other factors that may contribute to absorption variances in neonates are variable brush border enzymatic function, decreased intestinal surface area, varying pancreatic enzyme activity and biliary function, and shorter gut transit time.¹

IM Absorption

Decreased skeletal muscle blood flow in neonates may reduce absorption of IM administered medications. Less muscle contraction may also reduce absorption. However, neonates typically have capillary dense muscle, which may increase absorption.^7,8 IM administered medication absorption is considered unpredictable and not routinely recommended.¹

Percutaneous Absorption

Due to skin structure development, medication absorption through the skin may be increased in neonates. Three contributing factors include a larger body surface area to mass ratio, greater hydration of epidermis, and better perfusion of the cutaneous layer in neonates. Preterm neonates also have thinner stratum corneum.^1,7,8 Caution is recommended when applying localized, topical medication to neonates due to increased risk of systemic exposure.

Rectal Absorption

Medications administered rectally should have increased bioavailability in neonates. The anticipated increase in bioavailability may be attributed to limited first-pass metabolism or decreased hepatic enzyme metabolism in neonates.⁷ However, rectal contractions in neonates pulsate resulting in frequent medication evacuation that may limit absorption.^7,9,10

Distribution

After a medication enters the body of a patient, the medication is then distributed throughout the body. One main medication parameter, volume of distribution (Vd), encapsulates medication characteristics related to distribution throughout the body. Volume of distribution is a ratio of total body medication amount to plasma medication concentration. Small Vds indicate a relatively higher plasma medication concentration compared to the amount of medication in the body. The inverse is true for large Vds. Factors influencing medication Vd include medication properties related to lipophilicity and hydrophilicity, patient body composition, and protein and tissue binding.¹

As a patient ages, body composition as a percentage of total body weight changes. Total body water and total body fat approximate 85% and 1 to 2% in preterm neonates, respectively. Term neonate total body water and total body fat composition approximate 75% and 10 to 15%, respectively.^1,7 Due to the large percentage of total body water in neonates, both preterm and term, hydrophilic medications have larger Vds and require larger weight-based dosing strategies. Vds are larger for aminoglycosides in younger patients requiring larger weight-based dosing approaches. Gentamicin doses may be 4.5 to 5 mg/kg/dose for preterm neonates compared to 4 mg/kg/dose for term neonates.¹¹ Conversely, lipophilic medications have smaller Vds in neonates compared to adults.^1,7

Protein and tissue binding also affect medication distribution. Plasma protein concentrations and protein-binding affinities for medications are often reduced in neonates.¹ Protein-bound medications, such as phenytoin and benzodiazepines, may have increased Vds in neonates compared to adults due to the decreased number of plasma-binding proteins and the decreased binding affinity of medications compared to bilirubin and free fatty acids.¹² Circulating competitive protein-bound compounds are increased in neonates limiting medication binding to serum albumin, especially fetal albumin.^1,7 More unbound medication increases effect, toxicity risk, and clearance. Medication examples that compete with bilirubin for albumin-binding sites, increasing the risk of kernicterus, are ceftriaxone and sulfonamides.^13–15 These medications are not recommended for use in neonates.

Metabolism

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