Pediatric Pharmacology

Water-soluble drugs — non-depolarizing NMBs, antibiotics, propofol bolus, opioids — have a larger Vd in neonates → REQUIRE a higher mg/kg initial dose to achieve the target plasma concentration.

Counterintuitive: small patients often need higher mg/kg loading than adults.

Maintenance dosing then depends on clearance, which is REDUCED in neonates (see next section) — so the loading-vs-maintenance gap is wider than in adults.

Don't extrapolate adult-rate infusions to neonates.

CYP3A7 dominates in the fetus and neonate, then is replaced by CYP3A4 over the first year.

CYP2D6 reaches adult activity by 1-3 years.

Phase II glucuronidation matures even later — adult capacity by 2-3 years.

Fentanyl clearance slower in <6 mo.

Midazolam half-life prolonged in preterm and ill neonates.

Renal clearance also reduced — GFR matures over the first year.

Drugs cleared renally (aminoglycosides, vancomycin, some NMBs) require dose interval extension.

Drugs that are highly protein-bound in adults (local anesthetics, midazolam, diazepam, sufentanil) have proportionally more free drug in neonates → exaggerated effect at given total dose.

Bilirubin can displace drugs (and vice versa) — important for jaundiced neonates and kernicterus risk.

🧠Greater respiratory depression at a given dose.

Greater behavioral changes.

Reduce opioid loading carefully and titrate to effect, not to mg/kg.

Multimodal pain strategy (scheduled acetaminophen, regional anesthesia, dexmedetomidine) substantially reduces opioid requirement in neonates and infants — much safer than higher opioid doses.

By age 10 → ~2.0% (adult-equivalent).

Adult MAC sevoflurane ~1.8-2.0%.

Older adults: MAC decreases ~6% per decade after 40. Children require higher inhaled concentrations to achieve surgical depth, BUT hemodynamic depression is also more pronounced at high MAC values — neonate/infant blood pressure drops dramatically at MAC 1.5+.

Monitor BP and HR closely.

N₂O 50-70% adjunct reduces volatile requirement and hemodynamic effect.

Halothane (historic) had MAC ~0.8% in adults but is essentially gone from US practice.

💊Fentanyl: 1-2 mcg/kg standard.

Rocuronium: 0.6-1.2 mg/kg standard.

Atropine: 0.02 mg/kg pre-induction in infants (sevoflurane bradycardia + vagal tone).

Dexmedetomidine: 0.5-1 mcg/kg load + 0.5 mcg/kg/hr — useful adjunct.

Ketamine: 1-2 mg/kg IV, 4-6 mg/kg IM.

Acetaminophen: 15 mg/kg q6h IV or PR (max 75 mg/kg/day).

Ibuprofen: 10 mg/kg q6-8h (over 6 mo).

Avoid morphine in neonates if alternatives exist; if used, dose 0.05 mg/kg with close respiratory monitoring.

Ultra-rapid CYP2D6 metabolizers (1-7% of population, higher in N African / Ethiopian / Saudi populations) generate excess morphine → fatal respiratory depression.

Multiple post-tonsillectomy pediatric deaths drove the FDA boxed warning.

Tramadol shares the same activation pathway and the same contraindications.

Alternatives: scheduled acetaminophen + ibuprofen + regional + low-dose morphine or hydromorphone PRN with respiratory monitoring.

Rationale: unrecognized Duchenne muscular dystrophy (DMD) or Becker MD in pediatric males → upregulated extrajunctional acetylcholine receptors → massive K+ efflux on depolarization → hyperkalemic cardiac arrest.

Rocuronium + sugammadex is the preferred alternative for elective.

Same caution applies to other genetic myopathies (myotonic dystrophy, central core disease, mitochondrial myopathies).

Based on animal data (rats, primates) showing neurodegenerative changes with prolonged exposure to GABA-agonists and NMDA-antagonists.

Human data (GAS trial, PANDA, MASK) more reassuring: single brief exposures in healthy children do NOT show clinically significant cognitive impact.

Practical approach: don't delay urgent surgery; for elective procedures in <3-year-olds, discuss risks/benefits and consider whether the procedure can wait.

Document the discussion.

Use regional + sedation when possible to limit GA duration.