Neonatal Pharmacology

Physiological/Pharmacological Differences

  • There are many physiological differences between neonate and adult that result in differences in drug pharmacokinetics and pharmacodynamics
  • In general, in neonate
    • ↑ uptake and distribution
    • ↓ elimination →
    • ↑ risk overdose and toxicity
  • Faster speed of onset
    • ↑ cardiac output → faster circulation time → faster distribution of drug to site of action

 

Pharmacokinetic differences: neonate vs adult

Absorption

  • Poor compliance with oral intake + vomiting + ↓ gastric emptying unreliable oral/GI absorption
  • Unpredictable skin blood supply → unreliable transdermal, subcutaneous, intramuscular absorption kinetics
  • ↑ RR → ↑ minute ventilation → ↑ absorption of volatiles

Distribution

  • Volume of Distribution
    • Proportionally ↑ ECF → ↑ Vd especially for highly ionised, hydrophilic drugs eg muscle relaxants
      • Higher TBW (75% body wt vs adult 60%)
      • Larger % TBW contained in ECF compartment (ECF 40% body wt, ICF 35% body wt vs adult ECF 27%, ICF 33%)
  • Protein Binding
    • Lower protein concentrations and protein binding
      • 𝛼1 acid glycoprotein (LA binding)
      • albumin
    •   ↑ unbound fraction  of drugs
  • ↓ plasma pH → alter ionised fraction
  • Immature blood brain barrier → ↑ penetration of lipid soluble drugs

Metabolism

  • Immature liver enzyme system →
    • ↓ hepatic phase I and phase II metabolism
    • ↓ plasma cholinesterase levels
  • Hepatic enzymes mature at different times
    • ↓ activity of microsomal enzymes responsible for Phase I (non-synthetic)reactions involved in metabolism of synthetic opioids. Activity reaches adult levels with a few days of birth.
    • Ability to for conjugates (Phase II, synthetic reactions), eg with glucuronide, does not approach adult levels until 6 months of age → affects elimination of morphine

Elimination

  • Immature kidneys → ↓ GFR (~10% of adult) →
    • ↓ renal clearance of drugs
    • ↓ tubular secretion mechanisms
  • Proximal tubule secretion is important for elimination of conjugated drugs and reaches adult values by 7 months of age

Anaesthetic Drugs

Inhalational Agents

  • MAC lower in preterm infants than in term infants and increases with PCA
  • MAC  increases to maximum at 6 months of age then starts to decrease
    • Sevo is atypical. No change in MAC < 6 months. After 6 months, abrupt step down in MAC, following which it remains constant during childhood
  • Rate of rise in FA:FI is more rapid, due to 4 factors (listed in order of decreasing importance)
    • Greater alveolar ventilation in relation to FRC
    • Greater % cardiac output distributed to vessel rich group
    • Lower tissue/blood solubility
    • Lower blood/gas solubility

 

Intravenous Agents

  • ↑ Sensitivity to barbiturates and opioids
    • Due to immaturity of BBB → faster penetration and rise in conc
    • Also greater % CO to VRG
    • Greater sensitivity of respiratory centre to effects of opioids
  • Prolonged duration of action
    • ↓ hepatic metabolism and renal excretion

 

Muscle Relaxants

  • NMJ 3 times more sensitive to NDMR but balanced by
  • Vol of distribution ↑ x 3 times (large ECF vol) →
    • Same dosing as adults!
  • However, prolonged elimination times → ↓ dose and frequency of top ups
  • Suxamethonium
    • Higher Vd but counteracted by lower levels of psuedocholinesterase
      • Dose double that of adults 2mg/kg
    • Duration of action 5 - 8 minutes, terminated by plasma cholinesterase
    • Hydrolysis slower in preterm infant (immature liver)
    • Due to actions on mus ACh recs in SA node, may → bradycardia, asystole

 

Local Anaesthetics

  • Higher risk of toxicity
    • ↓ protein binding to 𝛼1 acid glycoprotein → ↑ free fraction → ↑ toxicity
    • Lower hepatic clearance

Morphine

  • Absorption
    • ↓ PO absorption, unreliable IM/SC absorption
  • Distribution
    • ↓ [protein] → ↑ unbound fraction; immature BBB → more CNS availability
  • Metabolism
    •   ↓ hepatic glucuronidation → ↑ duration of action
  • Elimination
    • ↓ renal function → ↓ renal clearance → ↑ duration of action

 

Bupivacaine

  • Absorption
    • unreliable cutaneous absorption → safe dose may be < 3mg/kg
  • Distribution
    • ↓ a1-acid glycoprotein → ↑ free drug; ↓ pH (pKa 8.1) → higher ionised fraction → slower onset of action
  • Metabolism
    • ↓ hepatic metabolism → ↑ duration of action → more prone to toxicity
  • Elimination
    • ↓ renal excretion (usu. 16% renally excreted) → ↑ duration of action

 

Suxamethonium

  • Absorption
    • IV administration ∴ unaffected
  • Distribution
    • ↑ Vd  →   ↓ availability at NMJ  →   need higher dose
  • Metabolism
    • ↓ plasma cholinesterases → ↑ duration of action
  • Elimination
    • as above

 

Sevoflurane

  • Absorption
    • ↑ MV → ↑ absorption of volatiles → faster induction
  • Also ↑ cardiac index → slightly reduced rise of FA/FI (less important than MV)

 

Vecuronium

  • Absorption
    • unchanged
  • Distribution
    • increased cardiac index → faster onset
    • ↑ Vd  →   ↓ availability at NMJ  →   may need higher dose
  • Metabolism
    • ↓ hepatic metabolism → ↑ duration of action
  • Elimination
    • ↓ renal excretion → ↑ duration of action