2008B05 Outline how the pharmacokinetics of morphine, bupivacaine and suxamethonium differ
 in the neonate compared to the adult. Briefly describe the clinical implications of these differences.

Morphine

Bupivacaine

Suxamethonium

Type

Opioid analgesic

Amide local anaesthetic

Depolarising muscle relaxant

Dose

0.1-0.2mg/kg

3kg baby: 0.3-0.6mg

Max 2mg/kg

3kg baby: 6mg

1-2mg/kg

3kg baby: 3-6mg

Toxicity

M: sedation, resp depression

M6G: same

M3G: neurotoxicity, seizure

CNS: seizure, coma

CVS: arrhythmia, arrest

Desensitisation blockade

Bradyarrhythmia

Neonate cf. adult

↑Sensitivity to opioid

↑M3G toxicity

↓Metabolism

↑Sensitivity

↓Metabolism

Kinetic changes cancel out

↑Sensitivity

↑Risk bradyarrhythmia

Oral

·   Vomiting, GORD -> unreliable effect PO morphine

·   ↓Absorption rate until 6-8 months (↓rate of onset PO morphine)

·   ↓Intestinal transit speed -> ↑oral bioavailability of morphine

Inhaled

·   V_A:FRC ratio 5:1 cf. 1.5:1 -> ↑rate of rise F_A/F_I volatiles (overrides cardiac output)

IM

·   ↑Muscle blood flow -> rate of absorption of suxamethonium

SC / transdermal

·   ↑Cardiac output:surface area -> ↑skin blood flow -> ↑rate of absorption S/C morphine

↑Cardiac output

·   ↑Rate of onset suxamethonium

·   ↓Rate of ↑ F_A/F_I volatile anaesthetic (overridden by ↑V_A:FRC)

Blood

·   ↑Blood volume

·   ↓Blood fat content -> ↓blood:gas partition coefficient volatiles

·   ↓pH 7.3 -> ↑ionisation of basic drugs e.g. bupivacaine -> ↓toxicity (minor effect)

·   ↓Albumin -> ↑%free bupivacaine -> ↑toxicity

·   ↓AAG -> ↑%free basic drugs -> toxicity (e.g. morphine)

Tissues

·   ↑Total body water -> ↑V_D water-soluble drugs e.g. suxamethonium

·   ↓Muscle mass -> ↑sensitivity to suxamethonium

·   ↓Fat mass -> ↓uptake of lipid-soluble drugs -> toxicity (e.g. bupivacaine)

·   Immature blood brain barrier -> ↑uptake of morphine (only 23% unionized) -> toxicity

Brain

·   Permeable blood-brain barrier -> ↑toxicity if

o Highly ionised (e.g. morphine 77%, bupivacaine 85%)

o Hydrophilic (e.g. M3G, M6G)

Enzyme systems mature at different rates

↓Phase 1 reactions

·   ↓Rate of bupivacaine metabolism -> ↑toxicity

·   Products: pipecolic acid, pipecolyxylidine

↓Phase 2 reactions

·   ↓Rate of morphine metabolism -> ↑toxicity

·   Products: morphine-3-glucuronide, morphine-6-glucuronide

↓Plasma cholinesterase

·   ↓Rate of suxamethonium metabolism -> ↑toxicity

·   Products: succinylmonocholine + choline -> succinic acid + another choline

↓GFR

·   Initially 10% of adult; normalised at 6 months

·   ↓Elimination of M3G and M6G -> ↑toxicity

↓Tubular secretion

·   Relevant to other drugs

Immature resp centre

·   ↑Morphine toxicity

Immature NMJ

·   ↓Reserve of ACh -> myasthaenic response to suxamethonium