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.

 

List:

·      Neonate

·      Summary table

·      Pharmacokinetics: ADME

·      (Pharmacodynamics)

 

Neonate:

·         0-28 days old

·         Born 37-40 weeks gestation

·         All changes more pronounced if premature

 

Summary:

 

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

 

Absorption:

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

·   VA:FRC ratio 5:1 cf. 1.5:1 -> ↑rate of rise FA/FI 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

 

Distribution:

↑Cardiac output

·   ↑Rate of onset suxamethonium

·   ↓Rate of ↑ FA/FI volatile anaesthetic (overridden by ↑VA: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 -> ↑VD 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)

 

Metabolism:

 

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

 

Excretion:

↓GFR

·   Initially 10% of adult; normalised at 6 months

·   ↓Elimination of M3G and M6G -> ↑toxicity

↓Tubular secretion

·   Relevant to other drugs

 

Pharmacodynamics:

Immature resp centre

·   ↑Morphine toxicity

Immature NMJ

·   ↓Reserve of ACh -> myasthaenic response to suxamethonium

 

 

 

Feedback welcome at ketaminenightmares@gmail.com