2007A02 After epidural injection in a health term pregnant woman,
discuss the factors influencing the distribution of bupivacaine to
a) the maternal CSF and spinal cord;
b) the maternal circulation;
c) the foetus

Fick’s law

·   Drug passes across each membrane down its concentration gradient

·   Modifiable factors increasing transfer rate: ↑C₁, ↓C₂, ↑area, ↓thickness

o C₁,C₂: concentration of unionised, unbound drug

·   Fixed factors for each drug: lipid solubility, MW

Bupivacaine

·   Amide local anaesthetic

·   Highly lipid soluble (1000x procaine)

·   Weak base, pKa 8.1, 15% unionised at pH 7.4 (cf. prilocaine 40%)

·   High protein binding

o  Plasma (95%) -> low free fraction

o  Tissue -> slow release

o  Na⁺ channel -> long dwell time

Epidural drug fate

·   Diffuse into CSF

·   Circumferential and longitudinal spread

·   Exit via intervertebral foramina

·   Sequestering in epidural fat (depot)

·   Absorption

Epidural drug: site of action

·   Spinal nerve roots (dorsal > ventral)

·   Dorsal root ganglia

·   Paravertebral SNS chain (?)

·   Spinal cord via spaces of Virchow-Robin (dorsal > ventral)

·   Time to peak: 10-30 mins

·   Bioavailability: 20%

↑C₁

·   ↑Concentration injected

·   ↑% unionised (but unable to safely add HCO₃^- to bupivacaine)

·   ↓% unbound

↓C₂

·   ↓CSF volume

·   ↑CSF flow rate (e.g. pregnant cf. elderly)

·   ↓% unionised (i.e. CSF pH 7.32 cf. plasma 7.4)

·   ↓% unbound (i.e. CSF protein 0.2g/L cf. plasma 70g/L)

↑A

·   ↑Volume injected -> ↑drug-membrane contact

↓T

·   Normal virgin meninges (cf. past surgery)

Biphasic absorption

1. Rapid: reabsorption from fluid phase

2. Slower: reabsorption of lipid-bound drug

↑C₁

·   ↑Concentration injected

·   ↑% unionised (see above)

·   ↑% unbound (see above)

↓C₂

·   ↑Tissue blood flow rate (↑ in pregnancy/labour, ↓ with added adrenaline)

·   ↓% unionised (e.g. acidaemia -> ion trapping)

·   ↓% unbound (note ↓AAG -> ↑% unbound)

↑A

·   ↑Volume injected -> ↑ contact with membranes

↓T

·   Normal membranes

↑C₁

·   ↑Placental blood flow rate (pressure passive 600mL/min)

·   ↑Concentration and volume injected

·   ↑% unionised (e.g. hyperventilation -> alkalaemia in labour)

·   ↑% unbound (e.g. progesterone surge in labour displaces bupivacaine)

↓C₂

·   ↑Umbilical flow rate (very high)

·   ↓% unionised (foetal acidosis -> ion trapping)

·   ↓% unbound (note ↓AAG -> ↑% unbound)

↑A

·   Normal placenta

↓T

·   Normal placenta