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

 

List:

·     Intro

·     Epi drug

·     Epidural -> subarachnoid

·     Neuraxis -> circulation

·     Mother->foetus

 

Intro:

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)

 

Epidural space -> subarachnoid space:

 

·  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)

 

Neuraxis -> circulation:

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

 

Maternal circulation -> foetal circulation:

↑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