Drug Response Variability — Pregnancy PK

PHARMACOKINETICS

Absorption

• ↓ Oral absorption
  • ↑ N/V
  • ↓ gastric emptying during labour
  • ↓ gastric motility 2° to intestinal compression
  • ↑ gastric absorption
  • ↓intestinal absorption due to ↓ intestinal blood flow
• ↑ IM/SC/transdermal absorption
  • ↑ skin blood flow
    • ↑ C.O. (by 30-40%)
    • ↓ SVR
• IV (↑ onset)
• Neuraxial
  • ↓ epidural space 2° to EDVs
  • ↓ spinal and epidural doses
• Inhalational
  • Progesterone-mediated ↑ MV (by 50-70%)
  • ↑ FA/FI ratio (= uptake

Distribution

• ↑ VD (↑ TBW/ECF and fat)
  • ↑ TBW/ECF (by 50%) (important for polar/ionized drugs)
  • ↑ body fat % (important for lipid soluble drugs)
• ↓ plasma protein 2° to dilutional effect
  • ↓ albumin →
    • ↑ free % of acidic drugs (Eg. STP, propofol)
    • ↓ dose required
    • ↑ transplacental transfer of drug.
  • ↓ A1AGP (by 30%) →
    • ↑ free % of basic drugs (Eg. LA, β blockers)
    • ↓ dose required
    • ↑ transplacental transfer of drug
• Ionisation (mild ↑pH alters ionisation based on pKa)
  • ↑ MV = mild respiratory alkalosis
    • ↑ transplacental transfer of basic drugs as they will have ↑ % in unionized form
      • (Base in base is less ionised)
      • ↑ ion trapping in more acidotic foetal circulation

Metabolism

• Progesterone:oestrogen ratio
  • Progesterone → induces hepatic enzymes
  • Oestrogen → inhibits hepatic enzymes
• ↓ plasma cholinesterase (30%)
• Placenta metabolises some drugs
• Foetal liver has functioning CYP450
  • Can metabolise drugs
  • But requires transfer back to maternal circ for conjugation

Excretion

• ↑ RBF/GFR (50%)
  • ↑ clearance/↓ elimination t1⁄2 of water-soluble drugs
• ↑ MV/↓FRC
  • ↑ washout of volatile agents

PHARMACODYNAMICS

• Decreased MAC – Increased sensitivity to volatile anaesthetics
• Increased LA sensitivity due to decreased α1-glycoprotein
• Increased sensitivity to IV anaesthetics

Gladwin 2016

Answer by Gladwin