Drug Response Variability: Responses

Master answer

Physiological factors

• Drug transfer via diffusion, facilitated diffusion, secondary active transport, pinocytosis (e.g. immunoglobulins)/
• Diffusion according to Fick’s Law (see eqn):
  where
  • MW = Molecular weight
    • Drugs <500da freely permeable
  • Δ[Drug] = Concentration gradient between maternal anf foetal blood
  • SA = Surface area for diffusion
    • 16m² compared to alveolar surface area of 60m²
  • h = thickness of diffusion membrane
    • 3.5 microns compared with 0.5 for alveolar diffusion membrane

• Drug delivery to uterus
  • Blood flow ~750ml/min (Aprrox 600ml/min to placenta)
  • No autoregulatory mechanisms
• Placental transporters
  • MDR1 and p-glycoprotein efflux drugs out of foetal circulation
• Placental metabolism
  • P450 reactions
    • Pentobarbitol metabolized by placenta

Drug factors

• Drug size
  • Heparin too large to permeate (Warfarin can)
• Lipophilicity
  • Highly lipophilic drugs more permeable (Fentanyl > morphine)
• Ionization
  • Charged molecules less permeable (Glycopyrrolate < atropine)
  • Ionization trapping
    • Alfentanyl (pKa 6.5) ~90% unionized at physiological pH → more permeable
    • As alfentanyl crosses into foetal circulation, becomes more ionized in lower pH → trapped in foetal circulation
• Protein binding
  • Reduces permeability

Disease factors

• Inflammation of placental barrier increases permeability of drugs

Sakurai 2016

Answer by Sakurai