T2 L13: PK2 - Drug distribution

• Where do most drugs end up after absorption?

  Systemic circulation
• What is drug distribution?


  Process by which the drug is:

  • transferred reversibly from the systemic circulation into the tissues as concentrations in the blood increase, and
  • from the tissues into blood when the blood concentrations decrease during elimination
• How does distribution occur?


  • Most drugs transfer by passive diffusion
  • Across capillary walls down a concentration gradient
  • Into interstitial fluid until concentration of free drug molecules in interstitium is equal to that in plasma
• How does plasma protein binding work?

  Drugs bind non-specifically to albumin in plasma

  Drug + Protein ⇌  Drug–Protein complex

  • reversible and saturable
  • unbound / free fraction distributes
  • unbound portion is responsible for clinical effect

  
• What are the factors that influence drug distribution?

  • Drug physiochemical properties (lipid / water solubility)
  • Drug particle size
  • Drug protein binding
  • Environment - blood flow; pH
• What is Apparent volume of distribution (Vd)?


  Volume into which a drug appears to be distributed with aconcentration equal to that of plasma

  A concept that seeks to predict how extensively a drug isdistributed throughout the body

  Vd=Dose (mg)/Concentration (mg/L)
• What does a Low volume of distribution mean?

  drug remains largely in plasma
• What do we mean if a drug has a low Vd?

  Vd<10L (eg warfarin)

  Highly protein bound drug so retained in plasma
• What do we mean if a drug has a high Vd?


  Vd>100L (eg amiodarone)

  Fat soluble drug distributes into tissues
• What does it mean if a drug has Vd not high but not low (in the middle)?


  Vd10-30L (eg gentamicin)

  • Water soluble drugs, low lipid solubility,
  • Distributes into interstitial fluid but not cells
  • Dose on Ideal Body Weight to avoid toxicity