FRCA Notes

Distribution

  • The distribution of a drug describes its reversible movement from one location to another

Physicochemical drug factors

  • Molecular size (Graham's Law)
  • Lipid solubility
  • Degree of ionisation
  • Degree of protein binding

Tissue factors

  • Vascular permeability
  • Regional blood flow
  • Cardiac output

  • Drugs can be broadly categorised into three different groups of pharmacokinetic distribution

Confined to plasma

  • Drugs that are too large to cross the vascular endothelium e.g. albumin, dextran 70
  • Drugs that are intensely protein bound, so only very small amounts leave the circulation e.g. warfarin

Limited distribution

  • Drugs that are polar, poorly lipid soluble and bulky e.g. non-depolarising NMBA
    • Cannot cross cell membranes and function extra-cellularly
    • Distribution limited to tissues supplied by capillaries with fenestrae (to allow drug to leave vasculature)

Extensive distribution

  • Drugs that are highly lipid-soluble, of low molecular weight and/or poorly protein bound
  • Such drugs are distributed to tissues according to blood flow
    • High blood flow first (brain, lungs, kidneys, thyroid, adrenals)
    • Moderate blood flow (e.g. muscles)
    • Low blood flow last (fat)

  • Some drugs are sequestered in tissues, removing them from circulation;
    • Amiodarone - fat
    • Iodine - thyroid
    • Tetracyclines - bone

  • The blood-brain barrier is an anatomical and functional barrier between the CNS and the circulation
  • There is tightly controlled transport across the BBB:
    • Active transport (e.g. glucose, insulin)
    • Facilitated diffusion (e.g. lipid soluble, low MW drugs)

  • Some drugs won't cross the BBB
    • Large polar molecules e.g. muscle relaxants
    • Quaternary amines e.g. glycopyrrolate

  • Some drugs are subject to enzymatic activity at the BBB
  • For example, monoamines are converted to non-active metabolites upon passing the BBB due to the presence of MAO enzymes (explains why levodopa is used in Parkinson's disease)

  • Some drugs pass readily through the BBB, e.g. most inhaled and intravenous anaesthetic agents

  • In disease, physical disruption may cause central neurotransmitters to be leaked into systemic circulation and cause disturbance
  • This effect is taken advantage of by using penicillin in meningitis; the BBB is usually poorly penetrated by penicillin
  • However it may also prove detrimental e.g. mannitol crossing BBB and increasing cerebral oedema

  • The placenta is a phospholipid membrane more readily crossed by lipid-soluble molecules
  • It is less selective than the BBB

  • Additional factors determine the dstribution of drugs to the foetus, and the rate of equilibrium between maternal and foetal circulations
    • Placental blood flow
    • Materno-placental free drug concentration gradient

  • The foetal circulation is of a lower pH than maternal circulation and plasma binding of drugs may differ
    • Higher protein binding in the foetus will increase transfer across the placenta (as free drug concentrations are low)
    • High maternal protein binding has the opposite effect

Drug transfer to the foetus

  • Some drugs given in pregnancy have very late effects e.g. stilboesterol can cause ovarian cancer in teenagers if taken in pregnancy

  • Thiopental cross the placenta rapidly and peak foetal levels occur within 3 mins, but there is no evidence that foetal outcome is affected

  • Pethidine is highly lipid soluble and crosses the placenta easily
    • It is metabolised to norpethidine, which is less lipid soluble and can accumulate in the foetus
    • Peak plasma levels occur 4hrs post-IM dosing
    • Half-life in foetus increased 3x due to reduced foetal clearance

  • Neuromuscular blocking agents
    • Non-depolarising NMBA are large, polar molecules and therefore don't cross the placenta
    • Small amounts of suxamethonium cross the placenta with little foetal effect - not an issue unless sux. apnoea present

Ion trapping

  • Bupivacaine has a higher pKa than lidocaine so is more ionised at physiological pH
  • It cross into the foetal circulation but becomes more ionised in the relatively acidic foetal pH
  • As pH drops further (e.g. placental insufficiency) the drug becomes more ionised and may become trapped

  • Drugs that are acidic/neutral are typically bound to albumin e.g. propofol, phenytoin, lidocaine, diazepam
  • Drugs that are basic/quaternary nitrogens are usually bound to alpha-1 acid glycoprotein e.g. fentanyl, lidocaine