Distribution

Describe factors influencing the distribution of drugs.

Drug distribution is dependent on many factors, all of which can be related to Fick's Law of Diffusion:

• Concentration gradient

• Tissue mass

• Molecular Weight
  Larger molecules are less able to cross cell membranes, and so a greater portion will remain in the compartment they are delivered to.

• Lipid Solubility

• Ionisation
  Ionised drugs are polar, and so are less lipid soluble.
  • Ionisation is a function of:
    • pKa
      The pKa is the pH at which a weak acid or weak base will be 50% ionised.
      • As solvent pH changes, the proportion of ionised vs. unionised drug will differ
      • How depends on whether the drug is an acid or base:
        • Bases are ionised Below their pKa
        • Acids are ionised Above their pKa
    • pH
      In combination with pKa, affects the ionised portion.
  • Unionised drugs:
    • Cross cell membranes more readily than the ionised form
    • Are typically hepatic metabolised
    • Are typically not renally eliminated
  • Ionised drugs:
    • Are typically renally excreted without undergoing metabolism
    • Are poorly lipid soluble and do not cross cell membranes readily
    • May be ion trapped
      This occurs when an unionised drug moves across a membrane and becomes ionised due to a change in pH. The now-insoluble drug is trapped in the new compartment. This is relevant in:
      • Placenta
        Foetal pH is lower than maternal pH, which can trap basic drugs (e.g. LA, opioids) in foetus.
        • This becomes more significant with a greater divergence of pH (e.g. placental insufficiency)
      • Renal elimination
        Urinary alkalinisation is used to accelerate elimination of acidic drugs, as they become ionised and trapped in urine.

• Protein binding
  Proteins and drugs may be bound together by weak bonds. These include ionic bonds, van der Waal's forces, and hydrogen bonds.
  • Drugs may bind to proteins in:
    • Plasma
      • Albumin
        Binds acid and neutral drugs.
        • High capacity
        • Two major binding sites (six total)
          • Site I (warfarin)
          • Site II (diazepam)
      • α1-acid glycoprotein
        Binds basic drugs.
        • Single binding site
        • Low capacity
          Typically results in lower total binding (compared to albumin) of alkaline drugs, despite its increased affinity.
      • Lipoprotein
        For lipid soluble drugs.
    • Tissue
    • Receptor
  • Protein binding is important as:
    • Only unbound drugs are able to:
      • Cross cell membranes
      • Interact with receptors
      • Undergo metabolism
        Reduced protein binding increases clearance of drugs with low extraction ratios.
      • Be filtered by the kidney
    • Highly tissue bound drugs:
      • Have a long duration of action
      • Have a high volume of distribution, prolonging their elimination
      • May build up in tissues, leading to adverse effects
        e.g. Corneal deposition, lung fibrosis.
  • Protein binding is affected by:
    • Affinity of drug for protein
      • Ionised drugs do not bind to protein
        pH.
      • Competition between drugs for binding sites
    • Amount of protein
      • Disease
        Due to:
        • Hypoalbuminaemia
          Negative acute phase reactant.
        • Increased α1-acid glycoprotein
          Acute phase reactant.
      • Competition
        Source of pharmacokinetic interactions.
  • Protein binding typically:
    • Correlates with lipid solubility
    • Is important only when it is very high
    • Results in a decreased V_Dss when plasma binding is high
    • Results in an increased V_Dss when tissue binding is high
    • Is important in duration of action as it also relates to affinity for tissue proteins

• Regional blood flow
  Affects concentration gradients between blood and tissue, and is affected by cardiac output. Regions include:
  • Vessel Rich Group
    • Brain
    • Heart
    • Liver
    • Kidneys
  • Vessel Poor Group
    Connective tissues:
    • Bones
    • Ligament
    • Teeth
    • Hair
  • Muscle groups
  • Fat

References

1. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
2. Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.