FRCA Notes

Principles of Metabolism

  • Metabolism describes the process of chemically altering a drug, which usually serves to reduce drug activity
  • There are examples, however, of metabolic processes increasing drug activity through conversion of pro-drugs e.g.
    • Diamorphine → 6-monoacetyl morphine
    • Enalapril → enalaprilat

Hydrolysis | Oxidation | Reduction

  • Phase I metabolic reactions are non-synthetic reactions
  • They mostly function to make substances polar and/or water soluble

  • Following Phase I reactions, drugs may become:
    • A substrate for Phase II metabolism
    • Sufficiently water soluble so as to be excreted
    • Bioactivated
    • Toxic, requiring further metabolism

  • Phase I reactions take place in a variety of organs/tissues, although a large proportion take place in the liver

Locations and enzymes of phase I metabolism

  • Smooth endoplasmic reticulum - the CYP450 enzyme system (metabolises multiple substances)

  • Mitochondria - mitochondrial MAO (metabolises monoamines)
    • Genetic variations and exogeneous inhibitors can increase mono-amine levels

  • Cytoplasm - alcohol dehydrogenase (metabolises alcohol)

  • Tissue esterases
    • Muscle esterases metabolise remifentanil
    • RBC esterases metabolise esmolol
    • Other drugs such as etomidate, aspirin and atracurium are metabolised by esterases

  • Lung tissue - angiotensin converting enzyme (metabolises angiotensin I and bradykinin)

  • Plasma - cholinesterases (metabolise suxamethonium and mivacurium)
  • Other non-enzymatic degradation processes also occur in the plasma e.g. Hoffman degradation

Glucuronidation | Sulphation | Acetylation | Methylation | Glutathione conjugation | Glycine conjugation

  • Many drugs undergo phase I then phase II metabolism, although some will undergo phase II metabolism only
  • Generally undertaken by transferase enzymes, it involves conjugation to hydrophilic substrates to make drugs more water soluble, allowing excretion in the urine and bile
  • Occurs mainly in the hepatic smooth endoplasmic reticulum, although other sites partake (e.g. acetylation in the lungs and spleen)

  • Genetic polymorphisms of acetylation enzymes can lead to fast/slow acetylator status
  • This affects the pharmacokinetics and pharmacodynamics of drugs such as hydralazine and isoniazid