Dvii: Explain the mechanisms and significance of pharmacogenetic disorders

Malignant Hypertension

  • Trigger: sux, volatiles, caffeine
  • Mechanism
    • Defective ryanodine receptor on SR
    • Trigger binds receptor
    • Uncontrolled Ca2+ release from SR of skeletal m.
    • Causes hypermetabolic state
    • ↑O2 consumption, ↑CO2 production, ↑temp, rigidity, tetanus, rhabdomyolysis

Porphyria

  • Trigger: drugs (esp. drugs which induce CYP450 → BARBTUATES, PHENYTOIN, ANTIEPILEPTICS, RIFAMPICIN), alcohol, hormonal changes
  • Mechanism
    • Disorder of the enzyme in the heme biosynthetic pathway
    • 8 enzymes → 4 cytosol, 4 mitochondria
    • Each porphyria is due to abnormality of one of these enzymes
    • Results in heme deficiency
    • Clinical manifestation due to ↑[Porphyrins]

Atypical Cholinesterase (‘pseudocholinesterase deficiency’)

  • Triggers: sux, mivacurium, ester LAs
  • Mechanism
    • Pseudocholinesterase (aka butyrylcholinesterase) hydrolyses ‘choline-based esters’
    • Made in liver, found in plasma
    • Hydrolyses + inactivates 95% of sux dose before it can reach NMJ
    • ∴absence of enzyme = prolonged NM blockade

Disturbances Cytochrome Function

  • Differences in enzyme activity will result in different drug action
    • Clopidogrel → prodrug
      • Requires CYP2C19
      • Genetic variation = ↓metabolic variation = ↓antiplatelet effect
    • Warfarin
      • CYP2C9
      • Different allotypes assoc with haemorrhage
      • Due to ↓metabolism & ↑DoA