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
- Clopidogrel → prodrug