A 67-year-old man with coronary heart disease developed chest pain again on the sixth day after a percutaneous cardiac intervention. Redo coronary angiogram revealed stent thrombosis. He had good medication compliance. Suboptimal response to clopidogrel was suspected. He had a past medical history of hypertension, diabetes mellitus, and gastroesophageal reflux disease.

His medications included: metoprolol 25 mg twice daily; metformin 1000 mg twice daily; omeprazole 20 mg once daily; rosuvastatin 20 mg once daily; clopidogrel 75 mg once daily; aspirin 80 mg once daily. 

(a) Describe the mechanism of action and metabolism of clopidogrel. (4 marks)

Clopidogrel is an anti-platelet drug which inhibits the P2Y₁₂ receptor on platelets and stops them from aggregating.

Clopidogrel is a prodrug and needs to be metabolised by CYP in order to be activated (bioactivation).

Clopidogrel is well absorbed from the GIT, but once absorbed around 85% of the clopidogrel is deactivated by other liver enzymes, and only the remaining 15% can be bioactivated by CYP.

The bioactivation is a two step process involving several different CYP enzymes, the main one where pharmacogenetics is involved is CYP2C19.

EMC

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