Chemistry + Pharmacokinetics- formed from spoiled sweet clover silage --> hemorrhagic disease in cattle
- researchers found toxic agent = bishydroxycourarin
- synthesised derivative = warfarin (Wisconsin Alumni Research Foundation, arin from coumarin)
- initially used as rodenticides
- pharmacokinatics
- 100% oral bioavailability
- T1/2 36 hrs = hence take 2-3 days to establish the levels
- 99% albumin bound
- MOA
- block g-carboxylation of glutamine residue in factor 2,7,9,10, protein C, S --> inactive
- also oxidises Vit K
- Vit K needs to be reduced to be active - warfarin blocks activity of Vit K
- mutational change to Vit K epoxide reductase = genetic resistance to warfarin in human, especially rats
- 8-12 hr delay in warfarin action
- T1/2 of factor 2,7,9, 10 are 60, 6,24,40
- larger initial dose of warfarin to 0.75mg/kg hasten anticoagulant efx, above that effect is independent
- toxicity
- crosses placenta --> hemorrhagic disease of fetus, birth defect
- reduced protein C activity --> thrombosis --> cutaneous necrosis in skin, breast, fatty tissue, intestine, extremities
- warfarin resistance
- progression/recurrence of thrombotic event with therapeutic INR
- cancer pt most at risk, typically GIT ca --> can change to LMWH
- can have INR target raised
- drug interactions
- most drugs do
- but NOT ethanol, phenothiazines, benzos, paracetamol, opioids, indocid, most abs except (flagyl different)
- reversal
- may need longer FFP/factor VIIa due to long T1/2
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