This medication inhibits epoxide reductase. Due to this, vitamin K is unable to be reduced to its active form--hydroquinone (vitamin KH2). This prevents gamma-carboxylation of glutamic acid on the clotting factors II, VII, IX, X and proteins C and S. These factors are then incapable of binding to blood vessel endothelium, and become biologically inactive.
The effect of warfarin takes several days to develop because of the half-lives of already activated factors. This medication acts on the extrinsic pathway by preventing the activation of vitamin K, warfarin reduces the production of factors II, VII, IX and X (also Protein C and S).
Heparin is usually administered with warfarin to prevent thrombosis. This is because for the first 4-5 days, though warfarin is preventing active factors from being formed, the previously formed factors must degrade. After administration, it causes a decline in factor VII, but takes more time to decrease factor II. Furthermore, proteins C and S are decreased, leading to a prothrombotic state initially.
This medication is used to decrease the tendency to form or to prevent clots in patients at risk for their formation. Common ailments requiring chronic anticoagulation include atrial fibrillation, artificial heart valves, previous pulmonary embolism and previous deep vein thrombosis.
Hemorrhage is the most common side effect of warfarin administration. For this reason, physicians monitor patient PT and INR to make sure that it is only 2-4 times the normal range.
Though rare, warfarin necrosis is a very serious side effect seen in patients taking this medication and leads to massive thrombus formation, causing skin necrosis and gangrene. This side effect stems from the initial inhibition of proteins C and S, leading to a prothrombotic state when starting this medication. Patients who are protein C deficient are more susceptible to this effect.
Warfarin is metabolized through the cytochrome P-450 pathway, and medications which induce or inhibit this pathway may lead to adverse effects. P-450 inhibitors would decrease the metabolize of warfarin, and can lead to increased bleed risk. P-450 inducers could cause decreased bioavailability of warfarin and decreased anticoagulation.
This drug has several effects on the fetus. It passes through the placenta, and may cause fetal bleeding. It is also a known teratogen, and can lead to skeletal abnormalities. Administration in the third trimester may give rise to CNS disorders.
If reversal of warfarin action is necessary, or if there is a case of severe bleeding, vitamin K + fresh frozen plasma are administered. These can lead to rapid reversal of warfarin's effects.
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