Warfarin mechanism of action -
Ans. is 'c' i.e., Inhibiting Vitamin K dependent carboxylation o Warfarin inhibits vitamin K dependent carboxylation of clotting factors by inhibiting the enzyme Vitamin K epoxide reductase.Oral anticogulantso They act indirectly by interfering with the synthesis of vit K dependent clotting factors in liver,o They interfere with regeneration of the active hydroquinone form of vit K, which is required for the final step gamma carboxylating glutamate residues ofprothrombin (factor 11) and factor VII, IX and X. This carboxylation is essential for the ability of the clotting factors to bind Ca+2 and to get bound to phospholipid surface, necessary for coagulation sequence to proceed.Mechanism of actiono During g - carboxylation of the coagulant factor II, VII, IX and X in the liver, active vitamin K (Vit K hydroquimme) is oxidized to an epoxide (vit K epoxide),o Vit K epoxide must be reduced to vit K hydroquinone to become active once again (vit K cycle),o Vit K epoxide is reduced to vit K hydroquinone by vit K reductase.o This vit K reductase is inhibited by oral anticoagulants.o Factor VII has the shortest plasma t 1/2 (6 hrs), its level falls first when warfarin is given, followed by factor IX (t 1/2 A 24 hrs), factor X (t 1/2 40 hrs) and prothrombin (t t 1/2 60 hrs).o Though the synthesis of clotting factors diminishes within 2-4 hours of warfarin administration, anticoagulant effect develops gradually over the next 1-3 days as the levels of the clotting factors already present in plasma decline progressively. Thus oral anticoagulants are used for maintenance for anticoagulation (for initiation heparin is used).o Protein C, protein S, osteocalcin are also inhibited because these proteins also contain glutamate residues that require vit K dependent gamma carboxylation.o Protein C and Protein S are anticoagulant factor and have a shorter t 1/2 than the procoagulantfactors (II, VII, IX & X), and their more rapid decline in concentration creates a "transient hvpercoagulable" state - Initiate anticoagulation with heparin until the effect of warfarin is well established.o Warfarin is the most popular oral anticoagulant.o Bishydroxycoumarin (Dicumarol) is the longest acting oral anticoagulant.o Ethylbiscoumacetate is the shortest acting anticoagulant.o Warfarin is rapidly and completely absorbed from intestines and is 99% plasma protein bound. Its kinetics changes from first order to zero order at higher concentrations.o For monitoring the effect of oral anticoagulant prothrombin time (PT) is used because they selectively inhibit the extrinsic pathway.
Chelating Ca
Inhibiting antithrombin III
Inhibiting Vitamin K dependent carboxylation
Inhibiting thrombin
Anticoagulants and Coagulants