Which is not true about warfarin?
|A||Inhibit Vit K dependent clotting factors|
|B||Increased dose in hepatic disease|
|C||Half life 36 hrs|
Ref. KDT, 6th 602 – 04.
In liver disease the hepatic synthesis of clotting factors is reduced. Thus warfarin effect will be increased & it might lead to bleeding side effects.
a. These drugs act by inhibiting the activation of vitamin K dependent clotting factors. These factors include clotting factors II, VII, and X as well as anti-clotting proteins, protein C and protein S
b. These factors are synthesized by liver and activated by gamma – carboxylation of glutamate residues with the help of vitamin K. Hydroquinone form of vitamin K is converted to epoxide form in this reaction and regeneration of hydroquinone form is required for this activity.
c. Oral anticoagulants prevents this regeneration, thus vitamin K dependent factors are not activated..
d. As already activated factors are not affected, the effects of these drugs depend on disappearance of already activated factors from the blood.
e. Protein C has shortest half life, so it is the first factor to decline and its deficiency may lead to dermal vascular necrosis and hyper coagulation (Protein C is anti-clotting) as early appearing adverse effects of warfarin and other drugs of this group.
f. Among clotting factors, first to disappear is factor VII (t1/2 = 6 hours) and last to disappear is factor II (t1/2 = 60 hours). Therefore, the effect of oral anticoagulants is always delayed (develops gradually over 1-3 days) and these are thus used for maintenance of anticoagulation rather than initiation of treatment.
g. Bleeding is the most common adverse effect. Prothrombin time is used to adjust the dose of warfarin.
h. Warfarin is absorbed well from GIT and it is highly plasma protein bound (99%). Its kinetics changes from first order to zero order within therapeutic concentrations.
a. Drug increasing the effect of warfarin, broad spectrum antibiotics phenylbutazone and various microsomal enzyme inhibitors (erythromycin, cimetidine etc.)
b. Enzyme inducers (like rifampicin, griseofulvin, etc. and oral contraceptives (increase clotting factor) decrease the effect and thus require increase in dose of warfarin.