All are true about warfarin, except -
Ans. is 'd' i.e., Dose is increased in liver disease Warfarin is an oral anticoagulant. It acts by inhibiting vitamin K dependent coagulation factors.Other oral anticoagulants are -BishydroxycoumarinAcenocoumarinPhenindioneRole of vitamin K in coagulation:- Vitamin K is involved in the activation of clotting factors synthesized in the liver i.e. 77, VII, IX and X.These coagulation factors are originally synthesized as inactive precursor molecules.Formation of active clotting factor requires the vitamin K dependent carboxylation of glutamic acid residues present in these clotting factors.Mechanism of action of warfarinWarfarin is an indirectly acting anticoagulant i.e. it inhibits vitamin K which in turn inhibits coagulation factors.Vitamin K activates these factors by l carboxylation of their glutamate residues. While catalyzing this reaction vitamin K itself gets converted into its epoxide form from the hydroquinone form. Regeneration of hydroquinone form is required to resume the procoagulant activity of vitamin K. Oral anticoagulants prevent this regeneration, thus vitamin K dependent factors are not activated.* The effect of oral anticoagulant is not seen until the vitamin K dependent coagulation factors made before the drug was administered are cleared from the circulation.The process occurs at different rates for individual coagulation factors because each coagulation factor has different half life:- VII - 6 hoursIX and X - 24 hours Prothrombin - 72 hoursTherefore the effect of oral anticoagulant is always delayed (develops gradually over 1-3 days). Thus they are used for maintenance of anticoagulation rather than initiation of t/t. (If prompt anticoagulation is required heparin is used)."The t 1/2 of warfarin is 36 hr - 48 hr"Warfarin is a racemic mixture of approximately equal amounts of two isomers S (t 1/2 35h) and R (t 1/2 50h). 5 warfarin is four times more potent than R warfarin.Monitoring of warfarin therapy is done by prothrombin time and the result is expressed as the international normalized ratio (I.N.R.), which is the ratio of the prothrombin time in the patient to that in a normal anticoagulated person.Warfarin is well absorbed from the G.I.T. and it is highly plasma protein bound (99%). Its kinetics changes from first to zero order within therapeutic concentrations.Warfarin can cross the placenta and cause fetal warfarin syndrome. Therefore it is contraindicated in pregnancy. Patient is switched to heparin from warfarin during pregnancy.Adverse effects of warfarinBleedingCommon complication of warfarin therapy Skin necrosisIt occurs when induction of warfarin therapy is over abrupt and the patient has a genetically determined or acquired deficiency of the anticoagulant protein C or its cofactor protein S.RememberBesides activating coagulation factors vitamin K also activates certain anti-coagulant proteins such as proteins C and protein S.These anticoagulant proteins have shorter half-lives than regular coagulation factors.Thus when warfarin is administered the inhibitory effect of warfarin on coagulation factors is not manifested initially because of their long half-lives. Whereas, the inhibitory effect on anticoagulant proteins is manifested early because of their shorter half-lives.Thus a situation arises whereAnticoagulant effect is yet to be manifested (half-life of coagulation factors is long)Procoagulant effects are seen (half-life of anticoagulant protein is quite short)*Asa result OF procoagulant action, skin necrosis can develop.Teratogenic effect of warfarinWarfarin given in early pregnancy increases birth defects especially skeletal abnormalities i.e. -Foetal warfarin syndrome, i.e.Hypoplasia of nose, eye socket, hand bones andGrowth retardationGiven later in pregnancy it causesCNS defects,Foetal death andAccentuates neonatal hypothrombinemia Effect of liver disease on warfarinIn liver diseases the dose of oral anticoagulant needs to be decreased because in liver disease the hepatic synthesis of clotting factors is reduced. Thus there is already a deficiency of clotting factors (i.e. there is a preexisting anticoagulant state). Administration of warfarin in this state increases the risk of bleeding.Factors enhancing the effect of oral anticoagulants Liver disease, chronic alcoholism * Synthesis of clotting factors may be deficient.Debility, malnutrition, malabsorption and prolonged antibiotic therapySupply of vitamin K to liver is reduced in these condition.HyperthyroidismClotting factors are degraded faster.NewbornsHave low level of vitamin K and clotting factors.Factors decreasing the effect of oral anticoagulantsPregnancyPlasma level of clotting factors is higher Nephrotic syndromeDrug bound to plasma protein is lost in urine Genetic warfarin resistanceThe affinity of warfarin (as well as Vit. K epoxide) to bind to the reductase enzyme, which generates the active vitamin K hydroquinone.
It causes inhibition of vitamin K dependent clotting factors
T 1/2 36 hours
Crosses placenta
Dose is increased in liver disease
Anticoagulants and Coagulants