Warfarin is an anticoagulant ( blood dilutant ) used in the bar and intervention of venous intercalation, transeunt ischaemic onslaughts and atrial fibrillation. ( Randall et al 2006 ) ( BNF 2010 ) . Thromboembolism is the unwanted formation of blood coagulum ( thrombus ) in the venous or arterial vass. ( Randall et al 2006 ) .These coagulums interrupt off and are carried to other blood vass where they hinder the free flow of blood. This may happen in the lungs ( pneumonic intercalation ) , in the encephalon ( transeunt ischaemic attacks/stroke ) or in any other portion of the organic structure. ( Walker et al.2003 ) .Warfarin as an decoagulant helps to guarantee normal blood flow in patients at high hazard of blood coagulum by forestalling coagulum formation. It does this by barricading the formation of proteins that create fibrin which facilitates coagulum formation. ( Hardman Joel G.et al 2001 ) . Warfarin inhibit vitamin K reductase ensuing in the production of modified factors vii, nine, x and factor II ( two ) . ( M.J. Neal. 2009 ) . This suppression leads to the accretion of oxidized Vitamin K, and the formation of decreased Vitamin K is decreased thereby cut downing the rate of coagulum formation. ( Grahame -Smith D.G et Al 2006 ) .
The pharmacokinetics and pharmacodynamics of Coumadin are affected by different disease provinces. Warfarin is wholly absorbed from the GI piece of land. ( Kourosh saeb-parsy et al.1999 ) . It is extremely soluble in H2O and intoxicant and has a high bioavailability ( Rang H.P et al.2003 ) . A GI upset e.g. diarrhoea inhibits the riddance of warfarin hence decrease in Coumadin dosage is required. In nephritic damage the half life of Coumadin is reduced because of increased hepatic clearance of unbound Coumadin or increased non- nephritic clearance ( Rang H.P et al.2003 ) . In end-stage nephritic disease, plasma protein binding is reduced taking to an addition in unbound concentration. In liver disfunction Coumadin dosage should be reduced because of its influence on coagulating factor synthesis. ( Hardman Joel G. et Al 2001 ) . Congestive bosom failure, hepatic congestion and primary liver disease could impact the factor II clip which may take to toxicity due to accumulation hence Coumadin dosage should be reduced. ( Grahame -Smith D.G et Al 2006 ) .
Warfarin is eliminated chiefly through the liver. The clearance of Coumadin is affected by the intrinsic factor ( enzymes ) but non the blood flow because it has a low hepatic extraction ratio ( 0.004 ) . ( Burton Michael.E. et a1.1992 ) .Warfarin has two different racemic mixtures R and S both of which have different half lives and solubility. R & A ; S enatiomers are metabolised by multiple enzyme systems. The S enatiomer which is more powerful than the R undergoes metabolic oxidization catalysed by CYP2C9 and CYP3A4. Patients with variant allelomorph of CYP2C9* or 2C9*3 have reduced ability to metabolize Coumadin hence requires dose decrease to avoid toxicity. ( Burton Michael.E. et a1.1992 ) .
There is a hapless connexion between Coumadin plasma concentration and its biological consequence therefore its pharmacokinetic actions and the biological response must be measured utilizing Prothrombin clip ( PT ) followed by the International Normalised Ratio ( INR ) to find the exact dosage for a peculiar patient to avoid side effects. PT monitors the pharmacodynamics of Coumadin while INR measures Prothrombin clip. ( Randall et al 2006 )
PT clip measures the sum of clip required to bring forth a blood coagulum in a known plasma sample while INR shows the ratio of patient ‘s blood curdling clip to the control plasma sample.
The early protraction in the PT observed in the few yearss after the induction of warfarin therapy is caused by the decrease of factor VII followed by decrease in factors xi, x and two. ( Hardman Joel G.et al 2001 ) . The maximal consequence of Coumadin is seen within 2-5 yearss after the replacing of old curdling factors with the freshly synthesised faulty factors and besides because of the varied half lives of the different curdling factors ( two, seven, Xi and X, C, S ) . The INR scope varies harmonizing to the status been treated ; INR 2.0- 2.5 for prophylaxis of deep vena thrombosis ; INR 2.0- 3.0 for intervention of Deep vena thrombosis, pneumonic intercalation or bar of venous thromboembolism in myocardic infarction. ( Burton Michael.E. et a1.1992 ) .
Drugs, herbal merchandise and nutrient can either inhibit or enhance Coumadin anticoagulant consequence. The most common mechanism includes decreased metamorphosis, alteration in drug soaking up and protein binding. A bile acid sequestrant ( cholestyramine ) and sulcralfate bind with Coumadin in the GI piece of land cut downing its bioavailability and anticoagulant consequence. Highly protein edge acidic drugs like Valporate can displace Coumadin from the protein adhering site thereby increasing the degree of unbound Coumadin in the organic structure. The consequence of this supplanting can be reduced by increased Coumadin clearance, taking to a minor alteration in its anticoagulant response. Drug interactions from enzyme inhibitors ( Metronidazole, Erythromycin, Allopurinol, Amiodarone etc ) and enzyme inducers ( sodium thiopental, Phenytoin, Rifampicin etc ) addition or cut down Warfarin plasma degrees. Amiodarone inhibit the metamorphosis ( CYP1A2, CYP2C9 ) of the R- and S-enatiomers of Coumadin. Combined usage should be avoided if possible. Aminoglutethimide increases warfarin clearance because of enzyme initiation. Patients on these drugs require reappraisal of their Coumadin dosage to guarantee that PT -based INR is within the clinically effectual scope. Fibric acerb displace Coumadin from protein adhering site and may impact the synthesis of curdling factor. Co -administration of Coumadin and Fibric acid should be avoided if possible or INR monitored.
Barbiturate affects the pharmacokinetics of Coumadin by increasing the metabolic clearance of warfain and should be avoided if possible. ( BNF 60, 2010 ) .
H2- receptor adversary ( Cimetidine ) and a proton pump inhibitor ( Omeprazole ) inhibits many CYP 450 enzymes thereby suppressing the metamorphosis of R- isomers while S-isomer metamorphosis is unaffected. ( Kourosh saeb-parsy et al.1999 ) . Warfarin and attendant usage with Tagamet should be avoided because of possible bleeding. Co- disposal of Coumadin and some herbal merchandises e.g. Ginkgo biloba should be avoided because of its linear consequence which may ensue in a life- threatening hemorrhage. ( Tatro David.S.2007 ) Ginkgo influences the metamorphosis of S- Coumadin by suppressing CYP2C9. St John ‘s wort should be avoided. Garlic should besides be taken with attention with close monitoring. ( Randall et al 2006 ) The concurrent usage of cranberry juice and Warfarin should be avoided because of hazard of shed blooding. ( Tatro David.S. 2007 ) . ( Kourosh saeb-parsy et al.1999 ) .
The presence of nutrient can cut down the rate of soaking up of Coumadin. The consumption of nutrient high in vitamin K ( liver, boodle ) or nutritionary addendum should be reduced or avoided ; they change the pharmacodynamic response thereby cut downing the curative response. Regular or big ingestion of nutrients like ice-cream, soya bean protein, alligator pear, sweetening aspartame can alter warfarin curative response. ( Randall et al 2006 )