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Warfarin is an anticoagulant (blood thinner) used in the prevention and treatment of venous embolism, transient ischemic attacks and atrial fibrillation. (Randall et al 2006) (BNF 2010). Thromboembolism is the unwanted formation of blood clot (thrombus) in the venous or arterial vessels. (Randall et al 2006).These clots break away and are carried to other blood vessels where they hinder the free flow of blood. This may occur in the lungs (pulmonary embolism), in the brain (transient ischemic attacks/stroke) or in any other part of the body. (Walker et al.2003).Warfarin as an anticoagulant helps to ensure normal blood flow in patients at high risk of blood clot by preventing clot formation. It does this by blocking the formation of proteins that create fibrin which facilitates clot formation. (Hardman Joel G .et al 2001). Warfarin inhibit vitamin K reductase resulting in the production of modified factors vii, ix, x and prothrombin (ii). (M.J. Neal. 2009). This inhibition leads to the accumulation of oxidised Vitamin K, and the formation of reduced Vitamin K is decreased thereby reducing the rate of clot formation. (Grahame -Smith D.G et al 2006).
The pharmacokinetics and pharmacodynamics of warfarin are affected by different disease states. Warfarin is totally absorbed from the gastrointestinal tract. (Kourosh saeb-parsy et al.1999). It is highly soluble in water and alcohol and has a high bioavailability (Rang H.P et al.2003). A gastrointestinal disorder e.g. diarrhoea inhibits the elimination of warfarin hence reduction in warfarin dose is required. In renal impairment the half life of warfarin is reduced because of increased hepatic clearance of unbound warfarin or increased non- renal clearance (Rang H.P et al.2003). In end-stage renal disease, plasma protein binding is reduced leading to an increase in unbound concentration. In liver dysfunction warfarin dose should be reduced because of its influence on clotting factor synthesis. (Hardman Joel G. et al 2001). Congestive heart failure, hepatic congestion and primary liver disease could affect the prothrombin time which may lead to toxicity due to accumulation hence warfarin dose should be reduced. (Grahame -Smith D.G et al 2006).
Warfarin is eliminated mainly through the liver. The clearance of warfarin is affected by the intrinsic factor (enzymes) but not 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&S enatiomers are metabolised by multiple enzyme systems. The S enatiomer which is more potent than the R undergoes metabolic oxidation catalysed by CYP2C9 and CYP3A4. Patients with variant allele of CYP2C9* or 2C9*3 have reduced ability to metabolise warfarin therefore requires dose reduction to avoid toxicity. (Burton Michael .E. et a1.1992).
There is a poor connection between warfarin plasma concentration and its biological effect therefore its pharmacokinetic actions and the biological response must be measured using Prothrombin time (PT) followed by the International Normalised Ratio (INR ) to determine the exact dose for a particular patient to avoid side effects. PT monitors the pharmacodynamics of warfarin while INR measures Prothrombin time. (Randall et al 2006)
PT time measures the amount of time required to produce a blood clot in a known plasma sample while INR shows the ratio of patient's blood clotting time to the control plasma sample.
The early prolongation in the PT observed in the few days after the initiation of warfarin therapy is caused by the reduction of factor VII followed by reduction in factors xi, x and ii. (Hardman Joel G .et al 2001). The maximum effect of warfarin is seen within 2-5 days after the replacement of old clotting factors with the newly synthesised defective factors and also because of the varied half lives of the different clotting factors (ii, vii, Xi and X, C, S). The INR range varies according to the condition been treated; INR 2.0- 2.5 for prophylaxis of deep vein thrombosis; INR 2.0- 3.0 for treatment of Deep vein thrombosis, pulmonary embolism or prevention of venous thromboembolism in myocardic infarction. (Burton Michael .E. et a1.1992).
Drugs, herbal product and food can either inhibit or enhance warfarin anticoagulant effect. The most common mechanism includes reduced metabolism, change in drug absorption and protein binding. A bile acid sequestrant (cholestyramine) and sulcralfate bind with warfarin in the gastrointestinal tract reducing its bioavailability and anticoagulant effect. Highly protein bound acidic drugs like Valporate can displace warfarin from the protein binding site thereby increasing the level of unbound warfarin in the body. The effect of this displacement can be reduced by increased warfarin clearance, leading to a minor change in its anticoagulant response. Drug interactions from enzyme inhibitors (Metronidazole, Erythromycin, Allopurinol, Amiodarone etc) and enzyme inducers (phenobarbitone, Phenytoin, Rifampicin etc) increase or reduce Warfarin plasma levels. Amiodarone inhibit the metabolism (CYP1A2, CYP2C9) of the R- and S-enatiomers of warfarin. Combined use should be avoided if possible. Aminoglutethimide increases warfarin clearance because of enzyme induction. Patients on these drugs require review of their warfarin dose to ensure that PT -based INR is within the clinically effective range. Fibric acid displace warfarin from protein binding site and may affect the synthesis of coagulation factor. Co -administration of warfarin and Fibric acid should be avoided if possible or INR monitored.
Barbiturate affects the pharmacokinetics of warfarin by increasing the metabolic clearance of warfain and should be avoided if possible. (BNF 60, 2010).
H2- receptor antagonist (Cimetidine) and a proton pump inhibitor (Omeprazole) inhibits many CYP 450 enzymes thereby inhibiting the metabolism of R- isomers while S-isomer metabolism is unaffected. (Kourosh saeb-parsy et al.1999). Warfarin and concomitant use with cimetidine should be avoided because of possible haemorrhage. Co- administration of warfarin and some herbal products e.g. Ginkgo biloba should be avoided because of its additive effect which may result in a life- threatening bleeding. (Tatro David .S.2007) Ginkgo influences the metabolism of S- warfarin by inhibiting CYP2C9. St John's wort should be avoided. Garlic should also be taken with care with close monitoring. (Randall et al 2006) The concurrent use of cranberry juice and Warfarin should be avoided because of risk of bleeding. (Tatro David .S. 2007). (Kourosh saeb-parsy et al.1999).
The presence of food can reduce the rate of absorption of warfarin. The intake of food high in vitamin K (liver, lettuce) or nutritional supplement should be reduced or avoided; they change the pharmacodynamic response thereby reducing the therapeutic response. Regular or large consumption of foods like ice-cream, soybean protein, avocado, sweetener aspartame can change warfarin therapeutic response. (Randall et al 2006)