The Clinical Use Of Warfarin Biology Essay

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Thromboembolism is a condition which involves the dislodging of a blood clot which travels through the blood stream to block blood vessels (Neil and Randall, 2004). Warfarin belongs to the class of drugs called oral anticoagulants. It can be used in the treatment and prophylaxis of thromboembolism. The target international normalised ratio (INR) for the treatment of pulmonary embolism is 2.5 (British National Formulary, 2010). The INR is indicative of the prothrombin time.

Warfarin exerts it anticoagulant activity by inhibiting the enzyme vitamin K epoxide reductase. This enzyme catalyses the conversion of vitamin K epoxide to a reduced form of vitamin K. Warfarin is thus a vitamin K antagonist (Grahame-Smith and Aronson,2002). They also suggest that the level of inhibition of vitamin K expoxide reductase enzyme is related to the concentration of warfarin in the liver.

According to (Wright et al, 2006) the action of warfarin brings about a decrease in the hepatic synthesis of vitamin K dependent clotting factors II, VII, IX and X in a dose related manner. This results in lengthening of the bleeding time (prothrombin time) and therefore limiting the tendency of blood clot formation. Warfarin has no direct effect on previously circulating clotting factors (Dipiro et al, 2002). Dollery (1999) also explains that the onset of action of warfarin is delayed until there is catabolism of existing clotting factors.

The pharmacokinetic factor involves altering of the plasma level of the drug whilst the pharmacodynamic factor is associated with the risk of bleeding without a change in warfarin plasma level. According to (Jones, 2008), a change in plasma levels of warfarin result in a change in (INR). Jones (2008) also explains that a drug that would affect platelet aggregation will raise the risk of bleeding without a change in the INR.

Disease states namely hyperthyroidism, hypothyroidism, fever, congestive heart failure and liver disease can have an effect on the pharmacokinetics and pharmacodynamics warfarin. Hypermetabolic events such as hyperthyroidism and fever can result in increase catabolism of clotting protein (Regal and Tsui, 2007). Jones (2008) also explains that due to hyperthyroid activity and fever, there is increase clearance of vitamin K clotting factors and the amount of warfarin required for anticoagulation will reduce. (Stephens et al, 1989) states that hypothyroidism brings about a reduction in metabolism of coagulation factors. These factors stay in circulation for a long time and this result in an increase in the dose of warfarin for anticoagulant activity. Hyperthyrodism thus brings about an increase in wafarin sensitivity and hypothyroidism is also associated with a decrease in warfarin sensitivity.

Liver is the organ that is associated with the production of plasma proteins and clotting factors (Fox, 2004). Demirkan et al (2000) explains that liver dysfunction is associated with an increase response to warfarin. Liver dysfunction is also linked to a decreased production of vitamin K clotting factors and this account for a prolonged prothrombin time (Lenham, 2008). According to Jones (2008) defects in the function of platelets and fibrinogen is found in many patients with liver dysfunction. This as result can lead to a higher risk of bleed in such patients. Warfarin sensitivity is increased in liver dysfunction.

Grahame-Smith and Aronson (2002) states that hepatic congestion linked to heart failure brings about an increase to warfarin sensitivity. Congestive heart failure reduces the metabolism of warfarin which leads to an increase anticoagulant activity and therefore a high chance of bleeding (Jones, 2008).

Jones (2008) also suggests that warfarin is metabolized by several cytochrome p450 (CYP450) iso enzymes and drugs that affect the CYP2C9 enzyme system can have an effect on increasing or reducing the INR. The more potent form of warfarin (s-isomer) is metabolized by CYP2C9 enzyme system (Jones, 2008). The other form the warfarin (r-enantiomer) is metabolised by CYP1A2 and CYP3A4. (www.medicines.org.uk). Drugs can interact with warfarin through several mechanisms and this include impaired warfarin absorption, displacement of warfarin from plasma protein-binding sites and alteration in warfarin metabolism (www.parkinsons-information-exchange-network-online.com). Grahame-Smith and Aronson (2002) suggest that certain drugs induce the metabolism of warfarin and this includes drugs like phenytoin, rifampicin and cabamazepine. Drugs that can inhibit warfarin metabolism include amiodarone, fluconazole and erythromycin. The reaction of warfarin with these drugs needs to be monitored very closely if not avoided.

Drugs that displace warfarin from protein-binding sites, increase warfarin's anticoagulant effect. Non steroidal anti-inflammatory drugs (NSAIDs) displace warfarin from its binding site and also cause gastric ulceration as they erode the lining of the stomach. (e.g Phenylbutazone). NSAIDs generally inhibit platelet aggregation. However, the cyclogenase inhibitors (cox 2 inhibitors) have a slightly different mechanism (Grahame-Smith and Aronson, 2002). Erythromycin which belongs to a class of drug called the macrolides, inhibits the metabolism and reduces the clearance of warfarin from the body. The activity of warfarin may also be lengthened due to changes in the intestinal flora and its synthesis of vitamin K for clotting factor (www.scoup.net). Rifampicin is a potent inducer of the cytochrome CYP3A4. It increases the elimination of warfarin and decreases its anticoagulant action (Dollery, 1999).

Cholestryamine is known to reduce the action of warfarin by decreasing its absorption and also interfering with its enterohepatic recirculation (Dollery, 1999).

According to researchers (Daugherty and Smith, 2006), anticoagulant effect of warfarin can be affected by certain food products. Jones (2008) also explains that, foods rich in vitamin K tend to have an effect on the warfarin action and this include green leafy vegetables (broccoli, brussels sprout, lettuce, spinach e.t.c). These food products can lower the prothrombin time and therefore a decrease in the INR. This action will decrease the action of warfarin and it can result in increase incidence of blood clots (www.uptodate.com). According to some experts, cranberry juice can increase the anticoagulant effect of warfarin and this can lead to a high risk bleeding. However, a study conducted revealed that a small portion of canberry juice has no effect on the INR. (www.uptodate.com). Daugherty and Smith (2006) proposed that the presumed mechanism of action when warfarin interacts with avocado involves degradation of warfarin as a result of the action of microsomal liver enzymes. Intestinal absorption of warfarin is interrupted. Jones (2008) suggests that a patient on warfarin needs to have a balanced diet as major changes in diet can have effect on warfarin action and therefore eating high portions of these food products needs to be avoided. However, patients who need to change their diet need to seek advice from their doctor or practice nurse. Wright et al, (2006) explains that patients should be well informed about the implications risks and benefits associated with the use of warfarin. According to these researchers the yellow anticoagulant book is well use for monitoring of the patient in terms of recording the INR, the dosing information for the patient, appointment dates for clinics and the safe use of warfarin.

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