Warfarin is an anticoagulant, which is used to treat and to prevent life threatening conditions such as deep vein thrombosis, pulmonary embolism, atrial fibrillation, recurrent myocardial infarction and also for patients undergoing surgery particularly orthopaedic surgery.
It exerts its action by inhibiting the enzyme vitamin k reductase, which is responsible for the convertion of vitamin k epoxide into vitamin k hydroquinone. When vitamin k hydroquinone is inhibited, the É£ carboxylation of the vitamin k dependant clotting factors is also inhibited. This then leads to the formation of inactive clotting factors.
Warfarin only acts to interfere with the synthesis of the vitamin k dependant clotting factors II (prothrombin), VII, IX and X as well as protein C and protein S , which then inhibits blood clot formation. However, the clotting factors have various half life with clotting factor 2 (prothrombin) having the longest half life of 48 to 72 hours and clotting factor 7 with the shortest half life of 2-6 hours. Warfarin is therefore a reflection of the prothrombin clotting factor 2 as the the É£ carboxylation of the vitamin k dependant clotting factors and their synthesis only occurs once all the clotting factors have been eliminated. Warfarin does not exert its effects on the already formed clotting factors II (prothrombin) , VII, IX and X protein C and protein S, which are already present in the blood. Warfarin only acts to prevent the formation of subsequent clotting factors by its interference with their synthesis. Hence the reason warfarin is used in patients who are at risk of developing thrombosis or embolism.
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There are factors that can contribute to the increase or decrease in the sensitivity of warfarin to the tissues in the body and alter prothrombin time, which is the time it takes for the blood to clot. These factors include various disease states, concomitant use with interacting drugs and also lifestyle factors.
The types of disease states that can influence warfarin's actions include hepatic dysfunction, hyperthyroidism, hypothyroidism, congestive heart failure and jaundice.
The functions of the liver includes the synthesis of albumin, which is one of the main transport plasma proteins for the drugs that are not water soluble, synthesis of vitamin k clotting factors and metabolism of drugs. However, when there is a dysfunction of the liver, such as liver cirrhosis this compromises the ability of the liver to produce albumin, metabolise drugs efficiently and synthesize the vitamin k dependant clotting factors.
Warfarin is 99% bounded to albumin in the plasma and about 1 % is free to exert warfarin's therapeutic action by inhibition of the formation of blood clots. Also, warfarin has a low extraction ratio, meaning that as it mainly bound to albumin, there is low concentration of unbound warfarin, which is available to be metabolised by the liver. A reduction in the albumin levels increases the fraction of the warfarin that is unbound. An increase in the unbound warfarin is made available to exert therapeutic effects in the tissue compartment as its volume of distribution increases and in turn, increasing its clearance. The therapeutic effect is also exaggerated and the prothrombin time is increased as the warfarin plasma concentration decreases. This increases the risk of haemorrhage.
Liver dysfunction causes a reduction in the clotting factors being synthesized. Therefore, the liver dysfunction would already lead to the prolongation of the prothrombin time as (R) according to a study that was carried out by Gallus et al, which involved 104 hospitalized patients who had infectious hepatitis. 57 of them were seen to have mild coagaulation defects of prolonged prothrombin time and 26 of the patients who were reported to have had liver failure had severe coagulation defects. Bleeding was reported to have occurred in 15 of the patients. (R)
This study demonstrated the effects of hepatic dysfunction without the use of warfarin or another anticoagulant. When warfarin is then introduced in a patient with concomitant hepatic dysfunction, the anticoagulation effect is further enchanced.
Hepatic dysfunction such as liver cirrhosis also leads to fibrous scars replacing the normal functional units of the liver; the hepatocytes. The liver becomes unable to metabolise warfarin and this leaves it exposed to tissues for longer, while the plasma concentration of warfarin remains unchanged. The therapeutic effects of warfarin are exaggerated and this also leads to the risk of haemorrhage.
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The thyroid hormones are mainly responsible for growth and metabolism (R internurse). Thyroid dysfunction causes an increase or decrease in the rate at which metabolic processes occur in the body would be increased in the case of hyperthyroidism and decreased in hypothyroidism. A patient diagnosed with hypothyroidism means that the elimination rates of the vitamin k clotting factors in the plasma would be decreased (R therapeutic drugs +current concepts). However hyperthyroidism is thought to cause an increase in the elimination of the clotting factors and also D-thyroxine increases the affinity of warfarin for receptor sites in the liver. This increases the risk of haemorrhage and increase in prothrombin time.
Warfarin is metabolised by the liver enzymes cytochrome P450 into active and inactive metabolites. As warfarin is a racemic mixture consisting of 50% of its R enanationmer and 50% of its S enantionmer, the S enaantionmer, which is more active in anticoagulation (R therapeutic drugs),is metabolised by cytochrome P450 2C9 while the R enantionmer is metabolised by the cytochrome P450 1A2 and 3A4. I will be mainly focusing on the metabolism of the S enantionmer.
Warfarin is a low extraction ratio drug meaning that the ability of the liver to extract the drug to metabolize is dependent on the activity of the cytochrome P450 enzymes. Any drug that interferes with the activity of the cytochrome P450 2C9 metabolising enzyme can increase or decrease warfarin's clearance.
The main drug interaction that occurs with warfarin is induction and inhibition. Drugs including carbamazepine, rifampicin and phenytoin are enzyme inducers. They act by increasing the transcription of mRNA for the production of the cytochrome P450 2C9 enzyme to increase the metabolism of warfarin. A reduced anticoagulant effect of warfarin observed as the concentration present is not enough to interfere with the synthesis of vitamin k dependant clotting factors.
Enzyme inhibitors are drugs including erythromycin, amiodarone and allopurinol. They act by inhibiting the binding of warfarin to its cytochrome P450 2C9 enzyme. A decrease in metabolism of warfarin occurs and a decrease in its clearance. This leads to an increase in its half life as the body is exposed to warfarin for longer the prothrombin time is also increased leading to an increased risk of haemorrhage.
As warfarin is highly plasma protein bounded another drug, which is highly protein bounded such as chlorpromazine may lead to warfarin being displaced, which increases the fraction of warfarin unbound exposed to the tissues. The plasma concentration of warfarin decreases as a result the prothrombin time is prolonged increasing the risk of haemorrhage.
Tetracyclines are broad spectrum antibiotics that act by inhibiting the growth of the micro organisms by interfering with their protein synthesis. In the gut flora, micro organisms perform various activities including the synthesis of vitamins such as vitamin k (R). Tetracycline disrupts these micro organisms producing vitamin K and the level or the amount of vitamin K that is available for the É£ Carboxylation of the vitamin K dependant clotting factors is reduced. The use of warfarin and tetracycline will lead to its anticoagulant effects being enhanced further as there is less vitamin K available for warfarin to antagonize (R).
Cholestryramine is an anion exchange resin, which forms insoluble complexes with bile acids in the gastro intestinal tract and prevents its reabsorption back into the liver. Therefore, cholestyramine is also capable of forming insoluble complexes with vitamins including vitamin k and also drugs including warfarin. As vitamin k causes a decrease in vitamin k reabsorption, this increases the risk of bleeding as the prothrombin time is increased, while the decrease in the absorption of warfarin decreases antiocoagulant effect. Both of these effects may counteract each other effects.
Foods that are high in vitamin K including spinach, broussell sprouts, avocadoes, asparagus, canola oil (cooking oil) and chick peas may decrease warfarin's response and prothrombin time as they antagonise the anticoagulant effect of warfarin by providing the cofactor for the É£ Carboxylation of the vitamin K dependant clotting factors.
Cranberry juice inhibits the cytochrome P450 2C9, which is the enzyme responsible for the metabolism of the active S enantionmer of warfarin. Taking warfarin at the same time may reduce the metabolism of warfarin. This may lead to an increase in the prothrombin time and increased risk of haemorrhage.
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