Mechanism Of Action Of Warfarin Biology Essay

Mechanism Of Action Of warfarin Biology EssayWarfarin is an decoagulant medication that is used to prevent thrombosis (clots) and embolism in m each disorders. Warfarin activity has to be monitored by frequent blood testing for the international Normalized Ratio (INR). Warfarin is a synthetic derivative of coumarin, a chemical substance found natur wholey in many rigs it decreases blood curdling by interfering with vitamin K metabolism.Mechanism of Action of WarfarinWarfarin is vitamin K antagonist that produce its anticoagulant medication meat by interfering with the cyclic inter metempsychosis of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the posttranslational carboxylation of glutamate residues to -carboxyglutamates on the N-terminal regions of vitamin K-dependent proteins (Whitlon, et al., 1978 Fasco, et al., 1982).123456 These coagulation factors (factors II, VII, IX, and X) pack -carboxylation for their biological activity. Coumarins produce their anticoagulant number by inhibiting the vitamin K conversion cycle, thereby create liverwort production of parti each(prenominal)y carboxylated and decarboxylated proteins with reduced procoagulant activity.78 In profit to their anticoagulant effect, the vitamin K antagonists inhibit carboxylation of the regulatory anticoagulant proteins C and S and therefore comport the potential to exert a procoagulant effect.In the presence of calcium ions, carboxylation causes a conformational swap in coagulation proteins91011 that promotes rachis to cofactors on phospholipid surfaces. The carboxylation reaction requires the reduced form of vitamin K (vitamin KH2), molecular oxygen, and coulomb dioxide, and is linked to the oxidation of vitamin KH2 to vitamin K epoxide. Vitamin K epoxide is then recycled to vitamin KH2 through devil reductase steps. The first, which is mass medium to vitamin K antagonists,123 reduces vitamin K epoxide to vitamin K1 (the natural nourishme nt form of vitamin K1), charm the second, which is relatively insensitive to vitamin K antagonists, reduces vitamin K1 to vitamin KH2. Treatment with vitamin K antagonists leads to the depletion of vitamin KH2, thereby change the -carboxylation of the vitamin K-dependent coagulant proteins. The effect of coumarins give the axe be counteracted by vitamin K1 (e real ingested in food or administered therapeutic every last(predicate)y) because the second reductase step is relatively insensitive to vitamin K antagonists (Fig 1). Patients handle with a king-size dose of vitamin K1 can as well as become warfarin resistant for up to a week because vitamin K1 accumulates in the liver and is acquirable to the coumarin-insensitive reductase.Pharmacokinetics and Pharmacodynamics of WarfarinWarfarin is a racemic mixture of cardinal optically participating i both(prenominal)rs, the R and S forms in roughly equal proportion. It has amply bioavailability,1920 is speedily absorbed from th e GI tract, and reaches maximal blood concentrations in healthy volunteers in 90 min after oral administration.1921 Racemic warfarin has a half life of 36 to 42 h, circulates bound to plasma proteins (mainly albumin), and accumulates in the liver where the two isomers ar metabolically transformed by different pathways.22 The dose-response relationship of warfarin is influenced by genetic and environmental factors, including a recently identified special K mutation in the gene coding for one of the common cytochrome P450 enzymes (2C9), the hepatic enzyme responsible for oxidative metabolism of the warfarin S-isomer.2324 This mutation likely contri moreoveres to the variant in dose response to warfarin among healthy subjects.25 In addition to known and unknown genetic factors, various disease states, doses, and dietetical factors can interfere with the response to warfarin.The anticoagulant response to warfarin is influenced by pharmacokinetic factors, including drug fundament al interactions that affect the absorption or metabolic headway of warfarin, and pharmacodynamic factors that alter the styptic response to given concentrations of the drug. Variability in anticoagulant response also occurs as a result of inaccuracies in laboratory testing, patient noncompliance, and miscommunication betwixt patient and physician. Other drugs may influence the pharmacokinetics of warfarin by decrease GI absorption or by disrupting its metabolic clearance. For example, the anticoagulant effect of warfarin is reduced by cholestyramine, which impairs its absorption, and is potentiated by drugs that inhibit warfarin clearance through stereoselective or nonselective pathways.252627 Stereoselective interactions affect oxidative metabolism of either the S-isoner or R-isomer of warfarin.2627 Inhibition of S-warfarin metabolism is more important clinically because this isomer is five quantify more potent as a vitamin K antagonist than the R-isomer.2627 dynamic headroom o f S-isomer warfarin is inhibited by phenylbutazone,2829 sulfinpyrazone,30 metronidazole,31 and trimethoprim- sulfamethoxazole,32 each of which potentiates the effect of warfarin on the prothrombin time (PT). In contrast, drugs such as cimetidine and omeprazole that inhibit clearance of the R-isomer have only moderate potentiating effects on the PT in patients handle with warfarin.272833 Amiodarone inhibits the metabolic clearance of twain the S-isomer and R-isomer and potentiates the anticoagulant effect of warfarin.34 The anticoagulant effect is inhibited by barbiturates,32 rifampicin,34 and carbamazepine,32 which step-up its metabolic clearance by inducing hepatic mixed oxidase activity. Although long-term alcohol use has a potential to maturation the clearance of warfarin through a alike mechanism, consumption of even relatively large amounts of wine was shown in one study29 to have little influence on PT in subjects case-hardened with warfarin. For a more thorough actio nment of the effect of enzyme induction on warfarin therapy, the reader is referred to a life-sustaining review (Table 2 ).35The pharmacodynamics of warfarin are subject to genetic and environmental variability. Hereditary resistance to warfarin occurs in rats36 as well as in human beings.3738 Patients with genetic warfarin resistance require doses quintuple to 20-fold higher than average to achieve an anticoagulant effect. This disorder is attributed to altered chemical attraction of the receptor for warfarin since the plasma warfarin levels required to achieve an anticoagulant effect are increase.Two mis-sense mutations in the factor IX propeptide have been described394041 that cause haemorrhage without excessive prolongation of PT. When affected individuals are treated with coumarin drugs, factor IX activity decreases to about 1 to 3%, small-arm levels of other vitamin K-dependent coagulation factors decrease to 30 to 40% of normal. These mutations are funny and have been es timated to occur in Subjects receiving long-term warfarin therapy are sensitive to fluctuating levels of dietary vitamin K,4243 which is provided predominantly by phylloquinone in plant material.43 The phylloquinone content of a wide range of foodstuffs has been listed by Sadowski and associates.44 phytonadione acts through the warfarin-insensitive reductase reaction.45 Important fluctuations in vitamin K intake occur in both apparently healthy and sick subjects.46 Increased intake of dietary vitamin K sufficient to reduce the anticoagulant response to warfarin42 occurs in patients on weight-reduction diets consuming green vegetables or receiving vitamin K-containing supplements, and in patients treated with IV supplements containing vitamin K. cut back dietary vitamin K1 intake potentiates the effect of warfarin in sick patients treated with antibiotics and IV fluids without vitamin K supplementation and in states of fat malabsorption. Hepatic disfunction potentiates the response to warfarin through impaired synthesis of coagulation factors. Hypermetabolic states produced by fever or hyperthyroidism increase warfarin responsiveness, probably by increasing the catabolism of vitamin K-dependent coagulation factors.4748 Drugs may influence the pharmacodynamics of warfarin by inhibiting synthesis or increasing clearance of vitamin K-dependent coagulation factors or by interfering with other pathways of hemostasis (Table 3 ). The anticoagulant effect of warfarin is adjoined by the second-generation and tierce-generation cephalosporins, which inhibit the cyclic interconversion of vitamin K,4950 by thyroxine, which increases the metabolism of coagulation factors,48 and by clofibrate, through an unknown mechanism.51 Doses5253 of salicylates 1.5 g/d also augment the anticoagulant effect of warfarin,54 possibly because these drugs have warfarin-like activity. Acetaminophen has also been account to augment the anticoagulant effect of warfarin,52 although this cont ention has been challenged (see be embarrassed). Although heparin potentiates the anticoagulant effect of warfarin, in therapeutic doses, it produces only slight prolongation of the PT.Drugs such as aspirin,55 nonsteroidal anti-inflammatory drugs,56 high doses of penicillins,5758 and moxolactam50 increase the risk of warfarin-associated bleeding by inhibiting platelet function. Of these, aspirin is the most important because of its widespread use and draw out effect.59 Aspirin and nonsteroidal anti-inflammatory drugs can also produce gastric erosions that increase the risk of upper-GI bleeding.58 The risk of clinically important bleeding is heightened when high doses of aspirin are taken in combination with high-intensity warfarin therapy (INR, 3.0 to 4.5).5560 In two studies, one study61 in patients with prosthetic nerve valves and the other study62 in asymptomatic individuals at high risk of coronary artery disease, low doses of aspirin (100 mg/d and 75 mg/d, respectively) were also associated with increased rates of minor bleeding when combined with moderate-intensity and low-intensity warfarin anticoagulation.The mechanisms by which erythromycin63 and some anabolic steroids64 potentiate the anticoagulant effect of warfarin are unknown. Sulfonamides and several(prenominal) broad-spectrum antibiotic compounds may augment the anticoagulant effect of warfarin by eliminating bacterial flora and aggravating vitamin K deficiency in patients whose diet is deficient of vitamin K.65Wells and associates66 performed a critical analysis of articles reporting assertable interaction between drugs or foods and warfarin. Studies were assigned to one category if the interaction was considered highly probable, to a second category if interaction was probable, to a third level if judged contingent, and to a fourth level if doubtful. Of 751 citations retrieved, pertinent results from 172 original articles are summarized in Table 3. Strong evidence of interaction was found for 39 of the 81 different drugs and foods appraised 17 potentiate warfarin effect, 10 inhibit, and 12 produce no effect. Many other drugs have been reported to either interact with oral anticoagulants or alter the PT response to warfarin,6768 but convincing evidence of a causal association is lacking. In a case-control study,52 low to moderate doses of acetaminophen (nine or more tablets per week) were reported to be associated with excessively prolonged INR values. The presence of a causal association between acetaminophen use and potentiation of a warfarin effect is uncertain. The article52 was supported by an editorial,53 but has been challenged by personal experiences (case series) cited in two letters6970 and by the results of a prospective study71 in normal volunteers. However, until more information is presented, it would be discreet to monitor the INR more frequently when acetaminophen is used in this measuring stick by patients during warfarin therapy. Indeed, it would be reasonable to monitor the PT more frequently when any drug therapy is added or withdrawn from the regimen of a patient treated with an oral anticoagulant.DRUG INTERACTIONS Your amend or chemist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any drug, vitamin, or herb tea product without checking with your impact or pharmacist first.Warfarin interacts with many prescription, nonprescription, vitamin, and herbal products. This includes medications that are applied to the cutis or inside the vagina or rectum. The following interactions listed do not contain all possible drug interactions. The interactions with warfarin usually result in an increase or decrease in the blood-thinning (anticoagulant) effect. Your doctor or other health care professional should closely monitor you to prevent serious bleeding or clotting problems. While taking warfarin, it is very important to sort out your doc tor or pharmacist of any changes in medications, vitamins, or herbal products that you are taking.This drug should not be used with the following medications because very serious interactions may occur imatinib, mifepristone.If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting warfarin.Aspirin and aspirin-like drugs (salicylates) and nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, naproxen, celecoxib) may have effects similar to warfarin. These drugs may increase the risk of bleeding problems if taken during treatment with warfarin. conservatively check all prescription/nonprescription product labels (including drugs applied to the skin such as pain-relieving creams) since the products may contain NSAIDs or salicylates. Talk to your doctor about using a different medication (such as acetaminophen) to treat pain/fever. Low-dose aspirin and related drugs (such as clopidogrel, ticlopidine) should be continued if confirming by your doctor for specific medical reasons such as heart attack or stroke prevention. Consult your doctor or pharmacist for more details.Many herbal medications have blood-thinning or blood-clotting effects, and some may straight affect warfarin. Tell your doctor before taking any herbal products, especially bromelains, coenzyme Q10, cranberry, danshen, dong quai, fenugreek, garlic, ginkgo biloba, ginseng, goldenseal, and St. Johns wort, among others.This medication may interfere with a certain laboratory test to measure theophylline levels, possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist