3 mg (blue), 5 mg (pink) and 1 mg (brown)<unk>  tablets (UK colours) Pharmacokinetics<unk>  consists of a racemic mixture of two active enantiomers—R- and S- forms—each of which is cleared by different pathways. S-warfarin is 2–5 times more potent than the R-isomer in producing an anticoagulant response. Both the enantiomers of<unk>  undergo CYP-mediated metabolism by many different CYPs to form 3',4',6,7,8 and 10-hydroxy<unk>  metabolites, major being 7-OH<unk>  formed from S-warfarin by CYP2C9 and 10-OH<unk>  from R-warfarin by CYP3A4.<unk>  is slower-acting than the common anticoagulant heparin, though it has a number of advantages. Heparin must be given by injection, whereas<unk>  is available orally.<unk>  has a long half-life and need only be given once a day. Heparin can also cause a prothrombotic condition, heparin-induced thrombocytopenia (an antibody-mediated decrease in platelet levels), which increases the risk for thrombosis. It takes several days for<unk>  to reach the therapeutic effect since the circulating coagulation factors are not affected by the drug (thrombin has a half-life time of days).<unk> 's long half-life means that it remains effective for several days after it is stopped. Furthermore, if given initially without additional anticoagulant cover, it can increase thrombosis risk (see below). Mechanism of action While<unk>  is one of several drugs popularly referred to as a "blood thinner", this is a misnomer since it does not affect the viscosity of blood.<unk>  inhibits the vitamin K-dependent synthesis of biologically active forms of the clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z. Other proteins not involved in blood clotting, such as osteocalcin, or matrix Gla protein, may also be affected. The precursors of these factors require gamma carboxylation of their glutamic acid residues to allow the coagulation factors to bind to phospholipid surfaces inside blood vessels, on the vascular endothelium. The enzyme that carries out the carboxylation of glutamic acid is gamma-glutamyl carboxylase. The carboxylation reaction will proceed only if the carboxylase enzyme is able to convert a reduced form of vitamin K (vitamin K hydroquinone) to vitamin K epoxide at the same time. The vitamin K epoxide is in turn recycled back to vitamin K and vitamin K hydroquinone by another enzyme, the vitamin K epoxide reductase (VKOR).<unk>  inhibits vitamin K epoxide reductase (specifically the VKORC1 subunit), thereby diminishing available vitamin K and vitamin K hydroquinone in the tissues, which decreases the carboxylation activity of the glutamyl carboxylase. When this occurs, the coagulation factors are no longer carboxylated at certain glutamic acid residues, and are incapable of binding to the endothelial surface of blood vessels, and are thus biologically inactive. As the body's stores of previously produced active factors degrade (over several days) and are replaced by inactive factors, the anticoagulation effect becomes apparent. The coagulation factors are produced, but have decreased functionality due to undercarboxylation; they are collectively referred to as PIVKAs (proteins induced by vitamin K absence), and individual coagulation factors as PIVKA-number (e.g., PIVKA-II). When<unk>  is newly started, it may promote clot formation temporarily. This is because the level of protein C and protein S are also dependent on vitamin K activity.<unk>  causes decline in protein C levels in first 36 hours. In addition, reduced levels of protein S lead to a reduction in activity of protein C (for which it is the co-factor) and therefore reduced degradation of factor Va and factor VIIIa. Although loading doses of<unk>  over 5 mg also produce a precipitous decline in factor VII, resulting in an initial prolongation of the INR, full antithrombotic effect does not take place until significant reduction in factor II occurs days later. The haemostasis system becomes temporarily biased towards thrombus formation, leading to a prothrombotic state. Thus, when<unk>  is loaded rapidly at greater than 5 mg per day, it is beneficial to co-administer heparin, an anticoagulant that acts upon antithrombin and helps reduce the risk of thrombosis, with<unk>  therapy for four to five days, in order to have the benefit of anticoagulation from heparin until the full effect of<unk>  has been achieved. Pharmacogenomics<unk>  activity is determined partially by genetic factors. Polymorphisms in two genes (VKORC1 and CYP2C9) play a particularly large role in response to<unk> . VKORC1 polymorphisms explain 30% of the dose variation between patients: particular mutations make VKORC1 less susceptible to suppression by<unk> . There are two main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B). VKORC1 polymorphisms explain why African Americans are on average relatively resistant to<unk>  (higher proportion of group B haplotypes), while Asian Americans are generally more sensitive (higher proportion of group A haplotypes). Group A VKORC1 polymorphisms lead to a more rapid achievement of a therapeutic INR, but also a shorter time to reach an INR over 4, which is associated with bleeding. CYP2C9 polymorphisms explain 10% of the dose variation between patients, mainly among Caucasian patients as these variants are rare in African American and most Asian populations. These CYP2C9 polymorphisms do not influence time to effective INR as opposed toVKORC1, but does shorten the time to INR >4. Despite the promise of pharmacogenomic testing in<unk>  dosing, its use in clinical practice is controversial. In August 2009, the Centers for Medicare and Medicaid Services concluded that "the available evidence does not demonstrate that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict<unk>  responsiveness improves health outcomes in Medicare beneficiaries." A 2014 meta-analysis showed that using genotype-based dosing did not confer benefit in terms of time within therapeutic range, excessive anticoagulation (as defined by INR greater than 4), or a reduction in either major bleeding or thromboembolic events.
Warfarin
Palladin
Clopidogrel
Ticlopidine
Apixaban
Ticagrelor
Heparin
Dabigatran