Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Sun Pharmaceutical Industries Europe B.V., Polarisavenue 87, 2132 JH Hoofddorp, The Netherlands
Pharmacotherapeutic group: Antithrombotic agent (Vitamin K Antagonist)
ATC code: B01AA03
Warfarin is a synthetic anti-coagulant of the coumarin series and acts by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II-60 hours, VII-4-6 hours, IX-24 hours, and X-48-72 hours.
The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively.
The resultant in vivo effect is a sequential depression of Factors VII, IX, X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%.
An anticoagulation effect generally occurs within 24 hours after drug administration.
However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of warfarin sodium may become more pronounced as effects of daily maintenance doses overlap.
Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.
Warfarin is a racemic mixture of the R- and S-enantiomers with the S-enantiomer exhibiting 2-5 times greater anti-coagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.
Warfarin is essentially completely absorbed after oral administration with peak concentration generally reached within the first 4 hours.
There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in foetal plasma approach the maternal values, but warfarin has not been found in human milk (see Section 4.6). Approximately 99% of the drug is bound to plasma proteins.
The elimination of warfarin is almost entirely by metabolism. Warfarin sodium is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4-, 6-, 7-, 8- and 10-hydroxywarfarin.
The Cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 1A2, and 34A. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.
The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-Warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-Warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.
Warfarin has been shown to be teratogenic in animal studies and has been suspected of causing abnormalities and foetal death when administered during human pregnancy. Warfarin should not be used during pregnancy. No reports of mutagenicity studies involving warfarin have been found in published literature. Warfarin, however, is a long established drug with an extensive history of clinical use.
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