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SBA Answers and Explanations
Published in Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury, SBAs for the MRCS Part A, 2018
Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury
Warfarin is a synthetic derivative of dicoumarol, which is derived from coumarin, a chemical found naturally in many plants. It decreases blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles oxidized vitamin K to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombin and factor VII.
Precision medicine in coronary artery disease
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Melvin George, Luxitaa Goenka, Sandhiya Selvarajan
Presently the website WarfarinDosing.org is available to help clinicians to begin warfarin therapy by evaluating the required therapeutic dose among patients who are new to warfarin therapy. The evaluation is based on the patient's clinical and demographic factors. The genotypes of two genes—cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1)—are also evaluated.
Pharmacogenomics of Tamoxifen
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Warfarin is the most commonly used oral antithrombic in the world. However, adjustment of appropriate dose for each patient is sometimes difficult because of the large interindividual variation in the requirement of this drug. Insufficient dose of warfarin will fail to prevent thrombosis. On the other hand, overdosing will increase the risk of unexpected bleeding. Warfarin is metabolized to the 7- hydroxylated form in humans mainly by cytochrome P450, subfamily 2C, polypeptide 9 (CYP2C9) [46]. Moreover, vitamin K plays an important role in making blood-clotting proteins, and warfarin plays its anticoagulant effect by suppressing the regeneration of vitamin K. The vitamin K epoxide reductase is encoded by vitamin K epoxide reductase complex subunit 1 (VKORC1) [47, 48–49]. CYP2C9 and VKORC1 have been associated with this interindividual variation of the appropriate dose of warfarin leading to genotype-guided dosing tables in warfarin labeling. To improve the dose adjustment of the drug, FDA declared changes in warfarin labeling in 2007 and publicly issued the dosing tables in 2010 [50]. However, some physicians claim that there must be more elaboration on how to use the two-genotype information in prescribing warfarin. Hence, the guidelines for using the pharmacogenetic information are now expected to improve to maturely establish personalized antithrombic therapy [51].
Drugs in phase I and II clinical development for the prevention of stroke in patients with atrial fibrillation
Published in Expert Opinion on Investigational Drugs, 2021
Robert Bentley, Lewis J. Hardy, Laura J Scott, Parveen Sharma, Helen Philippou, Gregory Y. H. Lip
Warfarin is a VKA and, as described in Figure 1, its mode of action is to interfere with the hepatic synthesis of the pro-coagulant vitamin K-dependant clotting factors II, VII, IX and X, as well as the synthesis of the anticoagulant proteins C, S and Z [14]. These clotting factors undergo gamma-carboxylation of glutamic acid residues at the NH2-terminal molecular region [25] which requires the presence of the reduced and active form of vitamin K, which makes these coagulation factors fully functional (enabling them to be active following proteolytic cleavage). Under normal conditions, vitamin K epoxide reductase complex 1 (VKORC1) converts vitamin KO, the oxidized and inactive form of vitamin K, into the active vitamin KH2 form [25,26]. This provides a continuous supply of vitamin KH2 causing clotting factor synthesis. Warfarin specifically inhibits VKORC1 causing an accumulation of inactive vitamin KO, and effectively reduces the fully functional hepatic synthesis of vitamin K dependent clotting factors as well as proteins C, S and Z [25].
Pharmacological management of cerebral ischemia in the elderly
Published in Expert Opinion on Pharmacotherapy, 2021
Adithya Kannan, Mychael Delgardo, William Pennington-FitzGerald, Enoch X. Jiang, Brandon R. Christophe, E Sander Connolly
Historically, warfarin has been the most commonly used medication for AF related stroke prevention [23]. Warfarin prevents the activation of vitamin K by the vitamin K epoxide reductase complex 1, thereby reducing the synthesis of activated clotting factors. A meta-analysis of six studies and 2,900 patients with AF found that treatment with warfarin was associated with a relative risk reduction of 64% compared to placebo [45]. However, warfarin therapy is problematic due to the medication’s narrow therapeutic window and required monitoring. Some studies suggest that 50% of patients on warfarin do not reach their appropriate international normalized ratio (INR). Novel oral anticoagulants (NOACs) now tend to be preferred for stroke prevention as they are easier to use and do not require monitoring [23].
Pharmacogenomics of drugs used to treat brain disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
‘Active’ vitamin K is oxidatively converted into an ‘inactive’ form and subsequently re-activated by vitamin K epoxide reductase complex 1 (VKORC1). Warfarin competitively inhibits subunit 1 of multi-unit VKOR complex, thus depleting functional vitamin K reserves and hence reducing synthesis of active clotting factors. Its antithrombogenic effects generally occur only after functional coagulation factors IX and X are diminished (usually 2–7 days following initiation of therapy), with no effect on catabolism of blood coagulation factors. This anticoagulant inhibits thrombus formation when stasis is induced and prevents extension of existing thrombi, with no direct effect on established thrombi. Warfarin prolongs PT and APTT, and phytonadione (vitamin K1) reverses its anticoagulant effect. Warfarin is a substrate of CALU, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP3A4/5, CYP4F2, EPHX1 and GGCX, an inhibitor of CYP2C9, CYP2C19 and VKORC1, and an inducer of CYP2C9, and is transported by ABCB1 [8, 9]. CYP2C9 and VKORC1 variants are determinant in warfarin efficacy and safety.