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Encyclopedia > Warfarin
Warfarin
Systematic (IUPAC) name
(RS)-4-hydroxy-3-(3-oxo-1-phenylbutyl)-
2H-chromen-2-one
Identifiers
CAS number 81-81-2
ATC code B01AA03
PubChem 6691
DrugBank APRD00341
Chemical data
Formula C19H16O4 
Mol. mass 308.33 g/mol
SMILES search in eMolecules, PubChem
Pharmacokinetic data
Bioavailability 100%
Protein binding 99.5%
Metabolism Hepatic: CYP2C9, 2C19, 2C8, 2C18, 1A2 and 3A4
Half life 2.5 days
Excretion Renal (92%)
Therapeutic considerations
Pregnancy cat.

D(AU) X(US) Image File history File links Warfarin. ... IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences, mixtures and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A section of the Anatomical Therapeutic Chemical Classification System. ... PubChem is a database of chemical molecules. ... The DrugBank database available at the University of Alberta is a unique bioinformatics and cheminformatics resource that combines detailed drug (i. ... This article or section does not cite any references or sources. ... General Name, symbol, number carbon, C, 6 Chemical series nonmetals Group, period, block 14, 2, p Appearance black (graphite) colorless (diamond) Standard atomic weight 12. ... General Name, Symbol, Number hydrogen, H, 1 Chemical series nonmetals Group, Period, Block 1, 1, s Appearance colorless Atomic mass 1. ... General Name, Symbol, Number oxygen, O, 8 Chemical series nonmetals, chalcogens Group, Period, Block 16, 2, p Appearance colorless (gas) very pale blue (liquid) Standard atomic weight 15. ... The molecular mass (abbreviated Mr) of a substance, formerly also called molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... The simplified molecular input line entry specification or SMILES is a specification for unambiguously describing the structure of chemical molecules using short ASCII strings. ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... A drugs efficacy may be affected by the degree to which it binds to the proteins within blood plasma. ... Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ... Cytochrome P450 2C9 (abbreviated CYP2C9), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. ... Cytochrome P450 2C19 (abbreviated CYP2C19), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. ... This page is a candidate for speedy deletion. ... Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. ... It has been suggested that Effective half-life be merged into this article or section. ... Excretion is the process of eliminating waste products of metabolism and other materials that are of no use. ... The kidneys are organs that filter wastes (such as urea) from the blood and excrete them, along with water, as urine. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. ... For other uses, see Australia (disambiguation). ... Motto: (Out Of Many, One) (traditional) In God We Trust (1956 to date) Anthem: The Star-Spangled Banner Capital Washington D.C. Largest city New York City None at federal level (English de facto) Government Federal constitutional republic  - President George Walker Bush (R)  - Vice President Dick Cheney (R) Independence from...

Legal status

Prescription Only (S4)(AU) POM(UK) -only(US) The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... The Standard for the Uniform Scheduling of Drugs and Poisons, abbreviated SUSDP, is a document used in the regulation of drugs and poisons in Australia. ... For other uses, see Australia (disambiguation). ... A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained. ... A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained. ... Motto: (Out Of Many, One) (traditional) In God We Trust (1956 to date) Anthem: The Star-Spangled Banner Capital Washington D.C. Largest city New York City None at federal level (English de facto) Government Federal constitutional republic  - President George Walker Bush (R)  - Vice President Dick Cheney (R) Independence from...

Routes Oral or Intravenous

Warfarin (also known under the brand names of Coumadin, Jantoven, Marevan, and Waran) is an anticoagulant medication that is administered orally or, very rarely, by injection. It is used for the prophylaxis of thrombosis and embolism in many disorders. Its activity has to be monitored by frequent blood testing for the international normalized ratio (INR). It is named for the Wisconsin Alumni Research Foundation. In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. ... This article does not cite any references or sources. ... Prophylaxis refers to any medical or public health procedure whose purpose is to prevent, rather than treat or cure, disease. ... Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ... In medicine, an embolism occurs when an object (the embolus, plural emboli) migrates from one part of the body (through circulation) and cause(s) a blockage (occlusion) of a blood vessel in another part of the body. ... Blood tests are laboratory tests done on blood to gain an appreciation of disease states and the function of organs. ... The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ... WARF company logo The Wisconsin Alumni Research Foundation is the nonprofit technology transfer office of the University of Wisconsin-Madison. ...


Warfarin is a synthetic derivative of coumarin, a chemical found naturally in many plants, notably woodruff (Galium odoratum, Rubiaceae), and at lower levels in licorice, lavender and various other species. Warfarin was originally developed as a rat poison; however, more modern poisons are much more potent and toxic (e.g., brodifacoum). Warfarin and contemporary rodenticides belong to the same class of drugs (coumarins) and both decrease blood coagulation by interfering with vitamin K metabolism. For this reason, drugs in this class are also referred to as vitamin K antagonists. [1] Coumarin is a chemical compound; a toxin found in many plants, notably in high concentration in the tonka bean, woodruff, and bison grass. ... For other uses, see Plant (disambiguation). ... Binomial name Galium odoratum (L.) Scop. ... Type Genus Rubia L. Genera See text For a full list, see: List of Rubiaceae genera Egyptian Starcluster Pentas lanceolata White luculia gratissima Rubiaceae Juss. ... Species Glycyrrhiza acanthocarpa Glycyrrhiza aspera Glycyrrhiza astragalina Glycyrrhiza bucharica Glycyrrhiza echinata Glycyrrhiza eurycarpa Glycyrrhiza foetida Glycyrrhiza glabra Glycyrrhiza iconica Glycyrrhiza korshinskyi Glycyrrhiza lepidota Glycyrrhiza pallidiflora Glycyrrhiza triphylla Glycyrrhiza uralensis Glycyrrhiza yunnanensis Ref: ILDIS Version 6. ... Species About 25-30, including: Lavandula abrotanoides Lavandula angustifolia Lavandula canariensis Lavandula dentata Lavandula lanata Lavandula latifolia Lavandula multifida Lavandula pinnata Lavandula stoechas Lavandula viridis Lavandula x intermedia The Lavenders Lavandula are a genus of about 25-30 species of flowering plants in the mint family, Lamiaceae, native from the... A rat in urban environment Rat poisons are a category of pest control chemicals intended to kill rats. ... Brodifacoum is a highly lethal anticoagulant poison. ... Vitamin K1 (phylloquinone). ...

Contents

Mechanism of action

Warfarin inhibits the synthesis of biologically active forms of the vitamin K-dependent 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. Vitamin K1 (phylloquinone). ... Coagulation is the thickening or congealing of any liquid into solid clots. ... Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ... Factor VII (formerly known as proconvertin) is one of the central proteins in the coagulation cascade. ... Factor IX (or Christmas factor or Christmas-Eve factor) is one of the serine proteases (EC 3. ... Factor X, also known by the eponym Stuart-Prower factor or as thrombokinase, is an enzyme ( EC 3. ... Protein C is a major physiological anticoagulant. ... Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver and it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. ... Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. ... Osteocalcin is a protein found in bone and dentin; that plays a role in mineralization and calcium ion homeostasis ...


The precursors of these factors require 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 only proceed 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). Warfarin inhibits epoxide reductase[2] (specifically the VKORC1 subunit[3][4]), thereby diminishing available vitamin K and vitamin K hydroquinone in the tissues, which inhibits 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 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/antagonism). Hence, the effect of warfarin is to diminish blood clotting in the patient. Glutamic acid (Glu, E), is the protonated form of glutamate (the anion). ... Phospholipid Two schematic representations of a phospholipid. ... The endothelium is the layer of thin, flat cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. ... Glutamic acid (Glu, E), is the protonated form of glutamate (the anion). ... Gamma-glutamyl carboxylase is an enzyme which oxidizes Vitamin K hydroquinone. ... The most fundamental reactions in chemistry are the redox processes. ... Vitamin K epoxide reductase (VKOR) is an enzyme (EC 1. ... Glutamic acid (Glu, E), is the protonated form of glutamate (the anion). ... The endothelium is the layer of thin, flat cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. ...


Paradoxically, the initial effect of warfarin administration is to promote clot formation. This is because the level of protein S is also dependent on vitamin K activity. Reduced levels of protein S lead to a reduction in activity of protein C (for which it is the co-factor) and therefore reduced inhibition of factor Va and factor VIIIa. This then causes the hemostasis system to be temporarily biased towards thrombus formation, leading to a prothrombotic state. This is one of the benefits of co-administering heparin, an anticoagulant that acts upon antithrombin and helps reduce the risk of thrombosis, which is common practice in settings where warfarin is loaded rapidly. Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver and it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. ... Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. ... Factor VIII (FVIII) is an essential clotting factor. ... Heparin, a highly sulfated glycosaminoglycan is widely used as an injectable anticoagulant and has the highest negative charge density of any known biological molecule. ... Image:Antithrombin. ...


Uses

Medical use

Warfarin is prescribed to people with an increased tendency for thrombosis or as prophylaxis in those individuals who have already formed a blood clot (thrombus) which required treatment. This can help prevent formation of future blood clots and help reduce the risk of embolism (migration of a thrombus to a spot where it blocks blood supply to a vital organ). Common clinical indications for warfarin use are atrial fibrillation, artificial heart valves, deep venous thrombosis, pulmonary embolism, antiphospholipid syndrome and occasionally after myocardial infarction.[5] Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ... Blood clot diagram. ... In medicine, an embolism occurs when an object (the embolus, plural emboli) migrates from one part of the body (through circulation) and cause(s) a blockage (occlusion) of a blood vessel in another part of the body. ... Atrial fibrillation (AF or afib) is an abnormal heart rhythm (cardiac arrhythmia) which involves the two small, upper heart chambers (the atria). ... It has been suggested that this article or section be merged with Heart valve prosthesis. ... It has been suggested that Deep Vein Thrombosis be merged into this article or section. ... This article, image, template or category should belong in one or more categories. ... Acute myocardial infarction (AMI or MI), more commonly known as a heart attack, is a disease state that occurs when the blood supply to a part of the heart is interrupted. ...


Dosing of warfarin is complicated by the fact that it is known to interact with many commonly used medications and other chemicals that may be present in appreciable quantities in food. These interactions may enhance or reduce warfarin's anticoagulation effect. Many commonly used antibiotics, such as metronidazole or the macrolides, will greatly increase the effect of warfarin by reducing the metabolism of warfarin in the body. Other broad-spectrum antibiotics can reduce the amount of the normal bacterial flora in the bowel, which make significant quantities of Vitamin K, thus potentiating the effect of warfarin. In addition, food that contains large quantities of Vitamin K will reduce the warfarin effect; and medical conditions such as hypo- or hyperthyroidism will alter the rate of breakdown of the clotting factors. Metronidazole (INN) (IPA: ) is a nitroimidazole anti-infective drug used mainly in the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa. ... The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached. ...


Therefore, in order to optimise the therapeutic effect without risking dangerous side effects, such as bleeding, close monitoring of the degree of anticoagulation is required by blood testing (INR). Initially, checking may be as often as twice a week; the intervals can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose. The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ...


When initiating warfarin therapy ("warfarinisation"), the doctor will decide how strong the anticoagulant therapy needs to be. The target INR level will vary from case to case dependent upon the clinical indicators, but tends to be 2-3 in most conditions. In particular, target INR will be 2.5-3.5 in patients with artificial (mechanical) heart valves.


The oral anticoagulant ximelagatran (Exanta®) was expected to replace warfarin to a large degree when introduced; however, reports of hepatotoxicity (liver damage) prompted its manufacturer to withdraw it from further development. Other drugs offering the efficacy of warfarin without a need for monitoring, such as dabigatran, rivaroxaban, and Idraparinux are under development. Ximelagatran (Exanta®, H 376/95) is an anticoagulant that has been investigated extensively but is awaiting approval by the Food and Drug Administration (FDA). ... Hepatotoxicity (from hepatic toxicity) is chemical-driven liver damage. ... Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors. ... Rivaroxaban (also known as BAY 59-7939) is an oral anticoagulant under development by Bayer. ...


Pesticide use

Coumarins, a class of drugs of which warfarin is a member, are used as a rodenticide for controlling rats and mice in residential, industrial, and agricultural areas. The active ingredient in rat poison is brodifacoum, which is sometimes referred to as a super-warfarin, because it is longer acting than the drug warfarin. It is both odorless and tasteless. It is effective when mixed with food bait, because the rodents will return to the bait and continue to feed over a period of days, until a lethal dose is accumulated (considered to be 1 mg/kg b.w./day over four to five days for warfarin; for brodifacoum, no reliable cumulative toxicity datas are available at this time, but it could be concluded, given the similarity with other 4-hydroxycoumarin derivatives, that these would be in order of tens of µg/kg b.w./day for periods of 2-10 days). It may also be mixed with talc and used as a tracking powder, which accumulates on the animal's skin and fur, and is subsequently consumed during grooming. The use as rat poison is now declining because many rat populations have developed resistance to warfarin. A rat in urban environment Rat poisons are a category of pest control chemicals intended to kill rats. ... Species 50 species; see text *Several subfamilies of Muroids include animals called rats. ... Feral mouse A mouse (plural mice) is a rodent that belongs to one of numerous species of small mammals. ... Brodifacoum is a highly lethal anticoagulant poison. ... Bait is any substance used to attract prey, e. ... Suborders Sciuromorpha Castorimorpha Myomorpha Anomaluromorpha Hystricomorpha Rodentia is an order of mammals also known as rodents. ... Talc (derived from the Persian via Arabic talq) is a mineral composed of hydrated magnesium silicate with the chemical formula H2Mg3(SiO3)4 or Mg3Si4O10(OH)2. ...


The LD50 is 50–500 mg/kg. The IDLH value is 100mg/m³ (warfarin; various species). LD50(mouse, oral) = 0.40 mg/kg; (rat, oral) = 0.27 mg/kg (brodifacoum). The IDLH value for brodifacoum is not defined, but given the toxicity of brodifacoum, it would be substantialy lower, perhaps less than 1/100 of the warfarin value, i.e. <1 mg/m³. An LD50 test being administered In toxicology, the LD50 or colloquially semilethal dose of a particular substance is a measure of how much constitutes a lethal dose. ... Immediately Dangerous to Life and Health (IDLH or NIOSH IDLH) is a limit for personal exposure to a substance defined by the United States National Institute for Occupational Safety and Health (NIOSH), normally expressed in parts per million (ppm). ...


Side-effects

The only common side-effect of warfarin is hemorrhage (bleeding). The risk of severe bleeding is small but definite (1-2% annually) and any benefit needs to outweigh this risk when warfarin is considered as a therapeutic measure. Risk of bleeding is augmented if the INR is out of range (due to accidental or deliberate overdose or due to interactions), and may cause hemoptysis (coughing up blood), excessive bruising, bleeding from nose or gums, or blood in urine or stool. To meet Wikipedias quality standards, this article or section may require cleanup. ... Hemoptysis (US English) or haemoptysis (International English) is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs (e. ... This article or section is in need of attention from an expert on the subject. ... Look up stool in Wiktionary, the free dictionary. ...


A feared (but rare) complication of warfarin is warfarin necrosis, which occurs more frequently shortly after commencing treatment in patients with a deficiency of protein C. Protein C is an innate anticoagulant that, like the procoagulant factors that warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the blood's tendency to coagulate when treatment is first begun (many patients when starting on warfarin are given heparin in parallel to combat this), leading to massive thrombosis with skin necrosis and gangrene of limbs. Its natural counterpart, purpura fulminans, occurs in children who are homozygous for protein C mutations. Warfarin necrosis is acquired protein C deficiency due to treatment with the vitamin K inhibitor anticoagulant warfarin. ... Protein C is a major physiological anticoagulant. ... Heparin, a highly sulfated glycosaminoglycan is widely used as an injectable anticoagulant and has the highest negative charge density of any known biological molecule. ... Necrosis (in Greek Νεκρός = Death) is the name given to accidental death of cells and living tissue. ... Gangrene is necrosis and subsequent decay of body tissues caused by infection or thrombosis or lack of blood flow. ... Purpura fulminans is a haemorrhagic condition usually associated with sepsis or previous infection. ... Homozygote cells are diploid or polyploid and have the same alleles at a locus (position) on homologous chromosomes. ...


Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks) is purple toe syndrome. This condition is thought to result from small deposits of cholesterol breaking loose and flowing into the blood vessels in the skin of the feet, which causes a blueish purple color and may be painful. It is typically thought to affect the big toe, but it affects other parts of the feet as well, including the bottom of the foot (plantar surface). The occurrence of purple toe syndrome may require discontinuation of warfarin.[6]


Pharmacology

3mg (blue), 5mg (pink) and 1mg (brown) warfarin tablets (UK colours)
3mg (blue), 5mg (pink) and 1mg (brown) warfarin tablets (UK colours)

Warfarin tablets, 5, 3 and 1mg, photo by Gonegonegone, taken this date. ... Warfarin tablets, 5, 3 and 1mg, photo by Gonegonegone, taken this date. ...

Pharmacokinetics and antagonism

Warfarin consists of a racemic mixture of two active optical isomers - R and S forms - each of which is cleared by different pathways. S-warfarin has five times the potency of the R-isomer with respect to vitamin K antagonism.[5] In chemistry, isomers are molecules with the same chemical formula and often with the same kinds of chemical bonds between atoms, but in which the atoms are arranged differently (analogous to a chemical anagram). ...


Warfarin is slower acting than the common anticoagulant heparin, though it has a number of advantages. Heparin must be given by injection, while warfarin is available orally. Warfarin 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 paradoxically increases the risk for thrombosis. Warfarin's long half life, on the other hand, means it often takes several days to reach therapeutic effect. Furthermore, if given initially without additional anticoagulant cover, it can paradoxically increase thrombosis risk. For these main reasons, hospitalised patients are usually given heparin initially, and are then moved on to warfarin. Heparin, a highly sulfated glycosaminoglycan is widely used as an injectable anticoagulant and has the highest negative charge density of any known biological molecule. ... Heparin-induced thrombocytopenia (HIT) with or without thrombosis (HITT) is thrombocytopenia (low platelet counts) due to the administration of heparin. ... A 250 ml bag of newly collected platelets. ... Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ... For the record label, see Hospital Records. ...


Warfarin can be reversed with vitamin K, or for rapid reversal (e.g., in case of severe bleeding), with fresh frozen plasma but this treatment is being replaced by use of prothrombin complex concentrate. Blood plasma is the liquid component of blood, in which the blood cells are suspended. ... Prothrombin complex concentrate (PCC) is a combination of several blood clotting factors used to treat bleeding in patients using certain anticoagulants or to prepare them for emergency surgery. ...


Details on reversing warfarin are provided in clinical practice guidelines from the American College of Chest Physicians.[7] For patients with an international normalized ratio (INR) between 4.5 and 10.0, 1 mg of oral vitamin k is effective.[8] A medical guideline (also called a clinical guideline, clinical protocol or clinical practice guideline) is a document with the aim of guiding decisions and criteria in specific areas of healthcare, as defined by an authoritative examination of current evidence (evidence-based medicine). ... The American College of Chest Physicians (ACCP) is a medical organization consisting of physicians and non-physician specialists in the field of chest medicine, which includes pulmonology, thoracic surgery, and intensive care medicine. ... The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ...


Pharmacogenomics

Warfarin activity is determined partially by genetic factors. The American Food and Drug Administration "highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients" .[9] hi “FDA” redirects here. ...


VKORC1

Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) gene explain 30% of the dose variation between patients[10]: particular mutations make VKORC1 less susceptible to suppression by warfarin[4] There are a main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B).[11] For the three combinations of the haplotypes, the mean daily maintenance dose of warfarin was: In biology, polymorphism can be defined as the occurrence in the same habitat of two or more forms of a trait in such frequencies that the rarer cannot be maintained by recurrent mutation alone. ... Vitamin K epoxide reductase (VKOR) is an enzyme (EC 1. ...

  • A/A: 2.7+/-0.2 mg
  • A/B: 4.9+/-0.2 mg
  • B/B: 6.2+/-0.3 mg

VKORC1 polymorphisms also explain why African Americans are relatively resistant to warfarin (higher proportion of group B haplotypes), while Asian Americans are more sensitive (higher proportion of group A haplotypes).[11] An African American (also Afro-American, Black American, or simply black) is a member of an ethnic group in the United States whose ancestors, usually in predominant part, were indigenous to Africa. ... An Asian American is a person of Asian ancestry or origin who was born in or is an immigrant to the United States. ...


CYP2C9

CYP2C9 is an isozyme of cytochrome P450. Polymorphisms of CYP2C9 explain another 10% of variation in warfarin dosing[10], mainly among Causation patients as these variants are rare in African American and most Asian populations.[12] A meta-analysis of mainly Caucasian patients found[12]: Isozymes, (or isoenzymes) are isoforms (closely related variants) of enzymes. ... Cytochrome P450 Oxidase (CYP2E1) Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1. ... A meta-analysis is a statistical practice of combining the results of a number of studies. ...

  • CYP2C9*2 allele:
    • present in 12.2% of patients
    • mean reduction was in warfarin dose was 0.85 mg (17% reduction)
    • relative bleeding risk was 1.91
  • CYP2C9*3 allele:
    • present in 7.9% of patients
    • mean reduction was in warfarin dose was 1.92 mg (37% reduction)
    • relative bleeding risk was 1.77

Loading regimens

Because of warfarin's poorly predictable pharmacokinetics, several researchers have proposed algorithms for commencing warfarin treatment: Pharmacokinetics (in Greek: pharmacon meaning drug, and kinetikos meaning putting in motion) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. ...

  • The Kovacs 10 mg algorithm was better than a 5 mg algorithm.[13]
  • The Fennerty 10 mg regimen is for urgent anticoagulation[14]
  • The Tait 5 mg regimen is for "routine" (low-risk) anticoagulation (summary)[15]
  • From a cohort of orthopedic patients, Millican et al derived an 8-value model, including CYP29C and VKORC1 genotype results, that could predict 80% of the variation in warfarin doses. It is awaiting validation in larger populations and has not been reproduced in those who require warfarin for other indications.[16]

Adjusting the maintenance dose

Recommendations by the American College of Chest Physicians[7] have been distilled to help manage dose adjustments.[17] The American College of Chest Physicians (ACCP) is a medical organization consisting of physicians and non-physician specialists in the field of chest medicine, which includes pulmonology, thoracic surgery, and intensive care medicine. ...


Interactions and contraindications

There are many drug-drug interactions with warfarin, and its metabolism varies greatly between patients. Some foodstuffs have also been reported to interact with warfarin[18] This makes finding the correct dosage difficult, and accentuates the need of monitoring; when initiating a medication that is known to interact with warfarin (e.g. simvastatin), INR checks are increased or dosages adjusted until a new ideal dosage is found. Simvastatin (INN) (IPA: ) is a hypolipidemic drug belonging to the class of pharmaceuticals called statins. It is used to control hypercholesterolemia (elevated cholesterol levels) and to prevent cardiovascular disease. ...


Warfarin cannot be given to pregnant women, especially in the first trimester, as it is a teratogen causing deformations of the face and bones. During the third trimester, antepartum hemorrhage can occur. Instead of warfarin, low molecular weight heparin is generally used. (See anticoagulation in pregnancy.) A pregnant woman Pregnancy is the process by which a mammalian female carries a live offspring from conception until it develops to the point where the offspring is capable of living outside the womb. ... Teratogenesis is a medical term from the Greek, literally meaning monster making. ... In medicine, low molecular weight heparin (LMWH) is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis. ... It has been suggested that this article or section be merged into Anticoagulant. ...


Excessive use of alcohol is also known to affect the metabolism of warfarin and can elevate the INR. Patients should be cautioned against the excessive use of alcohol while taking warfarin. A common recommendation is limiting the maximum daily intake to no more than a few drinks. Patients suffering from liver damage or alcoholism are usually treated with heparin injections instead.


Warfarin also interacts with the following herbs: [19]

  • Ginkgo (a.k.a. Ginkgo Biloba), which is commonly used to increase brain blood flow, prevent dementia, and improve memory. However, ginkgo may increase blood pressure, and may increase bleeding, especially in people already taking certain anti-clotting medications such as warfarin.
  • St. John's Wort is commonly used to help with mild to moderate depression. However, it may prolong the effects of certain anesthetic drugs and reduce the effects oral contraceptives and anti-organ transplant rejection medications, and interfere with warfarin.
  • Ginseng is commonly used to help with fatigue and weakness. However, ginseng may increase blood pressure and heart rate and may increase bleeding, especially in people already taking certain anti-clotting medications such as warfarin.
  • Garlic (as a supplement, not in the diet) is commonly used to help lower high cholesterol levels, high triglycerides, and high blood pressure. However, may increase bleeding especially in people already taking certain anti-clotting medications such as warfarin.
  • Ginger is commonly used to help nausea and poor digestion. However, it may increase bleeding, especially in patients already taking certain anti-clotting medications such as warfarin.

Species G. biloba L. The Ginkgo (Ginkgo biloba; 銀杏 in Chinese), frequently misspelled as Gingko, and also known as the Maidenhair Tree, is a unique tree with no close living relatives. ... Binomial name Hypericum perforatum Linnaeus, St Johns wort used alone refers to the species Hypericum perforatum, also known as Klamath weed or Goat weed, but is used with qualifiers to refer to any species of the genus Hypericum. ... Not to be confused with ginger. ... Binomial name L. Allium sativum L., commonly known as garlic, is a species in the onion family Alliaceae. ... For other uses, see Ginger (disambiguation). ...

History

The early 1920s saw the outbreak of a previously unrecognized disease of cattle in the northern United States and Canada. Cattle would die of uncontrollable bleeding from very minor injuries, or sometimes drop dead of internal hemorrhage with no external signs of injury. In 1921, Frank Schofield, a Canadian veterinarian, determined that the cattle were ingesting moldy silage made from sweet clover that functioned as a potent anticoagulant.[20] In 1929, North Dakota veterinarian Dr L.M. Roderick demonstrated that the condition was due to a lack of functioning prothrombin.[21] This article does not cite any references or sources. ... Look up veterinarian in Wiktionary, the free dictionary. ... Silage (hay) somewhere in Allschwil or Schönenbuch, near Basel, Switzerland. ... Melilot, also known as Sweet Clover, Melilotus officinalis of the family Papilionaceae is a common grassland plant and as a weed of cultivated ground. ... Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ...


The identity of the anticoagulant substance in moldy sweet clover remained a mystery until 1940 when Karl Paul Link and his student Harold Campbell, chemists working at the University of Wisconsin, determined that it was the coumarin derivative 4-hydroxycoumarin.[22] Over the next few years, numerous similar chemicals were found to have the same anticoagulant properties. The first of these to be widely commericialized was dicoumarol, patented in 1941. Link continued working on developing more potent coumarin-based anticoagulants for use as rodent poisons, resulting in warfarin in 1948. (The name warfarin stems from the acronym WARF, for Wisconsin Alumni Research Foundation + the ending -arin indicating its link with coumarin.) Warfarin was first registered for use as a rodenticide in the US in 1952; although it was developed by Link, the WARF financially supported the research and was granted the patent. Karl Paul Gerhard Link (31 January 1901 - 21 November 1978) was an American biochemist best known for his discovery of the anticoagulant warfarin. ... “University of Wisconsin” redirects here. ... Coumarin is a chemical compound; a toxin found in many plants, notably in high concentration in the tonka bean, woodruff, and bison grass. ... WARF company logo The Wisconsin Alumni Research Foundation is the nonprofit technology transfer office of the University of Wisconsin-Madison. ...


The exact mechanism of action remained unknown until it was demonstrated, in 1978, that warfarin inhibited epoxide reductase and hence interfered with vitamin K metabolism.[2]


After an incident in 1951, where a naval enlisted man unsuccessfully attempted suicide with warfarin and recovered fully, studies began in the use of warfarin as a therapeutic anticoagulant. It was found to be generally superior to dicoumarol, and in 1954 was approved for medical use in humans. A famous early patient prescribed warfarin was Dwight Eisenhower, president of the USA, subsequent to his heart attack in 1955. Dwight David Ike Eisenhower (October 14, 1890&#8211;March 28, 1969), American soldier and politician, was the 34th President of the United States (1953&#8211;1961) and supreme commander of the Allied forces in Europe during World War II, with the rank of General of the Army. ... Acute myocardial infarction (AMI or MI), more commonly known as a heart attack, is a disease state that occurs when the blood supply to a part of the heart is interrupted. ...


A 2003 theory posits that warfarin was used by a conspiracy of Lavrenty Beria, Nikita Khrushchev and others to poison Soviet leader Joseph Stalin. Warfarin is tasteless and colorless, and produces symptoms similar to those that Stalin exhibited.[23] Lavrenty Beria Lavrentiy Pavlovich Beria (Georgian: ლავრენტი ბერია; Russian: Лаврентий Павлович Берия; (29 March 1899 – 23 December 1953), was a Soviet politician and chief of the Soviet security and police apparatus. ... Nikita Sergeyevich Khrushchev (Russian: , Nikita Sergeevič Chruščiov; IPA: , in English, , or , occasionally ); surname more accurately romanized as Khrushchyov[1]; April 17 [O.S. April 5] 1894[2]–September 11, 1971) was the chief director of the Soviet Union after the death of Joseph Stalin. ... Josef Vissarionovich Dzhugashvili (Georgian: , Ioseb Besarionis Dze Jughashvili; Russian: , Iosif Vissarionovich Dzhugashvili) (December 18 [O.S. December 6] 1878[1] – March 5, 1953), better known by his adopted name, Joseph Stalin (alternatively transliterated Josef Stalin), was General Secretary of the Communist Party of the Soviet Unions Central Committee from...


Other coumarins

In some countries, other coumarins are used instead of warfarin, such as acenocoumarol and phenprocoumon. These have a shorter (acenocoumarol) or longer (phenprocoumon) half-life, and are not completely interchangeable with warfarin. Acenocoumarol is a anticoagulant that functions as a vitamin K antagonist (like warfarin). ... Phenprocoumon is an anticoagulant, functioning as a Vitamin K antagonist. ...


References

  1. ^ Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):204S-233S. PMID 15383473.
  2. ^ a b Whitlon DS, Sadowski JA, Suttie JW. Mechanisms of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry 1978;17:1371–7. PMID 646989.
  3. ^ Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature 2004;427(6974):541-4. PMID 14765195.
  4. ^ a b Rost S, Fregin A, Ivaskevicius V, et al (2004). "Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2". Nature 427 (6974): 537-41. DOI:10.1038/nature02214. PMID 14765194. 
  5. ^ a b Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to Warfarin therapy. J Am Coll Cardiol 2003;41:1633-52. PMID 12742309.
  6. ^ Talmadge DB, Spyropoulos AC. Purple toes syndrome associated with warfarin therapy in a patient with antiphospholipid syndrome. Pharmacotherapy 2003;23:674-7. PMID 12741443.
  7. ^ a b Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E (2004). "The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest 126 (3 Suppl): 204S-233S. DOI:10.1378/chest.126.3_suppl.204S. PMID 15383473.  (summary)
  8. ^ Crowther MA, Douketis JD, Schnurr T, et al (2002). "Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial". Ann. Intern. Med. 137 (4): 251-4. PMID 12186515. 
  9. ^ FDA Approves Updated Warfarin (Coumadin) Prescribing Information. Retrieved on 2007-08-20.
  10. ^ a b Wadelius M, Chen LY, Downes K, et al (2005). "Common VKORC1 and GGCX polymorphisms associated with warfarin dose". Pharmacogenomics J. 5 (4): 262-70. DOI:10.1038/sj.tpj.6500313. PMID 15883587. 
  11. ^ a b Rieder MJ, Reiner AP, Gage BF, et al (2005). "Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose". N. Engl. J. Med. 352 (22): 2285-93. DOI:10.1056/NEJMoa044503. PMID 15930419. 
  12. ^ a b Sanderson S, Emery J, Higgins J (2005). "CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis". Genet. Med. 7 (2): 97-104. PMID 15714076. 
  13. ^ Kovacs MJ, Rodger M, Anderson DR, et al (2003). "Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial". Ann. Intern. Med. 138 (9): 714-9. PMID 12729425.  (summary of 10 mg algorithm)
  14. ^ Fennerty A, Campbell IA, Routledge PA (1988). "Anticoagulants in venous thromboembolism". BMJ 297 (6659): 1285-8. PMID 3144365. 
  15. ^ Tait RC, Sefcick A (1998). "A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation". Br. J. Haematol. 101 (3): 450-4. DOI:10.1046/j.1365-2141.1998.00716.x. PMID 9633885. 
  16. ^ Millican E, Jacobsen-Lenzini PA, Milligan PE, et al (2007). "Genetic-based dosing in orthopaedic patients beginning warfarin therapy" 110 (5): 1511-5. DOI:10.1182/blood-2007-01-069609. PMID 17387222.  Online tool based on the study.
  17. ^ Point-of-Care Guides - May 15, 2005 - American Family Physician. Retrieved on 2007-08-20.
  18. ^ Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, Wells PS. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005;165:1095-106. PMID 15911722.
  19. ^ Austin, Steve, and Forrest Batz. The A-Z Guide to Drug-Herb-Vitamin Interactions: How to Improve Your Health and Avoid Problems When Using Common Medications and Natural Supplements Together. Ed. Schulyer M. Lininger. 1st ed. New York: Three Rivers P, 1999. p.224.
  20. ^ Schofield FW. Damaged sweet clover; the cause of a new disease in cattle simulating haemorrhagic septicemia and blackleg. J Am Vet Med Ass 1924;64:553-6.
  21. ^ Roderick LM. A problem in the coagulation of the blood; "sweet clover disease of the cattle". Am J Physiol 1931;96:413-6.
  22. ^ Stahmann MA, Huebner CF, Link KP. Studies on the hemorrhagic sweet clover disease. V. Identification and synthesis of the hemorrhagic agent. J Biol Chem 1941;138:513-27 PDF.
  23. ^ Jonathan Brent, Vladimir Naumov. Stalin's Last Crime : The Plot Against the Jewish Doctors, 1948-1953. HarperCollins, 2003. ISBN 0-06-019524-X.

A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... is the 232nd day of the year (233rd in leap years) in the Gregorian calendar. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... is the 232nd day of the year (233rd in leap years) in the Gregorian calendar. ...

External links


  Results from FactBites:
 
Warfarin Therapy: Evolving Strategies in Anticoagulation - February 1, 1999 - American Academy of Family Physicians (5150 words)
Warfarin is an antagonist of vitamin K, a necessary element in the synthesis of clotting factors II, VII, IX and X, as well as the naturally occurring endogenous anticoagulant proteins C and S. These factors and proteins are biologically inactive without the carboxylation of certain glutamic acid residues.
Warfarin resistance is common after the administration of large doses of vitamin K. If anticoagulation therapy must be continued, heparin therapy should be initiated until the effects of vitamin K have been reversed and the patient is again responsive to warfarin.
Warfarin is more likely to be used safely by a patient who is aware of the potential for drug interactions, understands the rationale for monitoring and can identify the symptoms of warfarin toxicity early.
Parkinsn's List Drug DataBase warfarin / Coumadin (3842 words)
Warfarin is a racemic mixture of roughly equal amounts of two active isomers; the S-form is roughly 5 times as potent as a vitamin K antagonist than the R-form.
Warfarin is hydroxylated in the liver by hepatic microsomal enzymes to produce inactive metabolites.
Inactive metabolites of warfarin are excreted in the bile and are reabsorbed and excreted in the urine.
  More results at FactBites »

 
 

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