Warfarin
238097
224621095
2008-07-09T18:14:23Z
Fvasconcellos
1051513
link
{{drugbox |
| IUPAC_name = (RS)-4-hydroxy-3-(3-oxo-1-phenylbutyl)-<br />2''H''-chromen-2-one
| image = Warfarin.svg
| CAS_number = 81-81-2
| ATC_prefix = B01
| ATC_suffix = AA03
| PubChem = 6691
| DrugBank = APRD00341
| smiles = CC(=O)CC(c1ccccc1)C2=C(O)c3ccccc3OC2=O <!-- Starts at bottom right -->
| C = 19 | H = 16 | O = 4
| molecular_weight = 308.33 g/mol
| bioavailability = 100%
| protein_bound = 99.5%
| metabolism = Hepatic: [[CYP2C9]], [[CYP2C19|2C19]], 2C8, 2C18, [[CYP1A2|1A2]] and [[CYP3A4|3A4]]
| elimination_half-life = 2.5 days
| excretion = [[Kidney|Renal]] (92%)
| pregnancy_AU = D
| pregnancy_US = X
| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral or [[intravenous therapy|intravenous]]
}}
'''Warfarin''' (also known under the brand names '''Coumadin''', '''Jantoven''', '''Marevan''', and '''Waran''') is an [[anticoagulant]]. It is named for the [[Wisconsin Alumni Research Foundation]], which sponsored its development. It was initially marketed as a pesticide against rats and mice, and is still popular for this purpose, although more potent poisons such as [[brodifacoum]] have since been developed. A few years after its introduction, warfarin was found to be effective and relatively safe for [[prophylaxis|preventing]] [[thrombosis]] and [[embolism]] (abnormal formation and migration of blood clots) in many disorders. It was approved for use a medication in the early 1950s, and has remained popular ever since; warfarin is the most widely prescribed anticoagulant drug in [[North America]].<ref name=Holbrook/> Despite its effectiveness, treatment with warfarin has several shortcomings. Many commonly used medications [[drug interaction|interact]] with warfarin, and its activity has to be monitored by frequent [[blood test]]ing for the [[prothrombin time|international normalized ratio]] (INR) to ensure an adequate yet safe dose is taken.<ref name=Ansell>{{cite journal |author=Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E |title=The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy |journal=Chest |volume=126 |issue=3 Suppl |pages=204S–233S |year=2004 |pmid=15383473 |doi=10.1378/chest.126.3_suppl.204S|url=http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S}}</ref>
Warfarin is a synthetic derivative of [[coumarin]], a chemical found naturally in many [[plant]]s, notably [[woodruff]] (''Galium odoratum'', [[Rubiaceae]]), and at lower levels in [[licorice]], [[lavender]], and various other species. Warfarin and related coumarins decrease blood [[coagulation]] by inhibiting [[vitamin K epoxide reductase]], an [[enzyme]] that recycles [[oxidation|oxidated]] [[vitamin K]] to its reduced form after it has participated in the [[carboxylation]] of several blood coagulation proteins, mainly [[prothrombin]] and [[factor VII]]. For this reason, drugs in this class are also referred to as [[Anticoagulant#Vitamin K antagonists|vitamin K antagonists]].<ref name=Ansell/>
==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.<ref>{{cite journal|author=Schofield FW|title=Damaged sweet clover; the cause of a new disease in cattle simulating haemorrhagic septicemia and blackleg|journal=J Am Vet Med Ass|year=1924|volume=64|pages=553–6}}</ref> In 1929, North Dakota veterinarian Dr L.M. Roderick demonstrated that the condition was due to a lack of functioning [[prothrombin]].<ref>{{cite journal|author=Roderick LM|year=1931|title=A problem in the coagulation of the blood; "sweet clover disease of the cattle"|journal=Am J Physiol |volume=96|pages=413–6}} [http://ajplegacy.physiology.org/cgi/reprint/96/2/413 PDF (subscriber only)].</ref>
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-Madison|University of Wisconsin]], determined that it was the [[coumarin]] derivative 4-hydroxycoumarin.<ref>{{cite journal|author=Stahmann MA, Huebner CF, Link KP|year=1941|title=Studies on the hemorrhagic sweet clover disease. V. Identification and synthesis of the hemorrhagic agent|journal=J Biol Chem|volume=138|pages=513–27|url=http://www.jbc.org/cgi/reprint/138/2/513}}</ref> Over the next few years, numerous similar chemicals were found to have the same anticoagulant properties. The first of these to be widely commercialized was [[dicoumarol]], patented in 1941. Link continued working on developing more potent coumarin-based anticoagulants for use as [[rodenticide|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 1948, and was immediately popular; although it was developed by Link, the WARF financially supported the research and was granted the patent.<ref name="pmid13619027">{{cite journal |author=Link KP |title=The discovery of dicumarol and its sequels |journal=Circulation |volume=19 |issue=1 |pages=97–107 |year=1959 |pmid=13619027 |url=http://circ.ahajournals.org/cgi/reprint/19/1/97}}</ref>
After an incident in 1951, where an [[United States Army|army]] inductee unsuccessfully attempted suicide with warfarin and recovered fully,<ref name="pmid13619027"/> 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 recipient of warfarin was US president [[Dwight Eisenhower]], who was prescribed the drug after having a [[myocardial infarction|heart attack]] in 1955.<ref name="pmid13619027"/>
The exact [[mechanism of action]] remained unknown until it was demonstrated, in 1978, that warfarin [[enzyme inhibitor|inhibited]] the enzyme [[Vitamin K epoxide reductase|epoxide reductase]] and hence interfered with vitamin K metabolism.<ref name=Whitlon />
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.<!--when? Before his death?--><ref>{{cite book |author=Naumov, Vladimir Pavlovich; Brent, Jonathan |title=Stalin's last crime: the plot against the Jewish doctors, 1948–1953 |publisher=HarperCollins |location=London |year=2003 |pages= |isbn=0-06-019524-X}}</ref>
==Therapeutic uses==
Warfarin is prescribed to people with an increased tendency for [[thrombosis]] or as secondary prophylaxis (prevention of further episodes) in those individuals that have already formed a blood clot ([[thrombus]]). Warfarin treatment 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]], the presence of [[artificial heart valve]]s, [[deep venous thrombosis]], [[pulmonary embolism]], [[antiphospholipid syndrome]] and, occasionally, after [[myocardial infarction]].<ref name=Hirsh>{{cite journal |author=Hirsh J, Fuster V, Ansell J, Halperin JL |title=American Heart Association/American College of Cardiology Foundation guide to warfarin therapy |journal=J. Am. Coll. Cardiol. |volume=41 |issue=9 |pages=1633–52 |year=2003 |pmid=12742309 |url=http://content.onlinejacc.org/cgi/content/full/41/9/1633| doi=10.1016/S0735-1097(03)00416-9}}</ref>
Dosing of warfarin is complicated by the fact that it is known to [[drug interaction|interact]] with many commonly-used medications and even with chemicals that may be present in certain foods.<ref name=Holbrook/> These interactions may enhance or reduce warfarin's anticoagulation effect. In order to optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required by blood testing ([[prothrombin time|INR]]). During the initial stage of treatment, checking may be required daily; intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose.<ref name=Hirsh/>
When initiating warfarin therapy ("warfarinization"), the doctor will decide how strong the anticoagulant therapy needs to be. The target INR level will vary from case to case depending on the clinical indicators, but tends to be 2–3 in most conditions. In particular, target INR may be 2.5–3.5 (or even 3.0–4.5) in patients with one or more [[artificial heart valve#Mechanical valves|mechanical heart valve]]s.<ref>{{cite journal |author=Baglin TP, Keeling DM, Watson HG |title=Guidelines on oral anticoagulation (warfarin): third edition—2005 update |journal=Br. J. Haematol. |volume=132 |issue=3 |pages=277–85 |year=2006 |month=February |pmid=16409292 |doi=10.1111/j.1365-2141.2005.05856.x |url=http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1365-2141.2006.06379.x}}</ref>
In some countries, other coumarins are used instead of warfarin, such as [[acenocoumarol]] and [[phenprocoumon]]. These have a shorter (acenocoumarol) or longer (phenprocoumon) [[Biological half-life|half-life]], and are not completely interchangeable with warfarin. The oral anticoagulant [[ximelagatran]] (trade name 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]] and [[rivaroxaban]], are under development.<ref>{{cite journal |author=Hirsh J, O'Donnell M, Eikelboom JW |title=Beyond unfractionated heparin and warfarin: current and future advances |journal=Circulation |volume=116 |issue=5 |pages=552–60 |year=2007 |month=July |pmid=17664384 |doi=10.1161/CIRCULATIONAHA.106.685974 |url=http://circ.ahajournals.org/cgi/content/full/116/5/552}}</ref>
==Contraindications==
Warfarin is a [[teratogen]], causing deformations of the face (depressed nasal bridge) and bones (stippled epiphyses), [[neonatal seizures]], and [[miscarriage|spontaneous abortion]].<ref>Beckmann, Charles R. ''Obstetrics and Gynecology.'' 4th Ed. Baltimore: Lippincott Williams & Wilkins, 2002; p. 58.</ref> [[Anticoagulation in pregnancy]] may therefore pose a problem in women requiring warfarin for vital indications, such as [[stroke]] prevention in those with [[artificial heart valve]]s. Hence, warfarin is avoided in the first trimester, and [[low molecular weight heparin]] such as [[enoxaparin]] is substituted. Various solutions exist for the time around delivery.
==Adverse effects==
===Hemorrhage===
The only common [[adverse drug reaction|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 [[Human feces|stool]].
The risks of bleeding is increased when warfarin is combined with [[antiplatelet drug]]s such as [[clopidogrel]], [[aspirin]], or [[nonsteroidal anti-inflammatory drug]]s.<ref name="pmid17698822">{{cite journal |author=Delaney JA, Opatrny L, Brophy JM, Suissa S |title=Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding |journal=CMAJ |volume=177 |issue=4 |pages=347–51 |year=2007 |pmid=17698822 |doi=10.1503/cmaj.070186|url=http://www.cmaj.ca/cgi/content/full/177/4/347}} {{PMC|1942107}}</ref> The risk may also be increased in elderly patients<ref name="pmid17515465">{{cite journal |author=Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S |title=Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation |journal=Circulation |volume=115 |issue=21 |pages=2689–96 |year=2007 |pmid=17515465 |doi=10.1161/CIRCULATIONAHA.106.653048}}</ref> and in patients on [[hemodialysis]].<ref name="pmid17720522">{{cite journal |author=Elliott MJ, Zimmerman D, Holden RM |title=Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates |journal=Am. J. Kidney Dis. |volume=50 |issue=3 |pages=433–40 |year=2007 |pmid=17720522 |doi=10.1053/j.ajkd.2007.06.017}}</ref>
===Warfarin necrosis===
{{main|warfarin necrosis}}
A rare but serious complication resulting from treatment with 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.<ref name="pmid10718793">{{cite journal |author=Chan YC, Valenti D, Mansfield AO, Stansby G |title=Warfarin induced skin necrosis |journal=Br J Surg |volume=87 |issue=3 |pages=266–72 |year=2000 |pmid=10718793 |doi=10.1046/j.1365-2168.2000.01352.x}}</ref>
===Osteoporosis===
After initial reports that warfarin could reduce [[bone mineral density]], several studies have demonstrated a link between warfarin use and [[osteoporosis]]-related [[bone fracture|fracture]]. A 1999 study in 572 women taking wafarin for DVT, risk of vertebral fracture and rib fracture was increased; other fracture types did not occur more commonly.<ref>{{cite journal |author=Caraballo PJ, Heit JA, Atkinson EJ, ''et al'' |title=Long-term use of oral anticoagulants and the risk of fracture |journal=Arch. Intern. Med. |volume=159 |issue=15 |pages=1750–6 |year=1999 |pmid=10448778|doi=10.1001/archinte.159.15.1750}}</ref> A 2002 study looking at a randomly selected selection of 1523 patients with osteoporotic fracture found no increased exposure to anticoagulants compared to controls, and neither did stratification of the duration of anticoagulation reveal a trend towards fracture.<ref>{{cite journal |author=Pilon D, Castilloux AM, Dorais M, LeLorier J |title=Oral anticoagulants and the risk of osteoporotic fractures among elderly |journal=Pharmacoepidemiol Drug Saf |volume=13 |issue=5 |pages=289–94 |year=2004 |pmid=15133779 |doi=10.1002/pds.888}}</ref>
A 2006 retrospective study of 14,564 Medicare recipients showed that warfarin use for more than one year was linked with a 60% increased risk of osteoporosis-related fracture in men; there was no association in women. The mechanism was thought to be either reduced intake of vitamin K, which is necessary for bone health, or interaction by warfarin with carboxylation of certain bone proteins.<ref>{{cite journal |author=Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF |title=Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2 |journal=Arch. Intern. Med. |volume=166 |issue=2 |pages=241–6 |year=2006 |pmid=16432096 |doi=10.1001/archinte.166.2.241| url=http://archinte.ama-assn.org/cgi/content/full/166/2/241}}</ref>
===Purple toe syndrome===
Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks) is ''[[cholesterol embolism|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.<ref>{{cite journal |author=Talmadge DB, Spyropoulos AC |title=Purple toes syndrome associated with warfarin therapy in a patient with antiphospholipid syndrome |journal=Pharmacotherapy |volume=23 |issue=5 |pages=674–7 |year=2003 |pmid=12741443 |doi=10.1592/phco.23.5.674.32200}}</ref>
==Pharmacology==
[[Image:Warfarintablets5-3-1.jpg|thumb|3mg (blue), 5mg (pink) and 1mg (brown) warfarin tablets (UK colours)]]
===Pharmacokinetics=== <!--S-Waran redirects here-->
Warfarin consists of a racemic mixture of two active optical [[isomer]]s—''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.<ref name=Hirsh/>
Warfarin is slower-acting than the common anticoagulant [[heparin]], though it has a number of advantages. Heparin must be given by injection, whereas 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 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 increase thrombosis risk. For these main reasons, [[hospital]]ised patients are usually given heparin first, and are then moved on to warfarin.
===Mechanism of action===
Warfarin inhibits the [[vitamin K]]-dependent synthesis of biologically active forms of the [[calcium]]-dependent [[clotting]] factors [[thrombin|II]], [[factor VII|VII]], [[factor IX|IX]] and [[factor X|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|matrix Gla protein]], may also be affected.
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 proceed only if the carboxylase enzyme is able to convert a [[reduction (chemistry)|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<ref name=Whitlon>{{cite journal |author=Whitlon DS, Sadowski JA, Suttie JW |title=Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition |journal=Biochemistry |volume=17 |issue=8 |pages=1371–7 |year=1978 |pmid=646989|doi=10.1021/bi00601a003}}</ref> (specifically the VKORC1 subunit<ref>{{cite journal |author=Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW |title=Identification of the gene for vitamin K epoxide reductase |journal=Nature |volume=427 |issue=6974 |pages=541–4 |year=2004 |pmid=14765195 |doi=10.1038/nature02254}}</ref><ref name="pmid14765194">{{cite journal |author=Rost S, Fregin A, Ivaskevicius V, ''et al'' |title=Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2 |journal=Nature |volume=427 |issue=6974 |pages=537–41 |year=2004 |pmid=14765194 |doi=10.1038/nature02214}}</ref>), 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), and individual coagulation factors as PIVKA-''number'' (e.g. [[Des-gamma carboxyprothrombin|PIVKA-II]]). The end result of warfarin use, therefore, is to diminish blood clotting in the patient.
The initial effect of warfarin administration is to briefly ''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 degradation of [[factor V]]a and [[factor VIII]]a. 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.
===Antagonism===
The effects of warfarin can be reversed with vitamin K, or, when rapid reversal is needed (such as in case of severe bleeding), with [[prothrombin complex concentrate]]—which contains only the factors inhibited by warfarin—or [[fresh frozen plasma]] (depending upon the clinical indication) in addition to [[intravenous therapy|intravenous]] vitamin K.
Details on reversing warfarin are provided in [[clinical practice guidelines]] from the [[American College of Chest Physicians]].<ref name="pmid15383473">{{cite journal |author=Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E |title=The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy |journal=Chest |volume=126 |issue=3 Suppl |pages=204S–233S |year=2004 |pmid=15383473 |doi=10.1378/chest.126.3_suppl.204S |url=http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S}} ([http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S/T6 summary])</ref> For patients with an [[international normalized ratio]] (INR) between 4.5 and 10.0, 1 mg of oral vitamin K is effective.<ref name="pmid12186515">{{cite journal |author=Crowther MA, Douketis JD, Schnurr T, ''et al'' |title=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 |journal=Ann. Intern. Med. |volume=137 |issue=4 |pages=251–4 |year=2002 |pmid=12186515 |url=http://www.annals.org/cgi/reprint/137/4/251| format=PDF}}</ref>
===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".<ref>{{cite web |url=http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html |title=FDA Approves Updated Warfarin (Coumadin) Prescribing Information |accessdate=2007-08-20 |format= |work=}}</ref>
====VKORC1====
[[Polymorphism (biology)|Polymorphism]]s in the ''[[vitamin K epoxide reductase]] complex 1 (VKORC1)'' gene explain 30% of the dose variation between patients:<ref name="pmid15883587">{{cite journal |author=Wadelius M, Chen LY, Downes K, ''et al'' |title=Common VKORC1 and GGCX polymorphisms associated with warfarin dose |journal=Pharmacogenomics J. |volume=5 |issue=4 |pages=262–70 |year=2005 |pmid=15883587 |doi=10.1038/sj.tpj.6500313}}</ref> particular mutations make VKORC1 less susceptible to suppression by warfarin<ref name="pmid14765194"/> There are two main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B).<ref name="pmid15930419">{{cite journal |author=Rieder MJ, Reiner AP, Gage BF, ''et al'' |title=Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose |journal=N. Engl. J. Med. |volume=352 |issue=22 |pages=2285–93 |year=2005 |pmid=15930419 |doi=10.1056/NEJMoa044503}}</ref> For the three combinations of the haplotypes, the mean daily maintenance dose of warfarin was:
* 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 American]]s are relatively resistant to warfarin (higher proportion of group B haplotypes), while [[Asian American]]s are more sensitive (higher proportion of group A haplotypes).<ref name="pmid15930419"/> ''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.<ref name="pmid18322281">{{cite journal |author=Schwarz UI, Ritchie MD, Bradford Y, ''et al'' |title=Genetic determinants of response to warfarin during initial anticoagulation |journal=N. Engl. J. Med. |volume=358 |issue=10 |pages=999–1008 |year=2008 |pmid=18322281 |doi=10.1056/NEJMoa0708078}}</ref>
====CYP2C9====
''CYP2C9'' is an [[isozyme]] of [[cytochrome P450]]. Polymorphisms of CYP2C9 explain another 10% of variation in warfarin dosing,<ref name="pmid15883587"/> mainly among Caucasian patients as these variants are rare in African American and most Asian populations.<ref name="pmid15714076">{{cite journal |author=Sanderson S, Emery J, Higgins J |title=CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis |journal=Genet. Med. |volume=7 |issue=2 |pages=97–104 |year=2005 |pmid=15714076 |doi=}}</ref> ''CYP2C9'' polymorphisms do not influence time to effective INR as opposed to ''VKORC1'', but does shorten the time to INR >4.<ref name="pmid18322281"/>
A [[meta-analysis]] of mainly Caucasian patients found:<ref name="pmid15714076"/>
* 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:
* The Kovacs 10 mg algorithm was better than a 5 mg algorithm.<ref name="pmid12729425">{{cite journal |author=Kovacs MJ, Rodger M, Anderson DR, ''et al'' |title=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 |journal=Ann. Intern. Med. |volume=138 |issue=9 |pages=714–9 |year=2003 |pmid=12729425 |doi=|url=http://annals.org/cgi/content/full/138/9/714}} ([http://annals.org/cgi/content/full/138/9/714/F1 summary of 10 mg algorithm])</ref>
* The Fennerty 10 mg regimen is for urgent anticoagulation<ref name="pmid3144365">{{cite journal |author=Fennerty A, Campbell IA, Routledge PA |title=Anticoagulants in venous thromboembolism |journal=BMJ |volume=297 |issue=6659 |pages=1285–8 |year=1988 |pmid=3144365}} {{PMC|1834928}}</ref>
* The Tait 5 mg regimen is for "routine" (low-risk) anticoagulation<ref name="pmid9633885">{{cite journal |author=Tait RC, Sefcick A |title=A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation |journal=Br. J. Haematol. |volume=101 |issue=3 |pages=450–4 |year=1998 |pmid=9633885 |doi=10.1046/j.1365-2141.1998.00716.x}} [http://www.blackwell-synergy.com/action/showPopup?citid=citart1&id=f1&doi=10.1046%2Fj.1365-2141.1998.00716.x summary]</ref>
* 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.<ref>{{cite journal |author=Millican E, Jacobsen-Lenzini PA, Milligan PE, ''et al'' |title=Genetic-based dosing in orthopaedic patients beginning warfarin therapy |journal= Blood|volume=110 |issue=5 |pages=1511–5 |year=2007 |pmid=17387222 |doi=10.1182/blood-2007-01-069609}} [http://www.warfarindosing.org Online tool based on the study].</ref>
===Adjusting the maintenance dose===
Recommendations by many national bodies including the [[American College of Chest Physicians]]<ref name="pmid15383473"/> have been distilled to help manage dose adjustments.<ref>{{cite web |url=http://www.aafp.org/afp/20050515/pocform.html |title=Point-of-Care Guides: May 15, 2005. American Family Physician |accessdate=2007-08-20 |format= |work=}}</ref>
===Self-testing and home monitoring===
Patients are making increasing use of self-testing and home monitoring of oral anticoagulation. International guidelines were published in 2005 to govern home testing, by the International Self-Monitoring Association for Oral Anticoagulation.<ref name=Ansell>{{cite journal |author=Ansell J, Jacobson A, Levy J, Völler H, Hasenkam JM |title=Guidelines for implementation of patient self-testing and patient self-management of oral anticoagulation. International consensus guidelines prepared by International Self-Monitoring Association for Oral Anticoagulation |journal=Int. J. Cardiol. |volume=99 |issue=1 |pages=37–45 |year=2005 |month=March |pmid=15721497 |doi=10.1016/j.ijcard.2003.11.008}}</ref>
The international guidelines study stated: "The consensus agrees that patient self-testing and patient self-management are effective methods of monitoring oral anticoagulation therapy, providing outcomes at least as good as, and possibly better than, those achieved with an anticoagulation clinic. All patients must be appropriately selected and trained. Currently-available self-testing/self-management devices give INR results that are comparable with those obtained in laboratory testing."<ref name=Ansell/>
==Interactions==
Warfarin [[drug interaction|interact]]s with many commonly-used drugs, and the [[drug metabolism|metabolism]] of warfarin varies greatly between patients. Some foods have also been reported to interact with warfarin.<ref name=Holbrook>{{cite journal |author=Holbrook AM, Pereira JA, Labiris R, ''et al'' |title=Systematic overview of warfarin and its drug and food interactions |journal=Arch. Intern. Med. |volume=165 |issue=10 |pages=1095–106 |year=2005 |pmid=15911722 |doi=10.1001/archinte.165.10.1095 | url=http://archinte.ama-assn.org/cgi/content/full/165/10/1095}}</ref> 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]]), [[international normalized ratio|INR]] checks are increased or dosages adjusted until a new ideal dosage is found.
Many commonly-used antibiotics, such as [[metronidazole]] or the [[macrolide]]s, will greatly increase the effect of warfarin by reducing the [[drug metabolism|metabolism]] of warfarin in the body. Other [[broad-spectrum antibiotic]]s can reduce the amount of the normal [[gut flora|bacterial flora in the bowel]], which make significant quantities of vitamin K, thus potentiating the effect of warfarin.<ref name=Juurlink>{{cite journal |author=Juurlink DN |title=Drug interactions with warfarin: what clinicians need to know |journal=CMAJ |volume=177 |issue=4 |pages=369–71 |year=2007 |month=August |pmid=17698826 |pmc=1942100 |doi=10.1503/cmaj.070946 |url=http://www.cmaj.ca/cgi/content/full/177/4/369}}</ref> In addition, food that contains large quantities of vitamin K will reduce the warfarin effect.<ref name=Holbrook/> [[Thyroid]] activity also appears to influence warfarin dosing requirements;<ref name=Kurnik>{{cite journal |author=Kurnik D, Loebstein R, Farfel Z, Ezra D, Halkin H, Olchovsky D |title=Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland |journal=Medicine (Baltimore) |volume=83 |issue=2 |pages=107–13 |year=2004 |month=March |pmid=15028964 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0025-7974&volume=83&issue=2&spage=107}}</ref> [[hypothyroidism]] (decreased thyroid function) makes people less responsive to warfarin treatment,<ref>{{cite journal |author=Stephens MA, Self TH, Lancaster D, Nash T |title=Hypothyroidism: effect on warfarin anticoagulation |journal=South Med J |volume=82 |issue=12 |pages=1585–6 |year=1989 |month=December |pmid=2595433 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0038-4348&volume=82&issue=12&spage=1585}}</ref> while [[hyperthyroidism]] (overactive thyroid) boosts the anticoagulant effect.<ref>{{cite journal |author=Chute JP, Ryan CP, Sladek G, Shakir KM |title=Exacerbation of warfarin-induced anticoagulation by hyperthyroidism |journal=Endocr Pract |volume=3 |issue=2 |pages=77–9 |year=1997 |pmid=15251480 |doi= |url=http://aace.metapress.com/openurl.asp?genre=article&issn=1530-891X&volume=3&issue=2&spage=77}}</ref> Several mechanisms have been proposed for this effect, including changes in the rate of breakdown of clotting factors and changes in the metabolism of warfarin.<ref>{{cite journal |author=Kellett HA, Sawers JS, Boulton FE, Cholerton S, Park BK, Toft AD |title=Problems of anticoagulation with warfarin in hyperthyroidism |journal=Q J Med |volume=58 |issue=225 |pages=43–51 |year=1986 |month=January |pmid=3704105 |doi= |url=http://qjmed.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3704105}}</ref><ref name=Kurnik/>
Excessive use of alcohol is also known to affect the metabolism of warfarin and can elevate the INR.<ref>{{cite journal |author=Weathermon R, Crabb DW |title=Alcohol and medication interactions |journal=Alcohol Res Health |volume=23 |issue=1 |pages=40–54 |year=1999 |pmid=10890797 |doi=}}</ref> Patients are often cautioned against the excessive use of alcohol while taking warfarin.
Warfarin also interacts with many herbs, including—but not limited to—the following:<ref>{{cite book |author=Austin, Steve and Batz, Forrest|editor=Lininger, Schuyler W.|title=A-Z guide to drug-herb-vitamin interactions: how to improve your health and avoid problems when using common medications and natural supplements together |publisher=Prima Health |location=Roseville, Calif |year=1999 |pages=224 |isbn=0-7615-1599-2 |oclc= |doi=}}</ref>
* [[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.
Between 2003 and 2004, the UK [[Committee on Safety of Medicines]] received several reports of increased INR and risk of hemorrhage in people taking warfarin and [[cranberry|cranberry juice]].<ref>{{cite web |url=http://news.bbc.co.uk/1/hi/health/3120206.stm |title=Cranberry juice clot drug warning |work=BBC news |date=2003-09-18 |accessdate=2008-05-18}}</ref><ref name=Suvarna>{{cite journal |author=Suvarna R, Pirmohamed M, Henderson L |title=Possible interaction between warfarin and cranberry juice |journal=BMJ |volume=327 |issue=7429 |pages=1454 |year=2003 |month=December |pmid=14684645 |pmc=300803 |doi=10.1136/bmj.327.7429.1454 |url=}}</ref><ref name=Aston>{{cite journal |author=Aston JL, Lodolce AE, Shapiro NL |title=Interaction between warfarin and cranberry juice |journal=Pharmacotherapy |volume=26 |issue=9 |pages=1314–9 |year=2006 |month=September |pmid=16945054 |doi=10.1592/phco.26.9.1314 |url=}} [http://www.medscape.com/viewarticle/545631 Free full text with registration at Medscape]</ref> Data establishing a causal relationship is still lacking, and a 2006 review found no cases of this interaction reported to the FDA;<ref name=Aston/> nevertheless, several authors have recommended that both doctors and patients be made aware of its possibility.<ref name=Pham>{{cite journal |author=Pham DQ, Pham AQ |title=Interaction potential between cranberry juice and warfarin |journal=Am J Health Syst Pharm |volume=64 |issue=5 |pages=490–4 |year=2007 |month=March |pmid=17322161 |doi=10.2146/ajhp060370 |url=}}</ref> The mechanism behind the interaction is still unclear.<ref name=Aston/>
==Use as a pesticide==
To this day, coumarins are used as [[rodenticide]]s for controlling [[rat]]s and [[mouse|mice]] in residential, industrial, and agricultural areas. Warfarin is both odorless and tasteless, and is effective when mixed with food [[bait (luring substance)|bait]], because the [[rodent]]s 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/day over about six 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 [[LD50|LD<sub>50</sub>]] is 50–500 mg/kg. The [[IDLH]] value is 100 mg/m³ (warfarin; various species).<ref>{{cite web |url=http://www.cdc.gov/Niosh/idlh/81812.html |title=Documentation for Immediately Dangerous To Life or Health Concentrations (IDLHs): Warfarin |author=United States [[Occupational Safety and Health Administration]] (OSHA) |date=[[August 16]], [[1996]] |publisher=[[Centers for Disease Control and Prevention]] |accessdate=2008-07-07}}</ref>
The use of warfarin as a rat poison is now declining because many rat populations have developed resistance to it, and poisons of considerably greater potency are now available. Other coumarins used as rodenticides include [[coumatetralyl]] and [[brodifacoum]], which is sometimes referred to as "super-warfarin", because it is more potent, longer-acting, and effective even in rat and mouse populations that are resistant to warfarin. Unlike warfarin, which is readily excreted, newer anticoagulant poisons also [[bioaccumulation|accumulate]] in the liver and kidneys after ingestion.<ref name=NZToxins>{{cite book |title=Vertebrate pesticide toxicology manual (poisons) |author=Charles T. Eason |coauthors=Mark Wickstrom |year=2001 |publisher=[[Department of Conservation (New Zealand)|New Zealand Department of Conservation]] |chapter=2. Anticoagulant poisons |chapterurl=http://www.doc.govt.nz/upload/documents/science-and-technical/docts23b.pdf |pages=pp. 41–74 |isbn=0-478-22035-9 |accessdate=2008-07-07}}</ref>
==References==
{{reflist|2}}
==External links==
*[http://www.warf.org/about/index.jsp?cid=26&scid=34 Historical information on Warfarin] from the [[Wisconsin Alumni Research Foundation]]
*[http://www.chemsoc.org/exemplarchem/entries/2002/hook/warfarin.htm Warfarin factsheet] from the [[Royal Society of Chemistry]]
*[http://www.clotcare.com/clotcare/postings.aspx?by=med&medid=1&word=Warfarin Warfarin information for patients and healthcare providers]
*[http://dietary-supplements.info.nih.gov/factsheets/cc/coumadin1.pdf Important information to know when you are taking: Coumadin and Vitamin K] from the U.S. [[National Institutes of Health]]
*[http://www.pace-med-apps.com/CoumCalc.htm Free Online Coumadin Dosing Calculator] based on the [[University of Michigan]] CVS dosing algorithm
*[http://www.WarfarinDosing.org Free Online Warfarin Dosing Calculator]—clinical and pharmacogenetic dosing algorithms from [[Barnes-Jewish Hospital]], [[Washington University School of Medicine]]
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{{Antithrombotics}}
[[Category:Anticoagulants]]
[[Category:Rodenticides]]
[[Category:Teratogens]]
[[Category:Lactones]]
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