Warfarin , sold under the trademark Coumadin among others, is a drug used as an anticoagulant (blood thinner). It is commonly used to treat blood clots such as deep vein thrombosis and pulmonary embolism and to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves. Less commonly used after ST-segment elevation myocardial infarction (STEMI) and orthopedic surgery. It is generally drunk but can also be used with injections into the blood vessels.
A common side effect is bleeding. Less common side effects may include areas of tissue damage and purple toe syndrome. Usage is generally not recommended during pregnancy. It is recommended that warfarin effects are usually monitored by checking prothrombin time (INR) every one to four weeks. Many other drugs and dietary factors can interact with warfarin, either increasing or decreasing its effectiveness. The effects of warfarin may be reversed with phytonadione (vitamin K1), fresh frozen plasma, or prothrombin complex concentrations.
Warfarin lowers blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K 1 . Without enough vitamin K active 1 , clotting factor II, VII, IX, and X decreased freezing ability. Protein anticlotting C and S protein are also inhibited but to a lesser extent. A few days are required for full effect to occur and this effect can last up to five days.
Warfarin was first used commercially in 1948 as a rat poison. In 1954 it was approved for medical use in the United States. It's in the List of Essential Medicines of the World Health Organization, the most effective and safe drugs needed in the health system. Warfarin is available as a generic drug. Wholesale costs in developing countries are around US $ 1.12 to 7.20 for a typical month of care. In the United States it usually costs less than $ 25 per month.
Video Warfarin
Medical use
Warfarin is used to reduce the propensity for thrombosis or as secondary prophylaxis (prevention of further episodes) in people who have formed blood clots (thrombus). Warfarin treatment can help prevent the formation of blood clots in the future and help reduce the risk of embolism (migration of thrombus to a place where it blocks blood supply to vital organs).
Warfarin is best suited for anticoagulation (inhibition of clot formation) in slow-moving blood areas (such as blood vessels and blood gathered behind natural and artificial valves) and in the blood assembling in the dysfunctional heart's atrium. Thus, the general clinical indications for warfarin use are atrial fibrillation, presence of artificial heart valves, deep venous thrombosis, and pulmonary embolism (where the first embolization clumps are formed in the vein). Warfarin is also used in the antiphospholipid syndrome. It has been used occasionally after a heart attack (myocardial infarction), but is much less effective in preventing new thrombosis in the coronary arteries. Clotting prevention in the arteries is usually done with antiplatelet drugs, which act with different mechanisms of warfarin (which usually have no effect on platelet function).
Dose
Dose of warfarin is complicated because it is known to interact with many commonly used drugs and certain foods. These interactions may increase or decrease the effects of warfarin anticoagulation. To optimize therapeutic effects without the risk of harmful side effects such as bleeding, strict anticoagulation rate monitoring is required by blood tests that measure INR. During the initial stages of treatment, INR is checked daily; the interval between tests may be prolonged if the patient manages stable INR therapy levels at unchanged warfarin doses. Newer health-care tests are available and have improved the convenience of INR testing in ambulatory settings. Instead of drawing blood, the treatment test point involves a simple finger puncture.
When starting warfarin ("warfarinization") therapy, the doctor will decide how strong anticoagulant therapy is needed. The target INR rate varies from one case to another depending on the clinical indicator, but tends to be 2-3 in most conditions. Specifically, the target INR may be 2.5-3.5 (or even 3.0-4.5) in patients with one or more mechanical heart valves.
In addition, during the first three days of "warfarinization", the levels of protein C and protein S (anticoagulation factors) fall faster than procoagulation proteins such as factor II, VII, IX, and X. Therefore, bridging anticoagulant therapy (usually heparin) is often used to reverse the state of this intermittent hypercoagulation.
Dose maintenance
Recommendations by many national bodies, including the American College of Chest Physicians, have been refined to help manage dose adjustments.
Warfarin maintenance doses may fluctuate significantly depending on the amount of vitamin K 1 in the diet. Keeping vitamin K 1 intake at a stable level can prevent this fluctuation. Leafy green vegetables tend to contain more vitamin K 1 . The green parts of the Apiaceae family members, such as parsley, cilantro, and dill, are a rich source of vitamin K; cruciferous vegetables such as cabbage and broccoli, as well as darker lettuces varieties and other green vegetables, are also relatively high in vitamin K 1 . Green vegetables such as peas and green beans do not have a high vitamin K count 1 as green vegetables. Certain vegetable oils have high amount of vitamin K 1 . Low vitamin K 1 foods include roots, tubers, tubers, and most fruit and fruit juices. Cereals, grains and other milled products are also low in vitamin K 1 .
Automatic test
Patients increasingly use self-testing and monitor home oral anticoagulants. International guidelines on home tests were published in 2005. The guidelines state: "Consensus agrees that patients who perform self-test and patient self-management are effective methods for monitoring oral anticoagulation therapy, delivering results at least as well and perhaps better than those achieved anticoagulation clinics All patients should be selected and trained appropriately There is now a self-testing/self-management device that gives INR results comparable to those obtained in laboratory testing. "A systematic review and meta-analysis of 14 of 14 randomized trials showed home testing leads to reduced incidence of complications (thrombosis and major bleeding) and increased time in the therapeutic range.
Alternative anticoagulants
In some countries, other coumarin are used instead of warfarin, such as acenocoumarol and phenprocoumon. It has a shorter half-life (acenocoumarol) or longer (phenprocoumon), and is not completely interchangeable with warfarin. Some types of anticoagulants that offer warfarin benefits without the need for monitoring, such as dabigatran, apixaban, edoxaban and rivaroxaban, have been approved in a number of countries for the use of classical warfarin. There is an inverting agent available for dabigatran (idarucizumab) but not for apixaban, edoxaban and rivaroxaban.
Maps Warfarin
Contraindications
All anticoagulants are generally contraindicated in situations where reductions in freezing caused can lead to serious and potentially life-threatening hemorrhage. These include people with active bleeding conditions (such as gastrointestinal ulcers), or disease states with an increased risk of bleeding for example. low platelets, severe liver disease, uncontrolled hypertension. For patients undergoing surgery, treatment with anticoagulants is generally suspended. Similarly, spinal or lumbar punctures (eg spinal injections, epidurals, etc.) carry an increased risk so that treatment is stopped before this procedure.
Warfarin should not be administered to people with heparin-induced thrombocytopenia until platelet counts improve or return to normal. Warfarin is usually best avoided in people with protein C or protein S deficiency because this thrombophilic condition increases the risk of skin necrosis, which is a rare but serious side effect associated with warfarin.
Pregnancy
Warfarin is contraindicated in pregnancy, as it passes through the placental barrier and may cause fetal bleeding; the use of warfarin during pregnancy is commonly associated with spontaneous abortion, stillbirth, neonatal mortality, and premature birth. Coumarin (such as warfarin) are also teratogens, that is, they cause birth defects; The incidence of birth defects in infants exposed to warfarin in utero seems to be around 5%, although higher numbers (up to 30%) have been reported in several studies. Depending on when exposure occurs during pregnancy, two different combinations of congenital abnormalities may appear.
first trimester of pregnancy
Usually, warfarin is avoided in the first trimester, and low molecular weight heparin such as enoxaparin is replaced. With heparin, the risk of maternal bleeding and other complications is still elevated, but heparin does not cross the placental barrier, so do not cause birth defects. Various solutions are available for delivery time.
When warfarin (or other 4-hydroxycoumarin derivatives) are given during the first trimester - especially between the sixth and ninth weeks of pregnancy - the constellation of birth defects known as fetal warfarin syndrome (FWS), embryonic warfarin, or coumarin embryopathy. can occur. FWS is characterized primarily by skeletal abnormalities, which include nasal hypoplasia, narrow or narrowed bridge of the nose, scoliosis, and calcification in the spine, femur, and heel bone, which exhibit strange branched appearance on X-rays. Limb abnormalities, such as brachydactyly (unusually short fingers and toes) or less developed limbs, may also occur. Common non-skeletal features of FWS include low birth weight and developmental defects.
Second trimester and then
Giving warfarin in the second and third trimesters is much less commonly associated with birth defects, and when they occur, it is much different from fetal warfarin syndrome. The most common congenital abnormalities associated with the use of warfarin in late pregnancy are central nervous system disorders, including spasticity and seizures, and eye defects. Because of birth defects such pregnancy, anticoagulant with warfarin poses problems in pregnant women who need warfarin for vital indications, such as preventing stroke in those with artificial heart valves.
According to the American College of Chest Physicians (ACCP), warfarin can be used in breastfeeding women who want to breastfeed their babies. The available data does not indicate that warfarin enters into breast milk. Similarly, the INR rate should be checked to avoid any adverse effects.
Adverse effects
Bleeding
The only common side effect of warfarin is bleeding. The risk of hemorrhage is small but definite (usually a 1-3% annual rate has been reported) and any benefit needs to outweigh this risk when warfarin is considered. All types of bleeding occur more frequently, but the most severe are those involving the brain (intracerebral hemorrhage/hemorrhagic stroke) and spinal cord. The risk of bleeding increases if the INR is out of reach (due to accidental or intentional overdose or interaction). This risk greatly increases after the INR exceeds 4.5.
A number of risk scores exist to predict bleeding in people who use warfarin and similar anticoagulants. Commonly used scores (HAS-BLED) include known predictors of warfarin-related bleeding: uncontrolled high blood pressure (H), abnormal kidney function (A), previous stroke (S), previously known bleeding condition (B ), Prior INR labile when in anticoagulation (L), the elderly as defined by age above 65 (E), and drugs associated with bleeding (eg aspirin) or alcohol abuse (D). While its use is recommended in clinical practice guidelines, they are only moderately effective in predicting the risk of bleeding and not performing well in predicting a haemorrhagic stroke. The risk of bleeding may increase in people on hemodialysis. Another score used to assess the risk of bleeding in anticoagulants, particularly Warfarin or Coumadin, is the ATRIA score, which uses a weighted additive scale of clinical findings to determine the risk stratification of bleeding. The risk of bleeding increases further when warfarin is combined with antiplatelet drugs such as clopidogrel, aspirin, or nonsteroidal anti-inflammatory drugs.
Warfarin Necrosis
The rare but serious complications resulting from treatment with warfarin are warfarin necrosis, which occurs more often immediately after starting treatment in patients with protein deficiency C. Protein C is a congenital anticoagulant that, like procoagulant factors that inhibit warfarin, requires vitamin K. -carboxylated independent for its activities. Because warfarin initially decreases protein C levels faster than coagulation, paradoxically increases the blood's tendency to thicken when treatment is initiated (many patients when initiated warfarin are given parallel heparin to combat this), leading to major thrombosis with necrotic skin and gangrene limbs. Its natural partner, purpura fulminan, occurs in homozygous children for certain C protein mutations.
Osteoporosis
After initial reports that warfarin may reduce bone mineral density, several studies have shown an association between warfarin use and osteoporotic-related fractures. A 1999 study of 572 women using warfarin for deep vein thrombosis, the risk of vertebral fracture and rib fracture increased; Other types of fractures do not occur more frequently. A 2002 study that looked at random selection of 1523 patients with osteoporotic fractures found no increase in anticoagulant exposure compared with controls, and so did stratification of anticoagulation duration revealing tendency toward fracture.
A retrospective study in 2006 of 14,564 Medicare beneficiaries showed that the use of warfarin for more than one year was associated with an increased risk of osteoporotic fractures of 60% in men; no relationship to women. The mechanism is thought to be a combination of reduced vitamin K intake (a vitamin necessary for bone health) and inhibition by vitamin K-mediated protein carboxylicated warfarin from certain bone proteins, making them malfunctioning.
Purple foot syndrome
Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks of commencement) is purple foot syndrome . This condition is thought to result from a small deposit of cholesterol that looses and causes emboli in blood vessels in the skin of the foot, which causes purple and may be painful.
It is usually thought to affect the big toe, but also affects the rest of the foot, including the bottom of the foot (plantar surface). The occurrence of purple foot syndrome may require warfarin cessation.
Liming
Some studies also involve the use of warfarin in valve and vascular calcification. No special treatment is available, but some modalities are being investigated.
Overdose
The main side effect of using warfarin is bleeding. The risk of bleeding increases if the INR is out of reach (due to accidental or intentional overdose or interaction). Many drug interactions can increase the effects of warfarin, also causing an overdose.
For people requiring rapid reversal of warfarin such as for serious bleeding or needing emergency surgery, the effects of warfarin may be reversed with vitamin K, prothrombin complex concentrate (PCC), or fresh frozen plasma (FFP). Blood products should not be routinely used to reverse the overdose of warfarin when vitamin K can work on its own. PCC has been found to be better based on laboratory tests than FFP when rapid reversal is needed. But it is unclear whether there is a patient-oriented difference in 2018.
Details about reversing warfarin are provided in the clinical practice guidelines of the American College of Chest Physicians. For people with an international normalized ratio (INR) between 4.5 and 10.0, a small dose (about 1000 mcg = one milligram) of oral vitamin K is enough. When warfarin is given and INR in the therapeutic range, a simple five-day cessation of the drug is usually enough to reverse the effect and cause the INR to fall below 1.5.
Interactions
Warfarin interacts with many commonly used drugs, and warfarin metabolism varies greatly among patients. Some foods have also been reported to interact with warfarin. Regardless of metabolic interactions, high protein bound drugs can replace warfarin from serum albumin and cause an increase in INR. This makes it difficult to find the right dose, and emphasizes the need for monitoring; when initiating a treatment known to interact with warfarin (eg simvastatin), the INR examination is increased or the dose adjusted to the newly discovered ideal dose.
When taken with nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin increases the risk of gastrointestinal bleeding. This increased risk is due to the anti-platelet effects of NSAIDs as well as the possibility of damage to the gastrointestinal mucosa.
Many commonly used antibiotics, such as metronidazole or macrolide, will greatly enhance the effects of warfarin by reducing the metabolism of warfarin in the body. Other broad-spectrum antibiotics can reduce the amount of normal bacterial flora in the intestine, which makes a significant amount of vitamin K 1 , thus potentiating the warfarin effect. In addition, foods containing large amounts of vitamin K 1 will reduce the effects of warfarin. Thyroid activity also appears to affect warfarin dose requirements; hypothyroidism (decreased thyroid function) makes people less responsive to warfarin treatment, while hyperthyroidism (overactive thyroid) increases the anticoagulant effect. Several mechanisms have been proposed for this effect, including changes in the degree of clotting factor damage and alterations in warfarin metabolism.
Excessive use of alcohol is also known to affect warfarin metabolism and can increase INR and thus increase the risk of bleeding. The introduction of US Food and Drug products (FDA) to warfarin states that alcohol should be avoided.
Warfarin also interacts with many herbs and spices, some used in foods (such as ginger and garlic) and others used purely for medicinal purposes (such as ginseng and Ginkgo biloba ). All may increase bleeding and bruising in people taking warfarin; Similar effects have been reported with borage oil (starflower) or fish oil. St. John's Wort, sometimes recommended to help with mild to moderate depression, reduces the effectiveness of given dose of warfarin; it induces an enzyme that breaks down warfarin in the body, causing less anticoagulant effects.
Between 2003 and 2004, the UK Committee for Drug Safety received several reports of increased INR and risk of bleeding in people taking warfarin and cranberry juice. Data establishing causal relationships are lacking, and a 2006 review found no cases of this interaction reported to the FDA; however, some authors recommend that both physicians and patients be made aware of the possibilities. The mechanism behind the interaction remains unclear.
Chemistry
X-ray warfarin crystallographic studies show that it exists in tautomeric form, as cyclic hemikethal, formed from 4-hydroxycoumarin and ketone in 3-position substituents. However, the presence of many 4-hydroxycoumadine anticoagulants (eg phenprocoumon) which do not have ketone groups in 3-substituents to form such structures, indicates that hemiketal must tautomerize to 4-hydroxy form in order for warfarin to become active..
Stereochemistry
Warfarin contains a stereocenter and consists of two enantiomers. This is a racemate, a mixture of 1: 1 ( R ) - and ( S ) - the form:
Pharmacology
Pharmacokinetics
Warfarin consists of a racemic mixture of two active enantiomers - R - and S - shapes - each cleaned by a different path. S-warfarin 2-5 times stronger than R-isomer in producing anticoagulant response. Both warfarin enantiomers undergo CYP-mediated metabolism by many different CYPs to form 3 ', 4', 6,7,8 and 10-hydroxy warfarin metabolites, the main ones being 7-OH warfarin formed from S-warfarin by CYP2C9 and 10-OH warfarin from R-warfarin by CYP3A4.
Warfarin is slower to work than general anticoagulant heparin, although it has a number of advantages. Heparin should be given by injection, whereas warfarin is available orally. Warfarin has a long half-life and only needs to be given once a day. Heparin can also cause prothrombotic conditions, heparin-induced thrombocytopenia (decreased platelet mediated antibody level), which increases the risk of thrombosis. It takes several days for warfarin to achieve a therapeutic effect because the circulating coagulation factor is not affected by the drug (thrombin has a part-time of several days). The part-time Warfarin means that it remains effective for a few days after it is stopped. Furthermore, if given initially with no additional anticoagulant cover, it may increase the risk of thrombosis (see below). For these main reasons, hospitalized patients are usually given heparin with warfarin initially, heparin which covers a 3-5 day lag period and is withdrawn after a few days.
Action mechanism
While warfarin is one of several drugs that are popularly referred to as "blood thinners"; this is a misnomer because it does not affect the viscosity of the blood.
Warfarin inhibits the synthesis of vitamin K-dependent of the biologically active form of calcium-dependent coagulation factors II, VII, IX and X, as well as regulatory factors of protein C, protein S, and protein Z. Other proteins not involved in blood clotting, such as osteocalcin, or Gla's matrix protein, may also be affected. Precursors of these factors require gamma carboxylation of their glutamic acid residues to allow for coagulation factors to bind the phospholipid surface in the blood vessels, to the vascular endothelium. The enzyme that carries glutamic acid carboxylation is gamma-glutamyl carboxylase. Carboxylation reactions will only take place if the carboxylase enzyme is able to change the reduced form of vitamin K (vitamin K hydroquinone) to vitamin K epoxide at the same time. Vitamin K epoxides are in turn recycled back to vitamin K and vitamin K hydroquinone by another enzyme, vitamin K epoxide reductase (VKOR). Warfarin inhibits epoxide reductase (especially the VKORC1 subunit), thus reducing the availability of vitamin K and vitamin K hydroquinone in tissues, which inhibits the carboxylation activity of glutamyl carboxylase. When this occurs, the coagulation factor is no longer carboxylated to a particular glutamic acid residue, and is unable to bind the vascular endothelial surface, and thus is biologically inactive. Because the body stock of the previously produced active factor decreases (for several days) and is replaced by the inactive factor, the anticoagulation effect becomes apparent. Coagulation factor is produced, but it has functionality decreased due to undercarboxylation; they are collectively referred to as PIVKAs (proteins caused by vitamin K deficiency/antagonism), and individual coagulation factors as PIVKA- number (eg PIVKA-II). The end result of warfarin use, therefore, is to reduce blood clotting in patients.
When warfarin has just begun, it can promote the formation of a temporary clot. This is because protein levels of C and S protein also depend on vitamin K activity. Warfarin causes a decrease in protein C levels in the first 36 hours. In addition, a decrease in S protein leads to a decrease in protein C activity (which is a co-factor) and therefore reduces the degradation of Va and factor VIIIa. Although loading a dose of warfarin over 5 mg also resulted in a sharp decline in factor VII, resulting in an initial extension of INR, the full antithrombotic effect did not occur until a significant reduction in factor II occurred several days later. The hemostasis system becomes temporarily biased towards the formation of thrombus, leading to a prothrombotic state. Thus, when warfarin is loaded rapidly at more than 5 mg per day, it is beneficial to co-manage heparin, anticoagulants acting on antithrombin and help reduce the risk of thrombosis, with warfarin therapy for four to five days, to have anticoagulant benefits from heparin until the full effect of warfarin has been achieved.
Pharmacogenomics
Warfarin activity is determined in part by genetic factors. Polymorphisms in the two genes ( VKORC1 and CYP2C9 ) play a huge role in responding to warfarin.
VKORC1 polymorphism describes 30% of dose variation between patients: certain mutations make VKORC1 less susceptible to suppression by warfarin. There are two main haplotypes describing 25% variation: low dose haplotype group (A) and high dose haplotype group (B). VKORC1 polymorphism explains why African Americans on average are relatively resistant to warfarin (higher group B haplotype proportions), while Asian Americans are generally more sensitive (higher proportion of group A haplotype). Group A VKORC1 polymorphism leads to a faster achievement of the therapeutic INR, but also a shorter time to reach an INR over 4, which is associated with bleeding.
CYP2C9 polymorphism describes 10% of the dose variation between patients, especially among Caucasian patients because this variant is uncommon in African Americans and most of the Asian population. This CYP2C9 polymorphism does not affect the time for the effective INR compared to VKORC1 , but shortens the time to INR & gt; 4.
Despite the promise of pharmacogenomic testing in warfarin doses, its use in controversial clinical practice. In August 2009 the Medicare and Medicaid Service Centers concluded that "the available evidence does not indicate that the CK2C9 or VKORC1 allele pharmacogenomic test to predict the warfarin response improves health outcomes in Medicare beneficiaries." A 2014 meta-analysis shows that using genotype-based doses provides no benefit in terms of time in the therapeutic range, excessive anticoagulation (as defined by INR greater than 4), or reduction in either major haemorrhage or thromboembolic events.
History
In the early 1920s, there was an outbreak of cow disease previously unknown in the northern United States and Canada. Livestock bleeds after small procedures and on several occasions, spontaneously. For example, 21 of the 22 cows died after dehorning and 12 of the 25 cows died after castration. All these animals died out of blood.
In 1921, Frank Schofield, a Canadian animal pathologist, determined that the cows swallowed the moldy silage made of sweet clover, and that it served as a strong anticoagulant. Only dry hay is made from sweet clover (grown in the northern states of the United States and in Canada since the turn of the century) that produces disease. Schofield separates the good clover stems and the damaged clover stems from the same straw, and feeds each of them to different rabbits. The rabbits swallowing the good stalks are good, but the rabbits swallowing the damaged stems die of haemorrhagic disease. Duplicate experiments with different ant hay samples yielded similar results. In 1929, North Dakota veterinarian Lee M. Roderick pointed out that this condition is caused by a lack of functioning prothrombin.
The identity of the anticoagulant substance in the spoiled sweet clover remained a mystery until 1940. In 1933 Karl Paul Link and the chemistry lab working at the University of Wisconsin set out to isolate and characterize the haemorrhagic agent of the spoiled straw. It took five years for Link's student Harold A. Campbell to recover 6 mg of crystal anticoagulants. Furthermore, Link's student Mark A. Stahmann took over the project and initiated a large-scale extraction, isolating 1.8 g of recrystalline anticoagulant in about 4 months. This is sufficient material for Stahmann and Charles F. Huebner to examine their results against Campbell and thoroughly characterize the compound. Through their degradation experiments they determined that the anticoagulant was 3,3'-methylenebis- (4-hydroxycoumarin), which they then named dicoumarol. They confirmed their results by synthesizing dicoumarol and proving in 1940 that it was synonymous with naturally occurring agents.
Dicoumarol is a product of the coumarin plant molecule (not to be confused with Couma d in, later trade names for warfarin). Coumarin is now known to be present in many plants, and produces a very sweet aroma of freshly cut grass or straw and plants such as sweet grass; In fact, the high content of the coumarin plant is responsible for the original common name "sweet clover", which is named for its sweet aroma, not the bitter taste. They are present primarily in woodruff ( Galium odoratum , Rubiaceae), and to a lesser extent in licorice, lavender, and various other species. However, coumarin itself does not affect freezing or action such as warfarin, but must first be metabolized by various fungi into compounds such as 4-hydroxycoumarin, then further (in the presence of naturally occurring formaldehyde) to dicoumarol, to have any anticoagulants. property. Mushroom attacks from damaged and dying clover spurs explain the existence of anticoagulants only in spoiled clover clover; Dicoumarol is considered a fermentation product and mycotoxin.
Over the next few years, many similar chemicals (especially 4-hydroxycoumarins with large aromatic substitutions at 3 ) are found to have the same anticoagulant properties. The first drug in a widely commercialized class was its own dicoumarol, patented in 1941 and later used as a pharmaceutical. Karl Link continues to work on developing stronger coumarin-based anticoagulants to be used as rat poison, producing warfarin in 1948. The name "warfarin" comes from the WARF acronym , for the Wisconsin Alumni Research Foundation. end -arin that indicates the relationship with coumarin. Warfarin was first registered for use as a rodenticide in the US in 1948, and was soon popular. Although warfarin was developed by Link, the Wisconsin Alumni Research Foundation financially supported the research and was granted a patent.
After an incident in 1951, in which an induced US soldier attempted suicide with multiple doses of warfarin in rodenticide but fully recovered after coming to the hospital and treated with vitamin K (at the time known as a special antidote), the study began in use warfarin as a therapeutic anticoagulant. It was found to be generally superior to dicoumarol, and in 1954 it was approved for medical use in humans. An early warfarin recipient was US president Dwight Eisenhower, who was prescribed the drug after a heart attack in 1955.
The exact mechanism of action remained unknown until it was shown, in 1978, that warfarin inhibited enzyme reductase enzymes and thus interfere with vitamin K metabolism.
It has been argued that Lavrenty Beria, Nikita Khrushchev and others conspired to use warfarin to poison Soviet leader Joseph Stalin. Warfarin is tasteless and colorless, and produces symptoms similar to those exhibited by Stalin.
Pest control
Rodents
Coumarin (4-hydroxycoumarin derivative) is used as a rodenticide to control mice and rats in residential, industrial, and agricultural areas. Warfarin is odorless and tasteless, and effective when mixed with food bait, because the mice will return to the feed and continue feeding for several days until the lethal dose accumulates (considered 1 mg/kg/day over about six days). It can also be mixed with powder and used as a powder tracker, which accumulates on the skin and animal hair, and is then consumed during the treatment. LD 50 is 50-500Ã, mg/kg. The IDLH value is 100 mg/m 3 (warfarin, various species).
The use of warfarin itself as rat poison is now declining, as many rat populations have developed resistance to it, and toxins with much greater potential are now available. Other 4-hydroxycoumarins used as rodenticides include coumatetralyl and brodifacoum, sometimes referred to as "super-warfarin", because they are potent, acting longer, and effective even in populations of mice and rats that are resistant to warfarin. Unlike warfarin, which is ready to be excreted, newer anticoagulant toxins also accumulate in the liver and kidneys after consumption. However, the rodenticides can also accumulate in birds of prey and other animals that eat rats or poisonous feeds.
Vampire Bats
Warfarin is used to set aside the population of vampire bats in areas where human-wildlife conflict is of concern. Vampire bats are caught with mist nets and coated with a combination of petroleum jelly and warfarin. The bat returns to its cage and the other members of the roost become poisoned also by swallowing warfarin after mutual treatment. Alleged vampire vampire bats can also be coated in warfarin solution, though this kills other bat species and remains in the environment for years. The success of killing vampire bats to reduce rabies transmission remains questionable; a study in Peru showed that the culling program did not cause the rate of transmission of rabies to livestock and humans lower.
Workplace safety
People can be exposed to warfarin at work by inhaling, swallowing, skin absorption, and eye contact. Occupational Safety and Health (OSHA) has set a legal limit (allowable for exposure limits) for exposure to warfarin in the workplace as 0.1 mg/m 3 for 8 hours a day. The National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit (REL) of 0.1 m/m 3 for 8 hours. At a level of 100 mg/m 3 , warfarin is immediately harmful to life and health.
It is classified as a very dangerous substance in the United States as defined in Section 302 of the US Emergency Planning and Community Rights to Know Act (42 USC 11002), and is subject to strict reporting requirements by facilities that produce, store or use in quantities which is significant.
Name
Warfarin is a derivative of dicoumarol, an anticoagulant that was originally found in spoiled sweet clover. Dicoumarol, in turn, is from coumarin, a sweet-smelling chemical but does not contain the coagulation found in the "sweet" clover and tonka beans (also known as cumaru where the coumarin name comes from). The name warfarin comes from his discovery at the University of Wisconsin, incorporating an acronym for a major research funding organization,
These drugs are marketed under many brand name and generic, including Aldocumar, Anasmol, Anticoag, Befarin, Cavamed, Cicoxil, Circuvit, Cofarin, Coumadin, Coumadine, Cumar, Farin, Foley, Haemofarin, Jantoven, Kovar, Lawarin, Maforan, Marevan, Marfarin , Marivanil, Martefarin, Morfarin, Orfarin, Panwarfin, scheme, Simarc, Varfarin, Varfarins, Varfine, warrants, Warcok, Warf, Warfareks, Warfarin, Warfarina, Warfarine, Warfarinum, Warfen, Warfin, Warik, Warin, Warlin, and Zyfarin.
References
External links
- Historical information about warfarin from the Wisconsin Alumni Research Foundation
- Online sweet clover disease and warfarin history reviews
- US. National Library of Medicine: Portal-Warfarin Drug Information
- Warfarin is bound to proteins in GDP: R-warfarin, S-warfarin
- CDC - NIOSH A Pocket Guide for Chemical Hazards
- Warfarin in Pesticide Properties DataBase (PPDB)
- Blood risk calculator
- ATRIA Bleeding Risk Score from MDCalc
- HAS-BLED score from MDCalc
Source of the article : Wikipedia
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