Coumadin

Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, and Waran) is an anticoagulant. It is named after 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 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.Despite its effectiveness, treatment with warfarin has several shortcomings. Many commonly used medications interact with warfarin, and its activity has to be monitored by frequent blood testing for the international normalized ratio (INR) to ensure an adequate yet safe dose is taken.

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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 and related coumarins decrease blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles 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 vitamin K antagonists.
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. In 1929, North Dakota veterinarian Dr L.M. Roderick demonstrated that the condition was due to a lack of functioning prothrombin.

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. 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 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.
After an incident in 1951, where an army inductee 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 recipient of warfarin was US president Dwight Eisenhower, who was prescribed the drug after having a heart attack in 1955.
The exact mechanism of action remained unknown until it was demonstrated, in 1978, that warfarin inhibited the enzyme epoxide reductase and hence interfered with vitamin K metabolism.
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.
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 valves, deep venous thrombosis, pulmonary embolism, antiphospholipid syndrome and, occasionally, after myocardial infarction.
Dosing of warfarin is complicated by the fact that it is known to interact with many commonly-used medications and even with chemicals that may be present in certain foods. 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 (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.
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 mechanical heart valves.
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. 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 developmen

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