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Warfarin (also known under the brand name Coumadin®) is an anticoagulant medication that can be administered orally. 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).
In addition to its medical use, warfarin is frequently used as rat poison, although warfarin-resistant rat strains are becoming more common.
Mechanism of action
Normally, vitamin K is converted to vitamin K epoxide in the liver. This epoxide is then reduced by the enzyme epoxide reductase. The reduced form of vitamin K epoxide is necessary for the synthesis of many coagulation factors (II, VII, IX and X, as well as protein C and protein S). Warfarin inhibits the enzyme epoxide reductase in the liver, thereby inhibiting coagulation.
Uses
Warfarin is given to people with a thrombosis tendency. This can prevent growth or embolism (spread) of a thrombus. Common indications for warfarin use are atrial fibrillation, artificial heart valves, deep venous thrombosis and pulmonary embolism.
Therapeutic drug monitoring is required, as warfarin has a very narrow therapeutic index, which means the levels in the blood that are effective are close to the levels that cause bleeding. This means it is easy to over- or under-coagulate the patient. Warfarin's effects must be closely monitored: this is done by using the INR. Initially, checking may be as often as twice a week; the intervals can be lengthened if the patient manages correct INRs on a stable warfarin dose.
When initiating warfarin therapy ("warfarinisation"), the doctor will generally decide how strong the anticoagulant therapy needs to be. A common target INR level is 2.0-3.0, though it varies from case to case.
The new oral anticoagulant ximelagatran (Exanta®) does not require INR monitoring, and is expected to replace warfarin to a large degree when it is introduced.
Origin
Warfarin is a 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.
3mg (blue), 5mg (pink) and 1mg (brown) warfarin tablets (UK colours) Advantages and disadvantages
Pharmacokinetics and antagonism
Warfarin is slower acting than another 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. As well as these problems, heparin can also cause thrombocytopenia (a decrease in platelet levels), which may cause bleeding. For these main reasons, hospitalised patients are usually given heparin initially, and are then moved on to warfarin.
Heparin can be antagonised with protamine sulfate, while warfarin can be reversed with vitamin K.
Side-effects
Side-effects can include gastrointestinal bleeding and the feared (but rare) complication of warfarin necrosis, which occurs mainly in patients with a deficiency of protein C. Protein C is an innate anticoagulant, and as warfarin further decreases protein C levels by inhibiting vitamin K, it can lead to massive thrombosis with necrosis and gangrene of limbs. Its natural counterpart, purpura fulminans, occurs in children who are homozygous for protein C mutations. The patient's general tendency to bruise and bleed is raised somewhat, and incidents involving bleeding and its complications - especially when the INR has drifted too high - are not uncommon. Most bleeds are not serious, but a very small proportion develops a cerebral hemorrhage or a gastrointestinal bleed, both of which need urgent medical attention.
Interactions and contraindications
There are many drug-drug interactions with warfarin, and its metabolism varies greatly between patients. 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. amiodarone), INR checks are increased or dosages adjusted until a new ideal dosage is found.
In 2004 it was reported that cranberry juice could potentiate warfarin, and UK patients on warfarin were advised to avoid cranberry juice until the exact mechanism was understood1.
Warfarin cannot be given to pregnant women, especially in the first trimester, as it is a teratogen (it causes deformations of the face and bones). During the third trimester, antepartum hemorrhage can occur. Instead of warfarin, low molecular weight heparin is generally used.
Overdose
If an overdose of warfarin occurs (revealed by bleeding and/or a high INR), the effects can be reversed by administering a vitamin K injection, or (in case of severe bleeding) prothrombin complex or fresh frozen plasma infusion to replace coagulation proteins. A mildly elevated INR in a patient who is not bleeding may be corrected with oral vitamin K.
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 1922, Frank Schofield, a Canadian veterinarian, determined that the cattle were ingesting a toxin from moldy silage made from sweet clover that functioned as a potent anticoagulant.
The identity of the anticoagulant substance in moldy sweet clover remained a mystery until 1940 when Karl Link and 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 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. The attribution, sometimes quoted as fact even by doctors, to Wisconsin Anti-Rat Federation is folklore.)
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.
The use as rat poison is declining as many rat populations have developed resistance to warfarin.
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.
Notes
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