Warfarin: Encyclopedia - Warfarin

Warfarin

Warfarin

Warfarin (also known under the brand names of Coumadin® and Marevan®) is an anticoagulant medication that is 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). It is named for the Wisconsin Alumni Research Foundation.

Warfarin was originally developed as a rat poison, and is still widely used as such, although warfarin-resistant rats are becoming more common.

Warfarin - 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.

Warfarin - Uses

Warfarin - Medical use

Warfarin is given to people with an excessive tendency for thrombosis. 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. Dosing of warfarin is further complicated by the fact that it is known to interact with many other medications and other chemicals which may be present in appreciable quantities in food (including caffeine and ascorbic acid). These interactions range from enhancing warfarin's anticoagulation effect to reducing the effect of warfarin.

As a result, 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 stable therapeutic INR levels 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 was expected to replace warfarin to a large degree when introduced; however, it has run into approval problems and currently (2005) it is not clear if or when it will ever become available for general use.

Warfarin - Pesticide use

Warfarin is used as a rodenticide for controlling rats and mice in residential, industrial, and agricultural areas. 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/day over four to five 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.

Warfarin - Source

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.

Warfarin - Advantages and disadvantages

Warfarin - Pharmacokinetics and antagonism

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. 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.

Warfarin - 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.

Warfarin - 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.

Rigorous use of alcohol is also known to effect the metabolism of warfarin, although moderate drinking usually has little or no effect on the INR value. Patients suffering from liver damage or alcoholism are usually treated with heparin injections instead.

Warfarin - Overdose

Symptoms of overdose or side effect (see above) include hemoptysis, excessive bruising, bleeding from nose or gums, or blood in urine or stool. 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.

Warfarin - 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.) Warfarin was first registered for use as a rodenticide in the US in 1952.

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.

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.

Warfarin - Notes

• Note 1: "Current Problems in Pharmacovigilance" (pdf file) October 2004 - has cranberry juice caution, p. 10

Adapted from the Wikipedia article "Warfarin", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki