Warfarin

Warfarin (also known under the brand name Coumadin®) is an anticoagulant medication that can be given orally.

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 of a thrombus. Common indications for warfarin use are atrial fibrillation, artificial heart valves, deep venous thrombosis, pulmonary embolism and orthopedic surgery (where prolonged immobilisation is expected).

Therapeutic drug monitoring is required, as warfarin has a very narrow therapeutic range, 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.

When initiating warfarin therapy ("warfarinisation"), the doctor will generally decide how strong the anticoagulant therapy needs to be. A common target INR level is 2.5-3.5 though it varies from case to case.

Origin

Warfarin is a derivative of coumarin, a plant chemical found in low levels in licorice, lavender and various other species. As well as its use as an anticoagulant, warfarin-like compounds are used as rat poison.

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, so this cannot be done by the patient. Warfarin has a long half-life and needs 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. The downside of warfarin is that it is hard to antagonise, while heparin can be antagonised with protamine sulfate.

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, though they are not all serious by any means.

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.

An Autumn 2004 caution from the Committee on Safety of Medicines (the UK agency dealing with drug safety) advises warfarinsed patients to stay off cranberry juice after adverse effects were reported. The affected patients had INRs going too high, that is, the cranberry juice appears to have potentiated the warfarin and increased the incidence of bleeding. The mechanism for this is not yet understood, and the number of patients involved is small, but it may be sensible for patients to heed this advice pending further investigations. The notice will be found in the October 2004 "Current Problems in Pharmacovigilance".

Warfarin cannot be given to pregnant women, especially in the first trimester, as it is a teratogen. 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 severe bleeding or a high INR), the effects can be reversed by administering a vitamin K injection, or (in case of severe bleeding) fresh frozen plasma infusion to replace coagulation proteins.

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.

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.

External link

• "Current Problems in Pharmacovigilance" (http://www.mca.gov.uk/ourwork/monitorsafequalmed/currentproblems/currentproblems_oct04.pdf) October 2004 - has cranberry juice caution, p. 10

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