Article: Warfarin

Warfarin
Systematic (IUPAC) name
(RS)-4-hydroxy-3-(3-oxo-1-phenylbutyl)- 2H-chromen-2-one
Identifiers
CAS number	81-81-2
ATC code	B01AA03
PubChem	6691
DrugBank	APRD00341
Chemical data
Formula	C19H16O4
Mol. weight	308.33
Pharmacokinetic data
Bioavailability	100%
Protein binding	99.5
Metabolism	Hepatic: CYP2C9, 2C19, 2C8, 2C18, 1A2 and 3A4
Half life	2.5 days
Excretion	Renal (92%)
Therapeutic considerations
Pregnancy cat.	D (Au), X (U.S.)
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Oral

Warfarin (also known under the brand names of Coumadin®, Jantoven®, Marevan®, and Waran®) is an anticoagulant medication that is administered orally or, very rarely, by injection. 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.

Mechanism of action

Warfarin inhibits the effective synthesis of biologically active forms of the vitamin K-dependent clotting factors: II, VII, IX and X, as well as the regulatory factors protein C, protein S and protein Z. Other proteins not involved in blood clotting, such as osteocalcin, may also be affected.

The precursors of these factors require carboxylation of their glutamic acid residues to allow the coagulation factors to bind to phospholipid surfaces. This carboxylation is linked to oxidation of vitamin K to form Vitamin K epoxide, which is in turn recycled back to the reduced form by the enzyme epoxide reductase. Warfarin inhibits epoxide reductase, thereby diminishing vitamin K action and inhibiting production of functioning coagulation factors^[1]. As the body stores of previously-produced factors degrade (over several days), the anticoagulation effect becomes apparent. The coagulation factors are produced, but have decreased functionality due to undercarboxylation; they are collectively referred to as PIVKAs (proteins induced [by] vitamin K absence/antagonism).

Uses

Medical use

Warfarin is given to people with an increased tendency for thrombosis or as prophylaxis in those individuals who have already formed a blood clot (thrombus) which required treatment. This can help prevent formation of future blood clots and help reduce the risk of embolism (spread of a thrombus). Common clinical indications for warfarin use are atrial fibrillation, artificial heart valves, deep venous thrombosis and pulmonary embolism.^[2]

Dosing of warfarin is complicated by the fact that it is known to interact with many commonly used medications and other chemicals which may be present in appreciable quantities in food. These interactions may enhance or reduce warfarin's anticoagulation effect. Many commonly used antibiotics such as metronidazole or the macrolides, will greatly increase the warfarin effect by reducing the metabolism of warfarin in the body. Other broad spectrum antibiotics can reduce the amount of the normal bacterial flora in the bowel which make significant quantities of Vitamin K, thus potentiating the effect of warfarin. In addition, food which contains large quantities of Vitamin K will reduce the warfarin effect and medical conditions such as hypo- or hyperthyroidism will alter the rate of breakdown of the clotting factors.

Therefore, in order to optimise the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required by blood testing (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 an unchanged warfarin dose.

When initiating warfarin therapy ("warfarinisation"), the doctor will decide how strong the anticoagulant therapy needs to be. The target INR level will vary from case to case dependent upon the clinical indicators.

The oral anticoagulant ximelagatran (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 are under development.

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.

The LD50 is 50–500 mg/kg. The IDLH value is 100mg/m³.

Source

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.

Advantages and disadvantages

3mg (blue), 5mg (pink) and 1mg (brown) warfarin tablets (UK colours)

Pharmacokinetics and antagonism

Warfarin consists of a racemic mixture of two active optical isomers - R and S forms - each of which is cleared by different pathways. S-warfarin has five times the potency of the R-isomer with respect to Vitamin K antagonism.^[2]

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 a prothrombotic condition, heparin-induced thrombocytopenia (an antibody-mediated decrease in platelet levels), which paradoxically increases the risk for thrombosis. For these main reasons, hospitalised patients are usually given heparin initially, and are then moved on to warfarin.

Heparin can be neutralised with protamine sulfate, while warfarin can be reversed with vitamin K, or for rapid reversal, with fresh frozen plasma but this treatment is being replaced by use of prothrombin complex concentrate.

Side effects

Side effects can include gastrointestinal bleeding and the feared (but rare) complication of warfarin necrosis, which occurs more frequently in patients with a deficiency of protein C. Protein C is an innate anticoagulant that, like the procoagulant factors that warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the blood's tendency to coagulate when treatment is first begun (many patients when starting on warfarin are given heparin in parallel to combat this), leading to massive thrombosis with skin 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. Some foodstuffs have also been reported to interact with warfarin^[3] 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.

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.

Excessive use of alcohol is also known to affect 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.

Loading regimens

Because of warfarin's poorly predictable pharmacokinetics, several researchers have proposed algorithms for commencing warfarin treatment. For urgent anticoagulation, the Fennerty regimen^[4] is used commonly, while for "routine" (low-risk) anticoagulation, the Tait regimen^[5] is more popular.

Complications

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. An 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 1921, Frank Schofield, a Canadian veterinarian, determined that the cattle were ingesting moldy silage made from sweet clover that functioned as a potent anticoagulant^[6]. In 1929, North Dakota veterinarian Dr L.M. Roderick demonstrated that the condition was due to a lack of functioning prothrombin.^[7]

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.^[8] 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. Warfarin was first registered for use as a rodenticide in the US in 1952; although it was developed by Link, the WARF financially supported the research and was granted the patent.

The exact mechanism of action remained unknown until it was demonstrated, in 1978, that warfarin inhibited epoxide reductase and hence interfered with vitamin K metabolism^[1].

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. A famous early patient prescribed warfarin was Dwight Eisenhower, president of the USA, subsequent to his heart attack in 1955.

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^[9]

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.