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Warfarin Pharmacology

By Dr Liji Thomas, MD

Warfarin is a derivative of coumarin which interferes with the cyclic interconversion of vitamin K and its epoxide. Vitamin K is an important factor in the normal function of the coagulation system. It is absorbed from food, and reduced to vitamin KH2 by vitamin K reductase, which is not susceptible to the action of warfarin.

This is followed by the oxidation of vitamin KH2 to vitamin epoxide KO. Simultaneously vitamin K acts as a cofactor in a reaction which leads to the carboxylation of glutamic acid residues on certain coagulation factors.

These factors must be carboxylated to become biologically active, because it promotes their binding to cell membranes. This triggers the coagulation events. These are therefore called vitamin-K dependent coagulation factors. They include factors II, VII, IX and X, protein C and protein S. Vitamin K epoxide is then reduced to vitamin K1 by vitamin KO reductase and the cycle is repeated.

Mechanism of action of warfarin

Warfarin inhibits vitamin KO reductase, and thus limits the availability of vitamin K in the cyclic reaction. This thus reduces the coagulant activity of blood by reducing the production of vitamin K-dependent factors. The effect of warfarin can be overcome by administering vitamin K1 (phytonadione), either as medication or through the diet.

This makes vitamin KH2 available for carboxylation without the need for vitamin KO reductase. It can also be stored in the liver if given in large enough quantities, producing warfarin resistance in the patient for varying periods of time.

Warfarin also prevents the carboxylation of other proteins produced in bone, which accounts for its teratogenic effects on fetal bone formation when used in pregnancy. However, this does not seem to affect normal bone metabolism after birth.  

Pharmacokinetics of warfarin

Warfarin is a mixture of the R and S optical isomers in racemic proportions. The S-form is five times as potent as the R-form in inhibiting vitamin K activity. After being rapidly absorbed from the intestine, warfarin reaches peak blood concentrations in about 90 minutes from oral ingestion.

It has a half-life of 36-42 hours, and circulates bound mainly to plasma albumin (99%) as well as small amounts of other plasma proteins, until it is stored in the liver for further metabolism. Its maximum effect is observed at up to 48 hours after administration. Its actions last for up to 5 days.

Warfarin is metabolized in the liver and kidneys, mostly by hydroxylation, with the inactive products being excreted through urine and feces.

Factors that influence the dose-response relationship with warfarin

Both genetic and environmental factors influence the individual response to warfarin. Cytochrome P450 gene mutations are one common cause of variation in the dose-response relationship with warfarin. Warfarin in the liver is oxidized by the cytochrome enzyme CYPC29 from this.

Hereditary warfarin resistance is known to exist, and is due to a reduced affinity of warfarin for its hepatic receptor. Such patients need much higher doses to achieve a satisfactory level of anticoagulation. Various disease states and dietary factors also affect the pharmacological activity of warfarin.

Several drugs can influence the absorption and clearance of warfarin, such as cholestyramine (slows its absorption). Phenylbutazone and metronidazole reduce the clearance of the S-form which leads to higher levels of warfarin in the body, and possible bleeding manifestations.

Cotrimoxazole and amiodarone also potentiate warfarin-induced anticoagulant activity. On the other hand, barbiturates, rifampicin and carbamazepine reduce its pharmacologic efficacy by increasing its metabolism.

Malnutrition may lead to an inadvertent overdose at ordinary levels of warfarin because of the low vitamin K intake and serum albumin levels. Women also usually need less warfarin than men. If the INR increases too rapidly to therapeutic levels, it may mean that metabolic clearance is lower than normal, requiring a reduction in dosage, and vice versa.

In general, warfarin at therapeutic doses brings about a 30-50 percent reduction in the production of, and a 10-40 percent decrease in the carboxylation of, these coagulation factors, leading to deficient functioning of the coagulation system.

Pharmacologic effects of warfarin

The earliest change in coagulant activity is reflected in the INR, usually 24-36 hours after a dose of warfarin. This is not related to an actual cessation of thrombotic activity in the body but rather to the clearance of functional coagulation factors from the body, the first of which is factor VII, because of its short half-life of six hours.

Thrombus formation and expansion is actually affected by warfarin administration in about five days. This is how long it takes to clear functional prothrombin (factor II) from the body, with a half-life of about 50 hours.

This difference means that loading doses of warfarin are not useful and may be dangerous. This is because the long half-life of prothrombin delays the antithrombotic effects of warfarin, despite more immediate increases in the INR.

In fact, loading doses may require more hospitalization for monitoring purposes, and may induce a state of hypercoagulability by depleting protein C levels to dangerously low levels within 36 hours of the start of treatment.

References

Further Reading

Last Updated: Mar 27, 2016

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Comments
  1. Katerina Efstathiou Katerina Efstathiou United Kingdom says:

    Warfarin is an anticoagulant and does not 'promote' clot formation!!!

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