Warfarin Pharmacology

Pharmacokinetics

Warfarin consists of a racemic mixture of two active enantiomers—''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. (specifically the VKORC1 subunit), thereby diminishing available vitamin K and vitamin K hydroquinone in the tissues, which inhibits the carboxylation activity of the glutamyl carboxylase. When this occurs, the coagulation factors are no longer carboxylated at certain glutamic acid residues, and are incapable of binding to the endothelial surface of blood vessels, and are thus biologically inactive. As the body's stores of previously-produced active factors degrade (over several days) and are replaced by inactive factors, 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 vitamin K absence/antagonism), and individual coagulation factors as PIVKA-''number'' (e.g. PIVKA-II). The end result of warfarin use, therefore, is to diminish blood clotting in the patient.

The initial effect of warfarin administration is to briefly ''promote'' clot formation. This is because the level of protein S is also dependent on vitamin K activity. Reduced levels of protein S lead to a reduction in activity of protein C (for which it is the co-factor) and therefore reduced degradation of factor Va and factor VIIIa. This then causes the hemostasis system to be temporarily biased towards thrombus formation, leading to a prothrombotic state. This is one of the benefits of co-administering heparin, an anticoagulant that acts upon antithrombin and helps reduce the risk of thrombosis, which is common practice in settings where warfarin is loaded rapidly.

Antagonism

The effects of warfarin can be reversed with vitamin K, or, when rapid reversal is needed (such as in case of severe bleeding), with prothrombin complex concentrate—which contains only the factors inhibited by warfarin—or fresh frozen plasma (depending upon the clinical indication) in addition to intravenous vitamin K.

Details on reversing warfarin are provided in clinical practice guidelines from the American College of Chest Physicians. For patients with an international normalized ratio (INR) between 4.5 and 10.0, a small dose of oral vitamin K is sufficient.

Pharmacogenomics

Warfarin activity is determined partially by genetic factors. The American Food and Drug Administration "highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients". Polymorphisms in two genes are particularly important.

VKORC1

VKORC1 polymorphisms explain 30% of the dose variation between patients: particular mutations make VKORC1 less susceptible to suppression by warfarin. ''VKORC1'' polymorphisms explain why African Americans are on average relatively resistant to warfarin (higher proportion of group B haplotypes), while Asian Americans are generally more sensitive (higher proportion of group A haplotypes).

CYP2C9

''CYP2C9'' polymorphisms explain 10% of the dose variation between patients, These ''CYP2C9'' polymorphisms do not influence time to effective INR as opposed to ''VKORC1'', but does shorten the time to INR >4.

The Fennerty 10 mg regimen is for urgent anticoagulation
The Tait 5 mg regimen is for "routine" (low-risk) anticoagulation
From a cohort of orthopedic patients, Millican ''et al.'' derived an 8-value model, including ''CYP29C'' and ''VKORC1'' genotype results, that could predict 79% of the variation in warfarin doses. It is awaiting validation in larger populations and has not been reproduced in those who require warfarin for other indications.
Lenzini ''et al.'' derived and prospectively validated a model including ''CYP29C'' and ''VKORC1'' genotypes. This model could predict 70% of the variation in warfarin doses in a validation cohort (versus 48% without genotype). The pharmacogenetic protocol lead to a reduction in out of range INR values as compared to a historic control.
www.WarfarinDosing.org, is a non-profit website programmed with dosing calculators and other decision support tools for clinicians' use when initiating warfarin therapy.

Adjusting the maintenance dose

Recommendations by many national bodies including the American College of Chest Physicians

Self-testing and home monitoring

Patients are making increasing use of self-testing and home monitoring of oral anticoagulation. International guidelines were published in 2005 to govern home testing, by the International Self-Monitoring Association for Oral Anticoagulation.

The international guidelines study stated: "The consensus agrees that patient self-testing and patient self-management are effective methods of monitoring oral anticoagulation therapy, providing outcomes at least as good as, and possibly better than, those achieved with an anticoagulation clinic. All patients must be appropriately selected and trained. Currently-available self-testing/self-management devices give INR results that are comparable with those obtained in laboratory testing." Apart from the metabolic interactions, highly protein bound drugs can displace warfarin from serum albumin and cause an increase in the INR. 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. simvastatin), INR checks are increased or dosages adjusted until a new ideal dosage is found.

Many commonly-used antibiotics, such as metronidazole or the macrolides, will greatly increase the effect of warfarin 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 that contains large quantities of vitamin K will reduce the warfarin effect. hypothyroidism (decreased thyroid function) makes people less responsive to warfarin treatment, while hyperthyroidism (overactive thyroid) boosts the anticoagulant effect. Several mechanisms have been proposed for this effect, including changes in the rate of breakdown of clotting factors and changes in the metabolism of warfarin.

Excessive use of alcohol is also known to affect the metabolism of warfarin and can elevate the INR. Patients are often cautioned against the excessive use of alcohol while taking warfarin.

Warfarin also interacts with many herbs and spices, some used in food (such as ginger and garlic) and others used purely for medicinal purposes (such as ginseng and ''Ginkgo biloba''). All may increase bleeding and brusing in people taking warfarin; similar effects have been reported with borage (starflower) oil or fish oils. St. John's Wort, sometimes recommended to help with mild to moderate depression, interacts with warfarin; it induces the enzymes that break down warfarin in the body, causing a reduced anticoagulant effect.

Between 2003 and 2004, the UK Committee on Safety of Medicines received several reports of increased INR and risk of hemorrhage in people taking warfarin and cranberry juice. Data establishing a causal relationship is still lacking, and a 2006 review found no cases of this interaction reported to the FDA; The mechanism behind the interaction is still unclear.

The use of warfarin as a rat poison is now declining because many rat populations have developed resistance to it, and poisons of considerably greater potency are now available. Other coumarins used as rodenticides include coumatetralyl and brodifacoum, which is sometimes referred to as "super-warfarin", because it is more potent, longer-acting, and effective even in rat and mouse populations that are resistant to warfarin. Unlike warfarin, which is readily excreted, newer anticoagulant poisons also accumulate in the liver and kidneys after ingestion.