What causes warfarin and superwarfarin toxicity?

Updated: Jan 19, 2018
  • Author: Kent R Olson, MD, FACEP; Chief Editor: David Vearrier, MD, MPH  more...
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Coumarins inhibit hepatic synthesis of the vitamin K ̶ dependent coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S. Vitamin K is a cofactor in the synthesis of these clotting factors. The vitamin K ̶ dependent step involves carboxylation of glutamic acid residues and requires regeneration of the used vitamin K back to its reduced form.

Coumarins and related compounds inhibit vitamin K1 -2,3 epoxide reductase, preventing vitamin K from being reduced to its active form. The degree of effect on the vitamin K ̶ dependent proteins depends on the dose and duration of treatment with warfarin.

Since warfarin does not affect the activity of previously synthesized and circulating coagulation factors, depletion of these mature factors through normal catabolism must occur before the anticoagulant effects of the drug are observed. Each factor differs in its degradation half-life; factor II requires 60 hours, factor VII requires 4-6 hours, factor IX requires 24 hours, and factor X requires 48-72 hours. The half-lives of proteins C and S are approximately 8 and 30 hours, respectively. As a result, 3-4 days of therapy may be needed before complete clinical response to any one dosage is observed.

Because warfarin also reduces the activity of anticoagulant proteins C and S, a transient hypercoagulable state may occur shortly after treatment with warfarin is started. Rapid loss of protein C temporarily shifts the balance in favor of clotting until sufficient time has passed for warfarin to decrease the activity of coagulant factors.

The oral bioavailability of warfarin and the superwarfarins is nearly 100%. Warfarin is highly bound (approximately 97%) to plasma protein, mainly albumin. The high degree of protein binding is one of several mechanisms whereby other drugs interact with warfarin. Warfarin is distributed to the liver, lungs, spleen, and kidneys. It does not appear to be distributed to breast milk in significant amounts. It crosses the placenta and is a known teratogen.

The duration of anticoagulant effect after a single dose of warfarin is usually 5-7 days. However, superwarfarin products may continue to produce significant anticoagulation for weeks to months after a single ingestion. In one reported overdose case with measured serum levels, the half-life of brodifacoum was 56 days. [4]

Warfarin is metabolized by hepatic cytochrome P-450 (CYP) isoenzymes predominantly to inactive hydroxylated metabolites, which are excreted in the bile. It also is metabolized by reductases to reduced metabolites (warfarin alcohols), which are excreted in the kidneys. Warfarin metabolism may be altered in the presence of hepatic dysfunction or advanced age but is not affected by renal impairment. Drug interactions are extensive and many known examples are enumerated below. Excessive anticoagulation may also occur because of unintentional or intentional overdose.

Lack of familiarity with the interactions between warfarin and other drugs may lead to clinically relevant and avoidable increases or decreases in prothrombin time (PT).

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