Dicumarol and other natural anticoagulants are found in sweet clover. Coumarin derivatives are used both therapeutically and as rodenticides. Warfarin (Coumadin) is used widely as a therapeutic anticoagulant but is no longer popular as a rodenticide because of rodent resistance. The most common anticoagulant rodenticides available today contain long-acting "superwarfarins" such as brodifacoum, diphacinone, bromadiolone, chlorophacinone, difenacoum, pindone, and valone, which have profound and prolonged anticoagulant effects. Other rodenticides are described elsewhere (see Rodenticides, Miscellaneous).
All these compounds inhibit vitamin K 2, 3-epoxide reductase and vitamin K quinone reductase, two enzymes responsible for the conversion of vitamin K to its active form, necessary cofactors in the hepatic synthesis of coagulation factors II, VII, IX, and X. Only the synthesis of new factors is affected, and the anticoagulant effect is delayed until currently circulating factors have been degraded.
Overdose during pregnancy has caused fetal hemorrhage, spontaneous miscarriage, and still birth. Major congenital malformations, fetal warfarin syndrome, and spontaneous miscarriage may occur with chronic use during pregnancy.
Warfarin. The mean half-life of oral warfarin is approximately 40 hours. The onset of the anticoagulant effect may be apparent within 15–20 hours. Peak effects usually are not observed for 2–3 days because of the long half-lives of factors IX and X (24–60 hours).The duration of anticoagulant effect after a single dose of warfarin is normally about 5 days. (See also Table II–66)
Superwarfarins. The onset of anticoagulation after superwarfarin ingestion may not be evident for up to 2 days after ingestion and may continue to produce significant anticoagulation for weeks to months after a single ingestion.
The toxic dose is highly variable.
Generally, a single small ingestion of warfarin (eg, 10–20 mg) will not cause serious intoxication (most warfarin-based rodenticides contain 0.05% warfarin). In contrast, chronic or repeated ingestion of even small amounts (eg, 2 mg/d) can produce significant anticoagulation. Patients with hepatic dysfunction, malnutrition, or a bleeding diathesis are at greater risk.
Superwarfarins are estimated to be 100 times as potent as warfarin. The minimum toxic dose is unclear. Single, intentional adult poisonings have resulted in life-threatening and prolonged anticoagulation. In contrast, single, accidental pediatric ingestions are unlikely to result in clinical anticoagulation although minor elevation in coagulation studies and rare cases of anticoagulation have been reported. In contrast, repeated small superwarfarin ingestions have resulted in prolonged anticoagulation in both children and adults.
Multiple drug interactions are known to alter the anticoagulant effect of warfarin (see Table II–65 for selected examples of drug–drug interactions with warfarin).
TABLE II–65.WARFARIN INTERACTIONS (SELECTED EXAMPLES) ||Download (.pdf) TABLE II–65. WARFARIN INTERACTIONS (SELECTED EXAMPLES)
|Increased Anticoagulant Effect ||Decreased Anticoagulant Effect |
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