Plant Poisoning, Glycosides - Coumarin 

Toxicity from coumarins was first noted in animals. Livestock were difficult to feed on North American prairies until the introduction of melilots, or sweet clovers (ie, Melilotus alba, Melilotus officinalis), from Europe in the early 1900s.

In 1924, Schofield noted cattle in Alberta that were fed moldy spoiled sweet clover hay were dying from a previously undescribed hemorrhagic disorder; properly cured hay appeared harmless. Bishydroxycoumarin, the active ingredient responsible for this hemorrhagic disorder, was discovered in 1939 by Campbell and Link.

Bishydroxycoumarin is formed when fungi in moldy sweet clover oxidize coumarin to 4-hydroxycoumarin, an anticoagulant. In 1940, bishydroxycoumarin was synthesized and used clinically 1 year later as an oral anticoagulant under the American trade name dicumarol.

Coumarin-derivatives possessing a 4-hydroxy group with a carbon at the 3 position of the coumarin-base structure possess anticoagulant activity and are referred to as hydroxycoumarins, which are not present in coumarin itself.

Warfarin (name derived from Wisconsin Alumni Research Foundation and Coumarin) was synthesized and used as a rodenticide for nearly a decade prior to its 1954 introduction into clinical medicine.

Today, the 4-hydroxy coumarins are primarily used as anticoagulants and rodenticides. Second-generation rodenticides (long-acting anticoagulants, such as brodifacoum) are characterized by their clinical effects and very long half-lives.

Coumarin-derived products may be synthesized or obtained from tonka seeds (Dipteryx odorata, Dipteryx oppositifolia). Oral anticoagulants are divided into two groups, hydroxycoumarins (including warfarin) and indanediones.

This article focuses on hydroxycoumarins and their anticoagulant effects.

Vitamin K is a cofactor required for the postribosomal synthesis of active coagulation factors II, VII, IX, and X, as well as proteins S and C (important modulators of coagulation). Synthesis of these factors involves the carboxylation of specific glutamic acid residues in the liver, a step dependent on reduced vitamin K (vitamin K quinol). In this carboxylation reaction, vitamin K is oxidized to vitamin K 2, 3-epoxide. The 4-hydroxycoumarins block vitamin K 2, 3-epoxide reductase, which is needed for the reduction of vitamin K epoxide back to its active form. Dysfunctional coagulation factors are produced in the absence of reduced vitamin K. Half-lives of clotting factors are as follows:

• Factor II - 60 hours
• Factor VII - 4-6 hours
• Factor IX - 24 hours
• Factor X - 48 -72 hours

The bioavailability of warfarin is nearly complete when administered orally, intramuscularly, intravenously, or rectally. Therefore, orally ingested warfarin is completely absorbed and peak plasma concentrations occur about 3 hours postadministration. Ninety-nine percent is bound to plasma proteins, principally albumin, and distributes into a volume equivalent to the albumin space. Depletion of circulating coagulation factors must occur before any effects are evident. Factor VII has the shortest half-life; factor II has the longest. Clinical effects of a single massive dose of warfarin may begin to be apparent by 24 hours and are maximal by 36-48 hours. The patient may be hypercoagulable for a period of several hours after warfarin ingestion, prior to inhibition of factor production. Duration of action may be as long as 5 days.

Warfarin is metabolized extensively by hepatic microsomal enzymes and undergoes enterohepatic recirculation. Warfarin and its metabolites are excreted in urine and feces.

Long-acting anticoagulants, rodenticides, or superwarfarins (eg, difenacoum, brodifacoum) are 4-hydroxycoumarin derivatives; they are highly lipid-soluble and concentrate in the liver. Superwarfarins have a much longer duration of action than traditional warfarins. After intentional overingestion of superwarfarins, patients may be anticoagulated for weeks to months.

Numerous drug interactions with warfarin exist, both accelerating and inhibiting its metabolism. Lack of attention to possible interactions is a common cause of iatrogenic toxicity.

Drugs that potentiate anticoagulation are allopurinol, amiodarone, anabolic steroids, cephalosporins, cimetidine, cyclic antidepressants, erythromycin, ethanol, fluconazole, ketoconazole, metronidazole, nonsteroidal anti-inflammatory drugs (NSAIDs), omeprazole, sulfonylureas, thyroxine, and trimethoprim-sulfamethoxazole.

Drugs that antagonize anticoagulation are antacids, antihistamines, barbiturates, carbamazepine, corticosteroids, griseofulvin, oral contraceptives, phenytoin, and rifampin.

Frequency

United States

Intentional ingestion of warfarin-containing products is rare; however, excessive anticoagulation and bleeding are not uncommon in patients taking warfarin therapeutically. In 2008, 2422 single exposures to warfarin were reported to the American Association of Poison Control Centers (AAPCC).^[1] These centers cover approximately 95% of the US population, although reports to the AAPCC underestimate true incidence of exposures and poisonings. Of these exposures, 180 were intentional. Of all warfarin exposures, 21 major outcomes (life-threatening event or resultant disability) and 0 deaths were reported. In the same report, 11,201 single exposures to anticoagulant rodenticides (long-acting and warfarin type) were documented; 324 were intentional. A total of 17 major outcomes and no deaths were reported.

Mortality/Morbidity

Bleeding indicates major toxicity of 4-hydroxycoumarins.

• Mucocutaneous, genitourinary, and GI are the most frequent sites of bleeding.
• Serious bleeding includes massive hemorrhage with shock, intracranial bleeding, stroke, and pericardial tamponade.
• Upper airway compromise due to an expanding hematoma also may occur.

Age

• Intentional and chronic ingestions are more common in adolescents and adults than children. Munchausen syndrome or Munchausen syndrome by proxy may present as surreptitious ingestion or administration of one of these compounds by a caretaker.
• Single accidental ingestions are the most common exposures in children younger than 6 years. Such exposures to warfarin or brodifacoum rarely result in clinical toxicity.