You are in: eMedicine Specialties > Emergency Medicine > TOXICOLOGY Plant Poisoning, Glycosides - CoumarinArticle Last Updated: Mar 14, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Arasi Thangavelu, MD, FACEP, FAAEM, Consulting Staff, Department of Emergency Medicine, Phoebe Putney Memorial Hospital Arasi Thangavelu-Veluswamy is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians Coauthor(s): Lisandro Irizarry, MD, MPH, FAAEM, Chair, Department of Emergency Medicine, Brooklyn Hospital Center; Assistant Professor, Department of Emergency Medicine, Weill Cornell School of Medicine Editors: B Zane Horowitz, MD, FACMT, Professor, Fellowship Director, Department of Emergency Medicine, Oregon Health and Sciences University; Medical Director, Oregon Poison Center; Medical Director, Alaska Poison Control System; John T VanDeVoort, PharmD, ABAT, Director of Pharmacy, Sacred Heart Hospital; Michael Hodgman, MD, Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Bassett Healthcare; John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center; Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital Author and Editor Disclosure Synonyms and related keywords: warfarin, hydroxycoumarins, coumarin derivatives, coumarin toxicity, plant poisonings, glycoside toxicity, glycoside poisoning, coumarin exposure, coumarin anticoagulants, coumarin rodenticides INTRODUCTIONSection 2 of 10
  BackgroundToxicity 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 chapter focuses on hydroxycoumarins and their anticoagulant effects. PathophysiologyVitamin 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:
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. FrequencyUnited StatesIntentional ingestion of warfarin-containing products is rare; however, excessive anticoagulation and bleeding are not uncommon in patients taking warfarin therapeutically. In 1998, 1658 exposures to warfarin were reported to the American Association of Poison Control Centers (AAPCC). These centers cover approximately 95% of the US population, although reports to the AAPCC underestimate true incidence of exposures and poisonings. Of these exposures, 235 were intentional. Of all warfarin exposures, 47 major outcomes (life-threatening event or resultant disability) and 2 deaths were reported. In the same report, 17,724 exposures to anticoagulant rodenticides were documented; 58 were intentional. A total of 28 major outcomes and 1 death were reported. Mortality/MorbidityBleeding indicates major toxicity of 4-hydroxycoumarins.
Age
CLINICALSection 3 of 10
History
PhysicalBleeding diathesis does not occur until 24 hours postingestion. Continued re-evaluation for signs of coagulopathy is necessary. Complications of excessive anticoagulation may occur. Initially, assessment of hemodynamic status and neurologic status are most important.
CausesWarfarin anticoagulants and the anticoagulant rodenticides (Human toxicity from ingestion of plants and herbal medications is extremely rare.) DIFFERENTIALSSection 4 of 10
Abortion, Complete Abortion, Complications Abortion, Incomplete Abortion, Inevitable Abortion, Missed Anemia, Acute Anemia, Chronic Compartment Syndrome, Extremity Disseminated Intravascular Coagulation Dysfunctional Uterine Bleeding Epidural Hematoma Epistaxis Esophageal Perforation, Rupture and Tears Hemolytic Uremic Syndrome Hemophilia, Type A Hemophilia, Type B Idiopathic Thrombocytopenic Purpura Munchausen Syndrome Pediatrics, Child Abuse Pediatrics, Gastrointestinal Bleeding Plant Poisoning, Herbs Pregnancy, Postpartum Hemorrhage Shock, Hemorrhagic Stroke, Hemorrhagic Subarachnoid Hemorrhage Subdural Hematoma Thrombocytopenic Purpura Toxicity, Iron Toxicity, Rodenticide
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| Drug Name | Activated charcoal (Liqui-Char) |
|---|---|
| Description | Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water. For maximum effect, administer within 30 min after ingesting poison. |
| Adult Dose | 1 g/kg (50-100 g) PO; repeat doses of 0.25-0.5 g/kg q2-6h may be considered for enhanced elimination |
| Pediatric Dose | <2 years: Not recommended > 2 years: 1-2 g/kg (15-30 g) PO |
| Contraindications | Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies |
| Interactions | May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decrease with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases adsorptive properties of activated charcoal) |
| Pregnancy | A - Safe in pregnancy |
| Precautions | Not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before giving activated charcoal; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black |
Cholestyramine forms a nonabsorbable complex with bile acids in the intestine that inhibits enterohepatic reuptake of intestinal bile salts. Rifampin is used to speed up metabolism of warfarin by induction of hepatic cytochrome P-450 mixed function oxidases.
| Drug Name | Cholestyramine (Questran) |
|---|---|
| Description | Binds bile salts carrying warfarin and its metabolites, thus interfering with enterohepatic recycling. |
| Adult Dose | 12-16 g/d PO divided qid |
| Pediatric Dose | Not established Suggested dosing for children 6-12 years: 80 mg/kg PO tid |
| Contraindications | Documented hypersensitivity |
| Interactions | Inhibits absorption of numerous drugs including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution in constipation and phenylketonuria |
| Drug Name | Rifampin (Rifadin, Rimactane) |
|---|---|
| Description | Hepatic P-450 enzyme inducer that results in increased metabolism of warfarin and decreased drug half-life. |
| Adult Dose | 600 mg PO q12h |
| Pediatric Dose | 10 mg/kg PO q12h |
| Contraindications | Documented hypersensitivity |
| Interactions | Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Obtain CBCs and baseline clinical chemistries before and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruptions of therapy and high-dose intermittent therapy are associated with thrombocytopenia, which is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur; orange discoloration of urine, tears, and sweat may occur |
Promotes liver synthesis of clotting factors that, in turn, inhibit warfarin effects.
| Drug Name | Vitamin K-1 (Phytonadione, AquaMEPHYTON) |
|---|---|
| Description | Overcomes block produced by hydroxycoumarin in production of vitamin K dependent clotting factors; vitamin K-3 (menadione) is not effective for this purpose. Dose needed varies with clinical situation, including amount of anticoagulant ingested and whether it is a short- or long-acting anticoagulant. Daily doses of 50-200 mg have been required. Use extreme caution if considering IV administration. Complications of IV use include flushing, diaphoresis, hypotension, dyspnea, and anaphylactoid reactions. SC is preferable to IV administration, which carries a strong box warning against IV administration by the manufacturer. In the patient on chronic anticoagulation for medical reasons, reversal should be performed only very carefully if clinically indicated. Re-anticoagulation can be very difficult in this situation. |
| Adult Dose | Initial: 5-10 mg SC; with chronic overdose, repeat prn; PO doses tend to be larger |
| Pediatric Dose | Initial: 1-5 mg SC; may repeat in 6 h |
| Contraindications | Documented hypersensitivity |
| Interactions | Antagonizes effects of warfarin sodium and dicumarol; sucralfate may decrease oral vitamin K absorption |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Ineffective in hereditary hypoprothrombinemia |
Plant Poisoning, Glycosides - Coumarin excerpt
Article Last Updated: Mar 14, 2007
