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Compendium January 2005 (Vol 27, No 1)

Pharm Profile: Vitamin K

by Lotfi El Bahri, DVM, MSc, PhD

    Indication: Treating anticoagulant rodenticide toxicosis

    Vitamin K is the specific antidote for treating anticoagulant rodenticide toxicosis—one of the more common intoxications in dogs.1,2 It is used in treating an overdose with drugs that interfere with vitamin K metabolism.1,3 Vitamin K is also recommended in treating vitamin K deficiency associated with chronic liver disease.4 Because intestinal absorption requires the ability to digest fat, parenteral vitamin K is indicated in conditions of poor fat absorption such as bile duct obstruction, pancreatic insufficiency, lymphangiectasia, and severe protein-losing enteropathy. In addition, vitamin K is sometimes given to neonates because of impaired coagulation function.

    Phamacokinetics

    Vitamin K occurs essentially in two forms: vitamin K1 (i.e., phytonadione, phylloquinone) and vitamin K3 (i.e., menadione), which does not have a lipophilic side chain and is not recommended in veterinary patients. After oral administration, vitamins K1 and K3 are adequately absorbed from the gastrointestinal tract.5 Vitamin K1 is absorbed almost entirely by way of the lymph but only in the presence of bile salts and pancreatic juice.5,6 Oral absorption of vitamin K1 may be significantly enhanced by administering it with a fatty meal.7 Vitamin K3 enters the bloodstream directly.5 Absorption of the two forms of vitamin K differs significantly. Vitamin K1 is absorbed by an energy-dependent, saturable process in proximal portions of the small intestine. In contrast, vitamin K3 is absorbed by passive diffusion in the distal portions of the small intestine and in the colon.6 Some reports have indicated that vitamin K3 has been completely absorbed and vitamin K1 has been absorbed at a rate of only 50%.6 Oral doses of vitamin K1 may be poorly absorbed in hypovolemic animals.7 After parenteral administration, vitamin K1 is detectable in blood within 1 to 2 hours.8 In blood, 90% of vitamin K1 is bound to lipoproteins. It is concentrated and retained in the liver, but the concentration declines rapidly5; vitamin K3 is poorly retained in the liver. Vitamin K1 crosses the placenta in small amounts.7 Vitamins K1 and K3 are metabolized to more polar metabolites that are conjugated with glucuronate and excreted in the bile and urine.5 The half-life of vitamin K1 is estimated to be 6 hours.9

    Pharmacology

    Vitamin K1 has the same degree of activity as naturally occurring vitamin K.8 Vitamin K3, a synthetic analogue, is much less effective than vitamin K1.10 Vitamin K1 has hemostatic activity only in instances of vitamin K deficiency.10 It is necessary for the hepatic synthesis of the four clotting factors (i.e., II [prothrombin], VII [proconvertin], X [Stuart factor], IX [factor antihemophilic B]) and two inhibitors of coagulation (i.e., proteins C and S).5 Vitamin K1 is involved in the final carboxylation of several glutamic acid residues of these proteins, which confers hemostatic functionality.5 Anticoagulant rodenticides interfere with vitamin K epoxide reductase (a hepatic enzyme necessary to convert vitamin K epoxide [an inactive form] to vitamin K [an active form]).1 Second-generation (brodifacoum, bromadiolone, difenacoum) and third-generation (flofenacoum, diféthialone) anticoagulant rodenticides have an extremely long half-life and produce prolonged inhibition of vitamin K epoxide reductase.11 Therefore, up to 6 weeks of vitamin K1 therapy may be necessary.

    After ingestion of anticoagulant rodenticides, depletion of clotting factors depends on their half-lives. Factor VII, with a half-life of 6 hours, is affected first, followed by factors IX, X, and II, with half-lives of 24, 40, and 60 hours, respectively, in dogs.12 Synthesis of dysfunctional factors of coagulation called protein induced by vitamin K antagonist (PIVKA) occurs (e.g., PIVKA II, VII, X, and IX). These are biologically inactive, thereby creating coagulopathy.13 Some drugs, such as aspirin, sulfaquinoxaline, and cephalosporins that contain heterocyclic side chains, inhibit vitamin K epoxide reductase, resulting in vitamin K deficiency.1,14,15 Vitamin K may also have antiosteoporotic activity. In vivo studies have shown that vitamin K is involved in normal bone metabolism.16 Two vitamin K-dependent proteins are found in bone: osteocalcin (i.e., bone G1a protein) and the matrix G1a protein. Osteocalcin appears to act as a regulator of bone mineralization. Lower bone mineral density and higher fracture rates have been reported among patients with lower circulating vitamin K levels.16

    Indications

    Vitamin K1 is primarily indicated in treating anticoagulant rodenticide toxicosis.1 Appropriate blood samples should always be taken before beginning treatment with vitamin K1. Blood samples must be collected by fresh venipuncture using syringes and should be drawn into a tube containing 3.2% sodium citrate.17 A blood:citrate ratio of 9:1 is considered ideal, and a higher percentage of citrate (a small volume of the sample) may artificially prolong the results.17 Chemical analysis (i.e., product identification via blood or urine) may confirm the presence of anticoagulant. Vitamin K1 should be given only if there is evidence of significant anticoagulation (i.e., prolonged times in coagulation assays, such as prothrombin time [PT] and activated partial thromboplastin time [aPTT]).1 The prothrombin test is sensitive to the levels of factors II, VII, and X.8 Because of the short half-life of factor VII, the PT is affected before the aPTT.11 Animals that have ingested an anticoagulant and have a normal PT should not receive vitamin K1.1 Prophylactic administration of vitamin K1 is not effective in preventing PT prolongation in animal studies.18 Vitamin K3 should not be used in treating anticoagulant rodenticide poisoning because it is not as potent as vitamin K1 and has a delayed onset.19

    Vitamin K1 is indicated in marked prolongation of PT (reference ranges: 7 to 10 seconds for dogs; 8.7 to 10.7 seconds for cats) without bleeding and in severe prolongation of PT and frank bleeding.1,20,21 Vitamin K1 does not have a direct effect on coagulation. Intravenous administration may take 2 to 8 hours and oral treatment 24 to 48 hours to increase levels of coagulation factors.1 In emergency cases with ongoing hemorrhage, transfusion of fresh whole blood of fresh-frozen plasma should be administered concurrently with vitamin K1. Vitamin K1 is also indicated in treating vitamin K deficiency resulting from aspirin intoxication in cats and dogs, sulfaquinoxaline toxicosis, and long-term administration of third-generation cephalosporins.1,3,7,22 It is used in treating hepatic necrosis caused by acute overdose of acetaminophen in dogs.23

    Vitamin K1 is also used in coagulopathies associated with biliary obstruction or intrahepatic cholestasis.4 Cats with hepatic lipidosis, severe cholangiohepatitis, and severe inflammatory bowel disease develop coagulopathies responsive to parenteral vitamin K1 administration.13 Supplementation with vitamin K may prevent fractures, but evidence for this is not strong.16

    Cautions

    Anaphylactic reactions to rapid intravenous injection of vitamin K1 involving shock or cardiac or respiratory arrest have been reported in dogs.4,19 These reactions should be particularly anticipated in preparations containing polysorbate 80, a known histamine releaser in dogs, or castor oil, which is added to make vitamin K1 water-miscible.24,25 Intramuscular administration may result in hematoma formation in dogs with coagulopathies, and a small-gauge needle (i.e., 25 gauge or smaller) should be used to administer the dose in several sites.19 Subcutaneous injections may be associated with slow absorption if hypovolemia is present.26 Vitamin K1 will not reverse the anticoagulant effects of heparin.1 Severe hepatic failure results in loss of protein synthesis and hemorrhagic diathesis that is unresponsive to vitamin K1.7 Drugs (i.e., chloramphenicol, tetracyclines, erythromycin, neomycin, sulfonamide-trimethoprim, metro­nidazole) that reduce vitamin K2 (menaquinone) synthesis in the intestinal tract may increase the anticoagulant toxicosis.7,12,22 Vitamin K3 has caused retardation of skeletal ossification and increased fetal resorption in rats.8

    Acute Toxicity

    There is no known toxicity associated with high doses of vitamin K1. In animal studies, orally ingesting large amounts (i.e., 25 g/kg) of vitamin K1 produced no fatalities.6 The LD50 of orally administered vitamin K3 in mice is 0.5 g/kg.27 Vitamin K3 is irritating to the skin and respiratory tract.5 Vitamin K3 can interfere with the function of glutathione, resulting in oxidative damage to cell membranes and inducing hemolytic anemia and hyperbilirubinemia in premature infants.5,8 It is toxic to the renal tubules and causes irreversible nephrotoxicosis in horses.28 Thus vitamin K3 is not recommended in veterinary patients.

    Dosage and Administration

    Varying doses and protocols of vitamin K1 therapy have been recommended in treating anticoagulant rodenticide poisoning. One common protocol includes a loading dose of 5 mg/kg slow IV twice daily followed by 2.5 to 5 mg/kg/day PO.11 If possible, the anticoagulant rodenticide that the animal ingested should be identified. If the anticoagulant rodenticide is unknown, oral therapy with vitamin K1 for 5 weeks is recommended.11 The durations of administration for anticoagulants are 2 weeks for coumafene and coumatetralyl; 3 weeks for bromadiolone, diphacinone, and chlorophacinone; 4 weeks for difenacoum; and 5 weeks for brodifacoum, diféthialone, and flocoumafen.11

    Coagulation parameters should be monitored during therapy. PT should be measured daily for a minimum of 3 days.19 After the last dose of vitamin K, the patient's coagulation status should be checked in 48 to 72 hours. If coagulation function is normal, vitamin K1 can be discontinued.11 If coagulation is determined to be abnormal at this time, treatment with vitamin K1 should be reinstituted for another 3 weeks.11 Failure to respond to vitamin K may indicate other coagulation defects or irreversible hepatic damage.5

    If immediate hemostatic action is necessary in urgent cases, the deficient coagulation factors can be restored immediately by administering purified human blood clotting factors (i.e., 0.2 to 1 ml/kg IV of prothrombin, proconvertin, Stuart, and antihemophilic B).11 However, these products are extremely expensive. Other sources of clotting factors are fresh whole blood or fresh-frozen plasma. The recommended dosage of fresh whole blood should not exceed 22 ml/kg/hr. For plasma, the recommended dosage is 6 to 10 ml/kg bid or tid for 3 to 5 days or until bleeding stops.29 Blood components should be warmed at 98.6°F to 100.4°F (37°C to 38°C) before administration.29 Poisoned animals should be handled gently to minimize trauma and avoid hemorrhage during treatment and hospitalization. Supportive care to maintain normal respiration and body temperature and prevent respiratory compromise from thoracic hemorrhage is important.

    Treating an acute overdose of aspirin in cats and dogs may be attempted by administering vitamin K1 (2.5 mg/kg/day PO divided into two doses) if PT is prolonged.7 Acute overdose of acetaminophen in dogs also requires vitamin K1 (2.4 mg/kg SC bid or tid).23 In dogs with cholestasis or severe hepatic disease, long-term therapy with parenteral vitamin K1 (0.5 mg q7-20d IM or SC) is indicated.10

    Preparations

    Vitamin K1 is currently not approved by the FDA Center for Veterinary Medicine for use in dogs and cats. However, it is available in the United States as a veterinary pharmaceutical product. Nine injectable vitamin K1 products are listed in the 1999 edition of Compendium of Veterinary Products (see box).4,30

    Storage and Handling

    Vitamin K1, a naphthoquinone ring structure, is photosensitive and should therefore be protected from light and stored in well-closed, light-resistant containers. If used as an intravenous infusion, the container should be wrapped with an opaque material.7

    1. Dart RC: Antidotes, in The 5-Minute Toxicology Consult. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 158-159, 272-273.

    2. Hornfeldt CS, Murphy MJ: 1990 Report of the American Association of Poison Control Centers: Poisonings in animals. JAVMA 200(8):1077-1080, 1992.

    3. Neer TM, Savant RL: Hypoprothrombinemia secondary to administration of sulfaquinoxaline to dogs in a kennel setting. JAVMA 200(9):1344-1345, 1992.

    4. Burgess TM, Meyer EK, Bataller N: Practitioner report involving intravenous use of vitamin K prompts label review and revision. JAVMA 218(11): 1767-1769, 2001.

    5. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, ed 9. New York, McGraw-Hill, 1996, pp 1341-1351, 1582-1585.

    6. McDowell LR: Vitamins in Animal Nutrition. Comparative Aspects to Human Nutrition. San Diego, Academic Press, 1989, pp 133-154.

    7. Plumb DC: Veterinary Drug Handbook, ed 4. Ames, Iowa State University Press, 2002, pp 70-74, 665-668.

    8. Kastrup EK: Drug Facts and Comparisons. Philadelphia, Lippincott Williams & Wilkins, 1990, pp 225-227, 243-247.

    9. Park BK, Scott AK, Wilson AC: Plasma disposition of vitamin K1 in relation to anticoagulant poisoning. Br J Clin Pharmacol 18:655-662, 1984.

    10. The Merck Veterinary Manual, ed 8. Whitehouse Station, NJ, Merck & Co, 1998, pp 330-331, 1677.

    11. Pouliquen H: Intoxication par un rodenticide anticoagulant. Le Point Veterinaire 221:36-39, 2001.

    12. Osweiler GD: Disorders affecting coagulation (hemostasis), in Toxicology. Philadelphia, Lippincott Williams & Wilkins, 1996, pp 174-175.

    13. Center SA, Warner K, Corbett J, et al: Proteins invoked by vitamin K absence and clotting times in clinically ill cats. J Vet Intern Med 14(3):292-297, 2000.

    14. Preusch PC, Hazelett SE, Lemasters KK: Sulfaquinoxaline inhibition of vitamin K epoxide and quinone reductase. Arch Biochem Biophys 269:18-24, 1989.

    15. Sattler FR, Weitekamp MR, Ballard JO: Potential for bleeding with the new b-lactam antibiotics. Ann Intern Med 105:924-931, 1986.

    16. Fairfield KM, Fletcher RH: Vitamins for chronic disease prevention in adults: Scientific review. JAMA 287(23):3116-3126, 2002.

    17. Rozanski E: Hypocoagulation I and II, in Coagulation in Critical Care. Orlando, American College of Veterinary Emergency and Critical Care, 2000.

    18. Smolinske SC, Scherger DL, Kearns PS, et al: Superwarfarin poisoning in children: A prospective study. Pediatrics 84(3):490-494, 1989.

    19. Campbell A, Chapman M: Handbook of Poisoning in Dogs and Cats. Oxford, Blackwell Science, 2000, pp 64-73.

    20. Crystal MA, Cotter SM: Acute hemorrhage: A hematologic emergency in dogs. Compend Contin Educ Pract Vet 14(1):60-68, 1992.

    21. Gookin JL, Brooks MB, Catalfamo JL, et al: Factor X deficiency in a cat. JAVMA 211(5):576-579, 1997.

    22. Moulin M: Pharmacologie. Paris, Masson, 1998, pp 136-142.

    23. Adams HR: Drugs acting on blood and blood elements, in Veterinary Pharmacology and Therapeutics, ed 7. Ames, IA, Blackwell Publishing, 1995, pp 531-543.

    24. Taylor NS, Dhupa N: Acetaminophen toxicity in cats and dogs. Compend Contin Educ Pract Vet 22(2):160-170, 2000.

    25. Laurence Dr, Bennett PN: Clinical Pharmacology. Edinburgh, Churchill Livingstone, 1992, pp 475-476.

    26. Dorman DC: Anticoagulant, cholecalciferol and bromethalin-based rodenticides. Vet Clin North Am Small Anim Pract 20(2):339-352, 1990.

    27. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, ed 13. Whitehouse Station, NJ, Merck & Co, 2001, pp 1042, 1322.

    28. McConnico RS, Copedge K, Bischoff KL: Brodifacoum toxicosis in two horses. JAVMA 211(7):882-886, 1997.

    29. Authement JM, Wolfsheimer KJ, Catchings S: Canine blood component therapy: Product preparation, storage, and administration. JAAHA 23:483-493, 1987.

    30. Murphy M: A Field Guide to Common Animal Poisons. Ames, Iowa State University Press, 1996, pp 46-47.

    References »

    NEXT: Abstract Thoughts (January 2005)

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