Phytonadione Therapy in a Multiple-Drug Overdose Involving Warfarin

Duane Bates, B.Sc.(Pharm.), and Marcy Mintz, M.D.

Disclosures

Pharmacotherapy. 2000;20(10) 

In This Article

Pharmacology and Pharmacokinetics of Warfarin and Vitamin K

Short-acting anticoagulants can be divided into two classes: coumarin (warfarin, nicoumalone) and inandione (anisindione) derivatives. Warfarin is a racemic mixture of two optical isomers, R and S.[1,13] The S isomer is up to 5 times more potent than the R isomer.[1,13] Coumarin and inandione derivatives alter the synthesis of blood coagulation factors II (thrombin), VII (proconvertin), IX (Christmas factor), and X (Stuart-Prower factor). The anticoagulant effect is produced by interfering with cyclic interconversion of vitamin K and its 2,3 epoxide.[1] Vitamin K is a cofactor for the posttransitional -carboxylation of glutamate residues to -carboxyglutamates of the N-terminal regions of vitamin K-dependent proteins.[1] Carboxylation of vitamin K-dependent coagulation factors is catalyzed by a carboxylase that requires the reduced form of vitamin K (vitamin KH2), molecular oxygen, and carbon dioxide.[1] During this reaction vitamin KH2 is oxidized to vitamin K epoxide, which is recycled to vitamin K by vitamin K epoxide reductase, which then is reduced to vitamin KH2 by vitamin K reductase.[1] Vitamin K antagonists (warfarin) exert their anticoagulant effect by inhibiting vitamin K epoxide reductase and vitamin K reductase.[1] This leads to depletion of vitamin KH2 and limits carboxylation of vitamin K-dependent coagulant proteins (prothrombin, factor VII, factor IX, factor X).[1] Vitamin K antagonists also limit carboxylation of protein C and protein S, thus impairing their function.

The anticoagulant effect of warfarin occurs within 24 hours; however, peak effects may be delayed 72-96 hours due to the long half-lives of factors X (48-72 hrs) and II (60 hrs).[13] Warfarin is essentially completely absorbed, with peak plasma concentrations occurring within 2 hours.[13,14,15] It is highly protein bound, with more than 97% bound to plasma proteins, primarily albumin.[13,15] The volume of distribution is estimated to be 0.126 L/kg.[15] The serum half-life is 0.5-3 days but averages 36 hours.[13,15] Warfarin is metabolized extensively by the liver, with more than one isoenzyme involved in its metabolism. The predominant metabolizing enzymes for S- and R-warfarin are cytochrome P450 (CYP) 2C9 and 1A2, respectively.[16] Cytochrome P450 3A4 is involved in the metabolism of both enantiomers and 2C19 in the metabolism of R-warfarin.[16] As a result, drugs that preferentially inhibit the metabolism of S-warfarin decrease its clearance and enhance anticoagulation to a greater extent than drugs that would inhibit metabolism of the R isomer.

Paroxetine, omeprazole, and amitriptyline may have contributed to our patient's elevated INR on admission.[1,13,17] The woman was stabilized with these agents before admission; however, the drugs may affect clearance of warfarin until they are cleared metabolically from the body after 5 elimination half-lives. Urine was positive for fluoxetine, a drug that could inhibit warfarin metabolism and may have contributed to the elevated INR on admission and for several days due to its long half-life.[13,17]

Agents that possibly contributed to the prolonged elevated INR are ciprofloxacin, piperacillin-tazobactam, cloxacillin, vancomycin, gentamicin, and metronidazole. The combination of an inadequate diet and therapy with drugs that inhibit intestinal bacterial growth may lead to vitamin K deficiency, resulting in increased sensitivity to warfarin.[18] Ciprofloxacin inhibits CYP1A2, which metabolizes R-warfarin.[17] Metronidazole is a known inhibitor of the CYP2C9 isoenzyme and potentiates the effects of warfarin.[13,17]

After NAC was stopped on day 5, the INR increased to 6 within 24 hours, suggesting that acetaminophen may have contributed to the rebound increase. The initial warfarin ingested would still be present, as it would take approximately 7.5 days to complete 5 elimination half-lives. The patient ingested an unknown amount of acetaminophen. Twenty-four-72 hours after an acetaminophen overdose, hepatotoxicity may occur, and ALT, aspartate aminotransferase, bilirubin, and INR may increase.[3] In our patient an elevated INR was the only abnormality. However, a prothrombin time longer than 20 seconds was reported with overdoses of 9 g and with nontoxic acetaminophen levels and no evidence of hepatotoxicity.[19] Discontinuation of NAC and introduction of antibiotics make it difficult to determine whether or not the rebound increase in the INR was solely due to warfarin. Concurrent acetaminophen and warfarin therapy resulted in an increased INR,[16,20,21,22,23,24] and it was suggested that ingestion of acetaminophen 9100 mg/week results in a 10-fold increased risk of having an INR greater than 6.[20] It is not known what the effects of acetaminophen overdose have on warfarin metabolism.

Most of acetaminophen is metabolized by glucuronidation (60%) and sulfation (30%), with less than 7% excreted unchanged by the kidneys and the rest metabolized by the CYP pathway.[3] Its predominant metabolizing enzyme is isoenzyme 2E1, and to a lesser extent 1A2 and 3A4.[16,25] Cytochrome P450 2E1 is not involved in warfarin metabolism. Cytochrome P450 1A2 and 3A4 are responsible for metabolism of R-warfarin, the less potent anticoagulant of the two isomers.[16,25] The mechanism of the interaction between acetaminophen and warfarin is not well understood but may involve CYP inhibition. It has been suggested that acetaminophen reduces functional levels of factors VII and IX by directly inhibiting vitamin K carboxylase.[19]

Vitamin K is an essential fat-soluble vitamin that occurs in two natural forms, K1 and K2. Vitamin K1 or phytonadione (phylloquinone) is synthesized by plants and algae and is the natural vitamin available for therapeutic use.[3,18,26] Vitamin K2 (menaquinones) is synthesized by gram-positive bacteria and bacteria in the intestinal tract.[3,18] The recommended daily allowance of vitamin K is 1 µg/kg of phylloquinones for adults; infants require 10 times that amount to maintain normal homeostasis.[3] Plasma vitamin K is mainly in the form of phylloquinones, whereas liver stores are 90% menaquinones and 10% phylloquinones.[26] Phylloquinones are more biologically active. The healthy liver has approximately a 30-day store of vitamin K.[27]

Vitamin K3 (menadione) is a precursor for vitamin K2.. Vitamin K4 (menadiol sodium diphosphate) has 50% of the potency of vitamin K3. Vitamins K3 and K4 may produce hemolysis, hyperbilirubinemia, and kernicterus in neonates and hemolysis in glucose-6-phosphate-dehydrogenase-deficient patients.[3] The only advantage of menadione and menadiol sodium is that they do not require bile for absorption.[3] They are not interchangeable with, or a substitute for, vitamin K1 when anticoagulants are responsible for coagulation deficits.[3,15]

Menaquinones and phytonadione are solubolized with bile salts, free fatty acids, and monoglycerides to enhance absorption. Phytonadione is bound to chylomicrons, enters the circulation by way of the lymphatic system, and is taken up by the liver.[3] Its bioavailability varies from 10-63%.[28] It is absorbed by an energy-dependent, saturable process in proximal portions of the small intestine.[13,18] Menaquinones are absorbed by diffusion in the distal portion of the small intestine and in the colon.[18] After oral administration of phytonadione, blood coagulation factors increase in 6-12 hours and within 1-2 hours after parenteral administration.[13] Bleeding generally is controlled within 3-8 hours, and prothrombin time may be normal 12-14 hours after parenteral administration.[13] Malabsorption of phytonadione may occur in biliary obstruction, cystic fibrosis, sprue, Crohn's disease, ulcerative colitis, and enterocolitis, and in patients with extensive resection of the bowel.[18] Phytonadione is metabolized to more polar metabolites that are excreted in urine and bile.[18,27] High concentrations of menaquinones can be found in feces.[27] Phytonadione has a very short half-life of less than 2 hours.[28]

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