Biomed. Papers 145(2), 27–38 (2001) 27 © O. Řehulková INTERACTIONS OF WARFARIN

Olga Řehulková

Clinical Department of R&D, IVAX-CR a. s., Ostravská 29, 747 70 Opava 9, Czech Republic

Received November 9, 2001

Key words: Drug interactions / Warfarin / Oral anticoagulants / Anticoagulant treatment

In this article, the author reviews and updates the basis of interactions with warfarin, illustrated with appropri- ate examples. The interactions with drugs, medicinal herbs and foods are summarised.

INTRODUCTION have usually been shown to be due to other mecha- nisms5. Anticoagulated patients fed a vitamin K-free Optimum anticoagulant therapy should be aimed at diet developed further prolongation of prothrombin an adequate balance between effective prevention of time, while neomycin given to suppress vitamin K synt- intravascular thrombosis and the production of unwanted hesis by gut bacteria had a little effect on the degree of bleeding. Many factors may affect an individual pa- anticoagulation, suggesting the relative lack of impor- tient’s response to oral anticoagulants, including age, tance of gut bacterial synthesis of vitamin K. This is diet, environmental contaminants and disease status. especially because bacterial synthesis of vitamin K largely Interactions with warfarin are of particular importance takes place in the large bowel, from which absorption is not only because unexpected loss of anticoagulant con- poor6. trol may have serious consequences, but also because Chloramphenicol may alter the effects of warfarin by warfarin offer a useful mechanistic model to study the decreasing vitamin K production by bacteria in the gut, whole topic of interactions. The pharmacodynamics of but other mechanisms such as inhibiting hepatic me- warfarin can be easily and precisely measured, and with tabolism and/or altering the production of prothrombin modern analytical techniques, such as high-pressure li- may be involved7, 8, 9, 10, 11. quid chromatography (HPLC), liquid chromatography- Doxycycline and other tetracyclines, ampicillin, ben- mass spectroscopy (LC-MS), gas liquid chromatography zylpenicillin and aztreonam decrease vitamin K synthesis (GLC) and radioimmunoassay (RIA), the pharmacoki- secondary to alterations in intestinal flora and, there- netics of the drug can be monitored1. fore, may enhance the effect of warfarin4, 12. However, the significant potentiation is very rare if dietary intake of vitamin K is adequate4. DRUG-DRUG INTERACTIONS Cephamandole may enhance the hypoprothrombi- naemic response to warfarin due to interference with A very large number of drug interactions have been vitamin K synthesis in the gastrointestinal tract13, 14 and/ reported with warfarin. Interactions may occur through or with synthesis of vitamin K-dependent clotting fac- changes affecting either the pharmacodynamics or phar- tors4. Related cephalosporines with an N-methylthio- macokinetics of warfarin. Drugs may interact by more tetrazole side chain such as cefmetazole, cefmenoxime, than one mechanism. cefoperazone and latamoxef may be expected to behave similarly, although there appear to be no reports of an 1 Pharmacodynamic drug interactions interaction. Cephazolin, which has similar chain, may enhance the effect of warfarin to some extent14.

Warfarin acts by inhibiting the vitamin K1-depen- The interactions caused by interference with the dent γ-carboxylation of clotting factors II (prothrombin), bacterial synthesis of vitamin K in the gastrointestinal VII, IX and X at a postribosomal stage in the liver, tract are generally considered unlikely to be of clinical leading to a build-up of biologically inactive precursor significance except, perhaps, in patients with an inad- clotting proteins2, 3, 4. Pharmacodynamic interactions may equate vitamin K intake12. be a result of a number of different mechanisms. Mineral oils (such as liquid paraffin) may reduce the absorption of vitamin K and enhance the effect of warfa- 1.1 Drugs affecting availability of vitamin K rin, but there is a little evidence that this is clinically Broad-spectrum antibiotics suppress production of important15. Mineral oils might also impair the absorp- vitamin K by the bowel flora and should theoretically tion of warfarin and lessen the effect of the anticoagu- increase the response to warfarin. While certain antibio- lant7, 16, 17. tics may potentiate warfarin action, these interactions 28 O. Řehulková

Cholestyramine binds vitamin K in the gut, thus pre- euthyroid due to antithyroid agents may develop marked venting its absorption18. It also decreases the absorption hypoprothrombinemia if the antithyroid and may interrupt the enterohepatic recirculation of are ceased and they become thyrotoxic again46. warfarin, resulting in a reduced anticoagulant effect19, 20. The antiepileptic agent valproic acid decreases he- Colestipol does not affect the absorption of warfarin. patic synthesis of procoagulant factors and, therefore, When colestipol is administered with warfarin, no de- may cause an increase in response to warfarin47. pressant effects on blood levels are seen21. The ingestion of large amount of tonic water neces- sitated a reduction in warfarin dosage. The enhanced 1.2 Drugs affecting receptor sensitivity effect was attributed to quinine content in tonic water48. Estrogens increase the synthesis of various clotting The interaction may be explained by decreasing hepatic factors and may thus reduce the effect of anticoagu- synthesis of procoagulant factors with quinine4. lants22, 23. Oral contraceptives increase clotting factor Cyclophosphamide has been associated with an in- concentrations and inhibit warfarin metabolism. The crease in warfarin activity when given with methotrexa- net effect depends on balance between these factors. te and fluorouracil49, but with a decrease when given Oral contraceptives are generally contraindicated in most with non-antineoplastic drugs50. The mechanism of in- patients taking warfarin since they are trombogenic1, 24. teraction lead to enhancement of warfarin effect consist Steroids with anabolic or androgenic properties, such in decreasing hepatic synthesis of procoagulant factors4. as oxymetholone25, 26, 27, stanozolol28, 29 and danazol30, 31, 32, Azathioprine or mercaptopurine (the metabolite may potentiate the action of warfarin allegedly by re- of azathioprine) may reduce the anticoagulant activity ducing clotting factor synthesis. The 17-alpha-alkylated of warfarin51, 52. Mercaptopurine showed to increase pro- steroids appear to be more likely to induce this reaction thrombin synthesis or activation in animal studies53. than the non-substituted steroids25, 26, 27, 33. However, there The antiarrhytmics disopyramide54 and quinidine55 may has been a report of topically applied testosterone, which enhance the effect of warfarin probably by alteration of does not have 17-alpha-alkyl substituent, enhancing war- procoagulant factor synthesis. However, this interaction farin34. does not seem to be consistent56, 57. Diuretics may antagonise the action of warfarin by Glucagon has been shown to increase the hypo- two pharmacodynamic mechanisms18: (a) patients in prothrombinemic effect of warfarin, resulting in bleeding cardiac failure have impaired clotting factor synthesis episodes59. The precise mechanism for this interaction due to hepatic congestion – correction of this state leads is not known, although it may be due to a depression of to increased clotting factor synthesis; (b) diuretics also the production of clotting factors in the liver, or an reduce the plasma volume producing an increased increase in warfarin sensitivity for its receptor site. concentration of clotting factors which may alter the anticoagulant effect of warfarin35. Chlorthalidone36 and 1.3 Drugs affecting haemostasis spironolactone35 have both been associated with a reduc- Any drug that alters platelet function may potentiate tion of warfarin activity probably as a consequence of warfarin action even though the prothrombin time re- diuresis concentrating the circulating clotting factors. mains unchanged1. Aspirin binds irreversibly to the ac- Bumetanide, furosemide and appear to have no tive site of cyclooxygenase in the prostacyclin synthethase effect on warfarin23. pathway, producing irreversible effects on platelet func- Certain cephalosporines, such as cefotetan, cefaman- tion which persist for the life of the aspirin-treated dole, cefoperazone, or moxalactam may cause marked platelet60, 61. Thus, even small doses of aspirin may affect hypoprothrombinemia and/or prolonged bleeding time haemostasis. Aspirin in high doses has a direct hypo- at concurrent use with warfarin38, 39, 40, 41. The main mecha- prothrombinemic effect62, 63. The dual impairment of nism of interaction consists in decreasing synthesis of haemostasis by the effect of aspirin on platelet activity vitamin K-dependent clotting factors. and by the effect of warfarin on fibrin formation causes Clofibrate may potentiate warfarin action, probably the increased susceptibility to hemorrhagic episodes64. by altering receptor sensitivity23, 37. Although clofibrate Of other salicylates, sodium salicylate, choline salicylate, displaces warfarin from albumin binding sites this does salsalate and magnesium salicylate have little effect on not appear to be a principal mechanism of the interac- platelet function and cause less gastrointestinal erosion tion42. and bleeding65, 66. Drugs altering thyroid function may affect anticoagu- Similar, but usually lesser effects on platelet func- lant control, since rates of synthesis and degradation of tion than aspirin may be seen with most other non- clotting factors are dependent on thyroid function7. Thy- steroidal anti-inflammatory drugs, such as phenylbutazone1. roid compounds do enhance the activity of oral antico- Indomethacin showed no interaction with warfarin in agulants by increased metabolism of clotting factors12. early study by Vesell, however, isolated reports are sug- Dextrothyroxine increases the anticoagulant effect of gestive of a clinically significant interaction between the warfarin43, 44. Antithyroid compounds may diminish the two drugs63, 68. It can also cause gastrointestinal ulcera- effect of anticoagulant45, although paradoxically pro- tion, hemorrhage, and inhibition of platelet aggrega- pylthiouracil has shown to cause hypoprothrombinae- tion19, 69, 70. Of the other non-steroidal anti-inflammatory mia12. The patients on anticoagulant therapy who are drugs, flurbiprofen71, meclofenamate sodium72, mefenamic Interactions of warfarin 29 acid73, 74, piroxicam75, sulindac76, 77, tiaprofenic acid78, venous thrombosis. Although the mechanism is not tolmetin sodium79 may potentiate the anticoagulant ef- known, possible causes include mesalazine inhibiting or fect. In many cases the result of concomitant therapy preventing the absorption of warfarin94. was an increased prothrombin time which may or may Limited data suggest that acarbose may enhance the not be clinically significant; in other cases haemorrhage anticoagulant effect of warfarin, possibly by increasing occurred. It should also be noted that for many of these warfarin absorption95. drugs no enhancement of warfarin activity has been demonstrated. The non-steroidal anti-inflammatory 2.2 Drugs causing protein binding displacement drugs with an apparently minimal effect on warfarin In practice, protein binding displacement has been activity include etodolac80, ibuprofen81, naproxen82 and shown to produce only transient rise in prothrombin tenidap83. time. The drugs frequently quoted as producing signifi- The effects on haemostasis are also seen rarely with cant interactions with warfarin by binding displacement penicillins, particularly carbenicillin and relative com- also interact by other mechanisms which are probably of pounds84. greater significance (e.g. phenylbutazone96, oxyphen- Abciximab, alteplase, clopidogrel, lepirudin and rete- butazone97, azapropazone97 and clofibrate37, 42). plase have an additive anticoagulant effect at concur- Diflunisal administered in the dose of 500 mg twice rent use with warfarin, thus they may significantly daily increased the percentage of unbound warfarin by enhance the risk of bleeding. 30%, but at the same time there was 28% fall in total Dipyridamole concurrently used with warfarin may plasma warfarin concentration. Thus, free warfarin con- cause bleeding without any alteration in prothrombin centration was unaltered and the prothrombin time re- time. This interaction has involved a small number of mained the same. When diflunisal was continued, patients85 and its mechanism consists in inhibition of warfarin binding rapidly returned to pre-diflunisal le- platelet function by dipyridamole. However, in general vels, but the total warfarin concentration remained de- it does not appear to increase the risk of bleeding. pressed for almost 2 weeks – this delay was presumably Ubidecarenone has been reported to reduce the ef- due to time taken for a new steady-state to be reached. fect of warfarin and decrease INR values. It is chemi- Hence, there was a reduction in the free warfarin con- 98 cally related to vitamin K2, and has been proposed to centration and a loss of anticoagulant effect . Mefenamic have procoagulational effects87. Patients should avoid acid74, etodolac80, ibuprofen81, 99 and tenidap83 may also concomitant use of ubidecarenone and warfarin. displace coumarin anticoagulants from protein binding sites. However, the influence of etodolac, ibuprofen and tenidap on warfarin anticoagulant effect is minimal. 2 Pharmacokinetic drug interactions Ethacrynic acid19, quinolone antibacterial nalidixic acid100, 101, 102 and some oral antidiabetic agent, such as Pharmacokinetic interactions include effects on war- glibenclamide103 and phenformin104, may enhance the ef- farin absorption, protein binding and metabolism. fect of warfarin due to displacement of warfarin from protein-binding sites. Although an interaction between 2.1 Drugs affecting warfarin absorption sulfonylureas and dicumarol has been documented, there many drugs might decrease the rate or completeness of are no clinical reports indicating that an interaction absorption of warfarin from the gastrointestinal tract, between warfarin and has occurred105. Simi- particularly compounds that raise gastric pH (e.g. anta- larly, no report documenting the interaction between 7 cids or H2-receptor antagonists), alter gastrointestinal insulin and warfarin is published . motility (e.g. laxatives, anticholinergic) or interfere with The concomitant use of chloral hydrate and warfarin normal mucosal function (e.g. neomycin). In addition, may result in a temporary increase in the hypopro- drugs that form complexes with anticoagulants (choles- thrombinemic effect of warfarin due to sudden increase tyramine) or non-absorbable oils that dissolve coumarins in the free blood levels of warfarin. In addition, a reduc- may reduce anticoagulant absorption18. Cholestyramine tion in the elimination half-life of warfarin may be ob- has been shown to influence warfarin absorption signifi- served. Although the majority of patients are minimally cantly. affected, some patients may develop a considerable in- Antacids may or may not interact with warfarin. Bis- crease in a hypoprothrombinemic response106, 107. The muth carbonate and magnesium trisilicate may reduce increase was probably the result of displacement of warfarin absorption88. Aluminium hydroxide and magne- warfarin from plasma protein binding sites by the meta- sium hydroxide had no effect on warfarin, but the latter bolite tricholoroacetic acid108. increased the plasma concentrations of dicoumarol89. Emergency contraception with progestogen (levon- Sucralfate may diminish the effect of warfarin90, 91, 92. orgestrel) may enhance the anticoagulant effect of war- A marked increase in the effect of warfarin has been farin109. One of the possible explanation of this reported in one patient taking cisapride93. interaction is displacement of warfarin from binding Mesalazine has been associated with a reduction in site F1S on alpha 1-acid glycoprotein by levonorgestrel110. the response to warfarin leading to development of 30 O. Řehulková

2.3 Drugs causing enzyme induction The effect of cimetidine on warfarin appears to be dose- Induction of hepatic microsomal mixed-function oxy- dependent135 and to be a subject of interindividual varia- genase activity is well recognised as a cause of inter- tion137, 138. Studies with ranitidine have generally been action with oral anticoagulants. Enzyme induction unable to demonstrate the effect on metabolism of war- increases the rate of metabolism of warfarin, decreases farin138, 139, although in one study warfarin clearance was plasma half-life and steady-state concentration, and reduced135. There is one case report suggesting that therefore reduces its anticoagulant effect. potentiation of warfarin by ranitidine may occasionally Enzyme induction appears to be a property shared occur140. No significant alteration in the pharmacokine- by all barbiturates111, though there are differences in the tics or the anticoagulant activity of warfarin developed potency of individual . The extensively stu- during the concomitant administration of famotidine141, 142. died inducing agent is phenobarbitone. The administra- Nizatidine had no effect on the anticoagulant response tion of phenobarbitone to patients receiving long-term to warfarin143. Omeprazole may inhibit the metabolism warfarin therapy produced a change in warfarin con- of R-warfarin144, but the clinically significant effect on centration and a loss of anticoagulant effect within 6 days. activity of warfarin is unlikely. Similarly, pantoprazole The maximum effect was usually seen within 2 weeks112. appears to have no effect on warfarin145. Amobarbital112, phenobarbital107, secobarbital107 has also and some of its metabolites inhibit the been reported to diminish pharmacological activity of reduction of R-warfarin to R,S-warfarin -1 and warfarin. A number of other hypnosedatives and anti- the oxidation of both R- and S-warfarin to phenolic convulsant drugs such as gluthethimide107, 113, 114, carba- metabolites. Potentiation of warfarin by amiodarone mazepine115, 116, 117, 118 and phenytoin119 induce metabolism probably depends upon inhibition of P4502C9, the of warfarin. do not interact significantly isoenzyme P450 mainly responsible for the conversion with warfarin1. Reduced anticoagulant activity has been of S-warfarin to its major metabolite (S)-7-hydroxy- reported with haloperidol120. The reduction is suggested warfarin146. Concurrent use of and warfarin to be caused by accelerated metabolism of anticoagu- has resulted in an increased warfarin concentration and lant secondary to stimulation of hepatic microsomal an increased prothrombin time. The mechanism of in- enzyme activity4. Meprobamate121, 122 and methaqualone107 teraction consists in decreasing warfarin clearance147. appear to have no effect on anticoagulants. Sulfinpyrazone has been reported to produce a bi- Other inducers include griseofulvin121, 123, 124 and ri- phasic effect on warfarin action. The initial effect was fampicin125, 126. Rifampicin is one of the most potent an increase in prothrombin time followed by a loss of inducers of microsomal enzyme activity. It increases the anticoagulant effect with continued treatment. It is likely rate of clearance of warfarin, thus reducing its anti- that more than one mechanism exists to explain this coagulant effect. The similar effects have been demon- phenomenon148. Sulfinpyrazone exerts stereoselective strated with nafcillin127 and dicloxacillin sodium128. effect on warfarin metabolism and inhibits S-isomer Phenazone, an inducer of enzyme metabolism, re- metabolic clearance149. It also affects platelets7. Allopu- duces plasma concentrations of warfarin and may ne- rinol may enhance warfarin effect by inhibition of its cessitate an increase in warfarin dosage12. metabolism150, 151. However, a number of case reports Concurrent use of aminoglutethimide and warfarin have demonstrated an inconsistent effect of allopurinol or other oral anticoagulants results in a reduced hypo- on warfarin therapy152, 153, 154. prothrombinemic effect130, 131, 132. Aminoglutethimide in- Phenylbutazone stereoselectively inhibits warfarin duces hepatic microsomal enzymes resulting in enhanced metabolism96. It was demonstrated that the drug inhib- metabolism of warfarin133. Concomitant administration its the metabolism of S-warfarin (more potent ena- of warfarin and mitotane has been associated with ntiomer) while increasing the rate of elimination of a reduction in anticoagulant effect of warfarin, necessita- R-warfarin. The net effect was an increased anticoagu- ting increased warfarin doses to maintain therapeutical lant response to a single dose of racemic warfarin, but prothrombin time134. It is speculated that the mitotane, no apparent change in the racemic warfarin half-life155. being related to organochlorine insecticides, may accele- The restricted use of phenylbutazone greatly reduces rate warfarin metabolism secondary to microsomal en- the chance of this potentially fatal interaction being zyme induction. observed. Related drugs such as oxyphenbutazone97, azapropazone156, 157, 158, and fenprazone159, 97 behave simi- 2.4 Drugs causing inhibition of metabolism larly and should also be avoided.

H2-receptor antagonists and proton pump inhibitors: Paracetamol was associated with an increased hypo- cimetidine may inhibit warfarin metabolism and po- prothrombinemic effect of warfarin. This interaction is tentiate its effect resulting in haemorrhage. However, proposed to be due to inhibition of its metabolism and more precise studies have shown that cimetidine has no interference with formation of clotting factors. Gingival effect upon the kinetics of more active S enantiomer and bleeding and hematuria were observed in case reports only has a moderate effect upon R enantiomer, reduc- when paracetamol is given with warfarin160, 161, 162, 163, 164. ing its plasma clearance135, 136, 137, 138. Not all these studies, However, due to lack of a safer alternative, paracetamol however, demonstrated an increase in prothrombin time. is still the analgesic and antipyretic of choice in patients Interactions of warfarin 31 receiving warfarin therapy, as long as excessive amounts Fluorouracil decreases synthesis of cytochrome P450 and prolonged administration are avoided165. A combi- 2C9 enzymes which metabolise warfarin and, therefore, nation of paracetamol and codeine has enhanced warfa- may enhance its anticoagulant effect199, 200, 201, 202, 203. rin activity163. The commonly used analgesic Tricyclic antidepressants, such as and (propoxyphene plus paracetamol) may potentiate the ef- nortryptiline, may increase the half-life of oral anticoa- fect of warfarin161, 166, 167, 168. gulants204, 205. However, considerable interindividual dif- Topical methyl salicylate may potentiate the antico- ferences may be found206. There is a theoretical risk of agulant effect of warfarin86, 169, probably by inhibition of increased warfarin activity with MAO inhibitors12, fluvo- warfarin metabolism. xamine207 and other selective serotonin reuptake inhibi- Metronidazole and co-trimoxazole (combination of tors. Increased warfarin activity has been reported in sulfamethoxazole and trimethoprim) strereoselectively a few patients taking fluoxetine208. inhibit the metabolism of S-warfarin170. The interaction Concomitant gemfibrozil and warfarin therapy has with co-trimoxazole is generally attributed to the sul- resulted in an increased hypoprothrombinemic response famethoxazole moiety and there are isolated reports and bleeding. The mechanism of this interaction in- suggesting that the activity of warfarin may be enhanced volves decreasing warfarin metabolism and displace- by other sulphonamides including sulphafurazole171, sul- ment of warfarin from protein by gemfibrozil209. phamethizole172 and suphaphenazole173. Lovastatin210 and fluvastatin211 may enhance the effect of Ketoconazole174, miconazole175, 176, 177, 178, fluconazo- warfarin. Simvastatin has been reported to potentiate le179, 180 and itraconazole181 have been reported to increase effect of nicoumalone in one patient212. However, it did warfarin effect probably due to inhibiting its metabo- not change the INR in a patient on long-term warfa- lism. rin213. Pravastatin does not appear to cause any change Enoxacin decreases the clearance of R-warfarin, but in warfarin activity214. not S-warfarin; no prolongation of prothrombin time Tobacco smoke contains many substances that may occurred182. affect the metabolism of warfarin. Some of these sub- Erythromycin inhibits warfarin metabolism and thus stances will inhibit the metabolism of warfarin, other may enhance the effect of warfarin183. An enhanced substances will induce its metabolism. The effect of response to warfarin has also been reported with azithro- smoking tobacco on warfarin metabolism may vary from mycin184, 185 and roxithromycin, including reports of spon- one patient to the next. The INR or prothrombin time taneous bleeding with the latter. Clarithromycin may should be monitored carefully if the patient begins or potentiate the effect of warfarin, although other factors stops smoking while taking warfarin215. may also have been involved in this case186. Isoniazid may enhance the effect of warfarin possibly 3 Interactions of uncertain and/or unknown mechanisms by inhibition of its metabolism187. Lipid-soluble β-blockers (e.g. ) inhibits Corticosteroids and corticotrophin may increase the warfarin metabolism and may thus potentiate the effect risk of localised bleeding within the gastrointestinal tract of warfarin. However, although a number of studies in patients taking warfarin1, 4, 216. These drugs may also have shown pharmacokinetic interactions between some diminish the effect of anticoagulants by unknown mecha- beta-blockers and oral anticoagulants, no effect on anti- nism217. coagulant activity has been found188. Quinolone antibacterials, such as ciprofloxacin218, 219, Influenza vaccine significantly increased prothrombin 220, 221, 222, 223, norfloxacin224 and ofloxacin225, 226 may in- time and bleeding in two warfarin-stabilised patients189. crease the activity warfarin, although for some of these Present data suggests this interaction does not occur in drugs there are also studies indicating no effect. How- most patients190, 191, 192. ever, in the 64 cases of ciprofloxacin-warfarin coagu- Increased anticoagulation and serum warfarin con- lopathy reported to the Food and Drug Administration’s centration necessitating a reduction in warfarin dosage Spontaneous Reporting System database between 1987 have been shown with interferon alfa and interferon beta. and 1997, the median age of the patient was 72 years old It was suggested this interaction may have been due to and the mean number of medications which the patient decreased metabolism of warfarin193. An enhanced re- was receiving was 6.5. It appears that this coagulopathy sponse to warfarin has also been reported with sa- is most prevalent in elderly patients who require polyp- quinavir194. The mechanism involves competitive harmacy227. inhibition of warfarin metabolism and might also occur Proguanil may enhance warfarin effect and increase with other HIV-protease inhibitors12. risk of bleeding228. Disulfiram may augment the activity of warfarin195, 196. The addition of etretinate to patients on warfarin Although inhibition of liver enzymes by disulfiram was therapy may cause a decrease in anticoagulant effect229. considered responsible197, a later study suggested that Tramadol has been reported to enhance anticoagu- disulfiram directly affecting the hepatic mechanism re- lant activity of warfarin129, 230, 231. sponsible for hypoprothrombinemia198. 32 O. Řehulková

Etoposide with vindesine232 or with carboplatin233, if combined with an anticoagulant agent such as warfa- ifosfamide with mesna234 and tamoxifen235, 236, 237 may all rin. produce an increased anticoagulant effect. The anti- Ginkgo biloba showed to inhibit the platelet activa- androgen flutamide may increase the prothrombin time ting factor necessary for arachidonate-dependent aggre- in patients on long-term warfarin12. Cyclophosphamide gability of platelets248. Co-administration of ginkgo and may increase49 (see section 1.2) and/or decrease in war- warfarin may result in increased risk of bleeding com- farin activity50. The mechanism of interaction leads to plications. Cases of cause bilateral subdural hematoma decreasing warfarin effect is unknown4. have been reported in patients taking ginkgo alone255, 256. Concurrent therapy with warfarin and cyclosporine Therefore, patients should not take gingko with any was associated with reduced effect of both drugs238, 239. anticoagulant. Moracizine may enhance the anticoagulant effect of The products containing ginseng which is usually warfarin240. obtained from Panax ginseng, Panax pseudoginseng var. Bezafibrate has been reported to enhance the effect notoginseng or Panax quinquefolius may reduces the of phenprocoumon241, and fenofibrate enhanced the ef- effect of warfarin248. The mechanism of this interaction fect of warfarin242. is not clear, but may be associated with anti-platelet Piracetam caused an increase in prothrombin time in effect of its components257, 258. Since ginseng was likely a patient stabilised on warfarin243. involved in the interaction with warfarin in a human Ascorbic acid at large doses may reduce the warfarin case report, ginseng is best avoided in patients taking activity244, 245 and high doses of vitamin A246 and vitamin anticoagulants with narrow therapeutic ranges. E247 may enhance the activity. St. John’s Wort may induce cytochrome P450 en- zymes, including CYP1A2259and CYP2C9260, augmen- ting warfarin metabolism. Concomitant use of warfarin INTERACTIONS WITH MEDICINAL HERBS with St. John’s Wort is not recommended. If patients elect to remain on St. John’s Wort, symptoms of de- At present, herbal drugs are used in increasing num- creased warfarin efficacy and prothrombin times should bers. Plant market experiences an unprecedented growth be closely monitored. A stable dose of St. John’s Wort is all over the world. Drugs made on the basis of medicinal recommended and patients should be advised not to herbs are generally perceived as harmless. Neverthe- discontinue St. John’s Wort without consulting their less, there are already known and/or potential possibly physician. threatening interactions between various drugs and me- Fenugreek (Trigonela phoenum-graecum) contains dicinal herbs248. coumarins which may affect blood coagulation261. Con- Of herbs, warfarin may interact with feverfew (Chry- comitant use of fenugreek and warfarin is not recom- santhemum parthenium), garlic (Allium sativum), ginger mended due to increased risk of bleeding. (Zingiber officinale), Ginkgo biloba, ginseng, St. John’s Wort (Hypericum perforatum), mountain arnica (Arnica montana), camomile (Chamomilla recutita), primrose DRUG-FOOD INTERACTIONS (Primula veris) and common celery (Apium graveolens). Feverfew inhibits platelet aggregation in vitro and Although serum levels of warfarin tend to be lower may alter bleeding time. Feverfew interfers with the when administered with food, the total amount of drug initial step of thromboxane synthesis, inhibiting the re- absorbed is unaffected262. Avocado pears263 and ice lease of the arachidonic acid substrate from platelet cream264 have been reported to cause antagonism of phospholipids249, 250. With diminished amounts of ara- warfarin, perhaps due to interference with absorption. chidonic acid, decreased amounts of the proaggregatory Foods high in vitamin K content or those foods capable prostaglandin thromboxane A2 will be formed, resul- of enhancing intestinal sources of vitamin K may an- ting in decreased platelet aggregation. Theoretically, tagonise the anticoagulant effect of warfarin265, 266. Grape- antiplatelet activity of feverfew could lead to additive fruit juice may enhance warfarin effect by inhibition of anticoagulant effects when combined with warfarin. R-warfarin metabolism mediated by CYP1A2 and Garlic possesses the antiplatelet activity251, 252, thus CYP3A4267. may potentiate effect of warfarin and increase the risk Long-term ethanol consumption caused the induc- of bleeding complications. Concomitant use of garlic tion of drug-metabolising enzymes268, but when ethanol and warfarin is not recommended. Garlic therapy should was administered acutely to volunteers, warfarin clea- be discontinued at least 10 days prior to elective sur- rance was decreased112. However, moderate intake of gery253. Regular ingestion of food products containing alcohol does not appear to affect anticoagulant con- small amounts of garlic should not pose a problem. trol58. Ginger has been reported to inhibit the synthesis of In the studies on animals, it was demonstrated that thromboxane, but clinical significance of such effect is dietary protein has an influence on the response to war- undetermined254. Theoretically, any affect of ginger on farin. Rats fed higher protein diets were more tolerant platelet aggregation could contribute to adverse effects to warfarin269, 270. A possible interpretation of the results Interactions of warfarin 33 implicates the influence of dietary protein on plasma also necessary in patients taking foods or nutritionals albumin concentrations. 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