Drugs Affecting Therapy with Anticoagulants

Symposium on Hemorrhagic Disorders

Drugs Affecting Therapy with Anticoagu lants Joseph Eipe, MD., M.R.C'p.(Edin)*

Despite the prevailing controversy over their efficacy, anticoagulants are still widely employed in the management of thromboembolic disorders. Recently we have been increasingly aware of the phenomenon of drug interactions, and oral anticoagulants are the most widely studied compounds in this respect. Coumarin-type agents-particularly sodium warfarin (Coumadin)-are the most often prescribed anticoagulant drugs in the United States. An ever-increasing number of compounds, when administered simultaneously, are known to alter the response to anticoagulants, especially to the oral agents. Drugs can influence anticoagulants in both directions, some by potentiating their action and thus increasing the risk of hemorrhagic manifestations, others reducing their effectiveness.

PHYSIOLOGY AND MODE OF ACTION OF COUMARINS Link and his co-workers in 1941 identified 3,3' -methylene-bis(4hydroxycoumarin) (Dicumarol) as the toxic compound in spoiled sweet clover hay which was responsible for severe bleeding manifestations, often fatal for cattle. 23 Subsequently, several modifications of the parent compound became available for therapeutic use. The site of action of coumarins is the liver cell, where they act as antagonists to vitamin K, a fat-soluble vitamin. This vitamin is required by the liver for normal synthesis of four coagulation factors: prothrombin (factor II), factor VII, factor IX, and factor X. Vitamin K participates as the prosthetic group of enzyme systems responsible for the synthesis of these coagulation factors. The mechanism by which coumarins interfere with the action of vitamin K is not well understood, but it has been suggested that coumarins act as competitive inhibitors of vitamin K. The hypocoagulable state *Assistant Director, Department of Hematology, Cook County Hospital and Hektoen Institute

for Medical Research; Assistant Professor of Medicine, The Abraham Lincoln School of Medicine, University of Illinois, Chicago Medical Clinics of North America- Vol. 56, No. 1, January 1972 255

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produced by the decrease in the vitamin K-dependent clotting factors results in the suppression of fibrin clotting throughout the vascular tree. Some evidence exists to indicate that coumarin causes decreased platelet adhesiveness, but the significance of this during anticoagulant therapy is poorly understood . . Orally administered coumarins are completely absorbed from the small intestine. They are transported in the blood loosely bound to albumin. At therapeutic levels it is estimated that 97 per cent of these drugs are protein-bound. Coumarins are metabolized in the liver by enzymes located in the microsomes associated with endoplasmic reticulum in the hepatic parenchymal cells. Several other clinically useful compounds are metabolized in a similar manner. The degradation products, which possess no anticoagulant activity are excreted in the urine. The average half life of warfarin is estimated to be 42 hours, with wide variability (15 to 58 hours) in normal individuals. 27 Drugs can alter the effectiveness of coumarins by interacting at various stages of this metabolic pathway or by modulating the availability of vitamin K to liver.

DRUGS THAT MAY POTENTIATE THE EFFECT OF COUMARINS Drugs that decrease the availability of vitamin K are known to potentiate the effects of coumarins. Vitamin K is synthesized by the intestinal bacterial flora and supplied in the diet. Sulfonamides and antibiotics will suppress the growth of bacterial flora and will deplete one of these sources. This has been suggested as a cause for augmented hypoprothrombinemic responses in man and has been supported by animal ·experimental studies. However, recent controlled studies have shown that this becomes a significant factor only when the dietary supply of vitamin K is restricted as well. 14• 24 This problem is likely to be encountered when a patient taking coumarin is prepared with bowel-sterilizing antibiotics preoperatively and is on a restricted diet at the same time. l l Cholestyramine prevents absorption of vitamin K by trapping the bile salts necessary for its absorption. Phenothiazines may induce cholestasis with resulting diminished absorption of vitamin K. Drugs which displace coumarin from its binding protein will potentiate its action by making it more readily available to its site of biological action in the liver. The pyrazole derivative phenylbutazone is the best known example of a drug with this type of effect. It has been shown that the plasma concentration and biologic half-life of coumarins were significantly less when coumarins were given in conjunction with phenylbutazone than when the anticoagulant was administered alone. 1 This combination has also been shown to reduce the requirement of anticoagulant in a patient who has hereditary resistance to the prothrombinopenic effects of coumarins. In addition to this, phenylbutazone interferes with platelet function and can augment the bleeding tendency in patients on coumarin independent of its effect on the prothrombin time.

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Other drugs with similar properties include indomethacin, clofibrate, and sulfasoxasole. Certain drugs are known to compete with coumarins for its site of degradation in the liver. Diphenylhydantoin (Dilatin) and tolbutamide are examples of drugs which are metabolized in the liver in a manner similar to that of coumarins. Consequently, any of these drugs administered in combination will slow the metabolism of each other, with a delay of excretion leading to an increase of their blood level. Here reverse consequences can happen in the sense that a patient taking coumarins and tolbutamide together may develop hypo glycemia and a patient on coumarins and diphenylhydantoin is a potential risk for the development of diphenylhydantoin intoxication. On the contrary, if the patient who receives coumarins simultaneously with tolbutamide or diphenylhydantoin discontinues the latter, the degradation of coumarins is enhanced, thereby decreasing the effectiveness of the previously stable dosage schedule. Phenindione does not have similar effects on the metabolism of tolbutamide and is recommended as the anticoagulant of choice in cases of diabetics receiving tolbutamide. 22 Drugs such as chloramphenicol allegedly inhibit directly the activity of the degrading enzymes of coumarins. This is probably by virtue of their ability to suppress protein synthesis. In normal individuals chloramphenicol has been shown to increase the biological half-life of drugs such as tolbutamide, diphenylhydantoin, and coumarins. 6 A number of drugs are reported to act synergistically with coumarins by increasing the affinity of the hepatic anticoagulant receptor site for coumarin drugs. Plasma half-life of coumarins in this situation remain unchanged. Agents with antilipemic effect like clofibrate (Atromid-S) and d-thyroxine have similar modes of action. It was proposed that the hypolipemic effect of these drugs may cause a reduction in the plasma and hepatic levels of the lipid-soluble vitamin K. To support this concept, some investigators stated that patients with hypercholesterolemia require larger than usual doses of coumarin - a circumstance suggesting hypervitaminemia K. However, the validity of these statements is questioned, because it is now realized that these agents make the patients more sensitive to coumarins whether there is a change in the serum lipid levels or not. Anabolic steroids also potentiate the effect of coumarins by a similar mechanism. TlIis effect occurs in the absence of any detectable liver damage. Only the 17-alkyl substituted compounds like methandrostenolone (Dianabol) and norethandrolone (Nilevar) and oxymetholone are known to cause it, while others, norandrostenolone phenylpropionate (Durabolin) and methyltestosterone, have no such effect. Quinidine is also reported to potentiate the action of coumarin by increasing its affinity for the anticoagulant receptor site. Salicylates have many effects on hemostasis, including a coumarinlike hypoprothrombinemic action. The chemical similarity between these two compounds resides in the fact that salicylic acid is the primary degradation product of bishydroxycoumarin (Dicumarol) and it has been suggested that coumarins derive their effectiveness in vivo through the salicylic acid thus formed. When salicylates were given to rats on ar-

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tificial diets, a demonstrable decrease in prothrombin levels resulted, which could be corrected by vitamin K. In man, several studies evaluated the hypoprothrombinemic effect of salicylates, especially in patients receiving large doses for the treatment of rheumatic fever. Only a slight decrease in prothrombin levels occurred, and this was not sufficient to cause hemorrhagic manifestations. However, acetylsalicylic acid induces other more severe abnormalities in the hemostatic system. It interferes with platelet aggregation by inhibiting the release by a variety of stimuli of intrinsic adenosine diphosphate (ADP) from platelets. Salicylates on rare occasions will cause thrombocytopenia. Gastric irritation leading to hemorrhagic gastritis is a well established cause of gastrointestinal bleeding. Quick has reported that aspirin in relatively small doses (1.3 gm.) brings about the prolongation of the bleeding time in many normal subjects. 2R When patients on long-term anticoagulant therapy develop hemorrhagic manifestations after ingestion of moderate amounts of aspirin (about 3 gm. daily), bleeding is usually not the result of accentuation of a hypoprothrombinemic effect, but is due to the local irritation of the gastric mucosa in addition to the systemic effects on hemostasis. Alcohol has been suspected to be responsible for the augmented effects of oral anticoagulants. However, studies have shown that occasional imbibement of moderate or even large amounts of alcohol by patients stabilized on coumarin therapy will not alter their prothrombin time. 38 On the other hand, chronic alcoholics as a rule are unsuitable candidates for long-term anticoagulant therapy, because of the accompanying liver disease and the fact that they are quite unlikely to observe any type of complex therapeutic schedule. There are a number of other drugs which may cause augmentation of the hypoprothrombinemic effect of coumarins. These drugs have such effects only infrequently. The mechanisms by which most of these drugs exert their effect on anticoagulants is currently unknown. Phenyramidol (Analexin), a muscle relaxant, causes prolongation of prothrombin time and hemorrhagic manifestations when administered with oral anticoagulants. It is suggested that it inhibits the metabolism of oral anticoagulants by hepatic microsomal enzymatic inhibition. There have been reports of prolongation of prothrombin time secondary to administration of propylthiouracil. This is thought to be due to a factor V deficiency induced by this drug and probably does not alter the patient's response to coumarins. The effect does not appear to be due to its action upon the thyroid gland, for several studies have suggested that patients with myxedema usually have a decreased sensitivity to anticoagulants. When patients with myxedema return to the euthyroid state they require less anticoagulant. 20 As a rule these preparations will markedly augment the effects of coumarins. Cinchophen, which was used as a uricosuric and antirheumatic agent, has intensified the hypoprothrombinemic effect of oral anticoagulants in the absence of hepatic damage. Benziodarone (Amplivix), an antianginal agent, caused bleeding complications in patients receiving oral anticoagulants, and required reduction in anticoagulant dosage. Monamine oxidase inhibitors have been shown to potentiate the effect of coumarins when administered simultaneously and are potential risks in patients receiving oral anticoagulants, even though this fact lacks sufficient documentation. These compounds are known to interfere with platelet adhesiveness as well. Others like 6-mercaptopurine (Purinethol), acetaminophen

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(Paracetomal or Tylenol), methylphenidate (Ritalin), and glucagon are reported to have similar effects.

DRUGS THAT DECREASE THE EFFECT OFCOUMARINS The most important and well recognized group of compounds which opposes the action of coumarins are the hypnotics and sedatives, of which phenobarbital is the best known example. These drugs influence the effect of coumarins by a phenomenon referred to as "enzyme induction." They stimulate the synthesis of enzymes associated with the endoplasmic reticulum and increase the hepatic content of microsomal degradative enzymes. As a result of this increase in activity a number of drugs including coumarins are metabolized at a faster rate. It has been demonstrated that plasma levels of coumarins are lower when they are administered concomitantly with phenobarbital than when they are taken alone. This requires raising the coumarin dosage to achieve desired therapeutic levels. Conversely, when phenobarbital is discontinued, the dosage of coumarins should be carefully readjusted. Failing to do this will result in excessive depression of prothrombin levels and subsequent hemorrhagic consequences. Besides phenobarbital, other barbiturates with similar effect include secobarbital, amobarbital, and heptabarbital. Other compounds showing antagonism to the coumarins by similar mechanisms include glutethemide (Doriden), ethylchlorvynol (Placidyl), chlorobutanol (Chloretone), meprobamate, and griseofulvin. Chlordiazepoxide (Librium), diazepam (Valium), and haloperidol (Haldol) do not possess similar properties. It should be noted that many of the drugs mentioned are likely to be prescribed to patients who are on longterm anticoagulant treatment both in the hospital and at home. Addition or withdrawal requires readjusting of anticoagulant dosages. Chloral hydrate, another commonly used sedative, was found to decrease the plasma half-life of coumarins and was considered to antagonize oral anticoagulants in a manner analogous to that of barbiturates. Subsequently it was reported that chloral hydrate enhanced the hypoprothrombinemic effect of coumarins in spite of a reduction in the· plasma half-life of coumarin. This effect is now considered to be due to displacement of coumarins from their binding of protein, probably caused by trichloracetic acid, a metabolic product of chloral hydrate. A recent controlled study has shown that in the usual therapeutic dose chloral hydrate will not influence the effect of coumarins and can safely be used in patients undergoing long-term anticoagulant treatment. 13 Multivitamins containing vitamin K are said to reduce the effectiveness of coumarins. However, a review of the commercially available multivitamin preparations has revealed that vitamin K is not an ingredient of any of these products. There is some evidence to indicate that vitamin C in large doses will induce resistance to coumarins. Certain parenteral drug products Me buffered with ascorbic acid (such as tetracyclines). Whether this will have any influence on coumarins needs further evaluation.

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Estrogens and oral contraceptives may necessitate increasing the need for oral anticoagulants. This is perhaps due to a "hypercoagulable" state induced in this instance, which is similar to that reported in pregnant women. These compounds are shown to increase the amount of several clotting factors, including the vitamin K-dependent factors. Adrenocortical steroids are also stated to have a similar antagonistic effect on coumarins, but these reports are not well documented. Diuretics including mercurials and thiazides are shown to lessen the hypoprothrombinemic effect of coumarins in man and experimental animals. There is no satisfactory explanation for this phenomenon. An increased excretion of unchanged anticoagulants in the urine has not been demonstrated. The suggestion that the diuretic increases the concentration of clotting factors in the blood is not well documented either. A previously congested liver may synthesize coagulation factors at a normal rate when the congestion has been relieved by appropriate therapy including diuretics.

HEPARIN AND COUMARINS It is well documented, but probably not generally recognized, that heparin prolongs the Quick one stage prothrombin time. Heparin when administered concomitantly with oral anticoagulants will artefac tu ally influence the coumarin response. The prothrombin time in this instance depends to a large extent on the time interval between heparin administration and the collection of the blood sample. Consequently, when heparin administration is stopped, one might encounter a shortening of the prothrombin time which was considered an index of adequate coumarin dosage. This problem can be minimized if blood samples for prothrombin time determinations are drawn when the blood level of heparin becomes negligible. This varies somewhat with the route of administration and the amount given, but prothrombin time estimation 5 to 6 hours after the injection of heparin will be a satisfactory compromise. 25 Certain drugs which influence the platelet function despite their inability to augment the hypoprothrombinemic effect can cause hemorrhagic symptoms when administered concurrently with coumarins. The well known offender in this respect is aspirin and other preparations containing acetylsalicylic acid. Diphenhydramine, chlorpromazine, and dipyridamole also may accentuate the bleeding state by similar mode of action.

CONCLUSION Table 1 gives a list of drugs known to alter the responsiveness of coumarin anticoagulants. This will certainly become larger in time. New chemical compounds are being introduced at a rapid rate, and a few of these are bound to exhibit antagonism to coumarin derivatives. It is common practice today for patients to be given several medications at the same time. Unexpected alterations in the prothrombin time or similar tests during anticoagulant therapy are to be expected from a variety of

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Table 1.

Drugs That Affect the Hypoprothrombinemic Effect of Warfarin

DRUGS THAT MAY POTENTIATE THE EFFECT

Phenylbutazone Oxyphenylbutazone Salicylates Indomethacin (Indocin) Acetaminophen Clofibrate Bowel sterilizing antibiotics Chloramphenicol Sulfonamides Quinidine sulfate d-Thyroxin Anabolic steroids Methandrostenolone (Dianabol) N orethandrolone Oxymethalone Diphenylhydantoin (Dilantin) Tolbutamide Cincophen 6-mercaptopurine (Purinethol) Phenyramidol (Analexin) Monamine oxidase inhibitors Methylphenidate (Ritalin)

DRUGS THAT MAY REFERENCES

16 40 17 2 18 14 6 33 21 20, 36 28 33 31 15 22 19 3 4, 36 30 12

RETARD THE EFFECT

REFERENCES

Barbiturates Phenobarbital (Luminal) Secobarbital (Seconal) Amobarbital (Amy tal) Heptabarbital (Medomin) Meprobamate Glutethamide (Doriden) Ethylchlorvynol (Placidyl) Griseofulvin Estrogen Adrenocorticosteroids Oral contraceptive agents Diuretics (mercurials and thiazides) Vitamin C

18

18 18 7 7 38 5 38 10 31

factors, including physiologic, metabolic, hereditary, and psychologic influences as well as drug interactions, But the latter appear to be the most important. Whenever a drug is added to or deleted from a patient's therapeutic regimen, it should be considered as potentially causing an alteration in anticoagulant effectiveness, and treatment should be monitored closely. Finally it should be remembered that anticoagulants can interfere with the action of certain other drugs with hazardous consequences.

REFERENCES 1. Aggeler, P. M., O'Reilly, R. A., Leong, L., and Kowitz, P. E.: Potentiation of anticoagulant effect of warfarin by phenylbutazone. New Eng. J. Med .. 276:496-501. 1967. 2. Antlitz, A. M., Mead, J. A., Jr., and Tolentino, M. A.: Potentiation of oral anticoagulant therapy by acetaminophen. Curr. Ther. Res., 10:501-507, 1968. 3. Buu-Hoi, N. P., and Hien, D. P.: Potentiation of the anticoagulant effects of antivitamins K by 6-mercaptopurine. Naturwissenschaften, 55:134,1968. 4. Carter, S. A.: Potentiation of the effect of orally administered anticoagulants by phenyramidol hydrochloride. New Eng. J. Med., 273:423-426,1965. 5. Chatterjea, J. B., and Salomon, L.: Antagonistic effect of ACTH and cortisone on anticoagulant activity of ethyl biscoumacetate. Brit. Med. J., 2:790-792,1954. 6. Christensen,' L. K., and Skovsted, L.: Inhibition of drug metabolism by chloramphenicoL Lancet., 2:1397-1399,1969. 7. Cullen, S. I., and Catalano, P. M.: Griseofulvin-warfarin antagonism. J.A.M.A., 199:582-583,1967. 8. Deykin, D.: Current concepts: Warfarin therapy. New t;ng. J. Med., 283:691-694, 801-803, 1970. 9. Douglas, A. S.: Current status of anticoagulant treatment. In Poller, L., ed.: Recent Advances in Blood Coagulation. Boston, Little, Brown & Co., 1969, pp. 107-135.

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10. Egeberg, 0.: Effect of edema drainage on the blood clotting system. Scand. J. Clin. Lab. Invest., 15:14-19, 1963. 11. Frick, P. G., Riedler, G., and Brogli, H.: Dose response and minimal daily requirement for vitamin K in man. J. Appl. Physiol., 23:387-389, 1967. 12. Garrettson, L. K., Perel, J. M., and Day ton, P. G.: Methylphenidate interaction with both anticonvulsants and ethylbiscoumacetate. New action of methylphenidate. J.A.M.A., 207:2053-2056, 1969. 13. Griner, P. F., Raisz, L. G., Rickles, F. R, Wiesner, P. J., and Odoroff, C. L.: Chloral hydrate and warfarin interaction: Clinical significance. Ann. Intern. Med., 74:540-544, 1971. 14. Haden, H. T.: Vitamin K deficiency associated with prolonged antibiotic administration. Arch. Intern. Med., 100:986-988, 1957. 15. Hansen, J. M.: Dicoumarol-induced diphenylhydantoin intoxication. Lancet, 2:265-266, 1966. 16. Hobbs, C. B., Miller, A. L., and Thornley, J. H.: Potentiation of anticoagulant therapy by oxyphenylbutazone. Post Graduate Medical Journal, 41 :563-565, 1965. 17. Hoffbrand and Kininmonth: Potentiation of anticoagulants (Letter). Brit. Med. J., 2:838-839, 1967. 18. Hunninghake, D. B., and Azarnoff, D. L.: Drug interactions with warfarin. Arch. Intern. Med., 121:349-352, 1968. 19. Jarnum, S.: Cinchophen and acetylsalicylic acid in anticoagulant treatment. Scand. J. Clin. Lab. Invest., 6:91-93, 1954. 20. J ones, R J., and Cohen, L.: Sodium dextro-thyroxine in coronary disease and hypercholesteremia. Circulation, 24:164-170,1961. 21. Koch-Weser, J.: Quinidine-induced hypoprothrombinemic hemorrhage in patients on chronic warfarin therapy. Ann. Intern. Med., 68:511-517, 1968. 22. Kristensen, M., and Hansen, J. M.: Potentiation of tolbutamide effect by dicoumarol. Diabetes, 16:211-214, 1967. 23. Link, K. P.: The discovery of dicumarol and its sequels. Circulation, 19:97-107, 1959. 24. Messinger, W. J., and Samet, C. M.: Effect of a bowel sterilizing antibiotic on blood coagulation mechanisms. The anti-cholesterol effect of paromomycin. Angiology, 16:29-36, 1967. 25. Moser, K. M., and Hajjar, G. C.: Effect of heparin on the one-stage prothrombin time. Source of artifactual "resistance" to prothrombinopenic therapy. Ann. Intern. Med., 66: 1207-1213, 1967. 26. O'Reilly, R A., and Aggeler, P. M.: Determinants of the response to oral anticoagulant drugs in man. Pharmacological Reviews, 22:36-96, 1970. 27. O'Reilly, RA., Aggeler, P. M., and Leong, L. S.: Studies on the coumarin anticoagulant drugs: The pharmacodynamics of warfarin in man. J. Clin. Invest., 43:1542-1551, 1963. 28. Pyorata, K., and Kekki, M.: Decreased anticoagulant tolerance during methandrostenolone therapy. Scand. J. Clin. Invest., 15:367-371, 1963. 29. Quick, A. J.: Salicylates and bleeding. The aspirin tolerance test. Amer. J. Med. Sci., 252:265-269, 1966. 30. Reber, K., and Studer, A.: Beeinflussung der Wirkung einiger indirekter durch Monoaminoxydase-Hemmer. Thromb. Diath. Haemorrh., 14:83-87, 1965. 31. Robinson, B. H. B., Hawkins, J. B., and Ellis, J. E.: Decrease anticoagulant tolerance with oxymethalone (Letter). Lancet, 1: 1356, 1971. 32. Rosenthal, G.: Interaction of ascorbic acid and warfarin. J.A.M.A., 215:1671,1971. 33. Schrogie, J. J., and Solomon, H. M.: Anticoagulant response to bishydroxycoumarin. 11. Effect of d-thyroxine, clofibrate and norethandrolone. Clin. Pharmacol. Ther., 8:70-77, 1967. 34. Seegers, W. H.: Influence of certain drugs on blood coagulation and related phenomena. Pharmacol. Rev., 3:278-344, 1951. 35. Sigell, L. T., and Flessa, H. C.: Drug interaction with anticoagulants. J.A.M.A., 24:2035-2038, 1970. 36. Solomon, H. M., and Schrogie, J. J.: Effect of phenyramidol on the metabolism of diphenylhydantoin. Clin. Pharmacol. Ther., 8:554-556, 1967. 37. Solomon, H. M., and Schrogie, J. J.: Change in receptor site affinity: a proposed explanation for the potentiating effect of d-thyroxine on the anticoagulant response to warfarin. Clin. Pharmacol. Ther., 8:797-799,1967. 38. Ulutin, O. N.: Sex hormones and blood coagulability. In Poller, L., ed.: Recent Advances in Blood Coagulation. Boston, Little, Brown & Co., 1969, pp. 215-228. 39. Waris, E.: Effect of ethyl alcohol on some coagulation factors in man during anticoagulant therapy. Ann. Med. Exp. Bio. Fenn., 41 :54-59, 1963. 40. Watson, R M., and Piers on, R M., Jr.: Effect of anticoagulant therapy upon aspirininduced gastrointestinal bleeding. Circulation, 24:613-616, 1961. Cook County Hospital Chicago, Illinois 60612