Some aspects of the pharmacology of oral anticoagulants The pharmacology of oral anticoagulants ls discussed with particular rejerence to data of value in the management of therapy. The importance of individual variability in response and drug interaction is stressed. Other effects of these agents which may have clinical utility are noted. William W. Coon, M.D., and Park W. Willis 111, M.D., Ann Arbor, Mich. The Departments of Surgery (Section of General Surgery) and Medicine, University of Michigan Medical School In the twenty-five years sinee the isola­ dividual struetural features but by a com­ tion of the hemorrhagie faetor in spoiled bination of several: molecular shape, in­ sweet clever," the gradually inereasing creased aetivity with 6 membered hetero­ utilization of oral antieoagulants for the eyclic rings with a substituent in position prevention and therapy of thromboembolie 8 and with a methoxyl rather than a free disease has made them one of the most hydroxl group. Also important is the dernon­ widely used groups of pharmacologic stration that levorotatory warfarin is seven agents. This review is restrieted to as­ times more aetive than its enantiomer.F" peets of the pharmaeology of these agents As Hunter and Shepherd'" have pointed whieh may be important to their proper out, the failure to obtain a precise cor­ clinieal utilization. relation between strueture and antieoagu­ lant aetivity is "not surprising in view of Relation of structure to function the influence of small struetural changes The oral antieoagulants have been di­ on sueh variables as solubility, rate of ab­ vided into four main groups on the basis sorption, ease of distribution, degree of of ehemieal strueture (Fig. 1). binding by tissues or plasma protein and Although a number of investigators have rate of detoxieation and excretion." attempted to define the struetural char­ All eoumarin-type antieoagulants are 4­ aeteristies neeessary for the produetion of hydroxyeoumarins. Mead and associates an antieoagulant effeet, eaeh theory has have shown that 3-, 5-, 6-, 7-, and 8-hy­ been partially invalidated by the diseovery droxyeoumarins are phenolie in nature and of exeeptions. Arora and Mathur" have are metabolized in rabbits principally by reeently proposed that antieoagulant ac­ direct eonjugation with glueuronic and tivity of eoumarins is governed not by in- sulfuric acids. However, 4-hydroxyeou­ marin differs from its isomers in conju­ Supported by grants from the Michigan Heart Asso­ gating only with glucuronic acid. It forms ciation and Grant FR-üS383 from the National Institutes of Health. no ethereal sulfates since it is a relatively 312 Volume 11 Oral anticoagulants 313 Number3 1. Compounds with two coumarin rings: "Dicoumaro1s" OH R OH Bishydroxycoumarin R=H I eH-CO"""I Ethylbiscoumacetate R=COOC2HS m~ 0"""·~O cf 0 "I- 2. 3-substituted 4-hydroxycoumarins: IMono-coumaro1s" CH2CH3 Phenprocoumon R=CH~ OH ~R ~O)~O Warfarin 3. Cyclic acetals: "Cyclocoumarols" Cyclocumarol Rl-Q R2 CH3 R 3 CH3 4. Indandiones Phenindione R=-Q Diphenadione R=-COC.'bD Anisindione R=-o 0CH3 Chlorphenylindandione R=~Cl Fig, 1. Four main groups of oral anticogulants on the basis of chemical structure. strong acid with a pK of 5.8.98 This differ­ Newer agents ence may have pharmacologic implica­ A number of reports conceming new tions since almost all other naturally oc­ oral anticoagulants have appeared in the curring derivatives of coumarin are either past several years. Most have been newly 7-hydroxy derivatives or 7-0-ethers, and synthesized derivatives of 4-hydroxycou­ the 7-position may be more susceptible to marirr'" 48, 53, 67 or phenylindandione'": 113, biologic attack." 162 without unique properties or clinical 314 Coon and Willis Clinical Pharmacology and Therapeutics utility. The isolation of a complex 4­ tive or noncompetitive type. They propose phenylcoumarin with anticoagulant and that the action of an oral anticoagulant quinidine-like aetivity from an Indian me­ depends upon the irreversible inhibition dicinal plant" is of interest chiefly because of transport of vitamin K1 to its intraceUu­ of the rarity of naturally occurring 4-sub­ lar site of action in the liver." With a stituted coumarins. much larger dose of vitamin K1 , however, New compounds of potential interest this inhibition can be surmounted, pos si­ have recently been prepared by esterifica­ bly because vitamin K can enter the cell tion of polyvinyl alcohol with the lactone by an aIternate mechanism which cannot of bis 4-hydroxy-3-coumaryl acetie acid; be inhibited by oral anticoagulants." As the product is a copolymer of vinyl alco­ to its intracellular site of action, Olson-" hol and the vinyl ester of pelentanic acid. postulates that vitamin K may be necessary Fractions of varying molecular weight and for the derepression of a regulator gene degree of esterification have been ob­ which controls the synthesis of elotting tained. Anticoagulant activity has been ob­ factors and that an anticoagulant may in­ served in rabbits after oral or intravenous terfere with the action of vitamin K on administration of a fraction of 30,000 the repressor substance. There is no evi­ molecular weight; fractions of higher dence in support of any chemical altera­ molecular weight were very toxic, After a tion of prothrombin (or other cIotting Iac­ single dose, an anticoagulant effect was tors) or inhibition of its release or any observed for as long as 15 days; as with increased rate of utilization or degrada­ other coumarin derivatives, onset of a tion." measurable anticoagulant effect took place None of the oral anticoagulants has a after a lag period of 20 to 24 hours. An signincant anticoagulant effect when added unexpected aspect of these studies was the to blood in vitro. When these agents are ad­ discovery that this agent produced a pro­ ministered to animals or man, the func­ nounced increase in coagulation time of tional aetivities of several cIotting factors whole blood as weIl as prothrombin decrease. A decrease in activity of factor time.1 28 VII is followed sequentially by decreases in factors IX, X, and II (true prothrom­ Mechanism of action bin). The rate of decrease in functional The keto isomer of 4-hydroxycoumarin activity of these coagulation factors ap­ has a elose structural relationship to mena­ pe ars to be related to the half-lives of the dione ( vitamin K~). Substitution of a individual proteins. After termination of methoxy group for the methyl in menadi­ therapy, these elotting factors return to one (2-methyl-1,4 naphthoquinone) con­ normal levels in the same order." All anti­ verts this synthetic vitamin K into a com­ coagulants produce the same effect. John­ pound with anticoagulant activity.''" Cou­ son," who proposes that purffied pro­ marin and related anticoagulants are thrombin can be converted to factor VII thought to act by means of some antago­ or factor IX by varying the activators, has nistic effect upon the action of vitamin K. suggested that the actions of oral antico­ AIthough originally postulated to be com­ agulants on these multiple elotting factors petitive inhibitors of vitamin K, Lowen­ may be interrelated, possibly representing thaI and Macli'arlane'" have presented minor structural alterations of a single pro­ data derived from experiments with the tein. simultaneous administration of warfarin Inhibition of thrombosis and moderate doses of vitamin K1 to rats which they have interpreted as indicating The therapeutic value of oral anticoagu­ that the antagonism between these two lants in the prevention of thrombus forma­ agents is neither of the elassical competi- tion or inhibition of propagation of pre- Valurne 11 Oral anticoagulants 315 Nurnber3 existing thrombi has been attributed to stage prothrombin time, the less the inci­ their effects in reducing activities of the dence of thrombosis. Thrombus formation above-mentioned clotting factors. In recent in rats is not reduced by bishydroxycou­ years contradictory data have appeared marin unless prothrombin time is twice concerning a possible additional effect normal or greater; in fact, the incidence of upon platelet function. Platelets play an thrombosis in animals receiving a small important role in the initiation of throm­ dose of drug is higher than that in con­ bus formation, particularly in arteries. The trols." In experiments with "serum throm­ true effect of oral anticoagulant therapy bosis," the antithrombotic effect of bishy­ upon platelets is difficult to assess because droxycoumarin is demonstrable only if the of differences in experimental methods drug has been administered for one week (some in vitro, others in vivo) , different or more before thrombosis is produced animaI species, and measurement of differ­ (unless very massive doses of drug are ing effects ( adhesiveness, aggregation, administered).178 This delay in demonstra­ thrombus weight, etc.). In man, adequate tion of antithrombotic effect is not present doses of bishydroxycoumarin have been if thrombosis is produced by vascular in­ reported to bring ab out a prolongation of jury. 77 platelet survival and a decrease in platelet If a comparable delay in appearance of turnover and platelet adhesiveness.vv v"­ antithrombotic effect is present in human 161, 186 Inadequate dosage may have the beings with thrombotic disease, these find­ opposite eflect." Platelet-rich plasma from ings may have implications for clinical anticoagulant-treated patients tested in vi­ therapy. The thrombus produced by injec­ tro in the Chandler apparatus