Agents and Actions

427

vol. 8/4 (1978) Birkh~iuser Verlag, Basel

Aspirin and Prostaglandins: Some Recent Developments by M.J.H. SMITH Biochemical Pharmacology Research Unit, Department of Chemical Pathology, King's College Hospital Medical School, Denmark Hill, London SE5 8RX, England

/1 bstract

The results of experiments designed to test the validity of the hypothesis that the anti-inflammatory and antirheumatic aetlons of aspirin are due to the inhibition of prostaglandin synthetase activity are reviewed.

There are two main schools of thought with respect to the mechanism of the antiinflammatory and antirheumatic actions of aspirin. The proponents of a unifying hypothesis contend that these effects of the drug are mediated by inhibition of the biosynthesis of prostaglandins and allied prostanoids [1, 2]. The alternative view [3] is that aspirin exerts further and independent anti-inflammatory actions which are more relevant to its antirheumatic effects. Some recent observations have clarified several aspects of the controversy. An important question concerns the doses of aspirin necessary to elicit its various pharmacological and clinical effects. Much larger amounts of the d r u g are required to produce effective antirheumatic actions than are necessary for either analgesia [4] or inhibition of prostaglandin synthetase activity [5]. This situation is exemplified by the finding that doses of aspirin (600 mg per day), insufficient to cause a clinical antirheumatic effect, completely inhibit the activity of prostaglandin synthetase in synovial tissues removed from patients with rheumatoid arthritis [6]. Similar results in animal experiments have also been obtained in that doses of aspirin, markedly below those necessary to produce antiinflammatory actions, block both the aggregation of and the generation of thromboxane A 2 by blood platelets in the rat [7]. This is a clear-cut dissociation between the anti-inflammatory and antirheumatic effects of aspirin and its inhibitory

action on prostaglandin synthetase. The dose of indomethacin required to inhibit joint swelling in established monoarticular arthritis in the rabbit [8] is well in excess of that required to almost completely inhibit prostaglandin production in the rabbit knee joint [9]. It has been concluded [ 10] that these results provide a serious challenge to the exclusive role of inhibition of the enzyme system as a site of action of aspirin-like antiinflammatory drugs. When the rank order of the anti-inflammatory activities of non-steroidal acidic antiinflammatory drugs (NSAID) is compared to the order of potency against prostaglandin synthetase activity in vitro, a notable anomaly is sodium salicylate. This drug is equipotent to aspirin either as an experimental anti-inflammatory or as a clinical antirheumatic agent but is a very much weaker inhibitor of the synthetase enzyme in vitro [1]. Nevertheless when administered to the rat in comparable amounts, both drugs reduce the content of prostaglandins in developing inflammatory exudates, such as those formed in carrageenan-induced air blebs [11] and in implanted sponges [12]. One suggestion which has been advanced to explain this discrepancy is that salicylate is converted in vivo to an 'active metabolite', i.e. one that is comparable to aspirin in being a much more potent inhibitor of prostaglandin synthesis than salicylate [11]. The results of two recent studies in vivo fail to support this proposal. A dose of 200 mg kg -1 of salicylate had no effect on either the aggregation of or the formation of thromboxane A 2 by circulating rat platelets under conditions where a dose of 10 mg kg -1 of aspirin was inhibitory [7]. In the rabbit, sodium salicylate was inactive at a dose 25 times

428 greater than the dose of aspirin which protected 50% of the animals against death induced by the intravenous injection of arachidonic acid [13]. A more likely explanation is that the action of salicylate in vivo in inhibiting the formation of prostaglandins in inflammatory exudates is peculiar to the rat. In this species salicylate is only weakly bound to plasma proteins [ 14] and it has been shown that the drug accumulates very rapidly in sponge exudates [15]. The concentrations of the drug attained in such exudates in the rat are sufficient not only to inhibit prostaglandin synthetase activity but also to interfere with many other enzyme systems [16]. In other species, including man, salicylate is bound more extensively and firmly to the circulating proteins and will not achieve the concentrations of the free, i.e. non-protein bound, form of the drug which occurs in inflammatory exudates in the rat. The mechanism by which aspirin inhibits prostaglandin biosynthesis has also become much clearer. The O-acetyl group of the drug is capable of acetylating a large variety of other molecules, including proteins [17]. The non-enzymatic acetylation of prostaglandin cyclooxygenase, however, appears to be both a selective and quantitative process [18] near or within the active site of the enzyme. This irreversible inactivation of prostaglandin synthetase explains why aspirin is so effective as an inhibitor of the enzyme activity in vitro, e.g. against microsomal preparations, and when it is in contact in vivo with readily accessible tissues such as blood platelets [19]. In contrast, salicylate is virtually inactive against prostaglandin synthetase and even when weakly inhibitory activity is observed this must occur by a totally different mechanism. It is suggested that the experimental antiinflammatory and clinical antirheumatic effects of aspirin are due to its metabolic conversion to salicylate in the body. In this context, salicylate is the 'active metabolite' of aspirin. This is the mechanism by which aspirin, which has only a short half-life in vivo, is able to reduce carrageenan-induced paw oedema in animals raised on a diet so that their tissues are markedly deficient in the normal precursors of prostaglandins [20]. It also explains why aspirin and salicylate are equipotent in reducing the infiltration of leucocytes into inflammatory exudates since this effect is independent of an interaction with the prostaglandin synthetase system

Aspirin and Prostaglandins: Some Recent Developments

[21]. An interference of leucocyte emigration may play an equally important role in the antiinflammatory and antirheumatic actions of other NSAID including indomethacin [22] and flurbiprofen [23]. Received 15 December 1977.

References [1] S.H. FERREIRA, Prostaglandins and Non-Steroidal Anti-Inflammatory Drugs, in: Prostaglandins and Thromboxanes (Eds. F. Berti, B. Samuelsson and G.P. Velo; Plenum Press, N.Y., 1977), pp. 353-361. [2] S. MONCADAand J.R. VANE,Interaction betweenAntiInflammatory Drugs and Inflammatory Mediators. A Reference to Products of Arachidonic Acid Metabolism, in: Inflammation: Mechanisms and their Impact on Therapy (Eds. I.L. Bonta, J. Thompson and K. Brune; Agents and Actions Supplements 3, Birkh/iuser Verlag, Basel, 1977), pp. 141-148. [31 M.J.H. SMITH,Prostaglandins and Aspirin: An Alternative View, Agents and Actions 5, 315-317 (1975). [4] P.L. BOARDMANand F.D. HART, Clinical Measurements of the Anti-Inflammatory Effects of Salicylate in Rheumatoid Arthritis, Br. Med. J. 4, 264-268 (1967). [5] S.H. FERREIRA and J.R. VANE, New Aspects of the Mode of Action of Action of Non-Steroid AntiInflammatory Drugs, Ann. Rev. Pharmac. 14, 57-71 (1974). [6] D. CROOK, A.J. COLLINS,P.A. BACONand R. CHAN, Prostaglandin Synthetase Activity from Human Rheumatoid Synovial Microsomes, Ann. Rheum. Dis. 35, 327-332 (1976). [71 B.B. VARGAFTIG, Salicylic Acid Fails to Inhibit Generation of Throm3oxane A 2 Activity after in vivo Administration to the Rat, J. Pharm. Pharmac. 30, 101-104 (1978). [8] A. BLACKHAM and H. RADZIWONIK, The Effect of Drugs in Established Rabbit MonoarticuIar Arthritis, Agents and Actions 7, 473-480 (1977). [9] A. BLACKHAM,J.B. FARMER, H. RADZIWONIKand J. WESTWlCK, The Role of Prostaglandins in Rabbit Monoarticutar Arthritis, Br. J. Pharmac. 51, 35-44 (1974). [10] B.B. VARGAFTIG, Platelets and Inflammation, in: Inflammation: Mechanisms and their Impact on Therapy (Eds. I.L. Bonta, J. Thompson and K. Brune; Agents and Actions Supplements 3, Birkh~iuser Verlag, Basel, 1977), pp. 75-92. [11] A.L. WILLIS, R. DAVlSON, P.W. RAMWELL, W.D. BROCKLEHtJRSTand B. SMITrLRelease and Actions of Prostaglandins in Inflammation and Fever: Inhibition by Anti-Inflammatory and Antipyretic Drugs, in: Prostaglandins in Cellular Biology (Eds. P.W. RamweU and B.B. Pharris; Plenum Press, N.Y., 1972), pp. 227-259. [121 G.A. HIGGS, E.A. HARVEY, S.H. FERREIRAand J.R. VANE, The Effects of Anti-Inflammatory Drugs on the Production of Prostaglandins in vivo, in: Advances in Prostaglandin and Thromboxane Research, vol. 1 (Eds. B. Samuelsson and R. Paoletti; Raven Press, N.Y., 1976), pp. 105-110.

429

Aspirin and Prostaglandins: Some Recent Developments [13] G. DIPASQUALE and D. MELLACE, Inhibition of

Arachidonic Acid Induced Mortality in Rabbits with Several Non-Steroidal Anti-Inflammatory Agents, Agents and Actions 7, 481-485 (1977). [14] J.A. STURMAN and M.J.H. SMITH, The Binding of

Salicylate to Plasma Proteins in Different Species, J. Pharm. Pharmac. 19, 621-623 (1967). [15] N.S. DOHERTY, M. AATTILA and

P.B.

DEAN,

Penetration of Naproxen and Salieylate into Inflammatory Exudates in the Rat, Ann. Rheum. Dis. 36, 244-248 (1977). [16] M.J.H. SMITH and P.D. DAWKINS, Salicylate and Enzymes, J. Pharm. Pharmac. 23, 729-744 (1971). [17] R.N. PINCKARD,D. HAWKINSand R.S. FARR,In vitro

Acetylation of Plasma Proteins, Enzymes and DNA by Aspirin, Nature 219, 68-69 (1968). [18] T.Y. SHEN, Prostaglandin Synthetase Inhibitors, in: Prostaglandins and Thromboxanes (Eds. F. BERTI, B. SAMUELSSON and G.P. VELO; Plenum Press, N.Y., (1977), pp. 111-136. [19] D. CROOKand A.J. COLLINS,Comparison of Effects of

Aspirin and Indomethacin on Human Platelet Prostaglandin Synthetase, Ann. Rheum. Dis. 36, 459-463 (1977). [20] LL, BONTA,H. BULT,J.E. VINCENTand F.J. ZtrLSTRA,

Acute Anti-Inflammatory Effects of Aspirin and Dexamethazone in Rats Deprived of Endogenous Prostaglandin Precursors, J. Pharm. Pharmac. 29, 1-7 (1977). [21] M.J.H. SMITH, A.W. FORD-HUTCHINSONand P.N.C. ELLIOTT, Prostaglandins and the Anti-Inflammatory Activities of Aspirin and Sodium Salicylate, J. Pharm. Pharmac. 27, 473-478 (1975). [22] J.R. WALKER, M.J.H. SMIT~ and A.W. FOgDHUTCHrNSON, Antilnflammatory Drugs, Prostaglandins and Leucocyte Migration, Agents and Actions 6, 602-606 (1976). [23] A.W. FORD-HtrrCH~SON, J.R. WALKER, N.S. CONNO~ A.M. OLIVER and M.J.H. SMITH, Separate

Anti-Inflammatory Effects of Indomethacin, Flurbiprofen and Benoxaprofen, J. Pharm. Pharmac. 29, 372-373 (1977).

Aspirin and prostaglandins: some recent developments.

Agents and Actions 427 vol. 8/4 (1978) Birkh~iuser Verlag, Basel Aspirin and Prostaglandins: Some Recent Developments by M.J.H. SMITH Biochemical P...
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