Parasetamol ve siklooksijenaz enzim inhibisyonu

Year 2013, Volume: 30 Issue: 1s, 9 - 14, 28.11.2013

Osman Karakuş Fatih İlkaya , Mehmet Ziya Yılmaz

Abstract

Parasetamol yüz yılı aşkın süredir analjezik ve antipiretik olarak kullanılan güvenilir bir ilaçtır ancak parasetamolün etki mekanizması halen tam olarak anlaşılamamıştır. Her ne kadar siklooksijenaz (COX) enzim inhibisyonu da parasetamolün etki mekanizmasında rol oynasa da özellikle analjezik etki mekanizmasında serotonerjik ve opioiderjik sistem gibi diğer mekanizmaların da katkısı artık iyi bilinmektedir. Antiinflamatuar etkisinin ise çeşitli hayvan deneylerinde ve klinik araştırmalarda diğer non-steroid antiinflamatuar ilaçlara (NSAİİ) yaklaştığı belirtilse de romatoid artrit gibi otoimmün hastalıklardaki inflamasyona karşı etkisiz olması onun diğer NSAİİ’lar sınıfından ayrı tutulmasını gerektirmiştir. Parasetamol siklooksijenaz enzimini indirekt olarak inhibe eder. Bu inhibisyonun rölatif olarak yüksek peroksit varlığında ortadan kalktığı iddia edilmiştir. Düşük peroksit yoğunluğunun olduğu merkezi sinir sisteminde (MSS) siklooksijenaz enzim inhibisyonunun analjezi ve antipiretik etki oluşturduğu belirtilse de, peroksit yoğunluğunun fazla olduğu trombosit ve immün hücrelerde ise etkisinin olmadığı ve bu yüzden parasetamolün romatoid artrit gibi yüksek peroxidaz aktivitenin gözlendiği hastalıklarda etkisiz olduğu iddia edilmiştir. İkibinli yılların başlarında yeni bir COX enzim varyantı keşfedilmiş ve bunun COX-3 olarak adlandırılması parasetamolün etki mekanizmasında bu enzimin rolünün olabileceğini düşündürmüştür. Ancak yapılan çalışmalarda hem COX-3 enziminin tek başına ayrı bir enzim hem de parasetamol ile etkileşiminin olup olmadığı netlik kazanmamıştır. Bu derlemenin amacı parasetamolün COX enzim inhibisyonu üzerindeki etkileri konusunda okuyucuya bilgi vermektedir. 

Keywords

COX-1 enzimi, COX-2 enzimi, COX-3 enzimi, Parasetamol, Peroksit, Prostaglandin, Etki mekanizması

References

• Aronoff, D.M., Oates, J.A., Boutaud, O., 2006. New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin. Pharmacol. Ther. 79, 9-19.
• Ayoub, S.S., Colville-Nash, P.R., Willoughby, D.A., Botting, R.M., 2006. The involvement of a cyclooxygenase 1 gene-derived protein in the antinociceptive action of paracetamol in mice. Eur. J. Pharmacol. 538, 57-65.
• Bambai, B., Kulmacz, R.J., 2000. Prostaglandin H synthase. Effects of peroxidase cosubstrates on cyclooxygenase velocity. J. Biol. Cem. 275, 27608-27614.
• Bertolini, A., Ferrari, A., Ottani, A., Guerzoni, S., Tacchi, R., Leone, S., 2006. Paracetamol: New vistas of an old drug. CNS. Drug. Rev. 12, 250-275.
• Bhattacharya, S.K., Rao, P.J., Das, G.G., 1989. Effect of centrally administered prostaglandin D2 and some prostaglandin synthesis inhibitors on carrageenan-induced paw oedema in rats. J. Pharm. Pharmacol. 41, 569-571.
• Björkman, R., 1995. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat. Acta Anaesthesiol. Scand. 103, 1-44.
• Björkman, R., Hallman, K.M., Hedner, J., Hedner, T., Henning, M., 1994. Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. Pain. 57, 259-264.
• Boardman, P.L., Hart, F.D., 1967. Clinical measurement of the antiinflammatory effects of salicylates in rheumatoid arthritis. BMJ. 4, 264-268
• Botting, R., Ayoub, S.S., 2005. COX-3 and the mechanism of action of paracetamol/acetaminophen. Prostaglandins Leukotr. Ess. 72, 85-87.
• Boutaud, O., Aronoff, D.M., Richardson, J.H., Marnett, L.J., Oates, J.A., 2002. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. P. Natl. Acad. Sci. USA. 99, 7130-7135.
• Bujalska, M., 2004. Effect of nitric oxide synthase inhibition on antinociceptive action of different doses of acetaminophen. Pol. J. Pharmacol. 56, 605-610.
• Celik, M., Saricaoglu, F., Canbay, O., Dal, D., Uzumcigil, A., Leblebicioglu, G., Aypar, U., 2005. The analgesic effect of paracetamol when added to lidocaine for intravenous regional anesthesia. Akush Ginekol (Sofiia). 44, 50-54.
• Chandrasekharan, N.V., Dai, H., Roos, K.L., Evanson, N.K., Tomsik, J., Elton, T.S., Simmons, D.L., 2002. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. P.Natl. Acad. Sci. U.S.A. 99, 13926- 13931.
• Committee on Infectious Disease AAoP, 1982. Aspirin and Reye’s syndrome. Pediatrics. 69, 810.
• Courade, J.P., Besse, D., Delchambre, C., Hanoun, N., Hamon, M., Eschalier, A., Caussade F., Cloarec, A., 2001. Acetaminophen distribution in the rat central nervous system. Life Sci. 69, 1455-1464.
• Feldberg, W., Gupta, K.P., 1973. Pyrogen fever and prostaglandinlike activity in cerebrospinal fluid. J. Physiol. 228, 41-53.
• Flower, R.J., Vane, J.R., 1972. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamidophenol). Nature. 240, 410-411.
• Graham, G.G., Robins, S.A., Bryant, K.J., et al. 2001. Inhibition of prostaglandin synthesis in intact cells by paracetamol (acetaminophen). Inflammopharmacology. 9, 131-142.
• Graham, G.G., Scott, K.F., 2005. Mechanism of action of paracetamol. Am. J. Ther. 12, 46-55.
• Jenkins, C., Costello, J., Hodge, L., 2004. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ. 328, 434.
• Lages, B., Weiss, H.J., 1989. Inhibition of human trombosit function in vitro and ex vivo by acetaminophen. Thromb. Res. 53, 603-613.
• Lewis, A.J., Nelson, D.J., 1975. Sugrue M.F. On the ability of prostaglandin E1, and arachidonic acid to modulate experimentally induced oedema in the rat paw. Brit. J. Pharmacol. 55, 51-56.
• Lucas, R., Warner, T.D., Vojnovic, I., Mitchell, J.A., 2005. Cellular mechanisms of acetaminophen: Role of cyclo-oxygenase. FASEB J. 19, 635-637.
• Mallet, C., Daulhac, L., Bonnefont, J., Ledent, C., Etienne, M., Chapuy, E., Libert, F., Eschalier, A., 2008. Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain. 139, 190-200.
• Murakami, M., Naraba, H., Tanioka, T., Semmyo, N., Nakatani, Y., Kojima, F., Ikeda, T., Fueki, M., Ueno, A., Oh, S., Kudo, I., 2000. Regulation of prostaglandin E2 biosynthesis by membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J. Biol. Chem. 276, 32783-32792.
• Muth-Selbach, U.S., Tegeder, I., Brune, K., Geisslinger, G., 1999. Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation. Anesthesiology. 91, 231-239.
• Morse, H.N., 1978. Ueber eine neue Darstellengsmethode der Acetylamidophenole. Ber. Deutscher. Chem. Ges. 11, 232-233.
• Niemi, T.T., Backman, J.T., Syrjälä, M.T., Viinikka, L.U., 2000. Rosenberg PH. Trombosit dysfunction after intravenous ketorolac cand. 44, 69-74.
• Ouellet, M., Percival, M.D., 2001. Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. Arch. Biochem. Biophys. 387, 273-280.
• Pickering, G., Estève, V., Loriot, M.A., Eschalier, A., Dubray. C., 2008. Acetaminophen reinforces descending inhibitory pain pathways. Clin. Pharmacol. Ther. 84, 47-51.
• Raffa, R.B., Walker, E.A., Sterious, S.N., 2004. Opioid receptors and acetaminophen (paracetamol). Eur. J. Pharmacol. 503, 209-210.
• Ring, E.F., Collins, A.J., Bacon, P.A., Cosh, J.A., 1974. Quantitation of thermography in arthritis using multi-isothermal analysis. II. Effect of nonsteroidal anti-inflammatory therapy on thethermographic index. Ann. Rheum. Dis. 33, 353-356.
• Robak, J., Wieckowski, A., Gryglewski, R., 1978. The effect of 4-acetamidophenol on prostaglandin synthetase activity in bovine and ram seminal vesicle microsomes. Biochem. Pharmacol. 27, 393-396.
• Roca-Vinardell, A., Ortega-Alvaro, A., Gibert-Rahola, J., Micó, J.A., 2003. The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic administration of acetaminophen. Anesthesiology. 98, 741-747.
• Saeed, S.A., Cuthbert, J., 1977. On the mode of action and biochemical properties of anti-inflammatory drugs-II. Prostaglandins. 13, 565-575.
• Seppälä E, Nissilä, M., Isomäki, H., Nuotio, P., Nykänen, E., Laitinen, O., Vapaatalo, H., 1985. Comparison of the effects of different anti- inflammatory drugs on synovial fluid prostanoid concentrations in patients with rheumatoid arthritis. Clin. Rheumatol. 4, 315-320.
• Schwab, J.M., Schluesener, H.J., Laufer, S., 2003. COX-3: Just another COX or the solitary elusive target of paracetamol? Lancet. 361, 981-982.
• Skjelbred, P., Lokken, P., 1979. Paracetamol versus placebo: Effects on post-operative course. Eur. J. Clin. Pharmacol. 15, 27-33.
• Swierkosz, T.A., Jordan, L., McBride, M., McGough, K., Devlin, J., Botting, R.M., 2002. Actions of paracetamol on cyclooxygenases in tissue and cell homogenates of mouse and rabbit. Med. Sci. Monit. 8, 496-503.
• Tablov, B., Popov, I., Tablov, V., Radev, R., 2005. Administration of Perfalgan (paracetamol) for postoperative analgesia in obstetrics and gynaecology. Akush. Ginekol. (Sofiia). 44, 50-54.
• Vane, J.R., 1971. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol. 231, 232-235.
• Von, Mering, J., 1893. Beitrage zur Kenntniss der Antipyretica. Ter Monatsch. 7, 577-587.
• Vogiagis, D., Brown, W., Glare, E.M., O’Brien, P.E., 2001. Rat colorectal tumours treated with a range of non-steroidal antiinflammatory drugs show altered cyclooxygenase-2 and cyclooxygenase-1 splice variant mRNA expression levels. Carcinogenesis. 22, 869-874.