Brazilian Journal of Anesthesiology
https://app.periodikos.com.br/journal/rba/article/doi/10.1590/S0034-70942004000300017
Brazilian Journal of Anesthesiology
Review Article

Analgésicos inibidores específicos da ciclooxigenase-2: avanços terapêuticos

Specific cyclooxygenase-2 inhibitor analgesics: therapeutic advances

Wilson Andrade Carvalho; Rosemary Duarte Sales Carvalho; Fabrício Rios-Santos

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Resumo

JUSTIFICATIVA E OBJETIVOS: Os antiinflamatórios não-esteroidais (AINE) estão entre as drogas mais prescritas e usadas no mundo, incluindo a utilização em Anestesiologia. O propósito desta revisão é discutir alguns aspectos atuais da bioquímica da ciclooxigenase, que vem servindo de base para o desenvolvimento dos novos AINE. CONTEÚDO: Estas drogas exercem suas ações principalmente através da inibição da ciclooxigenase (COX), a enzima chave que catalisa a conversão de ácido araquidônico em prostaglandinas e tromboxanos. Pelo menos duas isoformas da COX já foram identificadas, a COX-1, que é constitutivamente expressa na maioria dos tecidos, e a COX-2, que é uma forma induzível da enzima localizada principalmente nas células e tecidos envolvidos em processos inflamatórios. Com a descoberta da COX-2 e a determinação de sua estrutura, foi possível desenvolver drogas mais seletivas que reduzem a inflamação sem afetar a COX-1, protetora do estômago e rins, dando origem a uma nova geração de compostos antiinflamatórios denominados de inibidores específicos da COX-2. CONCLUSÕES: Embora estes compostos de última geração apresentem menor toxicidade para o trato gastrintestinal, outros efeitos adversos graves têm sido observados, incluindo insuficiência renal e efeitos cardiovasculares, como o infarto agudo do miocárdio e a trombose. A despeito destes efeitos colaterais, estes novos fármacos estão sendo testados em outras condições clínicas, principalmente no tratamento preventivo do câncer e da doença de Alzheimer.

Palavras-chave

ANTIINFLAMATÓRIOS, DOR, DOR

Abstract

BACKGROUND AND OBJECTIVES: Nonsteroidal Anti-inflammatory Drugs (NSAIDs) are among the most widely prescribed drugs, including for Anesthesiology. This review aimed at discussing some current cycloxygenase biochemical aspects, which have provided the basis for the development of new analgesic and anti-inflammatory drugs. CONTENTS: These drugs primarily act by inhibiting cycloxygenase (COX), which is the key-enzyme catalyzing the conversion of arachidonic acid into prostaglandins and thromboxane. At least two COX isoforms have already been identified: COX-1, which is constitutively expressed in most tissues, and the inducible enzyme COX-2, which is primarily found in inflammatory cells and tissues. The discovery of COX-2 has enabled the development of more selective drugs to decrease inflammation without affecting COX-1 that protects stomach and kidneys and giving origin to a new generation of anti-inflammatory compounds called specific COX-2 inhibitors. CONCLUSIONS: Although there is significantly lower gastrointestinal toxicity in patients treated with selective COX-2 inhibitors, other severe adverse effects have been observed, including renal failure and cardiovascular effects, such as myocardial infarction acute and thrombosis. Despite these potential side effects, these new drugs are being tested in different clinical conditions, especially in cancer prevention and Alzheimer's disease.

Keywords

ANTI-INFLAMMATORY, PAIN, PAIN

References

Dubois RN, Abramson SB, Crofford L. Cycloxygenase in biology and disease. FASEB J. 1998;12:1063-1073.

Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232-235.

DeWitt DL, Smith WL. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci. 1988;85:1412-1416.

Kujubu DA, Fletcher BS, Varnum BC. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/ciclooxygenase homologue. J Biol Chem. 1991;266:12866-12872.

Xie W, Chipman JG, Robertson DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci. 1991;88:2692-2696.

Crofford LJ. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol. 1997;24:15-19.

Vane JR, Bakhle YS, Botting RM. Cyclooxygenase 1 and 2. Annu Rev Pharmacol Toxicol. 1998;38:97-120.

Kulkarni SK, Jain NK, Singh A. Cyclooxygenase isoenzymes and newer therapeutic potential for selective COX-2 inhibitors. Methods Find Exp Clin Pharmacol. 2000;22:291-298.

Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxigenase-2. N Engl J Med. 2001;345:433-442.

Carvalho WA, Lemonica L. Mecanismos Celulares e Moleculares da Dor Inflamatória: Modulação Periférica e Avanços Terapêuticos. Temas de Anestesiologia: Curso de Graduação em Medicina. 2000:265-280.

Chandrasekharan NV, Dai H, Roos KL. COX-3, a cyclooxygensase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci. 2002;99:13926-13931.

Janeway CA, Travers P, Walport M. Immunobiology: The Immune System in Health and Disease. 2001.

Morrow JD, Roberts LJ. Lipid-Derived Autacoids: Eicosanoids and Platelet-Activating Factor. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 2001:669-685.

Carvalho WA. Analgésicos, Antipiréticos e Antiinflamatórios. Farmacologia. 2002:431-455.

Samuelsson B, Granstrom E, Green K. Prostaglandins. Ann Rev Biochem. 1975;44:669-694.

Samuelsson B. The leukotrienens: a new group of biologically active compounds including SRS-A. Trends Pharmacol Sci. 1980;1:227-230.

Carvalho WA. Mecanismos de ação das drogas anti- inflamatórias não-esteróides: I. Ações farmacológicas das prostaglandinas e leucotrienos. F Med. 1990;100:37-44.

Carvalho WA. Mecanismos de ação de drogas antiinflamatórias não-esteróides: II. Ações analgésicas, antiinflamatórias e antipiréticas. F Med. 1990;100:111-122.

Raz A, Wyche A, Needleman P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases. Proc Natl Acad Sci. 1989;86:1657-1661.

Fu JY, Masferrer JL, Seibert K. The induction and suppression of prostaglandin H2 synthase (cyclooxigenase) in human monocytes. J Biol Chem. 1990;265:16737-16740.

Mitchell JA, Akarasereenont P, Thiemermann C. Selectivity of nonsteroid anti-inflammatory drugs as inhibitors of constitutive and inducible ciclooxygenase. Proc Natl Acad Sci. 1993;90:11693-11697.

Meade EA, Smith WL, Dewitt DL. Differential inhibition of spinal nociceptive processing. Pain. 1993:9-43.

Vane JR, Bottingg RM. New insights into the mode of action of anti-inflammatory drugs. Inflamm Res. 1995:1-10.

Jouzeau Y, Terlain B, Abid A. Cyclo-oxygenase isoenzymes: How recent findings affect thinking about nonsteroidal anti-inflammatory drugs. Drugs. 1997;53:563-582.

Morisset S, Patry C, Lora, M. Regulation of cyclooxygense-2 expression in bovine chondrocytes in culture by interleukin 1alpha, tumor necrosis factor-alpha, glucocorticoids, and 17beta-estradiol. J Rheumatol. 1998;25:1146-1153.

Hinz B, Brune K. Cyclooxygenase-2 10 years later. J. Pharmacol. Exp Ther. 2002;300:367-375.

Kurumbail RG, Stevens AM, Gierse JK. Structural basis for selective inhibition of cyclooxigenase-2 by anti-inflammatory agents. Nature. 1996;384:644-648.

Cryer B, Dubois A. The advent of higly selective inhibitors of cyclooxigenase: A review. Prostaglandins. 1998;56:341-361.

Needleman P. In search of a better NSAID. Proceedings. 1994:6-10.

Devchand PR, Keller H, Peters JH. The PPARalpha- leukotriene B4 pathway to inflammatory control. Nature. 1996;384:39-43.

Hla T, Bishop-Bailey D, Liu CH. Cyclooxygenase-1 and -2 isoenzymes. Int J Bioch Cell Biol. 1999;31:551-557.

Coleman RA, Smith WL, Narumiya S. International Union of Pharmacology classification of prostanoid receptors and clinical potential distribution, and structure of the receptors and their subtypes. Pharmacol Rev. 1994;46:205-229.

Graziano MP, Gilman AG. Guanine nucleotide-binding regulatory protein: mediators of transmembrane signaling. Trends Pharmacol Sci. 1987;8:478-481.

Colville-Nash PR, Qureshi SS, Willis D. Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: correlation with induction of heme oxygenase 1. J Immunol. 1998;161:978-984.

Gilroy DW, Tomlinson A, Willoughby DA. Differential effects of inhibition of isoforms of cyclooxygenase (COX-1, COX-2) in chronic inflammation. Inflamm Res. 1998;47:79-85.

Gilroy DW, Colville-Nash PR, Willis D. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med. 1999;5:698-701.

Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998;391:82-86.

Ricote M, Huang J, Fajas L. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA. 1998;95:7614-7619.

Ricote M, Li AC, Willson TM. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79-82.

Willoughby DA, Moore AR, Colville-Nash PR. COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease. Lancet. 2000;355:646-648.

Carvalho WA, Lemonica L. Mecanismos Centrais de Transmissão e de Modulação da Dor: Atualização Terapêutica. Temas de Anestesiologia: para o Curso de Graduação em Medicina. 2000:281-296.

Ferreira SH, Vane JR. Mode of Action of Anti-Inflammatory Agents which are Prostaglandin Synthetase Inhibitory. Anti-Inflammatory Drugs. 1979:348-398.

Moncada S, Ferreira SH, Vane JR. Pain and Inflammatory Mediators. Hand Books of Experimental Inflammation. 1978:588-616.

Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev. 1978;30:293-331.

Piper P, Vane J. The release of prostaglandins from lung and other tissues. Ann N Y Acad Sci. 1971;180:383-385.

Fischer JW, Gross DM. Effects of Prostaglandins on Erythropoiesis. Prostaglandins in Haematology. 1977:159-185.

Cohn SM, Schloemann S, Tessner T. Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1. J Clin Invest. 1997;99:1367-1379.

Yamagata K, Andreasson KI, Kaufmann WE. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and gluccorticoids. Neuron. 1993;11:371-386.

Breder C, Saper CB. Expression of inducible cycloxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolyssaccharide. Brain Res. 1996;713:64-69.

Kaufmann WE, Worley PF, Pegg J. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci. 1996;93:2317-2321.

Fiebich BL, Hull M, Lieb K. Prostaglandin E2 induces interleukin-6 synthesis in human astrocytoma cells. J Neurochem. 1997;68:704-709.

Panara MR, Renda G, Sciulli MG. Dose-dependent inhibition of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by meloxicam in healthy subjects. J Pharmacol Exp Ther. 1999;290:276-280.

Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase 1. Nature. 1994;367:243-249.

Hull M, Lieb K, Fiebich BL. Anti-inflammatory drugs: a hope for Alzheimer's disease?. Expert Opin Investig Drugs. 2000;9:671-683.

Hawkeu CJ. COX-2 Inhibitors. Nature. 1999;353:307-314.

Williams CS, Smalley W, DuBois RN. Aspirin use and potential mechanisms for coloretal cancer prevention. J Clin Invest. 1997;100:1325-1329.

Baron JA, Cole BF, Sandler RS. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003;348:891-899.

Sandler RS, Halabi S, Baron JA. A randomized trial of aspirin to prevent corectal adenomas in patients with previous colorectal cancer. N Engl J Med. 2003;348:883-890.

Zhang Z, DuBois RN. Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor. Oncogene. 2001;20:4450-4456.

Steinbach G, Lynch PM, Phillips RKS. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Eng J Med. 2000;342:1946-1952.

Kundu N, Fulton AM. Selective cyclooxygenase COX-1 or COX-2 inhibits control metastatic disease in a murine model of breast cancer. Cancer Res. 2002;62:2343-2346.

Kaur BS, Khamnehei N, Iravani M. Rofecoxib inhibits cyclooxygenase-2 expression and activity and reduces cell proliferation in Barrett's esophagus. Gastroenterology. 2002;123:60-67.

Singh-Ranger G, Mokbel K. Current concepts in cyclooxygenase inhibition in breast cancer. J Clin Pharm Ther. 2002;27:321-327.

Wu GD. A nuclear receptor to prevent colon cancer. N Engl J Med. 2000;342:651-653.

He TC, Chan TA, Kinzler KW. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999;99:335-345.

Barnes CJ, Lee M. Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli min mouse model with aspirin. Gastroenterology. 1998;114:873-877.

Lynch HT, Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919-932.

Badawi AF, Badr MZ. Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma and levels of prostaglandin E2 and 15-deoxy-delta12,14-prostaglandin J2 in human breast cancer and metastasis. Int J Cancer. 2003;103:84-90.

Eibl G, Reber HA, Wente MN. The selective cyclooxygenase-2 inhibitor nimesulide induces apoptosis in pancreatic cancer cells independent of COX-2. Pancreas. 2003;26:33-41.

Subongkot S, Frame D, Leslie W. Selective cyclooxygenase-2 inhibition: a target in cancer prevention and treatment. Pharmacotherapy. 2003;23:9-28.

Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954-959.

Mukherjee D, Nissen SE, Topol EJ. COX-2 inhibitors and cardiovascular risk: we defend our data and suggest caution. Cleve Clin J Med. 2001;68:963-964.

Whelton A. Renal aspects of treatment with conventional nonsteroidal anti-inflammatory drugs versus cyclooxygenase-2 specific inhibitors. Am J Med. 2001;110(^sSuppl):33S-42S.

Grob M, Scheidegger P, Wuthrich B. Allergic skin reaction to celecoxib. Dermatology. 2000;201:383.

Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides?: Revisiting the meaning of 'sulfa' allergy. Drug Saf. 2001;24:239-247.

Ahmad SR, Kortepeter C, Brinker A. Renal failure associated with the use of celecoxib and rofecoxib. Drug Saf. 2002;25:537-544.

Ernst EJ, Egge JA. Celecoxib-induced erythema multiforme with glyburide cross-reactivity. Pharmacotherapy. 2002;22:637-640.

Rocha JL, Fernandez-Alonso J. Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet. 2001;357:1946-1947.

Schneider F, Meziani F, Chartier C. Fatal allergic vasculitis associated with celecoxib. Lancet. 2002;359:852-853.

FitzGerald GA. Parsing an enigma: the pharmacodynamics of aspirin resistance. Lancet. 2003;361:542-544.

MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 2003;361:573-574.

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