Skip to main content
SpringerLink
Log in

Nonsteroidal Anti-inflammatory Drugs

  • Chapter
  • First Online:
Nijkamp and Parnham's Principles of Immunopharmacology

Abstract

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) are the most widely used medicines globally. NSAIDs relieve pain (analgesic effect) and fever (antipyretic effect). They have also some anti-inflammatory properties, but as anti-inflammatory, they are noticeably less potent than GLUCOCORTICOIDS or DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (DMARDs). Non-selective NSAIDs also inhibit PLATELET aggregation, and acetylsalicylic acid (aspirin, ASA) is used in the (secondary) prevention of myocardial infarction and stroke.

Final manuscript submitted on April 21, 2018.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232–5.

    Article  CAS  PubMed  Google Scholar 

  2. Ferreira SH, Moncada S, Vane JR. Indomethacin and aspirin abolish prostaglandin release from the spleen. Nat New Biol. 1971;231:237–9.

    Article  CAS  PubMed  Google Scholar 

  3. Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol. 1971;231:235–7.

    Article  CAS  PubMed  Google Scholar 

  4. Collier JG, Flower RJ. Effect of aspirin on human seminal prostaglandins. Lancet. 1971;2:852–3.

    Article  CAS  PubMed  Google Scholar 

  5. Fu J-Y, Masferrer JL, Seibert K, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem. 1990;265:16737–40.

    CAS  PubMed  Google Scholar 

  6. Masferrer JL, Zweifel BS, Seibert K, Needleman P. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice. J Clin Invest. 1990;86:1375–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci U S A. 1991;88:2692–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A. 1992;89:7384–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B. Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci U S A. 1999;96:7220–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004;56:387–437.

    Article  CAS  PubMed  Google Scholar 

  11. Duggan KC, Hermanson DJ, Musee J, Prusakiewicz JJ, Scheib JL, Carter BD, Banerjee S, Oates JA, Marnett LJ. (R)-profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2. Nat Chem Biol. 2011;7:803–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96:7563–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116:4–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Marnett LJ. Cyclooxygenase mechanisms. Curr Opin Chem Biol. 2000;4:545–52.

    Article  CAS  PubMed  Google Scholar 

  15. Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, Stallings WC, Kurumbail RG, Marnett LJ. A novel mechanism of cyclooxygenase-2 inhibition involving interactions with ser-530 and tyr-385. J Biol Chem. 2003;278:45763–9.

    Article  CAS  PubMed  Google Scholar 

  16. Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol. 1995;2:637–43.

    Article  CAS  PubMed  Google Scholar 

  17. Spite M, Serhan C. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res. 2010;107:1170–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanisms of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology. 2013;21:201–32.

    Article  CAS  PubMed  Google Scholar 

  19. Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM. Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem. 2005;280:31405–12.

    Article  PubMed  CAS  Google Scholar 

  20. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S. Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006;12:250–75.

    Article  CAS  PubMed  Google Scholar 

  21. Ghanem CI, Pérez MJ, Manautou JE, Mottino AD. Acetaminophen from liver to brain: new insights into drug pharmacological action and toxicity. Pharmacol Res. 2016;109:119–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grosser T, Theken KN, FitzGerald GA. Cyclooxygenase inhibition: pain, inflammation, and the cardiovascular system. Clin Pharmacol Ther. 2017;102:611–22.

    Article  PubMed  Google Scholar 

  23. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ. Interleukin-1beta-mediated induction of cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;410:471–5.

    Article  CAS  PubMed  Google Scholar 

  24. Becker WJ. Acute migraine treatment in adults. Headache. 2015;55:778–93.

    Article  PubMed  Google Scholar 

  25. Marjoribanks J, Ayeleke RO, Farquhar C, Proctor M. Nonsteroidal anti-inflammatory drugs for dysmenorrhoea. Cochrane Database Syst Rev. 2015;7:CD001751.

    Google Scholar 

  26. Bartfai T, Conti B. Fever. SciWorldJ. 2010;10:490–503.

    Google Scholar 

  27. Patrono C. The multifaceted clinical readouts of platelet inhibition by low-dose aspirin. J Am Coll Cardiol. 2015;66:74–85.

    Article  CAS  PubMed  Google Scholar 

  28. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345:1809–17.

    Article  CAS  PubMed  Google Scholar 

  29. Schuijt MP, Huntjens-Fleuren H, de Metz M, Vollaard EJ. The interaction of ibuprofen and diclofenac with aspirin in healthy volunteers. Br J Pharmacol. 2009;157:931–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, Taylor RS. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess. 2008;12:1–278.

    Article  PubMed  Google Scholar 

  31. Laine L, Curtis SP, Cryer B, Kaur A, Cannon CP, MEDAL Steering Committee. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the multinational etoricoxib and diclofenac arthritis long-term (MEDAL) programme: a randomised comparison. Lancet. 2007;369:465–73.

    Article  CAS  PubMed  Google Scholar 

  32. Mallen SR, Essex MN, Zhang R. Gastrointestinal tolerability of NSAIDs in elderly patients: a pooled analysis of 21 randomized clinical trials with celecoxib and nonselective NSAIDs. Curr Med Res Opin. 2011;27:1359–66.

    Article  CAS  PubMed  Google Scholar 

  33. Yuan JQ, Yang M, Threapleton DE, Qi XS, Ye DQ, Mao C, Tang JL, Higgins JP. Systematic review with meta-analysis: the gastrointestinal benefits of COX-2 selective inhibitors with concomitant use of low-dose aspirin. Aliment Pharmacol Ther. 2016;44:785–95.

    Article  CAS  PubMed  Google Scholar 

  34. Pajdo R, Brzozowski T, Szlachcic A, Konturek PC, Ptak-Belowska A, Drozdowicz D, Targosz A, Konturek SJ, Pawlik WW. Lipoxins, the novel mediators of gastroprotection and gastric adaptation to ulcerogenic action of aspirin. Curr Pharm Des. 2011;17:1541–51.

    Article  CAS  PubMed  Google Scholar 

  35. Rostom A, Dube C, Wells GA, Tugwell P, Welch V, Jolicoeur E, McGowan J, Lanas A. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev. 2011;6:CD002296.

    Google Scholar 

  36. Lanza FL, Chan FK, Quigley EM, Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104:728–38.

    PubMed  Google Scholar 

  37. Chan FK, Wong VW, Suen BY, Wu JC, Ching JY, Hung LC, Hui AJ, Leung VK, Lee VW, Lai LH, Wong GL, Chow DK, To KF, Leung WK, Chiu PW, Lee YT, Lau JY, Chan HL, Ng EK, Sung JJ. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet. 2007;369:1621–6.

    Article  CAS  PubMed  Google Scholar 

  38. Bakhriansyah M, Souverein PC, de Boer A, Klungel OH. Gastrointestinal toxicity among patients taking selective COX-2 inhibitors or conventional NSAIDs, alone or combined with proton pump inhibitors: a case-control study. Pharmacoepidemiol Drug Saf. 2017;26:1141–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Patrono C. Cardiovascular effects of cyclooxygenase-2 inhibitors: a mechanistic and clinical perspective. Br J Clin Pharmacol. 2016;82:957–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mitchell JA, Kirkby NS. Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system. Br J Pharmacol. 2019;176:1038-50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382:769–79.

    Article  CAS  Google Scholar 

  42. Bally M, Dendukuri N, Rich B, Nadeau L, Helin-Salmivaara A, Garbe E, Brophy JM. Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. BMJ. 2017;357:j1909.

    Article  PubMed  PubMed Central  Google Scholar 

  43. García Rodríguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol. 2008;52:1628–36.

    Article  PubMed  CAS  Google Scholar 

  44. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA, Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092–102.

    Article  CAS  PubMed  Google Scholar 

  45. Solomon SD, Wittes J, Finn PV, Fowler R, Viner J, Bertagnolli MM, Arber N, Levin B, Meinert CL, Martin B, Pater JL, Goss PE, Lance P, Obara S, Chew EY, Kim J, Arndt G, Hawk E, Cross Trial Safety Assessment Group. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation. 2008;117:2104–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. https://www.ema.europa.eu/en/medicines/human/referrals/celecoxib

  47. https://www.ema.europa.eu/en/medicines/human/referrals/etoricoxib

  48. https://www.ema.europa.eu/en/medicines/human/referrals/diclofenac-containing-medicines

  49. https://www.ema.europa.eu/en/medicines/human/referrals/ibuprofen-dexibuprofen-containing-medicines

  50. Chan C, Reid C, Aw T, Liew D, Haas S, Krum H. Do COX-2 inhibitors raise blood pressure more than nonselective NSAIDs and placebo? an updated meta-analysis. J Hypertens. 2009;27:2332–41.

    Article  CAS  PubMed  Google Scholar 

  51. Ruschitzka F, Borer JS, Krum H, Flammer AJ, Yeomans ND, Libby P, Luscher TF, Solomon DH, Husni ME, Graham DY, Davey DA, Wisniewski LM, Menon V, Fayyad R, Beckerman B, Iorga D, Lincoff AM, Nissen SE. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION-ABPM (prospective randomized evaluation of celecoxib integrated safety versus ibuprofen or naproxen ambulatory blood pressure measurement) trial. Eur Heart J. 2017;38:3282–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kalafutova S, Juraskova B, Vlcek J. The impact of combinations of non-steroidal anti-inflammatory drugs and anti-hypertensive agents on blood pressure. Adv Clin Exp Med. 2014;23:993–1000.

    Article  PubMed  Google Scholar 

  53. Rahman S, Malcoun A. Nonsteroidal anti-inflammatory drugs, cyclooxygenase-2, and the kidneys. Prim Care Clin Office Pract. 2014;41:803–21.

    Article  Google Scholar 

  54. Vučković S, Vujovic KS, Srebro D, Medic B, Ilic-Mostic T. Prevention of renal complications induced by non-steroidal anti-inflammatory drugs. Curr Med Chem. 2016;23:1953–64.

    Google Scholar 

  55. Arfè A, Scotti L, Varas-Lorenzo C, Nicotra F, Zambon A, Kollhorst B, Schink T, Garbe E, Herings R, Straatman H, Schade R, Villa M, Lucchi S, Valkhoff V, Romio S, Thiessard F, Schuemie M, Pariente A, Sturkenboom M, Corrao G. Non-steroidal anti-inflammatory drugs and risk of heart failure in four european countries: nested case-control study. BMJ. 2016;354:i4857.

    Article  PubMed  Google Scholar 

  56. Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: a systematic review and meta-analysis of observational studies. Eur J intern Med. 2015;26:285–91.

    Article  CAS  PubMed  Google Scholar 

  57. Zhang X, Donnan PT, Bell S, Guthrie B. Non-steroidal anti-inflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease: systematic review and meta-analysis. BCM Nephrol. 2017;18:256.

    Article  CAS  Google Scholar 

  58. Fored CM, Ejerblad E, Lindblad P, Fryzek JP, Dickman PW, Signorello LB, Lipworth L, Elinder CG, Blot WJ, McLaughlin JK, Zack MM, Nyren O. Acetaminophen, aspirin, and chronic renal failure. N Engl J Med. 2001;345:1801–8.

    Article  CAS  PubMed  Google Scholar 

  59. Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ. 2004;328:434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rodriguez-Jiminez JC, Moreno-Paz FJ, Teran LM, Guani-Guerra E. Aspirin exacerbated respiratory disease: current topics and trends. Resp Med. 2018;135:62–75.

    Article  Google Scholar 

  61. Walgama ES, Hwang PH. Aspirin-exacerbated respiratory disease. Otolaryngol Clin North Am. 2017;50:83–94.

    Article  PubMed  Google Scholar 

  62. Aithal GP, Day CP. Nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Clin Liver Dis. 2007;11:563–75.

    Article  PubMed  Google Scholar 

  63. Unzueta A, Vargas HE. Nonsteroidal anti-inflammatory drug–induced hepatoxicity. Clin Liver Dis. 2013;17:643–56.

    Article  PubMed  Google Scholar 

  64. Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye’s syndrome in the united states from 1981 through 1997. N Engl J Med. 1999;340:1377–82.

    Article  CAS  PubMed  Google Scholar 

  65. Schrör K. Aspirin and reye syndrome: a review of the evidence. Pediatr Drugs. 2007;9:195–204.

    Article  Google Scholar 

  66. Stone S, Khamashta MA, Nelson-Piercy C. Nonsteroidal anti-inflammatory drugs and reversible female infertility: is there a link? Drug Saf. 2002;25:545–51.

    Article  CAS  PubMed  Google Scholar 

  67. Bloor M, Paech M. Nonsteroidal anti-inflammatory drugs during pregnancy and the initiation of lactation. Anesth Analg. 2013;116:1063–75.

    Article  CAS  Google Scholar 

  68. Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM, Dey SK. Multiple female reproductive failures in cyclooxygenase 2–Deficient mice. Cell. 1997;91:197–208.

    Article  CAS  PubMed  Google Scholar 

  69. Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic Clin Pharmacol Toxicol. 2008;102:10–4.

    CAS  PubMed  Google Scholar 

  70. Ranganathan K, Loder S, Agarwal S, Wong VW, Forsberg J, Davis TA, Wang S, James AW, Levi B. Heterotopic ossification: basic-science principles and clinical correlates. J Bone Joint Surg Am. 2015;97:1101–11.

    Article  PubMed  Google Scholar 

  71. Dodwell E, Latorre J, Parisini E, Zwettler E, Chandra D, Mulpuri K, Snyder B. NSAID exposure and risk of nonunion: a meta-analysis of case–control and cohort studies. Calcif Tissue Int. 2010;87:193–202.

    Article  CAS  PubMed  Google Scholar 

  72. Kurmis AP, Kurmis TP, O’Brien JX, Dalén T. The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review. J Bone Joint Surg Am. 2012;94:815–23.

    Article  PubMed  Google Scholar 

  73. Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359:285–92.

    Article  CAS  PubMed  Google Scholar 

  74. Ferner RE, Dear JW, Bateman DN. Management of paracetamol poisoning. BMJ. 2011;342:d2218.

    Article  PubMed  CAS  Google Scholar 

  75. Chiew AL, Gluud C, Brok J, Buckley NA. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018;2:CD003328.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Immunopharmacology Research Group, Tampere University, Tampere, Finland

    Eeva Moilanen & Katriina Vuolteenaho

Authors
  1. Eeva Moilanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katriina Vuolteenaho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eeva Moilanen .

Editor information

Editors and Affiliations

  1. Translational Drug Validation, Fraunhofer IME-TMP and Goethe University Frankfurt, Frankfurt am Main, Germany

    Michael J. Parnham

  2. Utrecht University, Utrecht, The Netherlands

    Frans P. Nijkamp

  3. The Queen’s Medical Research Institute, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK

    Adriano G. Rossi

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Moilanen, E., Vuolteenaho, K. (2019). Nonsteroidal Anti-inflammatory Drugs. In: Parnham, M., Nijkamp, F., Rossi, A. (eds) Nijkamp and Parnham's Principles of Immunopharmacology. Springer, Cham. https://doi.org/10.1007/978-3-030-10811-3_33

Download citation

Publish with us

Policies and ethics

Search

Navigation