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NSAIDs: Pharmacology and mechanism of action

Author
Daniel H Solomon, MD, MPH
Section Editor
Daniel E Furst, MD
Deputy Editor
Paul L Romain, MD

INTRODUCTION

More than 20 different nonsteroidal antiinflammatory drugs (NSAIDs) are available commercially, and these agents are used worldwide for their analgesic antipyretic and antiinflammatory effects in patients with multiple medical conditions. NSAIDs, including aspirin, do not generally change the course of the disease process in those conditions, where they are used for symptomatic relief.

The pharmacology and mechanisms of action of the NSAIDs will be reviewed here. The therapeutic variability and approach to the clinical use of NSAIDs, including their use in combination with other medications and in patients with comorbid conditions, the adverse effects of NSAIDs, an overview of cyclooxygenase (COX)-2 selective NSAIDs, and the mechanisms relevant to aspirin, its toxicities, and its uses in the rheumatic diseases are described in detail separately. (See "NSAIDs: Therapeutic use and variability of response in adults" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of selective COX-2 inhibitors" and "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases".)

PHARMACOLOGY

There are more than 20 different nonsteroidal antiinflammatory drugs (NSAIDs), from six major classes determined by their chemical structures, available for use worldwide. These drugs differ in their dose, drug interactions, and some side effects (table 1). Most NSAIDs are absorbed completely, have negligible first-pass hepatic metabolism, are tightly bound to serum proteins, and have small volumes of distribution.

NSAIDs undergo hepatic transformations variously by CYP2C8, 2C9, 2C19 and/or glucuronidation. Half-lives of the NSAIDs vary but in general can be divided into "short-acting" (less than six hours, including ibuprofen, diclofenac, ketoprofen and indomethacin) and "long-acting" (more than six hours, including naproxen, celecoxib, meloxicam, nabumetone, and piroxicam). Patients with hypoalbuminemia (due, for example, to cirrhosis or active rheumatoid arthritis) may have a higher free serum concentration of the drug.

Assessment of toxicity and therapeutic response to a given NSAID must take into account the time needed to reach the steady state plasma concentration (roughly equal to three to five half-lives of the drug). The pathogenesis of symptomatic peptic ulcer disease caused by exposure to NSAIDs is mainly a consequence of systemic (post-absorptive) inhibition of gastrointestinal mucosal cyclooxygenase (COX) activity. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity".)

         
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Literature review current through: Nov 2017. | This topic last updated: Aug 29, 2017.
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References
Top
  1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 231:232.
  2. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs--differences and similarities. N Engl J Med 1991; 324:1716.
  3. Abramson SB, Weissmann G. The mechanisms of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1989; 32:1.
  4. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1993; 268:6610.
  5. DeWitt DL, Meade EA, Smith WL. PGH synthase isoenzyme selectivity: the potential for safer nonsteroidal antiinflammatory drugs. Am J Med 1993; 95:40S.
  6. DeWitt DL, el-Harith EA, Kraemer SA, et al. The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases. J Biol Chem 1990; 265:5192.
  7. Shimokawa T, Smith WL. Prostaglandin endoperoxide synthase. The aspirin acetylation region. J Biol Chem 1992; 267:12387.
  8. Shimokawa T, Smith WL. Essential histidines of prostaglandin endoperoxide synthase. His-309 is involved in heme binding. J Biol Chem 1991; 266:6168.
  9. Shimokawa T, Kulmacz RJ, DeWitt DL, Smith WL. Tyrosine 385 of prostaglandin endoperoxide synthase is required for cyclooxygenase catalysis. J Biol Chem 1990; 265:20073.
  10. Toh H. Prostaglandin endoperoxide synthase contains an EGF-like domain. FEBS Lett 1989; 258:317.
  11. Hersh EV, Lally ET, Moore PA. Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray? Curr Med Res Opin 2005; 21:1217.
  12. Reinauer C, Censarek P, Kaber G, et al. Expression and translation of the COX-1b gene in human cells--no evidence of generation of COX-1b protein. Biol Chem 2013; 394:753.
  13. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 2002; 99:13926.
  14. Schwab JM, Schluesener HJ, Laufer S. COX-3: just another COX or the solitary elusive target of paracetamol? Lancet 2003; 361:981.
  15. Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease. FASEB J 1998; 12:1063.
  16. Lee SH, Soyoola E, Chanmugam P, et al. Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J Biol Chem 1992; 267:25934.
  17. O'Banion MK, Winn VD, Young DA. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci U S A 1992; 89:4888.
  18. Morham SG, Langenbach R, Loftin CD, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 1995; 83:473.
  19. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 1995; 378:406.
  20. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 2011; 31:986.
  21. Langenbach R, Morham SG, Tiano HF, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995; 83:483.
  22. Gilroy DW, Colville-Nash PR, Willis D, et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 1999; 5:698.
  23. Iñiguez MA, Punzón C, Fresno M. Induction of cyclooxygenase-2 on activated T lymphocytes: regulation of T cell activation by cyclooxygenase-2 inhibitors. J Immunol 1999; 163:111.
  24. Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997; 112:387.
  25. Reuter BK, Asfaha S, Buret A, et al. Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. J Clin Invest 1996; 98:2076.
  26. Newberry RD, Stenson WF, Lorenz RG. Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med 1999; 5:900.
  27. Roth SH. NSAID gastropathy. A new understanding. Arch Intern Med 1996; 156:1623.
  28. Patrignani P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 1994; 271:1705.
  29. Glaser K, Sung ML, O'Neill K, et al. Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol 1995; 281:107.
  30. Mitchell JA, Akarasereenont P, Thiemermann C, et al. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A 1993; 90:11693.
  31. Bombardier C, Peloso PM, Goldsmith CH. Salsalate, a nonacetylated salicylate, is as efficacious as diclofenac in patients with rheumatoid arthritis. Salsalate-Diclofenac Study Group. J Rheumatol 1995; 22:617.
  32. Marcus AJ. Aspirin as prophylaxis against colorectal cancer. N Engl J Med 1995; 333:656.
  33. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med 2004; 164:2017.
  34. Haroutiunian S, Drennan DA, Lipman AG. Topical NSAID therapy for musculoskeletal pain. Pain Med 2010; 11:535.
  35. Makris UE, Kohler MJ, Fraenkel L. Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review. J Rheumatol 2010; 37:1236.
  36. Díaz-González F, González-Alvaro I, Campanero MR, et al. Prevention of in vitro neutrophil-endothelial attachment through shedding of L-selectin by nonsteroidal antiinflammatory drugs. J Clin Invest 1995; 95:1756.
  37. Does the acetyl group of aspirin contribute to the antiinflammatory efficacy of salicylic acid in the treatment of rheumatoid arthritis? The Multicenter Salsalate/Aspirin Comparison Study Group. J Rheumatol 1989; 16:321.
  38. Stevenson DD, Hougham AJ, Schrank PJ, et al. Salsalate cross-sensitivity in aspirin-sensitive patients with asthma. J Allergy Clin Immunol 1990; 86:749.
  39. Amin AR, Vyas P, Attur M, et al. The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. Proc Natl Acad Sci U S A 1995; 92:7926.
  40. Hawkey CJ. Future treatments for arthritis: new NSAIDs, NO NSAIDs, or no NSAIDs? Gastroenterology 1995; 109:614.
  41. Goldfine AB, Fonseca V, Jablonski KA, et al. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med 2010; 152:346.
  42. Lu X, Xie W, Reed D, et al. Nonsteroidal antiinflammatory drugs cause apoptosis and induce cyclooxygenases in chicken embryo fibroblasts. Proc Natl Acad Sci U S A 1995; 92:7961.
  43. Pasricha PJ, Bedi A, O'Connor K, et al. The effects of sulindac on colorectal proliferation and apoptosis in familial adenomatous polyposis. Gastroenterology 1995; 109:994.
  44. Lynch PM, Ayers GD, Hawk E, et al. The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am J Gastroenterol 2010; 105:1437.
  45. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355:885.
  46. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355:873.