NSAIDs: Mechanism of action
- Daniel H Solomon, MD, MPH
Daniel H Solomon, MD, MPH
- Matthew H. Liang Distinguished Chair in Arthritis and Population Health
- Professor of Medicine
- Harvard Medical School
- Section Editor
- Daniel E Furst, MD
Daniel E Furst, MD
- Section Editor — Treatment Issues in Rheumatology
- Professor of Rheumatology, University of Washington, Seattle
- Professor of Rheumatology, Washington University of Florence, Florence, Italy
- Professor of Rheumatology, University of California in Los Angeles (Emeritus)
- Director of Research, Pacific
More than 17,000,000 Americans use various nonsteroidal antiinflammatory drugs (NSAIDs) on a daily basis, making this class of drugs one of the most commonly used in the world. The Centers for Disease Control in the United States predicts that, with the aging of the population, there will be a significant increase in the prevalence of painful degenerative and inflammatory rheumatic conditions, leading to a parallel increase in the use of NSAIDs.
Sodium salicylate, discovered in 1763, was the first nonsteroidal antiinflammatory drug (NSAID). Gastrointestinal toxicity (particularly dyspepsia) associated with the use of acetylsalicylic acid (ASA) led to the introduction of phenylbutazone, an indoleacetic acid derivative, in the early 1950s; this was the first nonsalicylate NSAID developed for use in patients with inflammatory conditions. Phenylbutazone is a weak prostaglandin synthetase inhibitor that also induces uricosuria. It was shown to be a useful agent in patients with ankylosing spondylitis and gout. Concerns related to bone marrow toxicity, particularly in women over the age of 60, have essentially eliminated the use of this drug.
Indomethacin, another indoleacetic acid derivative, was developed in the 1960s as a substitute for phenylbutazone. The following years witnessed the development of more and more NSAIDs in an effort to enhance patient compliance (by decreasing the absolute number of pills and frequency with which they are taken each day), reduce toxicity, and increase the antiinflammatory effect.
There are now at least 20 different nonsteroidal antiinflammatory drugs (NSAIDs), from six major classes determined by their chemical structures, available for use in the United States. These drugs differ in their dose, drug interactions, and some side effects. A comparison of the drugs, organized by chemical grouping, is presented in the table (table 1). Drug interactions and side effects are discussed separately. (See 'Drug interactions' below and "Nonselective NSAIDs: Adverse cardiovascular effects" and "Nonselective NSAIDs: Overview of adverse effects".)
Pharmacokinetics — 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 CYP-2C8, 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.
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- Drug interactions
- - Angiotensin converting enzyme inhibitors
- - Low-dose aspirin
- - Glucocorticoids
- - SSRIs
- - Warfarin
- MECHANISM OF ACTION
- Cyclooxygenase inhibition
- - COX enzymes
- - Studies with salicylates
- - Studies with topical NSAIDs
- Non-prostaglandin mediated effects
- INFORMATION FOR PATIENTS