COX-1, COX-2 and the topical effect in NSAID-induced enteropathy

Abstract

The side effects of NSAIDs are equally evident in the stomach and the small bowel. The latter is increasingly seen as being clinically significant, contributing substantially to the iron-deficiency anaemia that is so common in patients with rheumatoid arthritis. Furthermore, NSAID-enteropathy may be associated with life-threatening events. The pathogenesis of NSAID-enteropathy is uncertain but inhibition of COX-1 is believed to be of pivotal importance. However there is increasing evidence that COX-2 inhibition and the topical effect may have a synergistic detrimental action. We examined the role of COX-1, COX-2 and the so called topical effect of acidic NSAIDs. We found that COX-1 or COX-2 inhibition and the topical effect alone do not damage the GI tract. Dual inhibition of COX-1 and COX-2 results in intestinal inflammation similar to that caused by Indomethacin. The topical effect may act synergistically in this damage. The conventional view that the mechanism of gastrointestinal damage is principally caused by COX-1 inhibition needs to be revised in view of recent studies using selective inhibitors of the COX enzymes and COX knockout animals.

Current status of the therapeutic uses and actions of the preferential cyclo-oxygenase-2 NSAID, nimesulide

“…While there are many other factors that are involved in the development of adverse reactions (e.g. in the GI tract and kidney) the involvement of COX-1 inhibition plays a signifi cant part (Rainsford, 1996(Rainsford, , 2001Hotz-Behofsits et al, 2003;Tarnawski and Jones, 2003).…”

“…NSAIDs with low pKa values (e.g. carboxylic acids) have a greater tendency to be irritant to the gastric mucosa as a consequence of their selective absorption into GI mucosal cells (Brune et al, 1977;Rainsford and Brune, 1978;Rainsford et al, 1981Hotz-Behofsits et al, 2003;Rainsford, 1999a;Sigthorsson et al, 2000aSigthorsson et al, , 2000b leading to ion trapping (Brune et al, 1977;Rainsford and Brune, 1978;Rainsford et al, 1981Sigthorsson et al, 2000), as well as uptake into mitochondria and Gastrointestinal (GI) adverse events remain the main concern in the use of NSAIDs and GI tolerability is a central issue for clinicians who prescribe these drugs (Rainsford, 1996(Rainsford, , 2001Rothstein, 1998). Other important side effects should also be taken into consideration when prescribing these drugs such as allergic reactions, skin adverse reaction, renal complications, alteration of hepatic enzyme levels and rarely hepatopathies (Rainsford, 1996(Rainsford, , 1997(Rainsford, , 2001Rothstein, 1998;Teoh and Farrell, 2003;Uemura et al, 2003;Simon and Namazy, 2003;Sanchez-Borges et al, 2002McGettigan et al, 2000).…”

Conditioning and Scaffolding of Chondrocytes: Smart Steps Towards Osteoarthritis Gene Therapy

“…Acetaminophen treatment followed by non-steroidal anti-inflammatory drugs (NSAIDs) inhibits the activation of immune cells while NSAIDs suppress the inflammatory process by intervening with the prostaglandin synthesis. Long-term usage of NSAIDs is often accompanied by adverse side-effects such as gastrointestinal, renal or cardiovascular disorders, as most of these compounds inhibit cyclooxygenases (COX)-1 and -2 indiscriminatorily (Hotz-Behofsits et al, 2003;Scarpignato & Hunt, 2010;Wolfe et al, 1999). Selective COX-2 inhibitors reduce pain through prostaglandin blockade, but owing to their harmful effects on cardiovascular events they were recalled from the market (Park et al, 2006).…”

Non-steroidal Anti-inflammatory Drug Induced Injury to the Small Intestine

“…The pathogenesis of enteropathy was initially thought to be associated with COX-1 inhibition only. However, it has been proven that selective COX-1 inhibition (or absence) does not lead to a gastrointestinal lesion, and selective COX-2 inhibition (or absence) leads to ileocaecal mucosa damage, different from "classical" NSAID-enteropathy (43,76). Small bowel injury is induced by a combination of COX-1 inhibition with restricted mucosal blood flow and COX-2 inhibition probably through an unknown immunological effect (90).…”