Title

 

Authors

C. Blandizzi
 
Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa

 

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed, due to their efficacy in the treatment of inflammation, pain and fever. However, their use can induce adverse effects throughout the gastrointestinal (GI) tract. Such adverse reactions can be hardly avoided, since the main mechanism of NSAID action, consisting of the blockade of cyclooxygenase (COX) isoforms (COX-1, COX-2), largely accounts for both therapeutic and untoward actions [1]. As far as the upper GI tract is concerned, patients taking NSAIDs are at risk of developing: a) digestive symptoms without evidence of mucosal lesions; b) asymptomatic gastroduodenal erosions (affecting the mucosa only) or ulcers (penetrating the muscularis mucosae); c) symptomatic or complicated lesions, including ulcers, serious bleeding and perforation. Upper GI symptoms associated with NSAID use include dyspepsia, heartburn, abdominal bloating or cramping, nausea and vomiting. Factors that increase the risk of upper GI adverse events in NSAID users are well defined, and the most important include Helicobacter pylori infection, ageing, previous ulcer, treatment with anti-coagulant drugs, and therapy with high-dose or multiple NSAIDs [2]. Beside patient’s risk factors, the ability of harming the upper GI mucosa varies greatly among NSAIDs, as a result of significant differences in their individual pharmacodynamic profiles and physicochemical properties. Indeed, the pathogenesis of NSAID-induced upper GI damage depends partly on their systemic actions, resulting from the concomitant blockade of COX-1 and COX-2, and partly on COX-independent direct topical actions, related to their chemical structure [1,2]. The inhibition of COX isoforms is detrimental to the upper GI mucosa, mostly as a consequence of an increase in gastric acid secretion and a decrease in mucus/bicarbonate secretion, blood flow and epithelial cell turnover. To overcome problems related with COX-dependent GI toxicity, selective COX-2 inhibitors, such as celecoxib, etoricoxib and lumiracoxib, have been clinically developed, based on the evidence that the initiation of upper GI damage requires a simultaneous inhibition of both COX-1 and COX-2, while the blockade of COX-2 only ensures the control of inflammation and pain without being sufficient to harm the GI mucosa [1,2]. Most non-selective NSAIDs are endowed with lipophilic and weakly acidic chemical structures, which allow them to exert direct topic injuries on the upper GI mucosa. Owing to these properties, NSAIDs predominate as lipophilic undissociated forms once they are administered by oral route and enter the acidic environment of gastric lumen. Consequently, NSAIDs behave as detergent agents and interact with the mucosal hydrophobic phospholipid lining, leading to disruption of the mucus barrier. At the same time, NSAIDs accumulate into epithelial cells, where they dissociate, thus causing intracellular acidosis, and uncouple mithochondrial phosphorylation, with overproduction of reactive oxygen radicals and cell death [1,2]. When considering the chemical structures of selective COX-2 inhibitors, while some of them retain the same acidity as non-selective NSAIDs, celecoxib is devoid of acidic properties. Accordingly, celecoxib did not alter gastric permeability when tested in healthy humans [2]. Overall, based on current preclinical and clinical evidence, anti-inflammatory/analgesic drugs combining good COX-2 selectivity and non-acidic chemical structure are expected to display more favourable upper GI safety, as compared with traditional non-selective NSAIDs.
 
[1] C. Blandizzi et al. (2009) Role of coxibs in the strategies for gastrointestinal protection in patients requiring chronic non-steroidal anti-inflammatory therapy. Pharmacol Res 59, 90-100.
[2] C. Scarpignato, R. Hunt (2010) Non-steroidal anti-inflammatory drug-related injury to the gastrointestinal tract: Clinical picture, pathogenesis and prevention. Gastroenterol Clin North Am 39, 433-464.