Gastroenterology

Gastroenterology

Volume 154, Issue 3, February 2018, Pages 500-514
Gastroenterology

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs

https://doi.org/10.1053/j.gastro.2017.10.049Get rights and content

Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or cyclooxygenase [COX] 1) and PTGS1 (COX2), other factors are involved. We review the mechanisms of gastrointestinal damage induction by NSAIDs via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and inter-dependent factors. This model highlights the obstacles for the development of safer NSAIDs.

Section snippets

Biochemical Effects of Nonsteroidal Anti-Inflammatory Drugs

The biochemical actions common to all conventional NSAIDs are their topical effects, and inhibition of COX1 and COX2. These biochemical actions are brought about by the physicochemical properties that NSAIDs share,44, 45, 46 namely being lipid-soluble weak acids (see Figure 2). This combination provides them with detergent action (interaction with phospholipids), uncoupling of oxidative phosphorylation, and noncovalent inhibition of COX1 and COX2. These biochemical activities depend on the same

Inhibition of Cyclooxygenase 1 and 2 and Role of Prostaglandins

The 3-dimensional structure of the COX enzymes reveals the active site of both COX isoforms to be at the end of a hydrophobic channel. NSAIDs inhibit the enzyme by blocking the entrance of arachidonic acid to this channel and thereby denying substrate access to the active site.84, 85 The COX1 and 2 channels differ. Conventional NSAIDs have access to both channels and form an ionic bond via their carboxyl or enolic group.86 The COX1 channel is smaller than the channel in COX2 and does not

Tissue Reaction and Role of Luminal Aggressors

The tissue reaction is characterized by inflammation and the presence of erosions and ulcers, and this appears to be driven by COX inhibition and the luminal aggressive factors. The luminal aggressors differ between the stomach (acid, pepsin, and H pylori) and small bowel (bile and commensal bacteria). The importance of gastric luminal aggressors is widely appreciated, but the same does not hold true for small bowel aggressors. Our review focuses on effects in the small bowel.

Future Directions

Prevention and treatment of the adverse events of NSAIDs on the gastrointestinal tract require knowledge of mechanisms of pathogenesis of the lesions. The complexities of the pathways to this damage have been evident for a long time, but have not received much attention, presumably because the effects of inhibiting COX enzymes offer a simple and logical explanation for the damage. This hypothesis led to development of the COX2-selective agents with increased gastrointestinal safety. However,

Acknowledgments

Authors contributions: The study concept originated with IB. EH and MO wrote the first draft and carried out the literature search while IB supervised them and did most of the modifications before CS, KR, and AL contributed their expertise, as well as general comments. All authors contributed to the interpretation of data.

Writing assistance: Professor Brian Callingham, Department of Pharmacy, Queens College, University of Cambridge read and commented on the final version of the manuscript.

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    Conflicts of interest Drs Bjarnason, Scarpignato, Rainsford, and Lanas have received lecture fees, travel support, research grants and sat on advisory panels of a number of pharmaceutical companies, some of which are involved with NSAIDs or drugs to prevent or heal their adverse effects on the intestinal tract. The remaining authors disclose no conflicts.

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