ABSTRACT
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.
Subject(s)
Cyclooxygenase Inhibitors/adverse effects , Gastrointestinal Diseases/chemically induced , Gastrointestinal Tract/drug effects , Animals , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/adverse effects , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/metabolism , Gastrointestinal Diseases/microbiology , Gastrointestinal Microbiome , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/pathology , Helicobacter pylori/pathogenicity , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Oxidative Phosphorylation/drug effects , Phospholipids/metabolism , Prostaglandins/metabolismABSTRACT
OBJECTIVE: Published and regulatory advice is to take NSAIDs with fluids and/or food irrespective whether NSAIDs are taken over the counter or long-term. The basis for this recommendation is not clear and we sought to establish the reasons for it through a search of published literature and personal files. RESULTS: Results from experimental animals show that fasting increases the gastric side effects of NSAIDs while food increases small bowel damage, but this has not been tested in humans. The possible effects of food in modifying the gastric damage caused by NSAIDs are complex, as food quantity and composition modify the responses substantially. Food usually delays peak levels of NSAIDs (and hence onset of action) without affecting total bioavailability. This may not be important when a steady state is achieved, but rapid onset of action is highly relevant for over-the-counter use of NSAIDs. The safety of over-the-counter use of ibuprofen and naproxen appears to be excellent and comparable with paracetamol. CONCLUSION: The rapid onset of action of NSAIDs is most important during over-the-counter use, in which case it may be more appropriate to take the drugs on a fasting stomach.
