Mechanism of gastrointestinal toxicity of NSAIDs.
Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, mainly the stomach, by a local effect and by systemic interactions with prostaglandin synthesis. A local damaging effect was first suggested by Davenport, who demonstrated that aspirin, at an acid pH, enters the gastric mucosa by non-ionic diffusion, leading to a disruption of the gastric barrier and subsequent back-diffusion of hydrogen ions into the mucosa. Consequently, this leads to local haemorrhage and cell necrosis. Systemic damage is thought chiefly to occur by inhibition of prostaglandin synthesis, with consequent interaction of the defensive functions of the gastric mucosa. Inhibition of cyclo-oxygenase is the specific target of NSAIDs. However, the lipoxygenase pathway is also affected indirectly since cyclo-oxygenase inhibition results in a spill-over effect of leukotrienes, as both prostaglandins and leukotrienes are produced from arachidonic acid. Indeed, leukotriene B4, an extremely potent vasoconstrictor, may be responsible for some of the NSAID damage. In addition, cyclo-oxygenase inhibition blocks the integrity and synthesis of mucus, the secretion of bicarbonate and profoundly changes the life cycle of gastric mucosal cells. Following acute NSAID medication, the overall cell migration from the proliferative zone to the surface is accelerated and cell shedding is increased. However, during prolonged NSAID treatment, adaptation to the noxious effects of NSAIDs can occur with increased cell reproduction and subsequent compensation of the initially increased cell loss.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000633:toxicity*; D001696:Biomechanical Phenomena; D055598:Chemical Phenomena; D002621:Chemistry; D005753:Gastric Mucosa / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects*; D008084:Lipoxygenase / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D008084:Lipoxygenase