Mechanisms of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.
Non-steroidal anti-inflammatory drugs (NSAIDs) induce GI damage by multiple, in some cases interrelated, mechanisms. They vary in ulcerogenic activity in different regions of the GI tract. These differences in ulcerogenicity of NSAIDs are due to (a) differing kinetics of absorption in various regions of the GI tract, intracellular distribution within the mucosal cells, and systemic availability, and (b) quantitative and qualitative differences in the biochemical or physiologic systems affected by the drugs. In the stomach, where acid/pepsin influence the ulcerogenic effects of most NSAIDs, prostaglandin (PG)-dependent and PG-independent factors are responsible for the ulcerogenicity of NSAIDs. PG-dependent factors can include the influences of PGs on mucus-bicarbonate secretion, regulation of acid secretion, and blood flow. Recent evidence suggests that CO inhibition may, by diversion of arachidonate, cause enhanced production of vasoconstrictor peptidoleukotrienes and oxyradicals produced by the lipoxygenase pathway, and this may contribute to the genesis of vascular and other mucosal changes induced by NSAIDs. Non-PG-dependent effects of NSAIDs include (a) physical effects of the acidic molecules on surface mucosal cell membranes and mucus, (b) oxyradical production, (c) cytotoxic effects on parietal cells, and (d) inhibitory effects on mucus synthesis, mitochondrial ATP production, cyclic nucleotide production, and a range of other cellular metabolic effects influencing mucosal metabolism and cellular regeneration. In the intestinal tract, two major factors influence the ulcerogenicity of NSAIDs: their capacity to undergo enterophepatic recirculation and the presence of bacteria, which may in part contribute to a immunoinflammatory changes.
Rainsford
K D
KD
Arthritis Centre, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000633:toxicity; D005753:Gastric Mucosa / Q000187:drug effects*; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects*; D011448:Prostaglandin Antagonists / Q000009:adverse effects / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011448:Prostaglandin Antagonists