Gastrointestinal toxicity. Role of prostaglandins and leukotrienes

Gastrointestinal tissues have a high synthesising capacity for prostaglandins. As exogenous prostaglandins protect the gastrointestinal mucosa against potentially noxious agents, it has been suggested that the generation of prostaglandins plays a crucial role in the maintenance of mucosal integrity. Analgesic and anti-inflammatory drugs with a potent inhibitory action on gastrointestinal cyclo-oxygenase, such as indomethacin, induce gastric and intestinal ulcerations in experimental animals and frequently lead to gastrointestinal side effects in man. However, drugs that do not reduce gastrointestinal prostaglandin formation, such as paracetamol (acetaminophen), are devoid of gastrointestinal toxicity. Various factors, e.g. tissue-specific differences in the sensitivity of cyclo-oxygenase against inhibition and pharmacokinetic properties, modify the inhibitory activity of analgesic and anti-inflammatory drugs on gastrointestinal prostaglandin formation. As leukotriene C4 is a potent gastric vasoconstrictor, increased metabolism of arachidonic acid via the 5-lipoxygenase pathway in the presence of inhibition of cyclo-oxygenase could possibly contribute to drug-induced gastrointestinal damage.