Gastric ulcers associated with NSAID use

For several decades now it has been established that long term use of Non-Steroidal Anti Inflammatory Drugs (NSAIDs) causes gastric mucosal damage leading to several complications including dyspepsia, peptic ulcer disease and sometimes even gastric or duodenal perforation or bleeding (Patrono, 2001). In the normal gastric mucosa, there is a balance between gastric acid production and the normal protective mechanism of the gastric mucosa. When this balance is disturbed, gastric mucosal injury occurs.

According to the ‘dual-injury hypothesis’ of Schoen and Vender (Schoen RT, 1989), NSAID-induced gastroduodenal mucosal injury occurs both due to local effects i. e. topical injury and systemic effects. Topical Injury Aspirin and other NSAIDs are acidic in nature and have a low dissociation constant. Therefore, in the highly acidic gastric lumen these weak acids remain in their non-ionized lipophilic form. This promotes the migration of these ions through the gastric mucus across plasma membranes and into surface epithelial cells.

Once inside the gastric mucosal cells, these lipophilic particles are dissociated into the ionized form and lead to the trapping of hydrogen ions (Schoen RT, 1989). Another mechanism by which NSAIDs cause topical injury to the gastric mucosa is by decreasing the hydrophobicity of gastric mucus, which functions as a protective barrier. This allows endogenous gastric acid and pepsin to injure the surface epithelium (Wolfe MM, 1988 cited in Litchenstien, 1999). There are other indirect mechanisms involved in topical injury.

For instance, the biliary excretion of certain NSAIDS and subsequent duodenogastric reflux of their active metabolites causes topical injury to the mucosa due to the acidic properties of the metabolites (Graham DY, 1985). Systemic Effects The systemic effects of NSAIDs result from the inhibition of endogenous prostaglandin synthesis (Schoen RT, 1989). When prostaglandins are inhibited, most of the mucosal defense mechanisms such as epithelial mucus production, secretion of bicarbonate, mucosal blood flow, epithelial proliferation, and mucosal resistance to injury decrease (BJR, 1977).

Due to the impaired mucosal defense mechanisms, the gastric mucosa is predisposed to injury by both endogenous and exogenous factors. The endogenous factors include acid, pepsin, and bile salts, while the exogenous factors include NSAIDs, ethanol and other noxious agents. Prostaglandins are a group of lipid compounds which are derivatives of arachidonic acid, which originates from cell-membrane phospholipids through the action of phospholipase A.

Arachidonic acid is metabolized to prostaglandins and leukotrienes by two different pathways viz. the cyclooxygenase pathway and the 5-lipoxygenase pathway, respectively (Schoen RT, 1989). Mammalian cells contain two different isoforms of the enzyme cyclooxegenase, known as cyclooxygenase-1 and cyclooxygenase- 2 which are encoded by distinct genes and their distribution and expression in mammalian tissues is significantly different from each other (LJ, 1997).

An important difference between these two isoforms is that cyclooxygenase-1 gene is constitutively expressed since it contains promoter region without a TATA sequence while the cyclooxygenase-2 gene is inducible and is absent in most tissues under normal physiologic conditions. Research on the effects of NSAIDs on the functioning of these enzymes has shown that inhibition of cyclooxygenase-2 mediates the anti-inflammatory properties of NSAIDs while adverse effects, such as gastroduodenal ulceration, occur as a result of effects on the cyclooxygenase-1 (Needleman P, 1997).

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