NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies

Abstract

The mechanisms underlying the ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to cause ulceration in the stomach and proximal duodenum are well understood, and this injury can largely be prevented through suppression of gastric acid secretion (mainly with proton pump inhibitors). In contrast, the pathogenesis of small intestinal injury induced by NSAIDs is less well understood, involving more complex mechanisms than those in the stomach and proximal duodenum. There is clear evidence for important contributions to NSAID enteropathy of enteric bacteria, bile and enterohepatic recirculation of the NSAID. There is no evidence that suppression of gastric acid secretion will reduce the incidence or severity of NSAID enteropathy. Indeed, clinical data suggest little, if any, benefit. Animal studies suggest a significant exacerbation of NSAID enteropathy when proton pump inhibitors are co-administered with the NSAID. This worsening of damage appears to be linked to changes in the number and types of bacteria in the small intestine during proton pump inhibitor therapy. The distinct mechanisms of NSAID-induced injury in the stomach/proximal duodenum versus the more distal small intestine likely dictate distinct strategies for prevention.

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…2009; Castellsague et al. 2012; Wallace 2012). These drugs can also induce hepatotoxicity, mostly cytolytic hepatitis and cholestasis (Banks et al.…”

“…The most common NSAID‐induced GI toxicity seems to be gastric injury, albeit intestinal damage could also be a frequent side effect observed in treated patients (Wallace 2012; Boelsterli et al. 2013).…”

“…2013). Numerous studies have shown that a major mechanism of NSAID‐induced gastropathy is COX inhibition and the secondary decreased production of mucosal prostaglandins, which have a major cytoprotective action on the gastric mucosa (Rainsford and Willis 1982; Wallace 2012; Seminerio et al. 2014).…”

“…Indeed, oxidative stress, mitochondrial dysfunction, and TNF α release could be important mechanisms in NSAID enteropathy (Wallace 2012; Boelsterli et al. 2013).…”

NSAID enteropathy and bacteria: a complicated relationship

“…Nonsteroidal anti-inflammatory drugs (NSAIDs) remain among the most widely used drugs worldwide despite significant adverse effects that include gastrointestinal (GI) ulceration and bleeding [1,2] and an increased risk of serious cardiovascular events [3]. Although there are drugs available for preventing the upper GI tract adverse effects of NSAIDs (inhibitors of gastric acid secretion), no measures have been identified that have been proven to be effective at preventing the small intestinal injury caused by these drugs [1,4,5].…”