Managing the Adverse Effects of Nonsteroidal Anti-inflammatory Drugs

Paola Patrignani; Stefania Tacconelli; Annalisa Bruno; Carlos Sostres; Angel Lanas

Disclosures

Expert Rev Clin Pharmacol. 2011;4(5):605-621. 

In This Article

GI Toxicity of NSAIDs

Injury to the mucosa of the GI tract by NSAIDs is very common and ranges from minor lesions such as petechia or erosions to more serious (and also much less frequent) lesions such as ulcers, which can result in complications such as bleeding, perforation or obstruction. Patients may eventually die as a consequence of these complications.[21] Breaks in the epithelium of NSAID or aspirin users are usually rapidly repaired through a process called 'restitution'.[22] This process occurs rapidly without the need of cell division but it requires an undamaged basement membrane where healthy epithelial cells migrate. When damage does not penetrate the muscularis mucosa, the repair can be achieved within 1–3 days and involves cell proliferation and re-establishment of the glandular architecture. When an ulcer is formed (when the defect penetrates to the submucosa), repair can take from weeks to months involving re-establishment of the vasculature with new blood vessel growth. A number of growth factors including EGF and VEGF are involved in the process of ulcer repair.[23] Platelets seem to play an important role in ulcer healing outside their contribution to homeostasis.[24] Platelets contain a wide array or growth factors and can deliver those factors to the site of tissue damage. Drugs that affect the content of growth factors within the platelet may thereby affect rates of ulcer healing.

The mechanisms responsible for NSAID-induced ulcerative lesions of the GI tract are not yet completely understood, particularly with respect to the lesions in the small and large intestine.[21,25] NSAIDs injure the gut by causing topical injury to the mucosa and by systemic effects associated with mucosal prostaglandin depletion derived from COX inhibition (Figure 3). Platelet inhibition has also been considered to be a key mechanism of bleeding of lesions of the GI tract. The systemic effects of NSAIDs appear to have a predominant role, since visible topical injury disappear with continuous use of NSAIDs in most cases, but ulcers and complications may continue to develop. This systemic effect may be the reason why the use of enteric-coated aspirin preparations and parenteral or rectal administration of NSAIDs, in order to prevent topical mucosal injury, has not been successful to prevent the development of gastroduodenal ulcers and their complications.

Figure 3.

Mechanisms of NSAID-induced mucosal injury. NSAIDs injure the gut by causing topical injury to the mucosa and by systemic effects associated with mucosal prostaglandin depletion derived from COX inhibition.
COX: Cyclooxygenase.

The widespread use of NSAIDs as analgesic, anti-inflammatory and antipyretic drugs converts the associated upper GI complications into a major public health concern. The most recent of these was in 1990 when some NSAIDs were introduced in the market claiming a better GI safety than tNSAIDs.[14,26] These new NSAIDs are coxibs. Indeed, reduced incidence of serious GI adverse effects compared with tNSAIDs has been demonstrated for these selective COX-2 inhibitors in large randomized clinical trials.[27,28] This was a proof-of-concept that sparing COX-1 in the GI tract and possibly in platelets translates into a safer GI profile.[26] In fact, COX-1 is constitutively expressed in the stomach and platelets,[29] whereas COX-2 does not appear to be expressed there or is expressed at very low levels. Experimental results using selective pharmacological inhibition or genetic deletion of COX-1 and COX-2 in mice have shown that COX-2 plays an important role in the healing of pre-existing ulcers.[30,31] In fact, COX-2 is rapidly upregulated in response to growth factors and cytokines and it was demonstrated that both COX-2 mRNA and protein are strongly expressed in mouse stomachs in which ulcers had been induced.[32,33] Recent results may suggest that both COX isozymes are a source of cytoprotective prostanoids: thus, simultaneous inhibition translating into a profound suppression of prostanoids might be a hazard for the GI system.[3] This is mechanistically plausible, with results obtained in the mouse showing that inhibition of both COX-1 and COX-2 is required for the formation of gastric lesions.[34]

Prostanoids (mainly PGE2 and PGI2) have an important role protecting the gut by stimulating the synthesis and secretion of mucus and bicarbonate, increasing mucosal blood flow and promoting epithelial proliferation. The inhibition of prostanoids by NSAIDs creates an environment more susceptible to topical attack by endogenous and exogenous factors. Acid and Helicobacter pylori infection may play a key role in the pathogenesis of gastroduodenal mucosal damage but bile and bacteria seem the key intraluminal agents in the pathogenesis of intestinal mucosal damage. Inhibition of mucosal prostanoid synthesis also results in important changes in the GI microcirculation that appears to play a crucial role in the pathogenesis of ulceration.[21] Besides, the inhibition of platelet COX-1 blocks production of TXA2, which increases bleeding when an active GI bleeding site is present.[35] On the other hand, the COX-2 isoform is induced in most tissues in response to inflammatory stimuli. Prostaglandins derived from COX-2 can be generated at the ulcer margin and appear to play an important role in ulcer healing through triggering the cell proliferation, promotion of angiogenesis and restoration of mucosal integrity.[36]

The rate of blood flow to the luminal surface of the stomach is essential for mucosal integrity. If the blood flow decreases, the mucosa becomes more susceptible to acid and pepsin-induced injury. This rate allows the mucosa to tolerate the acid back-diffusion so long as there is sufficient blood flow to reach buffering of the acid. NSAIDs decrease mucosal blood flow to the upper GI tract, but appear to do so in a 'patchy' way. That is, blood flow is only reduced in some parts in the stomach and they are the sites where NSAIDs cause injury.[37] NSAID-induced inhibition of the synthesis of PGE2 and PGI2, which are vasodilators, is likely to be underlying the cause of focal ischemia produced by these agents. Selective COX-2 NSAIDs do not reduce gastric mucosa blood flow.[38,39]

Nonsteroidal anti-inflammatory drugs can also stimulate leukocytes, particulary neutrophils, which adhere to the vascular endothelium within GI microcirculation.[40,41] Neutrophils play an important role in the pathogenesis of NSAID mucosal injury by initiating the vascular mucosal damage; this conclusion is supported by the results of a study that shows that such damage was absent in neutropenic rats[42] and can be prevented by treatment of animals with neutralizing antibodies directed against leukocyte or endothelial adhesion molecules.[43,44]

Some NSAIDs, particularly those that are weak acids, produce epithelial damage at the sites of contact with the GI mucosa.[45] In locations where the acid is in contact with the surface of the mucosa, these drugs behave in concordance with the pH partition hypothesis. The acidic properties of most NSAIDs (including aspirin) initiate mucosal damage. These weak acids remain in their nonionized lipophilic form in the highly acidic gastric environment. These conditions favor migration into surface epithelial cells, where NSAIDs are dissociated into the ionized form that trap hydrogen ions, thus inducing mucosal injury.[46] NSAIDs can also cause topical mucosal damage by diminishing the hydrophobicity of gastric mucus, thereby allowing endogenous gastric acid and pepsin to injure the surface epithelium.[47] In addition, topical mucosal injury may occur as a result of indirect mechanisms, mediated through the biliary excretion and subsequent duodenogastric reflux of active NSAID metabolites.[48] These drugs may also uncouple mitochondrial respiration, leading to cell death.[25] Some studies have concluded that topical injury could be related to the time of contact of the drug with the GI mucosa.[49,50] However, in an experimental animal model of acid-and pepsin-induced esophagitis, both topical exposure to acidified aspirin and intravenous administration of aspirin increased mucosal injury and mucosal barrier dysfunction compared with controls.[51] In the stomach, the topical injury of NSAIDs may also be related to the ability of these drugs to decrease the hydrophobicitiy of the mucus gel layer in the stomach, which seems to be the first barrier to acid-induced damage.[52]

Topical side effects of NSAIDs appear to play an important role in the pathogenesis of small intestine damage, where the enterohepatic circulation of NSAIDs increases the exposure of intestinal epithelium to these drugs. Once the mucosal permeability is increased, bile, abdominal content and most importantly, bacteria, penetrate and increase the damage by inducing inflammation. Increased mucosal permeability and mucosal inflammation are often silent but occur with most NSAIDs.[53–57] Other findings include anemia, occult blood loss, malabsorption and protein loss. Video capsule endoscopy studies have shown that more than 50% of patients on NSAIDs or low-dose aspirin may have mucosal lesions or mucosal breaks in the small bowel.[58] As expected, antisecretory drugs do not offer protection to the distal gut.[59]

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