Topical Effects

Much of the topical injury induced by NSAIDs is related to their weakly acidic properties, which produce epithelial damage of the GI mucosa. In the highly acidic environment, these drugs become nonionized, lipophilic compounds that freely diffuse into surface mucosal cells. The higher pH of the intracellular environment favors acid dissociation, recreating the ionized form of the drugs, which then increase cell membrane permeability to hydrogen ions. This process leads to mucosal damage, erosion, and bleeding.

Another proposed mechanism of topical injury is an attenuation of the phospholipid content and surface hydrophobicity of the gastric mucosal gel layer, which normally limits the diffusion of hydrogen ions from the lumen to the mucosa. NSAIDs have been found to have an ability to form a chemical association with zwitterionic phospholipids, which line the luminal aspects of the gastric mucosal layer. This interaction likely contributes to the mechanisms by which NSAIDs attenuate the hydrophobic barrier of the upper GI tract. Modifying NSAIDs with exogenous zwitterionic phospholipids prevented these associations with the mucosal layer and protected rat models against GI damage.

NSAIDs have also been suggested to locally uncouple mitochondrial oxidative phosphorylation and disrupt electron transport, leading to reduced DNA synthesis and mucosal cell proliferation and ultimately increasing intestinal permeability. There is a subsequent intestinal inflammatory reaction driven by acid and pepsin at the mucosal layer and by bile and bacteria in the small intestine. Degradation products of bacteria recruit neutrophils, free radicals, and various inflammatory mediators, including inducible nitric oxide synthase, interleukins, and tumor necrosis factor (TNF). All of these mediators culminate in attributing to the ultimate development of erosions and ulcerations.

NSAIDs are known to alter GI mucosal blood flow through the inhibition of GI mucosal prostaglandin synthesis. These prostaglandins function as vasodilators and normally enhance mucosal blood flow after gastric acid production. Acid diffusion into the mucosa is tolerated in the presence of sufficient blood flow, which allows buffering of the increase in acid. Thus, this blood flow is integral to the preservation of the protective mucosal layer, and without appropriate vasodilation, the tissue become more susceptible to damage from acid and pepsin. Accordingly, selective COX-2 inhibitors do not reduce gastric mucosa blood flow, whereas indomethacin does decrease flow. These differences in mechanisms of action may contribute to the relative GI toxicities of different NSAIDs.

The topical effects of NSAIDs have been further elucidated in the pathogenesis of small intestine injury, in which injury seems to depend on the degree to which NSAIDs undergo enterohepatic recirculation. In a study by Reuter and colleagues, modification of diclofenac rendered it less available for enterohepatic recirculation and subsequently less toxic to the small intestinal mucosa. GI damage was not observed with NSAIDs that do not undergo enterohepatic recirculation, such as nabumetone and aspirin. With the NSAIDs that do undergo enterohepatic recirculation, there seems to be a concurrent increase of enteric bacterial numbers that exacerbates the initial injury from NSAIDs.

Systemic Effects

NSAIDs inhibit the enzyme COX, the rate-limiting enzyme in the biosynthesis of prostaglandins from arachidonic acid. There are 2 isoforms: COX-1 and COX-2 ( Fig. 3 ). The COX-1 isoform is a constitutive enzyme expressed in most of the tissues of the body that produces prostaglandins that facilitate renal perfusion and platelet activity in addition to mediating many GI cytoprotective effects. These prostaglandins stimulate the synthesis and secretion of mucus and bicarbonate, increase mucosal blood flow, and promote epithelial proliferation. More specifically, prostaglandin E increases surface hydrophobicity of the gastric mucosa by increasing surface active phospholipids. As stated previously, both prostaglandin E and I enhance mucosal blood flow after gastric acid production, preventing erosions that are seen when such vasodilatation does not occur. The inhibition of COX-1 also blocks platelet production of thromboxane, which exacerbates active GI bleeding. Thus, when NSAIDs inhibit COX-1, the resulting environment is more susceptible to injury.

Pharmacology of NSAIDs. Arachidonic acid, after its release from membrane, phospholipids can be metabolized by either COX-1 or COX-2 depending on which COX isoform is present in an organ system. Nonspecific NSAIDs inhibit both COX-1 and COX-2, whereas COX-2–specific NSAIDs inhibit only COX-2. Thus, COX-2–specific NSAIDs can be alternatively conceptualized as COX-1 sparing.

COX-2 is an inducible enzyme produced in most tissues in response to inflammatory stimuli and, contrary to COX-1, it has been shown to have little activity in the human GI tract or on platelets. The effects of COX-2 are mediated through prostaglandins, which result in inflammation, pain, and fever. Prostaglandins derived from COX-2 are generated at ulcer margins and seem to play an important role in ulcer healing by triggering cell proliferation, promotion of angiogenesis, and restoration of mucosal integrity.

Another proposed mechanism of NSAID-induced GI injury involves the stimulation of neutrophil adherence to the vascular endothelium in the GI microcirculation. Neutrophils seem to play a key role in the pathogenesis of NSAID-induced mucosal injury, shown by a lack of GI damage in neutropenic rats. Factors such as leukotriene B4 and TNF-α trigger not only the adherence of neutrophils to the vascular endothelium but also the activation of these cells, leading to production of oxygen-derived free radicals and proteases. These substances such as superoxide anion, elastases, and collagenase then mediate endothelial and epithelial injury. NSAID-induced injury is reduced by free radical scavengers. Damage can also be prevented by treatment with neutralizing antibodies directed against leukocyte or endothelial adhesion molecules. In addition, administration of prostaglandins at doses known to prevent gastric injury prevents NSAID-induced leukocyte adherence. In accordance with this theory, a clinical trial studying the use of famotidine for the prevention of NSAID-related gastroduodenal ulcers reported that an increased peripheral white cell count correlated positively with the risk of ulcer development. Neutrophil recruitment and adherence to the GI microvasculature also likely promote vascular congestion, decreased mucosal blood flow, and ischemia. Both selective COX-2 inhibitors and traditional NSAIDs cause leukocyte adherence to the vascular endothelium.

Traditional NSAIDs and acetylsalicyclic acid (ASA) inhibit both isoforms of COX. Aspirin irreversibly inhibits COX via acetylation, whereas other NSAIDs inhibit COX in a reversible, concentration-dependent manner. When COX is irreversibly inhibited, prostaglandin synthesis does not return to normal levels for several days until new COX enzyme is generated. After even low daily doses of aspirin, prostaglandins do not fully recover in the stomach for approximately 5 to 8 days and in the platelet until 14 days. This finding may explain why aspirin is one of the most potent inhibitors of prostaglandin and thromboxane synthesis.

These concepts of GI damage driven primarily via COX-1 inhibition have led to the development of COX-2 specific NSAIDs in hopes of achieving effective pain relief with reduced adverse GI effects. In December 1998, the first COX-2 inhibitor celecoxib was approved in the United States. Since then, several other COX-2 inhibitors have been introduced into clinical practice. Data from several randomized controlled trials have indeed shown more favorable safety profiles of COX-2 inhibitors regarding gastroduodenal ulcers and clinically important ulcer complications when compared with traditional nonselective NSAIDs. The Celecoxib Long-term Arthritis Safety Study (CLASS) compared high-dose celecoxib, diclofenac, and ibuprofen in patients with osteoarthritis and rheumatoid arthritis and showed that celecoxib was associated with significantly fewer symptomatic ulcers. The annual incidence rate of upper GI ulcer complications was 0.76% with celecoxib versus 1.45% with NSAIDs; when symptomatic ulcers were also considered, these rates were 2.08% for celecoxib and 3.54% for NSAIDs. The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial compared rofecoxib with naproxen in patients with rheumatoid arthritis and found that rofecoxib was associated with 50% fewer GI events, or 2.1 events per 100 patient-years versus 4.5 events per 100 patient-years for patients on naproxen. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) compared lumiracoxib with naproxen and ibuprofen and found a 75% decrease in adverse GI events in patients treated with lumiracoxib as opposed to those on nonselective NSAID therapy. The Successive Celecoxib Efficacy and Safety Study-1 (SUCCESS-I) compared celecoxib, naproxen and diclofenac in patients with osteoarthritis and found significantly fewer ulcer complications with celecoxib than with nonselective NSAIDs, 0.1 per 100 patient-years versus 0.8 per 100 patient-years with an odds ratio of 7.02. There is evidence that the safety advantage provided with selective COX-2 inhibition is reduced in patients receiving concomitant low-dose aspirin treatment. In the SUCCESS-I study, for those patients not on aspirin therapy, the risk of ulcer complications in those on naproxen or diclofenac was significantly higher than in those on celecoxib. However, for those patients on aspirin therapy, there was no significant difference in GI complications in patients on COX-2 inhibitors versus nonselective NSAIDs.

The COX-2 hypothesis is now being challenged in light of emerging evidence that suggests that gastric damage induced by traditional NSAIDs does not occur because of COX-1 inhibition alone, and that suppression of both COX-1 and COX-2 is needed for gastric ulceration to occur in rat models. In a study by Wallace and colleagues, selective inhibition of COX-1 significantly decreased prostaglandin synthesis, but did not produce gastric damage. Selective inhibition of COX-2 did not cause any detectable suppression of gastric prostaglandin synthesis and also did not cause gastric damage. However, coadministration of selective COX-1 and COX-2 inhibitors resulted in gastric damage consistently. In studies of mice with COX-1 gene knockout, there is negligible gastric prostaglandin synthesis but no spontaneous gastric damage as would be expected if COX-1 inhibition was the main mechanism underlying NSAID-induced GI damage. When these knockout mice were given a nonselective NSAID indomethacin, they consistently developed gastric damage. In addition, several outcomes studies, such as SUCCESS-1, showed that the use of low-dose aspirin in conjunction with selective COX-2 inhibitors negated the gastroprotective effect conferred by COX-2 inhibitors. These studies clearly suggest that both COX-1 and COX-2 play a part in maintenance of GI mucosal defense.

Inhibition of COX and subsequent diversion of arachidonate acid through the lipoxygenase (LOX) pathway enhances leukotriene synthesis. As discussed earlier, leukotrienes cause vasoconstriction and release of oxygen free radicals, which add to damage caused by impaired mucosal defense. Leukotrienes also serve to increase the expression of neutrophil adhesion molecules, leading to further microvascular congestion and ischemia and free radical release. The inhibition of prostaglandin synthesis results in reduced mucosal blood flow, increased acid secretion, and an impairment of the mucosal barrier. COX-2 is induced at ulcer margins in response to inflammation and generates prostaglandins that trigger cell proliferation, promote angiogenesis, and restore mucosal integrity. It should not be surprising, then, that COX-2 inhibition delays gastric ulcer healing. Epithelial damage is thus caused by both direct topical and prostaglandin-mediated systemic effects of NSAIDs, as well as combined effects of both COX-1 and COX-2 inhibition.

Other efforts to attenuate GI damage have focused on antisecretory agents or mucosal protective agents such as synthetic prostanoids or nitric oxide donors such as nitric oxide and hydrogen sulfide (H ₂ S). These mediators are important for maintaining gastric mucosal integrity, and share many biologic effects with the prostaglandins. There is some evidence that another mechanism by which NSAIDs exert GI damage is through the inhibition of synthesis of these mediators.

The Balance Between Topical and Systemic Effects

There has been some conflicting evidence about the relative balance of topical versus systemic effects in contributing to GI injury. Inhibition of COX-1 in rats and disrupting the COX-1 gene in mice depletes gastric mucosal prostaglandin levels to less than 1% without causing GI damage. This finding suggests that other mechanisms must contribute in GI damage. Recent studies suggest that topical effects of NSAIDs may have a larger role than previously believed. Topical effects are likely the major mechanism responsible for acute hemorrhages and erosions observed acutely after NSAID challenge. Enteric-coated NSAIDs produce considerably less acute topical erosive and hemorrhagic injury than plain, nonenteric-coated formulations during short-term (1 to 2 weeks) administration, an observation in support of local toxic effects of NSAIDs. However, with long-term administration of enteric-coated formulations, gastric ulcers develop at rates that are not different than with nonenteric-coated preparations, presumably as a result of the systemic mechanism of injury. In addition, selective COX-2 inhibitors differ from most traditional NSAIDs in that they are nonacidic and thus lack the local topical effects. This feature of COX-2 inhibitors may contribute to the cause of their low GI mucosal toxicity, separate from their lack of effects on COX-1.

Somasundarum and colleagues reported that both local uncoupling of oxidative phosphorylation and inhibition of COX are required for the development of NSAID-related enteropathy in rats. Dinitrophenol (DNP), an uncoupling agent, was used to represent topical effects of NSAIDs on intestinal mitochondria, and parenteral aspirin was used to represent the systemic effects of COX inhibition. Although both DNP and ASA were individually associated with increased intestinal permeability and decreased prostaglandins, respectively, neither were able to cause ulcerations alone. However, when these drugs were given together, the ensuing pathophysiologic changes and small intestinal lesions mirrored those caused by indomethacin, suggesting that both uncoupling of mitochondrial oxidative phosphorylation and inhibition of COX may be important in the pathogenesis of NSAID-induced intestinal ulcers.

Topical Effects

Much of the topical injury induced by NSAIDs is related to their weakly acidic properties, which produce epithelial damage of the GI mucosa. In the highly acidic environment, these drugs become nonionized, lipophilic compounds that freely diffuse into surface mucosal cells. The higher pH of the intracellular environment favors acid dissociation, recreating the ionized form of the drugs, which then increase cell membrane permeability to hydrogen ions. This process leads to mucosal damage, erosion, and bleeding.

Another proposed mechanism of topical injury is an attenuation of the phospholipid content and surface hydrophobicity of the gastric mucosal gel layer, which normally limits the diffusion of hydrogen ions from the lumen to the mucosa. NSAIDs have been found to have an ability to form a chemical association with zwitterionic phospholipids, which line the luminal aspects of the gastric mucosal layer. This interaction likely contributes to the mechanisms by which NSAIDs attenuate the hydrophobic barrier of the upper GI tract. Modifying NSAIDs with exogenous zwitterionic phospholipids prevented these associations with the mucosal layer and protected rat models against GI damage.

NSAIDs have also been suggested to locally uncouple mitochondrial oxidative phosphorylation and disrupt electron transport, leading to reduced DNA synthesis and mucosal cell proliferation and ultimately increasing intestinal permeability. There is a subsequent intestinal inflammatory reaction driven by acid and pepsin at the mucosal layer and by bile and bacteria in the small intestine. Degradation products of bacteria recruit neutrophils, free radicals, and various inflammatory mediators, including inducible nitric oxide synthase, interleukins, and tumor necrosis factor (TNF). All of these mediators culminate in attributing to the ultimate development of erosions and ulcerations.

NSAIDs are known to alter GI mucosal blood flow through the inhibition of GI mucosal prostaglandin synthesis. These prostaglandins function as vasodilators and normally enhance mucosal blood flow after gastric acid production. Acid diffusion into the mucosa is tolerated in the presence of sufficient blood flow, which allows buffering of the increase in acid. Thus, this blood flow is integral to the preservation of the protective mucosal layer, and without appropriate vasodilation, the tissue become more susceptible to damage from acid and pepsin. Accordingly, selective COX-2 inhibitors do not reduce gastric mucosa blood flow, whereas indomethacin does decrease flow. These differences in mechanisms of action may contribute to the relative GI toxicities of different NSAIDs.

The topical effects of NSAIDs have been further elucidated in the pathogenesis of small intestine injury, in which injury seems to depend on the degree to which NSAIDs undergo enterohepatic recirculation. In a study by Reuter and colleagues, modification of diclofenac rendered it less available for enterohepatic recirculation and subsequently less toxic to the small intestinal mucosa. GI damage was not observed with NSAIDs that do not undergo enterohepatic recirculation, such as nabumetone and aspirin. With the NSAIDs that do undergo enterohepatic recirculation, there seems to be a concurrent increase of enteric bacterial numbers that exacerbates the initial injury from NSAIDs.

Systemic Effects

NSAIDs inhibit the enzyme COX, the rate-limiting enzyme in the biosynthesis of prostaglandins from arachidonic acid. There are 2 isoforms: COX-1 and COX-2 ( Fig. 3 ). The COX-1 isoform is a constitutive enzyme expressed in most of the tissues of the body that produces prostaglandins that facilitate renal perfusion and platelet activity in addition to mediating many GI cytoprotective effects. These prostaglandins stimulate the synthesis and secretion of mucus and bicarbonate, increase mucosal blood flow, and promote epithelial proliferation. More specifically, prostaglandin E increases surface hydrophobicity of the gastric mucosa by increasing surface active phospholipids. As stated previously, both prostaglandin E and I enhance mucosal blood flow after gastric acid production, preventing erosions that are seen when such vasodilatation does not occur. The inhibition of COX-1 also blocks platelet production of thromboxane, which exacerbates active GI bleeding. Thus, when NSAIDs inhibit COX-1, the resulting environment is more susceptible to injury.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related posts:

Differential Diagnosis of Upper Gastrointestinal Bleeding Proximal to the Ligament of Trietz Pathology of Diseases that Cause Upper Gastrointestinal Tract Bleeding Epidemiology and Demographics of Upper Gastrointestinal Bleeding: Prevalence, Incidence, and Mortality Radiologic Techniques and Effectiveness of Angiography to Diagnose and Treat Acute Upper Gastrointestinal Bleeding Management of Nonvariceal Upper Gastrointestinal Bleeding New Diagnostic Imaging Technologies in Nonvariceal Upper Gastrointestinal Bleeding

Stay updated, free articles. Join our Telegram channel

Join