Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage

: REVIEW

Mechanisms of Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Damage ROBERTT. SCHOEN, M.D., F.A.c.P., RONALD J. VENDER, M.D. NewHaven, Connecticut

The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the gastric mucosa are well documented. The complex mechanisms of gastric damage, however, are not fully understood. This review examines current knowledge about the normal function of the gastric mucosal barrier; the role of prostaglandins in cytoprotection and repair; the mechanisms by which aspirin and other weak organic acids are absorbed by the stomach; and the subsequent cascade of events-including ion trapping and back diffusion of hydrogen ions-that leads to gastric erosion and bleeding. A hypothesis describing NSAIDs’ dual insult on the stomach is advanced.

From the Department of Internal Medicine, Yale University School of Medi- cine, New Haven, Connecticut. Requests for reprints should be addressed to Robert T. Schoen. M.D., F.A.C.P.. Internal Medicine and Rheumatology, P.C., 60 Temple Street, Suite 6A. New Haven, Connecticut 06510. Manu- ;c$ submitted May 12, 1988, and accepted in revised form January 13,

T he use of sodium salicylate in 1875 to treat patients with rheumatic disease [l] was followed by

reports of “dyspeptic indigestion” in patients receiv- ing salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs) [2]. Gastric mucosal damage is now recognized as the most important adverse effect of NSAIDs, causing gastrointestinal symptoms, erosions, ulcers, and upper gastrointestinal bleeding [3]. The synthesis of aspirin (acetylsalicylic acid) by Hoff- man in 1899 from the more toxic salicylic acid reduced toxicity and introduced the modern era of NSAID therapy [4]. Investigation continues in regard to the development of potent anti-inflammatory drugs that avoid gastric mucosal damage.

The problem of NSAID gastrointestinal toxicity has stimulated investigation of normal gastric defense mechanisms. Exactly how the stomach protects itself from the hydrochloric acid and pepsin it produces is not known. The protective mechanisms that must ex- ist, however, are grouped together by the term “gastric mucosal barrier” [5]. The study of how aspirin and other NSAIDs induce gastric damage has been the study of how these agents “break” this barrier [6].

Gastric Defense: The Gastric Mucosal Barrier More than two centuries ago, Reaumur recognized

that gastric juice is capable of digesting meat [?I. This observation led to the concept of a gastric mucosal barrier. Claude Bernard believed that the layer of mucus that covers the surface epithelium of the stomach acts as a “porcelain-like shell” separating the epitheli- urn from its gastric contents [B]. Although mucus may indeed be important [9], the concept of a gastric mucosal barrier must include modern observations of normal gastric physiology, including hydrogen ion, bicarbonate, and electrolyte secretion. For example, the electrolyte concentration in gastric juice varies with the rate of gastric secretion. At low secretory rates, gastric juice has a high sodium ion concentration and a low hydrogen ion concentration. At high secretory rates, these concentrations are reversed [lo]. This dis- covery suggested that the gastric mucosa is a diffusion barrier in which a sodium ion is exchanged for a hydrogen ion at the mucosal cell surface [II].

Gastric Defense: Mucus and Bicarbonate Secretion In 1954, Hollander [12] proposed a two-component

gastric mu.cosal barrier consisting of the mucus layer together with the epithelial cells beneath it. In this model, hydrogen ion concentration is reduced at the epithelial cell surface by sodium secreted from inter- stitial fluid. Heatley [13] suggested that an “unstirred” mucus layer allows the development of a pH gradient between the epithelial cell and the lumen. Allen and Garner [9] proposed that bicarbonate is secreted by the mucosa and that mucus has gel properties that limit the diffusion of hydrogen ion, creating a

April 1989 The American Journal of Medicine Volume 86 449

MECHANISMS OF NSAID-INDUCED GASTRIC DAMAGE / SCHOEN AND VENDER

Mltcosal cells (=retion)

HCO; -

Na+-

mucus giycoprctein -

I pH7 -pHgraclient- pH l-2

Cl-“Na+

rpeps’n i k desr=k+d

glycoprotein subunits

Lumen (mixing)

-H+

- ci-

pH gradient across the mucus layer (Figure 1). Dav- enport [7] viewed the mucus layer as having merely a lubricating function. He emphasized anatomic properties of the lipid and protein gastric cell membrane and tight junctions between cells in limiting penetration of water-soluble compounds, including hydrogen ion. Gastric mucus is in fact a high-viscosity gel composed of glycoprotein polymers that reduce the rate at which hydrogen ion from the lumen and bicarbonate from the epithelial cells can mix [9]. Recently, a pH gradient across the mucus layer has been demonstrated using pH-sensitive microelectrodes [14-161.

Bicarbonate is secreted by receptor-mediated active transport by the gastric mucosa [9,17,18]. In addition, vagus nerve stimulation increases bicarbonate output during the cephalic phase of gastric secretion [19]. Although bicarbonate is actively secreted, the rate of secretion is only about 5 to 10 percent of maximal acid output [9]. If a mucus-bicarbonate model is correct, the gel properties of mucus must significantly limit the rate of reaction between secreted bicarbonate and luminal hydrogen ion. In addition, other factors must maintain a gradient in which hydrogen ion is secreted in much higher concentration than bicarbonate. For example, it has been shown that gastric mucus significantly retards penetration of pepsin from the lumen [20]. It has also been suggested that the mucus layer may thicken in response to injury, forming a framework for re-epithelialization of the mucosa [21].

Gastric Defense: Surface Hydrophobicity Hills and associates [22] found canine gastric muco-

sa to be exceptionally hydrophobic in contrast to the duodenal mucosa, which is hydrophilic. They postulated that phospholipids, high levels of which have been identified in gastric mucosa and gastric secretions [23], are concentrated on the luminal surface of the gastric epithelium. This phospholipid layer cre-

450 April 1989 The American Journal of Medicine VOhne 86

Figure 1. Surface neutralization. A model in which the mucosa secretes bicarbonate, and an “unstirred” viscous mucus layer on the epithelial cell surface permits the development of a pH gradient that limits diffusion of hydrogen ion from the lumen. (Adapted with permission from [9].)

ates a hydrophobic surface, which may significantly limit the diffusion of hydrogen ion from the lumen into the mucosa [24].

Gastric Defense: Mucosal Blood Flow and Reconstitution Several studies show that gastric mucosal blood flow

protects the mucosa from acid injury [3]. If the gastric mucosal barrier is disrupted by acid, intracellular hydrogen ion is removed by a compensatory increase in mucosal blood flow. If this compensatory increase is prevented, cell death occurs [25]. There is also evidence that within the gastric microcirculation, transport of bicarbonate from the interstitium to surface epithelial cells helps to prevent acid injury [26].

Mucosal re-epithelialization within 30 minutes following injury (“reconstitution”) with agents such as hypertonic saline, ethanol, and aspirin occurs in the amphibian gallbladder, duodenum, and colon [27], as well as in the amphibian and mammalian stomach [28]. This process may be an important repair mechanism throughout the entire gastrointestinal tract. In an in vitro system, reconstitution is associated with a net alkalinization of the luminal solution during the first four hours, changing to a net acid secretion comparable to that in control tissues by six hours. If an acidic luminal pH is maintained, reconstitution does not occur [29]. Rapid epithelial reconstitution is probably important in maintaining the anatomic integrity of the gastric mucosal barrier [29].

Gastric Defense: Prostaglandins Prostaglandins are a vital component of gastric mu-

cosal defense. These short-acting, widely distributed, 20-carbon chain, unsaturated fatty acids are found throughout the gut in locally high concentration. A major stimulus for their synthesis is perturbation of cell membranes, including cell trauma by acid or alkali [30]. Prostaglandins have an anti-secretory effect on gastric acid production [31], but the ability of prosta-


glandins to defend the stomach against injury by luminal acid and other noxious agents at concentrations that do not inhibit gastric acid secretion is called “gastric cytoprotection” [32]. In addition, a variety of irritants, including ethanol, hydrochloric acid, alkali, hypertonic saline, and thermal injury, stimulates prostaglandin production. In association with such stimulation, gastric necrosis is prevented when ani- mals are subsequently challenged with agents that would ordinarily damage the stomach. This phenomenon, termed “adaptive cytoprotection,” may protect the mucosa from the damaging effect of gastric luminal contents [30].

Adaptive cytoprotection may result from prostaglandin-mediated mechanisms, but this is not proven. Mild irritants that are protective do not always stimulate endogenous prostaglandin synthesis, and prostaglandin suppression by indomethacin has not univer- sally abrogated adaptive cytoprotection [33]. Hawkey and associates [34] showed that the protective effect of 20 percent ethanol is present even after prostaglandin Es release is 86 percent inhibited by indomethacin. They found extensive superficial disruption of the surface epithelium following 20 percent ethanol administration and postulated that this desquamated debris may form a protective covering that could account for adaptive cytoprotection.

Although it is uncertain that adaptive cytoprotection critically depends on prostaglandin synthesis, it is clear that prostaglandins enhance many of the postulated components of gastric mucosal defense. Prosta- glandins stimulate bicarbonate secretion [33] and the synthesis of mucus [35]. Prostaglandins increase mucus gel thickness [36]. As a result, prostaglandin Es enhances the pH gradient in mucus between the lumen and epithelial cell surface [37].

Prostaglandin Es increases the surface hydrophobicity of gastric mucosa [38] by increasing surface- active phospholipids [39]. Both prostaglandin E and I enhance mucosal blood flow following gastric acid production [40], preventing erosions that are seen when such vasodilatation does not occur [41]. Prostaglan- dins may also protect the mucosa by stimulating sodium-active transport [42].

Prostaglandins probably also have a repair function, stimulating rapid resolution of disrupted surface epithelium [43], although this has not always been found [44]. Repair mechanisms may include migration of basal cells toward the lumen to repair mucosal injury [45]. Also possible is enhanced DNA, RNA, protein, and collagen synthesis, which has been demonstrated in cutaneous tissue [46], but not for the gastric mucosa [471.

Gastric Defense: Sulfhydryl Compounds Ethanol induces a decrease in gastric non-protein

sulfhydryl compounds in association with mucosal erosions [48]. Aspirin- [49] and ethanol- [48] induced erosions can be prevented by preadministration of sulfhydryl compounds. These observations suggest that sulfhydryl compounds may mediate gastric cytoprotection. It is possible that prostaglandin-induced cytoprotection requires sulfhydryl compounds, since sulfhydryl blocking agents such as N-ethylmaleiamide prevent the mucosal cytoprotective effect of prostaglandin Fsn [48]. In addition, ethanol-induced gastric damage is greater following administration of both a prostaglandin inhibitor, indomethacin, and a sulfhy-

dry1 blocker, N-ethylmaleiamide, than following either compound alone [50].

Sulfhydryl compounds, such as reduced glutathione, which is found in high concentration in the stomach [51], bind free radicals that form following tissue injury by noxious agents [52]. Sulfhydryl compounds may also protect mucus, since mucus subunits are joined by disulfide bridges that, if reduced, render mucus water-soluble [53]. A vasoprotective effect for sulfhydryl compounds following ethanol-induced injury is also postulated [50].

Much of the current understanding of the gastric mucosal barrier has been gained from investigating changes in mucosal integrity caused by acute manipu- lation with NSAIDs such as aspirin. Several studies, however, show that the stomach may become less susceptible to these compounds over time [54,55] by compensatory mechanisms, which may include increased cell turnover and the emergence of younger cell populations [56]. This phenomenon is called “gastric adaptation” [55].

NSAID Damage: Breaking the Gastric Mucosal Barrier Aspirin and most other NSAIDs are weak organic

acids. A solution of two aspirin tablets in 100 ml of drinking water has a pH of about 2.5 [57]. Aspirin damages the gastrointestinal tract in the absence of hydrochloric acid [58] and induces lesions in the buc- cal mucosa by direct acid damage [59]. Aspirin and indomethacin also increase basal [60] and maximally stimulated gastric acid secretion [61,62], which may contribute to NSAID-induced damage.

NSAID Damage: Ion Trapping Aspirin and other NSAIDs also damage the gastric

mucosal barrier by altering cell membrane permeability, allowing “back diffusion” of hydrogen ion. Weak organic acids such as aspirin are concentrated in the mucosal cell as a result of “ion trapping” [63-651. Be- cause of its lipid and protein membrane, the mucosal cell absorbs lipid-soluble compounds such as aspirin more readily than it does water-soluble compounds.

For example, acetic acid, which is lipid-soluble, diffuses across the mucosa three times faster than hydrochloric acid, which is not [7]. In the strongly acid environment of normal gastric juice (pH 2.5), aspirin (pKa 3.5) is mostly non-ionized. As an undissociated acid, aspirin freely diffuses into the mucosal cell. Once inside the cell, the much higher pH of the intracellular environment (pH 7) favors acid dissociation. In this ionized state, aspirin is water-soluble and “trapped” inside the cell. These events favor a strong concentration gradient, moving dissociated ions of weak organic acids such as aspirin (pKa 3.5) [66] (Figure 2), indomethacin (pKa 5.2), phenylbutazone (pKa 4.8), and other acidic NSAIDs into the gastric mucosa. This rapid absorption has been demonstrated for a variety of weak organic acids, including acetic acid (pKa 4.78), propionic acid (pKa 4.86), and butyric acid (pKa 3.90): as well as acetylsalicylic acid [7,67].

NSAID Damage: Back Diffusion The rapid intracellular penetration of aspirin and

its entrapment as an ionized salt are followed by alter- ation in cell membrane permeability and damage by luminal hydrogen ion.

Davenport [5] examined this damaging effect on the canine gastric pouch after exposure to 20 mM of aspi-



Ionized, Water Soluble UN-ionized, Fat Soluble

0 0

Hf + -O-C-CHa7b

T -F-O-

0 0

From HCI

? -0-C-CH,

-$-OH

0

Removal of Blood

Figure 2. Absorption of weak organic acids. Un-ionized aspirin (pKa 3.5) diffuses into the gastric mucosa, dissoci- ates, and accumulates in the cells. (Adapted with permission from [66].)

rin. The rate of absorption of aspirin into the mucosa is dependent on the luminal pH, as would be expected, with a low pH favoring more rapid absorption. The absorption of aspirin is associated within minutes with abnormal ion fluxes across the mucosa. Sodium and potassium enter the luminal fluid, and hydrogen ion disappears from the lumen into the mucosa (an observation termed “back diffusion of hydrogen ion”). In these experiments, frank mucosal bleeding is not observed when the gastric pouch is irrigated with 20 mM aspirin in relatively weak acid (1 mM hydrochloric acid or 10 mM hydrochloric acid), but gross bleeding occurs when aspirin in 100 mM hydrochloric acid is instilled. Davenport concluded that aspirin damages the mucosal barrier as it is absorbed by an unknown mechanism that renders the mucosa abnormally per- meable to water-soluble hydrogen ion. Back diffusion of strongly acid gastric juice then leads to mucosal damage, including erosion and bleeding [5] (Figure 3). These experiments may explain why achlorhydric patients are less susceptible to aspirin-induced gastric injury than normal persons [68] and why damage from aspirin is markedly reduced when gastric secretions are buffered to pH 6 to 7 [69].

Figure 3. Aspirin-induced back diffusion. Davenport [5] found that absorption (l), followed by ionization and entrapment (2), of aspirin is associated with abnormal ion flux across the gastric mucosa (3). Back diffusion of hydrogen ion from the lumen leads to gastric erosion and bleeding.

The aspirin-induced increase in hydrogen ion permeability observed experimentally [5] has been confirmed in normal volunteers [70-721. In addition, it has been demonstrated for other NSAIDs, including indomethacin [6,73,74] and fenoprofen [75]. Fenopro- fen causes less hydrogen ion flux than indomethacin or aspirin, but more than a control preparation. Indo- methacin causes sustained back diffusion associated with bleeding at both neutral and acidic pH [6].

NSAID Damage: Transmucosal Potential Difference The increased permeability to hydrogen ion caused

by aspirin occurs within minutes after exposure and is associated with additional evidence of damage to the gastric mucosal cell. Transmucosal electrical potential difference is a sensitive index of gastric mucosal function [75]. In numerous studies, aspirin (Figure 4) and indomethacin induce an immediate decrease in gastric potential difference [71,74,76,77]. Both the change in potential difference [77] and the increase in ion permeability [67] typically recover within 90 minutes, consistent with the hypothesis that weak organic acid NSAIDs are rapidly trapped, but diffuse out of the cell more slowly [67].

452 April 1989 The American Journal of Medicine Volume 86


Figure4. Potential difference. Aspirin induces an immediate decrease in gastric transmucosal electrical potential difference, a sensitive index of gastric mucosal function. (Adapted with permission from [73].)

Figure 5. Aspirin-induced injury. A pho- tomicrograph (toluidine blue stain; origi- nal magnification X 620, reduced by 25 percent) shows damage to surface mucous cells by 20 mM aspirin. Changes were observed within one minute of aspirin administration, with maximum damage occurring by eight minutes, (Adapted with permission from [78].)

Time-3 Min. Intervals

NSAID Damage: Ultrastructure The aspirin-induced injury that Davenport demon-

strated physiologically has been confirmed by electron microscopy. Hingson and Ito [78] administered 20 mM of aspirin to mice under experimental conditions similar to those of Davenport [5]. They found “sudden and drastic morphological alterations in many of the ex- posed surface mucus cells” [78] at all concentrations of aspirin and hydrochloric acid (Figure 5). These changes are seen within one minute after aspirin administration, with maximum damage occurring by eight minutes. Ten to 85 percent of the total surface areas show injury, including karyolysis, erosions, and bleeding. By four hours, there is marked resolution of these lesions [78]. Rainsford [79] observed similar changes and showed that damage was greatest for the

parietal cell and could be prevented if aspirin is buffered with bicarbonate. Using a freeze-fracture tech- nique, Meyer et al [80] showed that aspirin disrupts the tight junctions between cells. Hingson and Ito ex- perimented with other weak organic acids to demonstrate that the mechanism of damage is not unique to aspirin. Severe ultrastructural damage is seen with 20 mM solutions of acetic acid, benzoic acid (pKa 4.2), and salicylic acid (pKa 3.0). Salicylamide, a non-acid, does not induce damage (Table I) [78].

NSAID Damage: Autoradiographic Techniques Autoradiographic techniques also provide evidence

that gastric injury caused by aspirin and other acidic NSAIDs occurs because these compounds are selec- tively trapped within mucosal cells, whereas non-acid-


MECHANISMS OF NSAIDdNDUCED GASTRIC DAMAGE / SCHOEN AND VENDER

TABLE I

Frequency of Damage to the Gastric Surface Epithelium of Mice following Oral Administration of Aspiriri Analogues

Agent

Agent Electrolytes (mEq/liter)

Percent ml/liter H+ Na+ CI- Time (minutes) Frequency (D/n)

Salicylic acid

Benzoic acid Acetic acid

0.275 0.14

0.245 0.12 0.12

20

:oo :i

145 135

145 135 145

155 145

155 145 155

1:

1: 8

616 2/3

y: 3/a

Salicylamide 0.275 20 10 140 150 8 * D/n = number of stomachs with damaged surface mucosal cells/total number of stomachs. (Adapted with permission from [63].)

O/7

ic compounds are not. In a series of experiments, Brune and colleagues [Bl] demonstrated accumulation of radiolabeled aspirin, salicylic acid, phenylbutazone, and indomethacin within the stomach wall, but no such accumulation of the non-acidic compounds anti- pyrine, aminopyrine, or paracetamol. In addition, diflunisal, a derivative of salicylic acid reported to cause less gastric irritation than other salicylates [82], and proquazone, a non-acid anti-inflammatory agent with a low incidence of gastric irritation [83], are not detec- tably absorbed by the stomach [84,85]. Within one minute after drug administration, thin slices of the stomach wall show high concentrations of tritiated salicylic acid, which persists in the surface mucus and the mucus-producing superficial cells [84]. There is also selective trapping of salicylate within parietal cells [84]. After 20 minutes, when tritiated drug is concentrated in the stomach wall, gastric cell decay is demonstrated by electron microscopy [85]. No such changes are seen with proquazone [85]. These studies provide additional evidence that acidic NSAIDs reach high concentrations within the mucosa, and that this biodistribution of drug is important in the development of gastric toxicity [85].

These different lines of evidence suggest that NSAIDs damage the mucosal cell by altering membrane permeability, allowing back diffusion of hydrogen ion. The mechanisms by which the accumulation of acidic NSAIDs within mucosal cells leads to these changes are unknown. The dissociated acid may increase the osmolarity of the intracellular fluid and cause cell swelling [86]. Such changes in cell shape may increase membrane permeability [87]. Membrane permeability changes could also result from inhibition of active transport. Several experiments demonstrate that aspirin at low concentration inhibits active transport of sodium and hydrogen ion across the mucosal cell without an increase in membrane permeability [87,88]. At higher concentrations, both ion transport and permeability are affected, suggesting that inhibition of ion transport either by enzyme inhibition [89,90] or oxidative uncoupling [91,92] is the initial insult caused by aspirin, and that changes in membrane permeability are a secondary consequence [88]. Indomethacin also inhibits sodium-active transport [42]. Spenney [93] has demonstrated an acetylsalicylic e&erase in gastric mucosa that hydrolyzes aspirin (acetylsalicylic acid) to salicylic acid. Intracellular conversion of aspirin to salicylate could be important in aspirin-induced injury, since salicylate potently un- couples and/or inhibits mitochondrial oxidative phos- phorylation whereas nonhydrolyzed aspirin may not WI * 454 April 1989 The American Journal of Medicine Volume 86

NSAID Damage: MUCUS, Bicarbonate, and Surface Hy- drophobic@

Aspirin [95], indomethacin [96], and phenylbutazone 1971 inhibit gastric mucus secretion. Aspirin decreases the thickness of mucus [98], inhibits the incor- poration of radiolabeled precursors into the glycoprotein component of mucus, and inhibits the activity of enzymes necessary for mucus biosynthesis [99,100]. Aspirin increases pepsin-mediated proteoly- sis of mucus, decreases mucus viscosity, and increases the permeability of mucus to hydrogen ion [ 1011. Aspi- rin also diminishes the pH gradient across the mucus layer [16]. Aspirin induces ulcers in rats with a low percentage of high-molecular-weight glycoprotein in mucus, while sparing rats with a high percentage [102].

Aspirin [103] indomethacin [104,105], and fenclofenac [106] inhibit active bicarbonate secretion by the gastric mucosa. The restoration of ambient bicarbonate protects against aspirin-mediated erosions [ 1071. Aspirin also reduces the surface hydrophobic properties of the gastric mucosa, probably by altering surface phospholipids [39].

NSAID Damage: Mucosal Blood Flow and Cellular Regen- eration

The reported effects of NSAIDs on mucosal blood flow have been inconsistent. Aspirin has been found both to increase [108] and to decrease [61] mucosal blood flow. Indomethacin has been reported to decrease mucosal blood flow [41,61]. Such reduction in mucosal blood flow could increase NSAID-induced gastric damage.

Aspirin may retard the ordinarily rapid regenera- tion [log] and migration [llO] of normal gastric epithelium through diverse effects on normal cell metabolism [log]. Croft and Wood [ill] found that aspirin increases epithelial cell loss measured by the DNA content of gastric lavage, and postulated that rapid cell turnover and inability to replete cell populations at normal rates may lead to mucosal erosions.

NSAID Damage: Prostaglandin Inhibition In 1971, Vane [112] proposed that the biologic ac-

tions of aspirin-like drugs result from inhibition of prostaglandin synthesis, a theory that has gained widespread acceptance. Not only are prostaglandins “cytoprotective” [32] as described previously, but prostaglandins administered exogenously protect against NSAID-induced gastric injury [113,114] and accelerate the healing of gastric and duodenal ulcers [1X]. The doses of NSAIDs required to inhibit cyclo- oxygenase, the prostaglandin synthesizing enzyme, are well within the therapeutic range of these drugs


[116]. Since prostaglandins play an important, if as yet imperfectly understood, role as cytoprotective agents [32], it is likely that inhibition of prostaglandin synthesis by NSAIDs disrupts the functional integrity of the gastric mucosa. In experiments evaluating exogenously administered prostaglandins, however, it is un- clear whether such administration compensates for a drug-induced decrease in the mucosal prostaglandins or induces additional pharmacologic effects, unrelated to the correction of an NSAID-induced prostaglandin deficiency [74]. For example, exogenous prostaglandin therapy for peptic ulcer disease employs compounds that potently inhibit gastric acid production. This anti-secretory effect may be more pharmacologically important than any cytoprotective action [117].

A primary role for prostaglandin inhibition in NSAID-induced gastric injury is supported by studies that demonstrate gastric damage with parenteral as well as oral administration of NSAIDs [118,119]. These studies have been criticized, however, as using toxic doses of aspirin [120], or adding hydrochloric acid or acid-stimulating agents such as histamine [121]. More recent parenteral animal [122] and human [123,124] studies fail to demonstrate NSAID-induced damage when these drugs are given alone in therapeutic intravenous doses.

In addition, the finding that highly buffered aspirin [57], enteric-coated aspirin [125,126], and enteric- coated naproxen [127] are significantly less damaging to the stomach than the plain drug indicates that a direct topical effect of NSAIDs contributes to their gastric toxicity.

The potency of prostaglandin inhibition by different NSkIDs can be correlated with the degree of gastric damage in several studies. Whittle and associates [128] demonstrated that prostacyclin (PGIz) inhibition for six NSAIDs parallels the extent to which these drugs induce gastric erosions. Potent inhibitors of prostacyclin, including indomethacin, flurbiprofen, and naproxen, induce comparable gastric damage, which correlates with their inhibition of prostaglandin production. Aspirin produces more gastric erosions, which the authors attribute to a “synergistic interac- tion” between topical irritation and cycle-oxygenase inhibition. Sodium salicylate and the experimental drug BW755C, which do not inhibit mucosal cyclo- oxygenase, cause little gastric damage [128]. In a similar study, carboprofen is a less potent prostaglandin inhibitor than indomethacin, but also less toxic to the stomach [ 1291.

Rainsford and Willis [74] found that significant prostaglandin inhibition by aspirin, indomethacin, su- lindac, and diclofenac parallels significant mucosal damage. Flufenamic acid, azapropazone, and fenclofenac are intermediate. The non-acidic NSAID mese- clazone potently inhibits both mucosal and plasma levels of prostaglandins, but causes little gastric irri- tancy. A similar result is found for proquazone, a non- acidic NSAID that is less ulcerogenic than indometha- tin [83], but that is an equally effective inhibitor of prostaglandin synthesis [130]. Rainsford and Willis [74] conclude that NSAID-induced gastric damage is mediated by two components: “(1) The direct effects of the acidic drug on membrane permeability (which in turn is influenced by the rate of absorption of the drug), and (2) drug-related effects on prostaglandin production, which may be of particular importance in relation to the ischemia which appears to be of partic-

Figure 6. Dual-insult hypothesis. Current information suggests that most NSAlDs induce gastric damage by a dual-insult mechanism.

ular significance in the early stages of NSAID drug- induced injury” [74].

Several studies fail to correlate NSAID-induced gastric damage with prostaglandin suppression. Red- fern and associates [131] found significant individual variability in prostaglandin concentration following indomethacin suppression and no correlation between the degree of prostaglandin suppression and endoscopic evidence of mucosal damage. Ligumsky and associates [132] observed that 95 percent inhibition of cycle-oxygenase by parenteral aspirin is not by itself sufficient to induce gastric mucosal damage. They conclude that in addition to a high degree of cyclo- oxygenase inhibition, NSAID-induced gastric damage also involves direct mucosal toxicity.

Rainsford and Willis [74] evaluated the temporal relationship between changes in mucosal cell permeability and changes in prostaglandin levels associated with indomethacin-induced gastric lesions. They demonstrated a decrease in potential difference, an increase in hydrogen ion flux, and marked reductions in mucosal prostaglandins, as would be expected after indomethacin administration. In addition, although these changes occur rapidly in all variables, the increase in gastric cell permeability precedes the decrease in prostaglandin levels. They concluded that direct contact of the acidic drug with the mucosa initi- ates permeability changes and that the additive effect of prostaglandin inhibition follows secondarily.

NSAID-Induced Gastric Mucosal Damage: A Dual-Injury Hypothesis

NSAIDs are a chemically diverse group of compounds, most, but not all, of which are organic acids and most, but not all, of which mediate their anti- inflammatory effects through prostaglandin inhibition. How these drugs cause gastric mucosal injury has been extensively studied. Aspirin and its effects after short-term administration have received the most at- tention. Although information gained from the study of the effects of short-term aspirin administration cannot be extrapolated to the long-term clinical use of all NSAIDs (for example, phenylbutazone does not alter gastric potential difference [133]), a review of mechanisms of NSAID-induced gastric toxicity sug-



gests that these drugs share common pathogenic fea- tures.

There is strong evidence for an acid-mediated topical effect of these compounds on the gastric mucosa. Highly buffered NSAIDs [57], enteric-coated NSAIDs [125-1271, and non-acidic NSAIDs [74,83,130] do not induce significant gastric damage, despite potent prostaglandin inhibition and therapeutic effect. Most NSAIDs, however, are organic acids administered as the plain drug. Ion trapping of these weak organic acids facilitates their absorption by mucosal cells, set- ting off a cascade in which gastric mucosal cell permeability is increased, exposing these cells to the toxic effect of luminal hydrogen ion and pepsin. Back diffusion of hydrogen ion is caught up in this vicious cycle, whether as the cause or the effect.

Once this topical acid damage begins, it is com- pounded by prostaglandin inhibition. Were prostaglandin inhibition not present, the cell might recover through such prostaglandin-mediated mechanisms as increased mucosal blood flow [40], decreased acid secretion [31], or increased ATP-mediated ion transport [42]. Sodium salicylate and the experimental compound BW755C, which lower membrane potential difference but do not inhibit prostaglandin synthesis, are significantly less likely to induce gastric damage than aspirin [128], The success of exogenous prostaglandin therapy [113,114,134], although at least in part antisecretory [117], and of treatment with sucralfate, which may [135] or may not [136] protect the stomach via a prostaglandin-mediated mechanism, is additional evidence of the importance of prostaglandin inhibition in NSAID-induced gastric damage.

It is therefore possible that NSAID-induced gastric damage occurs as a result of a dual insult-first, by NSAID-mediated direct acidic damage, which is followed almost simultaneously by the deleterious effect of prostaglandin inhibition (Figure 6). This hypothesis incorporates currently available information about mechanisms by which NSAIDs induce gastric injury. In this hypothesis, both insults are necessary. Strate- gies that avoid this dual insult may significantly di- minish gastric damage, the most serious toxicity of this important group of drugs.

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Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage