mechanisms of nsaid-induced gastroenteropathy

Drugs 40 (Suppl. 5): 1-11, 1990 0012-6667/90/0500-0001/$5.50/0 © Adis International Limited All rights reserved. DRSUP1868a

Mechanisms of NSAID-Induced Gastroenteropathy

Allan H. Price and Michael Fletcher ADIS Drug Information Services, Chester, United Kingdom

Summary Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used and therapeutically effective groups of drugs in the Western world. However, gastrointestinal problems constitute all too frequently reported unwanted effects of NSAIDs; their effects on the gastric (and intestinal) mucosa are, therefore, well documented.

A review of the evidence suggests that NSAID-induced gastric damage occurs as a result of a dual insult, by NSAID-mediated direct (and indirect) acidic damage followed almost simultaneously by the deleterious (systemic) effect of prostaglandin inhibition.

A number of strategies have been used in the management of NSAID-induced gastric damage; however, not all have been entirely successful. Nonetheless, a number of approaches have met with a considerable amount of success, including direct gastroprotection, enhancement of mucosal defence mechanisms and, perhaps most encouragingly, the development of newer NSAIDs which display not only considerable clinical efficacy but a reduced gastrointestinal adverse event profile.

It is important that any discussion of nonsteroidal anti-inflammatory drug (NSAID)-induced gastroenteropathy should not detract from the fact that NSAIDs are one of the most commonly used and therapeutically effective groups of agents in the Western world. Over the decades, these drugs have brought about the clinical relief of symptoms to millions of arthritic patients. Nevertheless, most, if not all classes of NSAIDs (especially the older drugs) possess the ability to induce some form of gastrointestinal discomfort. Not surprisingly, therefore, a great deal of research has been undertaken in an attempt to elucidate the underlying mechanism(s) responsible for these effects.

The acute and chronic gastric mucosal injury caused by NSAIDs comprises a spectrum oflesions which have been labelled 'NSAID gastropathy' (Roth 1986). These drug-induced lesions may be

separated from classical 'peptic' ulcer disease not only by their age distribution (mostly in the elderly), but by their localisation (more frequently in the stomach than in the duodenum) [Roth 1986].

Although the incidence of nonspecific ulcers, especially in the duodenum, is declining, the prevalence of drug-induced lesions in the stomach, i.e. NSAID gastroenteropathy, is increasing (Armstrong & Blower 1987). The importance of these lesions is regularly debated; reports indicate that the magnitude of the risk of upper gastrointestinal bleeding associated with NSAIDs may be relatively low in the population as a whole, or moderate (at least with some of the drugs in this class). Nonetheless, the majority of surveys indicate that the association between acute gastric ulceration and NSAID use is substantial, especially in older patients who may not exhibit upper gastrointes-

2

tinal symptoms until serious complications occur (Sommerville et al. 1986). However, it is important to note that many elderly patients are already in a clinically compromised state at the onset of NSAID therapy; thus the gastrointestinal symptoms that do occur may not be due entirely to NSAID treatment.

Not surprisingly, therefore, it has been the aim of the pharmaceutical industry to develop either a NSAIDthat does not damage the gastric mucosa, or a drug or technique that would prevent or ameliorate damage associated with acute and chronic NSAID administration. Methods that reduce or prevent contact between NSAIDs and the gastric mucosa will often reduce (or in part limit) acute damage. Some of the approaches attempted include enteric coating, administration in microspheres, administration of 'prodrugs', administration of nonacid derivatives and the use of drugs that are not soluble at low pH (Graham 1989). Indeed, the pharmaceutical industry appears to have been partially successful in developing safer NSAIDs and this paper will review the current concepts on NSAID-induced gastroenteropathy and its possible prevention.

1. Gastrointestinal Problems Associated with NSAIDs

Gastrointestinal problems are the most frequently recognised adverse effects ofNSAIDs. They constitute a wide range of different clinical pictures ranging from upper abdominal discomfort to lifethreatening bleeding. Nevertheless, ascertaining the actual incidence of gastrointestinal adverse effects due to NSAIDs remains extremely difficult (Giercksky et al. 1989).

1.1 Gastric Mucosal Damage

Gastric mucosal damage, the most common adverse event following the administration of NSAIDs, is due to a combination of systemic effects and a high local drug concentration (O'Laughlin et al. 1981). If the site of absorption is advertently or inadvertently changed, this problem is

Drugs 40 (Suppl. 5) 1990

sometimes only transferred, leading to serious unsuspected damage of other tissue (such as smallbowel bleeding or perforation). Simple coating of aspirin has been demonstrated to reduce gastric mucosal damage and, recently, coating of some of the modern NSAIDs has been introduced. However, no large clinical studies have demonstrated a reduction in gastrointestinal complaints or less severe gastrointestinal side effects (Giercksky et al. 1989).

After ingestion of NSAIDs, acute gastric erosions and petechiae are regularly seen at gastroscopy. While some adaptation may occur with continuous drug challenge, this needs to be confirmed by further clinical experience. It should be noted that there is no correlation between endoscopic evidence of mucosal irritation and clinical symptoms (Giercksky et al. 1989).

1.2 NSAID-Induced Injury to the Intestinal Mucosa

NSAID-induced injury in the intestine has not been investigated as extensively as that in the stomach. Nevertheless, intestinal damage by NSAIDs has recently become a matter of considerable clinical concern (Bjarnason & Macpherson 1989; Rainsford 1989). Indeed, it has been reported that 70% of patients receiving long term NSAIDs have evidence of small-intestinal inflammation that causes loss of blood and protein. Furthermore, many patients have asymptomatic ileal dysfunction and may occasionally develop unique small-intestinal strictures necessitating surgery (Bjarnason & Macpherson 1989). Moreover, bile salts and/or the biliary excretion and subsequent enterohepatic circulation of conjugates of NSAIDs may be a factor in the development of serious intestinal ulcerations and perforations (Brune et al. 1986; Rainsford 1986). Indeed, reflux of bile into the stomach is well known in the elderly, and the irritant barrier-breaking effects of bile salts, especially in the acidic environment of the stomach and in the presence of potentially ulcerogenic NSAIDs, are well established (Rainsford 1986). However, as it is not the intention of this paper to deal with

Mechanisms of NSAID-Induced Gastropathy

NSAID-induced intestinal injury at length, readers are referred to recent comprehensive reviews by Bjarnason and Macpherson (1989), Langman et al. (1985) and Rainsford (1989) for more details.

2. Mechanisms of NSAID-Induced Gastric Mucosal Damage

Although the effects of NSAIDs on the gastric mucosa are well documented, the complex mechanisms of gastric damage are not yet fully understood. At present, it is proposed that there are 3 possible ways by which the potentially damaging NSAID and/or its metabolite(s) can gain access to the gastric mucosa; firstly, by a direct topical effect following administration of the drug; secondly, and probably the most important, systemically, leading to the resultant effects of prostaglandin inhibition; and thirdly, an indirect topical route whereby NSAIDs (or their metabolites) undergo enterohepatic circulation in the bile and are subjected to possible intestinal reflux into the stomach. To date there is little published information available concerning the indirect topical route. Nevertheless, the role of prostaglandins in cytoprotection and repair, and the mechanisms (including ion trapping and back diffusion of hydrogen ions) by which aspirin (acetylsalicylic acid) and other weak organic acids cause gastric erosion and bleeding are well established.

Schoen and Vender (1989) recently proposed that NSAID-induced gastric damage occurs as a result of a dual insult when NSAID-mediated direct (and indirect) acidic damage is followed almost simultaneously by the deleterious effect of prostaglandin inhibition (fig. 1). This hypothesis, which incorporates all the currently available information on the mechanisms by which NSAIDs induce gastric injury, will form the basis of the discussion in this section.

NSAIDs are a chemically diverse group of compounds (most of which are organic acids) that mediate their anti-inflammatory effects through prostaglandin inhibition (Schoen & Vender 1989). In general, most studies with the drugs have focused on aspirin (shoft term administration) and

NSAIDs (organic acids)

/ Primary insult

Direct aCid damage

"-Secondary Insult

Prostaglandin Inhibition

,/ ( Dual insult)

3

Fig. 1. NSAID-induced gastric damage by a dual insult mechanism (after Schoen & Vender 1989).

although the effects of this drug cannot be extrapolated to the long term clinical use of all NSAIDs, a review of the mechanisms of NSAID-induced gastric toxicity suggests that these drugs share common pathogenic features.

2.1 Primary Insult: Direct Gastric Acid Damage

Abundant evidence exists to support the hypothesis that NSAID gastric damage is caused by a gastric acid-mediated topical effect on the mucosa (as outlined below). Indeed, although highly buffered NSAIDs, enteric-coated NSAIDs and nonacidic NSAIDs do not induce significant gastric damage they still have a potent prostaglandin inhibitory and therapeutic effect (Schoen & Vender 1989).

2.1.1 Ion Trapping and Back Diffusion The majority of NSAIDs, being weak organic

acids, damage the gastric mucosal barrier as a consequence of becoming concentrated within the mucosal cells. This causes the cell membrane permeability to change, thus allowing back diffusion of hydrogen ions, which causes the damage (Schoen

4

& Vender 1989). Weak organic acids, such as aspirin, become concentrated in the mucosal cell through a process known as ion trapping (Martin 1963). This occurs because the lipid and protein membrane of the mucosal cell absorbs lipid-soluble compounds, such as aspirin, more readily than it does water-soluble compounds. For example, in the strongly acidic environment of normal gastric juice (pH 2.5), aspirin (pKa 3.5) is mostly nonionised. As an undissociated acid, aspirin is lipidsoluble and freely diffuses into the mucosal cell. Once inside the cell, the much higher pH of the intracellular environment (pH 7) favours acid dissociation. In this ionised state, aspirin is watersoluble and becomes 'trapped' inside the cell. These events favour a strong concentration gradient, moving dissociated ions of weak organic acids such as indomethacin (pKa 5.2), phenylbutazone (pKa 4.8), and other acidic NSAIDs into the gastric mucosa (Schoen & Vender 1989).

The rapid intracellular penetration of aspirin, and its entrapment as an ionised salt, are followed by alteration in cell membrane permeability, leading to the influx of hydrogen ions from the lumen, and subsequent cell damage. Animal experiments have shown that the rate of absorption of aspirin into the mucosa is dependent on the luminal pH, with a low pH favouring more rapid absorption. The absorption of aspirin is associated, within minutes, with abnormal ion fluxes across the mucosa. Abnormal sodium and potassium enter the luminal fluid, and hydrogen disappears from the lumen into the mucosa (an observation termed 'back diffusion of hydrogen ion'). Thus aspirin damages the mucosal barrier as a consequence of being absorbed into the mucosal cells (by an unknown mechanism) and rendering the mucosa abnormally permeable to water-soluble hydrogen ions; back diffusion of strongly acidic gastric juice then leads to mucosal damage including erosion and bleeding (Davenport 1965). These experiments may, in part, explain why achlorhydric patients are less susceptible to aspirin-induced gastric injury than normal persons, and why damage from aspirin is markedly reduced when gastric secretions are buffered to pH 6-7 (Ivey 1981; labbari & Val-


berg 1970). The increase in aspirin-induced hydrogen ion permeability observed experimentally has been demonstrated for other NSAIDs including indomethacin (Rainsford & Willis 1982) and fenoprof en (Cooke 1976). Moreover, indomethacin causes sustained back diffusion associated with bleeding at both neutral and acidic pH (Chvasta & Cooke 1972).

2.1.2 Transmucosal Potential Difference The increased permeability to hydrogen ions

caused by aspirin occurs within minutes after exposure, and is associated with evidence of damage to the gastric mucosal cell. Transmucosal electrical potential difference is a sensitive index of gastric mucosal function (Cooke 1976), and a number of studies have shown that aspirin and indomethacin induce an immediate decrease in gastric potential difference (Schoen & Vender 1989). The change in potential difference and increase in ion permeability typically recover within 90 minutes, an effect consistent with the hypothesis that those NSAIDs which are weak organic acids become rapidly trapped, but diffuse out of the cell more slowly (Bowen et al. 1977; Flemstrom 1971).

2.1.3 Effect on Mucus, Bicarbonate and Surface Hydrophobicity A great deal of research has been undertaken to

elucidate the structure and function of gastrointestinal mucus, particularly with regards to protection (for more detailed reviews see Allen 1978; Allen et al. 1976).

Moreover, the existence of an alkaline secretion by gastric and duodenal mucosa in man has now been established. Indeed, evidence indicates that it is able to create a pH gradient across the adherent mucus gel and that this mucus-bicarbonate barrier may constitute a first-line barrier against acid damage.

A number of experiments have been conducted to evaluate the functional significance of the mucus-bicarbonate barrier. Potentially damaging agents such as bile salts and NSAIDs inhibit gastric alkali secretion and reduce the magnitude of the mucus pH gradient. In contrast, prostaglandins can


either increase alkali and the magnitude of the pH gradient or prevent the detrimental effects of bile salts and NSAIDs (Rees 1987). Ross et al. (1981) were able to show the presence of a pH gradient in mucus in vivo which can be compromised by agents which interfere with mucus structure and/ or bicarbonate secretion and by high intraluminal hydrogen ion concentrations. Such results support the role for this barrier in gastric mucosal protection. In order to provide effective mucosal protection, the mucus-bicarbonate barriers need to be maintained in dynamic equilibrium with luminal acid and pepsin so that the pH gradient is preserved and the epithelium undamaged. In this regard, Crampton et al. (1987) showed that in healthy volunteers mechanisms exist to adjust the rate of gastric bicarbonate secretion to the prevailing intraluminal pH and that this may occur through the release of prostaglandin E2.

Aspirin, indomethacin and phenylbutazone all inhibit gastric mucosal secretion (Schoen & Vender 1989). Aspirin has been shown to decrease the thickness of mucus, inhibit the incorporation of radiolabelled precursors into the glycoprotein component of mucus, and inhibit the activity of enzymes necessary for mucus biosynthesis (Schoen & Vender 1989). Moreover, aspmn increases pepsin-mediated proteolysis of mucus to hydrogen ions, as well as diminishing the pH gradient across the mucus layer. Indomethacin and fenclofenac inhibit active bicarbonate secretion from the gastric mucosa. It has been reported that the mucosal surface of the stomach has a hydrophobic lining that may be attributed to surface-active phospholipids known to be present in both gastric mucosa and juice. Barrier breakers, such as bile and aspirin, have been shown to virtually eliminate the hydrophobicity (Hills et al. 1983).

In a series of in vitro studies Lichtenberger et al. (1985) reported that the surface hydrophobicity of the stomach could be significantly reduced by aspirin. However, this change was reversed by the addition of 16, 16-dimethyl prostaglandin E2. This suggests that prostaglandins may protect the stomach by the maintenance of a non wettable hydro-

5

phobic lining between damaging agents in the lumen and the gastric epithelium.

2.1.4 Effect of Mucosal Blood Flow During the past 20 years, knowledge of gastric

microcirculation and the role of mucosal blood flow in gastric physiology and pathophysiology has increased substantially (Guth 1980). As a result of this it is now established that gastric mucosal blood flow plays an important role in protecting the gastric mucosa against injury (Cheung 1984). It has been shown that when disruption of the gastric mucosal barrier by acid back-diffusion occurs hydrogen ions (H+) enter the interstitial tissue, resulting in a compensatory increase in mucosal blood flow. If this increased blood flow is sufficient to dilute, buffer and remove excess H+ then mucosal injury may not occur. Conversely, if mucosal blood flow is decreased than marked lesion formation results (Guth 1980). Consequently, the effects of NSAIDs on mucosal blood flow are very important, as any reduction in mucosal blood flow may enhance NSAID-induced gastric damage. However, the reported effects of NSAIDs on mucosal blood flow have been inconsistent. For instance, aspirin has been found to both increase and reduce mucosal blood flow, whereas indomethacin has been shown only to reduce it (Schoen & Vender 1989). Nevertheless, it is possible to speculate that any NSAID which preserves or even enhances mucosal blood flow could offer a considerable therapeutic advantage.

2.2 Secondary Insult: The Role of Prostaglandin Inhibition in Gastric Mucosal Damage by NSAIDs

It is well established that prostaglandins play an important role in the physiological regulation of a number of processes such as mucosal blood flow and bicarbonate secretion. Not surprisingly, therefore, inhibition by NSAIDs of the synthesis of 'cytoprotective' prostaglandins has long been regarded as a major factor in the development of gastric ulceration and haemorrhage by these drugs (Rainsford 1989). Indeed, the doses of NSAIDs re-

6

quired to inhibit cyclo-oxygenase, the prostaglandin synthesising enzyme, are well within the therapeutic range of most of these drugs. Since prostaglandins play an important, albeit not fully elucidated role as cytoprotective agents, it is likely that inhibition of prostaglandin synthesis by NSAIDs disrupts the functional integrity of the gastric mucosa (Schoen & Vender 1989). The role of prostaglandin inhibition in mediating NSAIDinduced gastric injury has been supported by studies showing that gastric damage occurs with parenteral as well as oral administration of NSAIDs (Grossman et al. 1961; Main & Whittle 1975). However, what remains to be established is the degree of prostaglandin inhibition required to induce damage.

The potency of prostaglandin inhibition by different NSAIDs has been shown to be correlated with the degree of gastric damage observed. Rainsford and Willis (1982) showed that significant prostaglandin inhibition induced by aspirin , indomethacin, sulindac and diclofenac occurred in parallel with significant mucosal damage; flufenamic acid, azapropazone and fenclofenac were associated with moderate damage. Nevertheless, several studies have failed to correlate NSAID-induced gastric damage with prostaglandin inhibition. For example, nonacidic NSAIDs (i .e. nabumetone, meseclazone and proquazone) have been shown to potently inhibit plasma levels of prostaglandins without causing significant gastric irritancy (Dandona & Jeremy, this issue p. 16; Schoen & Vender 1989). However, Redfern et al. (1987) reported significant individual variability in prostaglandin concentration following indomethacin suppression, and no correlation between the degree of prostaglandin concentration and endoscopic evidence of mucosal damage. Moreover, Ligumsky et al. (1983) observed that 95% inhibition of cyclo-oxygenase by parenteral aspirin is, by itself, not sufficient to induce gastric mucosal damage and that a combination of events is required; it was concluded that NSAID-induced gastric damage also involves direct mucosal toxicity. Indeed, Rainsford and Willis (1982) suggested that gastric damage induced by acidic NSAIDs is primarily due to their effects in

Drugs 40 (Suppi. 5) 1990

altering membrane permeability, and that their inhibitory effect on prostaglandin synthesis, although additive, is only secondary to this.

3. Management of NSAID-Induced Gastric Damage

A number of strategies have been forwarded for the management of NSAID-induced gastric damage. Principal among these should be the selection of a clinically effective NSAID that has displayed lower toxicity. Moreover, since such a drug is unlikely to induce significant gastric damage the need for its subsequent management would be avoided. Other potential options include a boost to one of the defence mechanisms or enhancement of the general metabolic function of the gastric mucosa, and removal or prevention of the access of potentially injurious substances (Hawkey 1988).

The most effective means of preventing gastric damage (i.e. by eliminating the primary aetiological agent) is rarely feasible with NSAIDs, as patients with severe inflammatory joint disease are rarely, if ever, able to cease using these anti-inflammatory drugs. However, the selection of a NSAID with less· toxic potential is a possible alternative method, and this is now a primary objective. Indeed, it may be possible to select drugs with fewer gastrointestinal effects from those identified in animal studies and although clinical investigations are necessary t~ confirm the findings in animals, this approach should prove useful. Nevertheless, at present, the only practical solution is to treat the NSAIDinduced gastric damage and a summary of some of the more rational methods for the management of NSAID-induced gastric damage is given below.

3.1 Nondrug Approaches

In addition to drug therapy, a number of nondrug approaches are also available to prevent or reduce the severity of NSAID gastroenteropathy.

3.1.1 Chronopharmac%gical Principles Chronopharmacological principles, when ap

plied to toxicology and pharmacology, have re-vealed that while maintaining therapeutic efficacy,


the toxicity of a drug may be reduced markedly if the drug is administered at certain points of the 24-hour light/dark cycle. For example, the acute gastrotoxicity of aspirin and alcohol administered to rats in the late evening is about 50% higher compared with early morning hours. Moreover, since circadian rhythms have been documented in gastrointestinal secretory, motility and metabolic functions (Venerk et al. 1987), it is not surprising that the susceptibility of the gastric mucosa to chemical injury also shows cyclic variability relating to these functions.

Most chronopharmacological data have been derived from animal studies. Nevertheless, there is evidence from clinical pharmacology to suggest that time-dependent variabilities also exist in humans. This finding is especially important for the management of NSAID gastroenteropathy, since it indicates that gastric damage induced by traditional NSAIDs may be lessened by administering these drugs at particular times of the day, and that this may obviate the need for restricting their intake (Szabo et al. 1989).

3.1.2 Food Intake Dietary intake may influence the mucosal con

centration of protective substances such as prostaglandins and sulfhydryl compounds. The presence of food in the stomach may delay the absorption of NSAIDs and may act as a buffer to diminish the concentration of hydrochloric acid. Traditional NSAIDs should therefore be taken with or shortly after meals and with plenty of fluid to assure adequate dissolution of tablets (Szabo et al. 1989).

Ingestion of alcohol with NSAIDs is contraindicated since alcohol, like stress, increases the gastrotoxicity of aspirin-like drugs (DeSchepper et al. 1978; Murray et al. 1974). The role of the dietary agent eicosapentaenoic acid (EPA) in reducing the mucosal generation of vasoactive leukotrienes has recently received much attention; however, major clinical trials with EPA are required to fully assess the true potential of this agent in managing NSAIDinduced gastroenteropathy (Szabo et al. 1989).

7

3.2 Drug Therapy

3.2.1 Prodrugs and Nonacidic NSAIDs As outlined previously, the most rational ap

proach to the management of NSAID-induced gastroenteropathy appears to be the selection of a NSAID with proven efficacy and safety. In this context, the design and use of prodrugs of NSAIDs has been a recent and interesting development in the attempt to solve the problem of NSAID gastroenteropathy. The underlying concept is that while the prodrugs themselves are weak inhibitors of mucosal prostaglandin synthesis, their metabolism by liver or plasma enzymes leads tothe formation of therapeutically active forms of the drug which are effective inhibitors of prostaglandin cyclo-oxygenase (Szabo et al. 1989).

Some prodrugs of NSAIDs have proved, without compromising their therapeutic efficacy, to be less damaging to the gastric mucosa than others. For example, nabumetone, fenbufen, proquazone and fluoroproquazone have been shown to exhibit low gastrointestinal toxicity (Szabo et al. 1989).

The situation with sulindac is more complicated; although some experimental data suggest that this drug produces less blood loss and endoscopic evidence of gastric mucosal damage than an equipotent drug such as indomethacin (Shen 1985), a number of reports have noted adverse reactions in the gastrointestinal tract (Hersey & Weisman 1988; Zoli et al. 1986). Sulindac and fenbufen are acidic drugs and may accordingly induce some gastric irritancy (Rainsford 1987). However, nabumetone and the older drug azapropazone are non acidic drugs and this may account, at least in part, for their low ulcerogenic actions (McCormack & Brune 1987). Since drug uptake into mucosal cells is a principal factor in ulcerogenicity, it would seem that although drugs such as proquazone and nabumetone are well absorbed from the gastrointestinal tract, their uptake into drug-sensitive cells in the stomach is minimised as a direct consequence of their nonacidic property (Brune et al. 1977a,b; McCormack & Brune 1987).

8

3.2.2 Direct Gastroprolection Gastroprotective agents were developed follow

ing the conceptualisation of gastric cytoprotection. Since mucosal protection against chemically induced damage is relative and does not necessarily involve the preservation of cells on the mucosal surface (especially with prostaglandin analogues), Szabo et al. (1989) suggested, for mechanistic clarification, the idea of gastroprotection as opposed to cell or cytoprotection.

Gastroprotection is independent of the inhibition of gastric acid production, although H2-receptor antagonists may also offer gastroprotection (Szabo et al. 1989). Clinical studies have demonstrated that aspirin- or indomethacin-induced gastric micro bleeding can be prevented by prostaglandin derivatives (for a more detailed review see Szabo et al. 1989). Indeed, in some of these investigations cimetidine or ranitidine were used either at low 'cytoprotective' or regular doses as positive controls.

While these studies were essentially performed under acute conditions, the results were particularly significant, as they indicated that drugs could protect against haemorrhage associated with gastric mucosal injury. This is important, as bleeding from multiple superficial erosions is one of the major clinical problems in patients ingesting large quantities of NSAIDs for prolonged periods (Domschke & Domschke 1984).

Blackburn and Alarcon (1990) reported that misoprostol may be a useful drug in prophylactic and symptomatic treatment of NSAID-induced gastroenteropathy. However, the exact role of this medication in long term therapy and prevention of perforation and bleeding has not been fully delineated.

Szabo et al. (1989) have recently reviewed the experimental and clinical studies with nonprostaglandin 'truly' gastroprotective agents that are devoid of the acid-suppressing adverse effects of prostaglandin and H2-antagonists. These compounds, such as sulfuydryl or nonsulfuydryl antioxidants, are thought to act by scavenging the free radicals involved in the pathogenesis of NSAIDinduced gastric mucosal damage; glucose citrate and


acetate have the added benefits of providing nutrient and energy sources (Szabo et al. 1989). Alternatively, these agents may act via multiple pathways that are, as yet, poorly understood. A clinically significant observation with these gastroprotective agents is that some (although not all) sulfuydryl compounds are effective in preventing haemorrhagic erosions when used as both pretreatment and coadministered with aspirin (Szabo et al. 1985). The mechanism of this gastroprotection seems to be related to the microvasculature in that early endothelial injury, which reaches a maximum about 6 minutes after administration of acidified aspirin, is prevented. Moreover, the active principle of sucralfate, clinically the most widely used gastroprotective agent, seems to be the sulphate moiety; the functional and structural target of protection is probably a reduction of early vascular injury in the gastric mucosa (Szabo & Brown 1987). Inhibition of leukotriene synthesis by EPA, inhibition of 5-lipoxygenase, and prevention of release of mast cey granules, all significantly reduced or completely prevented either aIcohol- or aspirin-induced gastric erosions in experimental animals (Szabo et al. 1989). Clearly, further clinical studies are required to fully establish the role of these agents in gastroprotection.

3.2.3 Drugs Acting Via Gastric Acid Gastric lesions caused by NSAIDs are located

mainly in the acid-producing part of the stomach. They are acid-sensitive, in contrast to alcoholinduced mucosal lesions which are not prevented by antacids or antisecretory agents (Szabo et al. 1989).

Studies of gastric lesions in animal models have demonstrated the efficacy of a number of agents which either neutralise hydrochloric acid in the gastric lumen, inhibit its secretion, or prevent the development of aggravation of gastric lesions in patients required to regularly take relatively large doses ofNSAIDs; nevertheless the clinical data remain inconclusive (Rainsford 1988; Silvestrini 1987). Moreover, these animal studies indicated that anti secretory agents control the acute NSAID-


induced erosion or ulcer development, and not, importantly, chronic lesions (Szabo et al. 1989).

Antisecretory Agents Initial clinical studies with histamine H2-recep

tor antagonists were very positive about their efficacy in reducing gastric mucosal injury and bleeding caused by NSAIDs (Domschke & Domschke 1984; MacKercher et al. 1977; Welch et al. 1978). More recent studies with newer H2-receptor antagonists have shown that these antisecretory drugs are effective not only in healthy volunteers receiving aspirin or other NSAIDs, but also in patients with rheumatoid arthritis receiving drugs (Manniche et al. 1987; Piotrowski et al. 1986; Zoli et al. 1986). These studies have helped to establish antisecretory agents (e.g. H2-receptor antagonists, omeprazole) in the management of NSAJD gastroenteropathy.

3.2.4 Other Options Although preparatory modification of NSAID

tablets (such as enteric coating or adding a buffer to the acidic tablet) should, in theory, offer clinical advantages, in practice, benefits are often less obvious and more complex (Rainsford 1984; Roth 1986; Semble & Wu 1987), especially in view of the unfavourable results obtained in the studies with aspirin tablets (Rainsford 1978). Nonetheless, nonacetylated salicylates (e.g. choline magnesium trisalicylate) produced fewer gastric lesions and less haemorrhage than aspirin (Semble & Wu 1987).

4. Conclusions

This review of the mechanisms of NSAIDinduced gastroenteropathy, although not exhaustive, suggests that there are 2 main modes to the development of gastric injury, i.e. NSAID-mediated direct acid damage (it should be noted that acid damage can also occur indirectly through bile containing NSAIDs and/or their metabolites refluxing into the stomach), followed almost simultaneously by the deleterious effect of prostaglandin inhibition. A number of approaches have been suggested as possible protective measures against the

9

clinically-significant damage induced by NSAIDs. Three of these approaches are, at least theoretically, feasible: firstly, the development and use of NSAJDs with less toxic potential; secondly, the reduction or elimination of the agent that actually causes the injury (such as gastric acid) ; finally, the enhancement of the mucosal defence mechanisms (direct gastroprotection). To date the elimination or reduction of gastric acid has proved the most successful method, with both H2-receptor antagonists and prostaglandins being adequately effective. However, despite the success obtained with such drugs, any real future improvement will lie in the development of highly specific NSAIDs which have minimal or even no gastrointestinal adverse effects. Indeed, the development of newer NSAIDs, especially the nonacidic derivatives, offers a possible and plausible means of overcoming the problem of NSAJD gastroenteropathy.

References

Allen A. Structure of gastrointestinal mucus glycoproteins and the viscous and gel-forming properties of mucus. British Medical Bulletin 34: 28-33, 1978

Allen A, Pain RH. Robson TR. Model fo r the structure of the gastric mucous gel. Nature 264: 88-89, 1976 .

Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. G ut 28: 527-532, 1987

Bjarnason I, Macpherson A. The changing gastrointestinal side effect profile of non-steroidal anti-inflammatory drugs. Scandinavian Journal of Gastroenterology 24 (Suppl. 163): 56-64, 1989

Blackburn WD, Alarcon GS. Misoprostol in treatment of gastropathy due to nonsteroidal anti-inflammatory drugs. American Journal of Medicine 88: 85, 1990

Bowen BK, Krause WJ, Ivey KJ. Effect of sodium bicarbonate on aspirin-induced damage and potential difference changes in human gastric mucosa. British Medical Journal 2: 1052-1055, 1977

Brune K, Graf P, Rainsford KD. A pharmacokinetic approach to the understanding of therapeutic effects and side effects of salicylates. Agents and Actions (Suppl. I): 9-26, 1977a

Brune K, Niirnberg B, Szelenyi I, Vergin H. the enterohepatic circulation of some anti-inflammatory drugs may cause intestinal ulcers. In Rainsford KD & Velo GP (Eds) Side-effects of anti-inflammatory drugs, pp. 29-39, MTP Press Ltd, Lancaster, 1986

Brune K, Scheitzer A, Eckert H. Parietal cells of the stomach trap salicylates during absorption. Biochemical Pharmacology 26: 1735-1740,1977b

Cheung L Y. Gastric mucosal blood flow: its measurement and importance in mucosal defence mechanisms. Journal of Surgical Research 36: 282-288, 1984

Chvasta T A, Cooke AR. The effect of several ulcerogenic drugs on the canine gastric mucosal barrier. Journal of Laboratory and Clinicill Medicine 79: 302-315, 1972

10

Cooke AR. The role of the mucosal barrier in drug-induced gastric ulceration and erosions. Digestive Diseases and Sciences 21: 155-164, 1976

Crampton JR, Gibbons LC, Rees WDW. Effect of luminal pH on the output of bicarbonate and PGE2 by the normal human stomach. Gut 28: 1291-1295, 1987

Davenport HW. Damage to the gastric mucosa: effects of sal icylates and stimulation. Gastroenterology 49: 189-196, 1965

DeSchepper PJ, Tjandramaga TB De Roo. Gastrointestinal blood loss after diflunisal and after aspirin: effect of ethanol. Clinical Pharmacology and Therapeutics 23: 669-676, 1978

Domschke S, Domschke W. Clinics in gastroenterology: peptic ulcer disease. In Boucheir et al. (Eds) Gastro-duodenal damage due to drugs, alcohol and smoking, Vol. 13, pp. 405-436, WB Saunders, London, 1984

Flemstrom G. Intracellular accumulation and permeability effects of some weak acids in the isolated frog gastric mucosa. Acta Physiologica Scandinavica 82: 1-16, 1971

Giercksky K-E, Huseby G, Rugstad H-E. Epidemiology of NSAIDrelated gastrointestinal side effects. Scandinavian Journal of Gastroenterology 24 (Suppl. 163): 3-8, 1989

Graham DY. Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinflammatory drug therapy. Gastroenterology 96: 675-681, 1989

Grossmann MI, Matsumoto KK, Lichter RJ. Fecal blood loss produced by oral and intravenous administration of various salicylates. Gastroenterology 40: 383-388, 1961

Guth PH. Gastric mucosal blood flow and resistance to injury. In Holtermiiller KH & Malagelada J-R (Eds) Advances in ulcer disease. International Congress Series 537, pp. 101-109, Excerpta Medica, Amsterdam, 1980

Hawkey CJ. Non-steroidal anti-inflammatory drugs and the gastric mucosa: mechanisms of damage and protection. Alimentary Pharmacology and Therapeutics 25: 57-64, 1988

Hersey DF, Weisman MH. Minutes of the 19th meeting FDA Arthritis Advisory Committee, pp. 1-22, Food and Drug Administration, Washington DC, 1988

Hills BA, Butler BD, Lichtenberger LM. Gastric mucosal barrier: hydrophobic lining to the lumen of the stomach. American Journal of Physiology 244: 567-568, 1983

Ivey KJ. Drugs, gastritis and peptic ulcer. Clinical Gastroenterology 3 (Suppl. 2): 29-34, 1981

Jabbari M, Valberg LS. Role of acid secretion in aspirin-induced gastric mucosal injury. Journal of the Canadian Medical Association 102: 178-181, 1970

Langman MJS, Morgan L, Worrall A. Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage. British Medical Journal 290: 347-349, 1985

Lichtenberger LM, Richards JE, Hills BA. Effect of 16,16-dimethyl prostaglandin E2 on the surface hydrophobicity of aspirin-treated canine gastric mucosa. Gastroenterology 88: 308-314, 1985

Ligumsky M, Golonska EM, Hansen DG, Kauffman GL. Aspirin can inhibit gastric mucosal cyc1o-oxygenase without causing lesions. Gastroenterology 84: 756-761, 1983

McCormack K, Brune K. Classical absorption theory and the development of gastric mucosal damage associated with the nonsteroidal anti-inflammatory drugs. Archives of Toxicology 60: 261-269, 1987

Mac Kercher PA, Ivey KJ, Baskin WM, Krause WJ. Protective effect of cimetidine on aspirin induced gastric mucosal damage. Annals ofinternal Medicine 87: 676-679, 1977

Main !HM, Whittle BJR. Investigation of the vasodilator and anti secretory role of prostaglandins in the rat gastric mucosa by use of non-steroidal anti-inflammatory drugs. British Journal of Pharmacology 53: 217-224,1975

Manniche C, Malchow-Moller A, Andersen JR, Pedersen C, Hansen TM. Randomised study of the influence of non-steroidal


anti-inflammatory drugs on the treatment of peptic ulcer in patients with rheumatic disease. Gut 28: 226-229, 1987

Martin BK. Accumulation of drug anions in gastric mucosal cells. Nature 198: 896-897, 1963

Murray HS, Strottman MP, Cooke AR. Effect of several drugs on gastric potential difference in man. British Medical Journal 1: 19-21, 1974

O'Laughlin JC, Hoftiezer JW, Ivey KJ. Effect of aspirin on the human stomach in normals: endoscopic comparison of damage produced one hour, 24 hours and 2 weeks after administration. Scandinavian Journal of Gastroenterology 16 (Suppl. 67): 211, 1981

Piotrowski J, Gabryeleqicz A, Konturek S, Kwiecien N, Rydzewska G. Ranitidine effect on gastric mucosa damage in patients with rheumatoid diseases on long-term treatment with non-steroidal anti-inflammatory drugs. Materia Medica Prologue 3: 170-176, 1986

Rainsford KD. Gastric mucosal ulceration induced by tablets but not suspensions of solutions of aspirin in pigs. Journal ofPharmacy and Pharmacology 30: 129-131, 1978

Rainsford KD. Aspirin and salicylates, Butterworths, London, 1984 Rainsford KD. Mechanisms of gastric contrasted with intestinal

damage by non-steroidal anti-inflammatory drugs. In Rainsford KD & Velo GP (Eds) Side-effects of anti-inflammatory drugs, pp. 3-28, MTP Press Ltd, Lancaster, 1986

Rainsford KD. Gastric ulcerogenicity of non-steroidal antiinflammatory drugs in mice with mucosa sensitized by cholinomimetic treatment. Journal of Pharmacy and Pharmacology 39: 669-672, 1987

Rainsford KD. Mechanisms of gastrointestinal damage by nonsteroidal anti-inflammatory drugs. In Ulcer disease: new aspects of pathogenesis and pharmacology, CRC Press, Boca Raton, 1988

Rainsford KD. Mechanisms of gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. Scandinavian Journal of Gastroenterology 24 (Suppl. 163): 9-16, 1989

Rainsford KD, Willis e. Relationship of gastric mucosal damage induced in pigs by antiinflammatory drugs to their effects on prostaglandin production. Digestive Diseases and Sciences 27: 624-635, 1982

Redfern JS, Lee E, Feldman M. Effect of indomethacin on gastric mucosal prostaglandins in humans: correlation with mucosal damage. Gastroenterology 92: 969-977, 1987

Rees WDW. Mucus-bicarbonate barrier - shield or sieve? Gut 28: 1553-1556, 1987

Ross IN, Habib M, Bahari M, Turnberg LA. The pH gradient across mucus adherent to rat fundic mucosa in vivo and the effect of potential damaging agents. Gastroenterology 81:.731-738, 1981

Roth SH. Nonsteroidal anti-inflammatory drug gastropathy. Archives ofinternal Medicine 146: 1075-1076, 1986

Schoen RT, Vender RJ. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. American Journal of Medicine 86: 449-458, 1989

Semble EL, Wu We. Anti-inflammatory drugs and gastric mucosal damage. Seminars in Arthritis and Rheumatism 16: 271-286, 1987

Shen TY. Indomethacin, sulindac and their analogues. In Rainsford (Ed.) Anti-inflammatory and antirheumatic drugs, Vol. 1, pp. 149-159, CRe Press, Boca Raton, 1985

Silvestrini B. Benzydamine, a unique model of anti-inflammatory activity. International Journal of Tissue Reactions 9: 87-91, 1987

Somerville K, Faulkner G, Langman M. Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer. Lancet I: 462-464, 1986

Szabo S, Brown A. Prevention of ethanol-induced vascular injury and gastric mucosal lesions by sucralfate and its components:


possible role of endogenous sul/hydryls. Proceedings of the Society for Experimental Biology and Medicine 185: 493-497,1987

Szabo S, Spill WF, Rainsford KD. Non-steroidal anti-inflamrlratory drug-induced gastropathy. Mechanisms and management. Medical Toxicology and Adverse Drug Experience 4: 77-94, 1989

Szabo S, Spill WF, Rainsford KD. Non-steroidal anti-inflammatory drug-induced gastropathy: mechanisms and management. Medical Toxicology and Adverse Drug Experience 4: 77-94, 1989

Yener KJ, Moore JG, Szabo S. Chronobiologyand ulcerogenesis. Chronobiology [nternational 4: 1-2, 1987

Welch RW, Bentch LH, Harris Sc. Reduction of aspirin induced

II

gastrointestinal bleeding with cimetidine. Gastroenterology 74: 459-463, 1978

Zoli G, Pasquinelli G, Bonvicini F, Gasbarrini G, Laschi R. SEM Study II: protective effect of rimitidine against gastric and duodenallesions induced by non-steroidal anti-inflammatory drugs. [nternational Journal of Tissue Reactions 8: 71-77, 1986

Correspondence and reprints: AI/an H. Price, Adis Drug [nfor

mation Services. The Old Palace. Lillie St John Street, Chester CH I I RE. England.

mechanisms of nsaid-induced gastroenteropathy

Documents