Bagaimana NSAID dapat menyebabkan ulcer disease.pdf

7/28/2019 Bagaimana NSAID dapat menyebabkan ulcer disease.pdf

http://slidepdf.com/reader/full/bagaimana-nsaid-dapat-menyebabkan-ulcer-diseasepdf 1/13

How do NSAIDs cause ulcer disease?

John L. Wallace PhD

ProfessorDepartment of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary,Alberta, Canada

Gastroduodenal ulceration and bleeding are the major limitations to the use of non-steroidalanti-in¯ammatory drugs (NSAIDs). The development of safer NSAIDs or of eective therapiesfor the prevention of the adverse eects of existing NSAIDs requires a better understandingof the pathogenesis of NSAID-induced ulcer disease. NSAIDs can cause damage to thegastroduodenal mucosa via several mechanisms, including the topical irritant eect of thesedrugs on the epithelium, impairment of the barrier properties of the mucosa, suppression of gastric prostaglandin synthesis, reduction of gastric mucosal blood ¯ow and interference withthe repair of super®cial injury. The presence of acid in the lumen of the stomach alsocontributes to the pathogenesis of NSAID-induced ulcers and bleeding, by impairing therestitution process, interfering with haemostasis and inactivating several growth factors thatare important in mucosal defence and repair. In recent years, a fuller understanding of thepathogenesis of NSAID-induced ulcer disease has facilitated some new, very promisingapproaches to the development of stomach-sparing NSAIDs.

Key words: ulcer; non-steroidal anti-in ammatory drug; acid; neutrophils; cyclo-oxygenase;nitric oxide.

The ability of non-steroidal anti-in¯ammatory drugs (NSAIDs) to cause ulceration and

bleeding in the upper gastrointestinal tract was ®rst documented by the endoscopicstudy of Douthwaite and Lintott in 1938.1 In that study, the investigators demonstratedthe ability of aspirin to damage the stomach. In the years that followed, more potentNSAIDs, such as indomethacin, phenylbutazone and the fenamates, were brought tomarket. Shortly thereafter, case reports of melaena associated with the use of aspirinand the newer NSAIDs began to appear in the literature, and in the 1960s and 70s,case-control studies began to document the gastrointestinal toxicity of this class of drug. In recent years, the upper gastrointestinal tract damage caused by NSAIDs hasbeen referred to as an `epidemic' by a number of investigators.2,3 This is in partattributable to the widespread use of these drugs, particularly by patients with osteo-arthritis and rheumatoid arthritis. The world market for NSAIDs is approximately $8billion. The cost of treating NSAID-related gastrointestinal adverse eects almostcertainly exceeds this amount (the annual cost of treating NSAID gastropathy inrheumatoid arthritis patients in the USA, for example, having been reported toexceed $4 billion).4

Developing anti-in¯ammatory drugs that do not produce ulceration or bleeding inthe gastrointestinal tract, or developing prophylactic therapies that substantially

1521-6918/00/010147+13 $35.00/00 *c 2000 Harcourt Publishers Ltd.

BaillieÁ re's Clinical GastroenterologyVol. 14, No. 1, pp. 147±159, 2000doi:10.1053/bega.1999.0065, available online at http://www.idealibrary.com on

11



reduce the toxicity of existing NSAIDs, depends upon clearly understanding thepathogenesis of NSAID-induced ulceration. In this chapter, the mechanisms by whichNSAIDs damage the mucosa, interfere with repair and promote bleeding will bereviewed. In general, the properties of NSAIDs that contribute to ulcerogenesis can bedivided into two categories: (1) topical irritancy, and (2) the suppression of pro-

staglandin synthase activity. In addition, the presence in the stomach and duodenum of acid and, in some cases, Helicobacter pylori (H. pylori), may contribute to the ability of NSAIDs to damage the mucosa.

TOPICAL IRRITATION OF THE MUCOSA

Studies in the 1960s by Davenport suggested that aspirin could directly damage thegastric epithelium.5 The breaking of the `barrier' permitted the back-diusion of acid

into the mucosa, which eventually led to the rupture of mucosal blood vessels. Thesetopical irritant properties were subsequently found to be predominantly associatedwith those NSAIDs with a carboxylic acid residue. The unionized forms of these drugscan enter epithelial cells in the stomach and duodenum. Once in the neutral intra-cellular environment, the drugs are converted to an ionized state and cannot diuseout. This has been referred to as `ion trapping'.6 As the drug accumulates within theepithelial cell, the osmotic movement of water into the cell results in swelling of theepithelial cell, eventually to the point of lysis.6,7

Another mechanism by which NSAIDs could damage the gastroduodenal epithel-ium is via the uncoupling of oxidative phosphorylation in the epithelial cells.7,8 Various

NSAIDs have been shown to uncouple mitochondrial respiration7,8, leading to adepletion of ATP and therefore a reduced ability to regulate normal cellular functions,such as the maintenance of intracellular pH. The ability of NSAIDs to uncoupleoxidative phosphorylation also appears to be related to some extent to acidic moieties(such as carboxylic acid residues), since substitution at these sites interferes with theability of these compounds to act as uncouplers.8

The theory that NSAIDs cause topical injury by virtue of their eects on mito-chondrial respiration has been challenged, mainly based on the observation that gastricand duodenal ulcers are observed following the parenteral or rectal administration of

NSAIDs9,10

. Erosions and ulcers can also be produced in experimental circumstances inwhich NSAIDs are administered parenterally.11 It is also dicult to comprehend howthe uncoupling of oxidative phosphorylation would occur in gastrointestinal epithelialcells but not in the numerous other cells with which an NSAID would have contactsubsequent to its absorption. On the other hand, the small intestine would berepeatedly exposed to NSAIDs that are excreted in bile and recycled enterohepa-tically, so it is conceivable that the uncoupling of oxidative phosphorylation is animportant component of the pathogenesis of NSAID-induced enteropathy.

A third mechanism that could account for the topical irritant properties of NSAIDsis their ability to decrease the hydrophobicity of the mucus gel layer in the stomach.

Lichtenberger and co-workers have proposed that this layer is a primary barrier toacid-induced damage in the stomach.12,13 They demonstrated that the surface of thestomach is hydrophobic and that this hydrophobicity can be reduced by variouspharmacological agents. For example, NSAIDs were shown to associate with thesurface-active phospholipids within the mucus gel layer, thereby reducing its hydro-phobic properties.13±15 These investigators further demonstrated that the mucusgel layer in the stomach of rats and mice given NSAIDs was converted from a

148 J. L. Wallace



non-wettable to a wettable state. This eect was found to persist for several weeks ormonths after the cessation of NSAID administration.12,14

Attempts have been made to produce NSAIDs with reduced topical irritant eects.These include formulations in slow-release or enteric coated tablets, as well as thepreparation of the drug as a pro-drug that requires hepatic metabolism in order to be

active (e.g. sulindac). However, the incidence of gastroduodenal ulceration with pro-drugs is comparable to that seen with standard NSAIDs.16±18 This is taken as evidencethat the topical irritant properties of NSAIDs are not paramount in terms of theirability to induce frank ulceration in the stomach. However, one cannot completelyexclude this possibility. Most NSAIDs are excreted in bile. Even with parenteraladministration of the NSAID, therefore, a re ux of duodenal contents into thestomach would result in the topical exposure of the gastric mucosa to these drugs.

Eorts have recently been made to develop gastrointestinally safe NSAIDs on thebasis of a reduced ability to interfere with the surface-active phospholipid layer in the

gastrointestinal mucus. Lichtenberger et al proposed that pre-associating NSAIDs withzwitterionic phospholipids prior to their administration should reduce the ability of the NSAIDs to associate the phospholipids in the mucus gel, and should thereforereduce their ulcerogenicity.12 They demonstrated this to be the case by pre-associatingaspirin and other NSAIDs with dipalmitoyl-phosphatidylcholine (DPPC) and demon-strating that the complex produced signi®cantly less damage in the gastrointestinaltract than did the parent drug.14 Importantly, the pre-association of aspirin with DPPCdid not interfere with the eectiveness of the aspirin to reduce fever or in¯am-mation.19 Similar eects could be obtained with other NSAIDs.14,19

SUPPRESSION OF PROSTAGLANDIN SYNTHESIS

Vane's discovery in 1971 that NSAIDs inhibit prostaglandin synthesis20 led directly tothe discovery of the ability of minute quantities of exogenous prostaglandins to protectthe gastrointestinal tract from injury induced by topical irritants and NSAIDs.21 This inturn led to extensive research into the roles of prostaglandins in mucosal defence.There is substantial evidence that the ability of an NSAID to cause gastric damagecorrelates well with its ability to suppress gastric prostaglandin synthesis22±25; agents

that are weak inhibitors of gastric prostaglandin synthesis are less ulcerogenic.24,25

There is also a good correlation between the time- and dose-dependency of suppres-sion of gastric prostaglandin synthesis by NSAIDs and their ability to cause gastriculcers.22±24 Why does the suppression of gastric prostaglandin synthesis lead tomucosal injury? As mentioned above, it is now clear that prostaglandins play a centralrole in modulating mucosal defence. Endogenous prostaglandins are involved in theregulation of mucus and bicarbonate secretion by the gastric and duodenal epithelium,mucosal blood ¯ow, epithelial cell proliferation, epithelial restitution and mucosalimmunocyte function.26 This is not to say that prostaglandins are the only endogenoussubstances regulating these components of mucosal defence; indeed, nitric oxide

appears to perform many of the same functions as the prostaglandins in this respect.26

Thus, the inhibition of prostaglandin synthesis alone may not result in the formation of gastric erosions or ulcers. For example, mice in which the gene for cyclo-oxygenase-1was disrupted exhibited negligible levels of gastric prostaglandin synthesis yet did notspontaneously develop gastric erosions or ulcers.27 Of course, one would, in such asituation, anticipate that adaptation of the stomach to the chronic absence of prosta-glandins would occur (i.e. there might be an enhanced production of other

Pathogenesis of NSAID ulceration 149



gastroprotective substances). On the other hand, the suppression of mucosal pro-staglandin synthesis, while not necessarily resulting in ulcer formation, will reduce theability of the gastric mucosa to defend itself against luminal irritants. This has beendemonstrated very clearly in experimental animals. Doses of NSAIDs that substantiallyreduced mucosal prostaglandin synthesis did not cause overt gastric injury but did

greatly increase the susceptibility of the gastric mucosa to damage induced by irritants(e.g. bile salts).28

In terms of the pathogenesis of ulcer disease, is there one component of mucosaldefence that is more important than others with respect to its impairment byNSAIDs? This question has not yet been completely answered. The fact that gastriculcers can be induced by parenterally administered NSAIDs9±11, and that this damagecan be produced independently of the presence of luminal acid29,30, suggests that theimpairment of mucus and/or bicarbonate secretion may be of lesser signi®cance. Whileprostaglandins are extremely potent inhibitors of mast cell degranulation31, and mast

cells are capable of releasing a variety of mediators (e.g. leukotriene C4 and platelet-activating factor) that can contribute to mucosal injury32,33, the eects of NSAIDs onmast cells do not seem to be crucial to the pathogenesis of mucosal injury. This latterconclusion is based on the observation that rats in which mucosal mast cells have beendepleted by chemical means, or mice that are genetically de®cient of mast cells, exhibitsimilar susceptibility to NSAID-induced gastric injury as do their respective controls.34

The rate of epithelial turnover has been shown to be reduced by NSAIDs and couldcontribute to the pathogenesis of ulcer disease.35 However, it is unlikely that thiseect is the principal one that leads to the development of an ulcer.

The component of mucosal defence that appears to be most profoundly altered by

NSAIDs is the gastric microcirculatory response to injury. When the mucosa isexposed to an irritant, or when super®cial epithelial injury occurs, mucosal blood ¯owsubstantially increases. This is probably a response aimed at removing any toxins orbacterial products that enter the lamina propria, neutralizing back-diusing acid andcontributing to the formation of a microenvironment at the surface of the mucosa thatis conducive to repair.36 As described in greater detail below NSAIDs can reducegastric mucosal blood ¯ow and profoundly alter the behaviour of neutrophils ¯owingthrough the gastric microcirculation.

EFFECTS ON THE MICROCIRCULATION

The ability of NSAIDs to reduce gastric mucosal blood ¯ow has been recognized forseveral decades.37±39 Prostaglandins of the E and I series are potent vasodilators thatare continuously produced by the vascular endothelium, so the inhibition of theirsynthesis by an NSAID leads to a reduction in vascular tone. Several lines of evidencehave suggested that damage to the vascular endothelium is an early event following theadministration of NSAIDs to experimental animals.40,41 Endothelial injury is also anearly event in the pathogenesis of gastrointestinal damage associated with ischaemia±

reperfusion42, in which neutrophils have been demonstrated to play a critical role asmediators of endothelial injury.43 This observation led us to examine the possible roleof the neutrophil in the pathogenesis of experimental NSAID gastropathy (Figure 1).

Our studies and those of others demonstrated that NSAID administration to ratsresulted in a rapid and signi®cant increase in the number of neutrophils adhering tothe vascular endothelium in both gastric and mesenteric venules.25,44±46 This eect wastypically seen within 15±60 minutes after the administration of an NSAID, consistent

150 J. L. Wallace



with the period of time required for the suppression of prostaglandin synthesis bythese drugs.47 Subsequent studies demonstrated that this adherence was dependent onthe expression of the b2-integrins (CD11/CD18) on the neutrophil and intercellularadhesion molecule-1 (ICAM-1) on the vascular endothelium.46 Such adherence couldalso be demonstrated to occur in vitro using isolated human neutrophils and endo-thelial cells from human umbilical vein.48 Furthermore, the upregulation of ICAM-1 onthe vascular endothelium in the gastric microcirculation was shown to occur within15±30 minutes of the administration of an NSAID to rats, and this could be preventedby the administration of exogenous prostaglandins.49

Of course, the fact that neutrophils adhere to the vascular endothelium followingNSAID administration does not necessarily mean that these cells contribute to theendothelial injury of the mucosal tissue injury that can be induced by NSAIDs. To testthis hypothesis, a number of studies were carried out. First, we demonstrated thatdepleting circulating neutrophils in the rat, either with an anti-neutrophil serum orwith methotrexate, greatly reduced the severity of the gastric damage induced byindomethacin or naproxen.50 Importantly, the induction of neutropenia also prevented

Figure 1. Role of changes in the gastric microcirculation in the pathogenesis of NSAID-induced ulceration.NSAIDs suppress prostaglandin (PG) synthesis, and cause an increase in the liberation of leukotriene (LT) B4and tumour necrosis factor (TNF). The net result is an increase in expression of various adhesion molecules,leading to neutrophil adherence to the vascular endothelium.




the damage to the vascular endothelium induced by the NSAIDs.50 Second, wedemonstrated that treating rabbits or rats with monoclonal antibodies that blockedNSAID-induced neutrophil adherence to the vascular endothelium also markedlyreduced the extent of NSAID-induced gastric damage.41,46 Third, we found thatadministration of prostaglandins at doses previously shown to prevent gastric injury

prevented NSAID-induced leukocyte adherence.44,45

Further evidence for a link between neutrophil adherence and NSAID-inducedgastric injury came from studies of arthritic rats.51 These animals, like humans withrheumatoid arthritis, exhibit an increased susceptibility to NSAID-induced gastricdamage. Interestingly, these rats also exhibited an increased level of neutrophil adher-ence to the vascular endothelium. This appeared to be due to an increase in expressionof ICAM-1 on the vascular endothelium of arthritic rats, since pre-treatment with anantibody against ICAM-1 reduced leukocyte adherence and the susceptibility toNSAID-induced gastric damage to levels seen in healthy controls.51

These studies suggest that, in response to the suppression of prostaglandin synthesisby NSAIDs, there is a rapid upregulation of expression of ICAM-1 on the vascularendothelium and possibly an upregulation of b2-integrin expression on circulatingneutrophils, resulting in an increased adherence of neutrophils to the endothelium.This begs the question of whether the enhanced adhesion molecule expression ispurely a consequence of the reduction of prostaglandin synthesis, or whether there isanother chemical signal produced in response to diminished prostaglandin synthesisthat triggers the events leading to neutrophil adherence.

Santucci et al suggested that tumour necrosis factor-a (TNFa) might be the keysignal for NSAID-induced neutrophil adherence within the gastric microcirculation.52

The release of TNFa from macrophages and mast cells has been shown to be sup-pressed by prostaglandins31,53, and TNFa is a well-characterized stimulus for adhesionmolecule expression.54 Santucci et al demonstrated that the levels of TNFa in theplasma of rats signi®cantly increased following the administration of indomethacin, thisbeing accompanied by a parallel accumulation of neutrophils within the gastricmicrocirculation and the development of gastric injury.52 Furthermore, pre-treatmentwith a TNFa synthesis inhibitor, pentoxifylline, dose-dependently reduced neutrophilaccumulation in the gastric microcirculation and gastric damage.52 These results havebeen con®rmed and extended by Appleyard et al using a number of structurally

unrelated inhibitors of TNFa synthesis and an anti-TNFa antibody.55

Another group of mediators that might contribute to the increase in neutrophiladherence following NSAID administration is the leukotrienes. Like prostaglandins,leukotrienes are derived from arachidonic acid. They have been shown to be capable of altering the susceptibility of the gastric mucosa to injury44,56±58, at least in part throughstimulatory eects on neutrophil adherence to the vascular endothelium.44 Inhibitorsof leukotriene synthesis and leukotriene receptor antagonists have been shown toexert some protective eects in experimental models of NSAID-induced gastricdamage.56±58 There is also evidence of an elevated leukotriene B4 production followingNSAID administration to laboratory animals44 and man59, and inhibitors of leukotriene

synthesis and a leukotriene B4 receptor antagonist have been shown to preventNSAID-induced neutrophil adherence to the vascular endothelium both in vivo44 andin vitro.48

Evidence for a role for neutrophils in the pathogenesis of gastric ulceration inhumans has recently been provided.60 Patients taking NSAID therapy who had signi®-cant numbers of neutrophils within the gastric mucosa were approximately six timesmore likely to develop an ulcer over the course of 24 weeks than were patients who

152 J. L. Wallace



did not have signi®cant numbers of neutrophils in their gastric mucosa. It is alsonoteworthy that, in a clinical trial examining the potential bene®t of famotidine for theprevention of NSAID-related gastroduodenal ulcers, Taha et al observed that anincreased peripheral white cell count was a signi®cant risk factor for ulcer develop-ment.61 They suggested that this observation was consistent with the hypothesis that

NSAID-induced gastropathy was mediated, at least partially, by neutrophils.How would the adherence of neutrophils to the vascular endothelium contribute to

the formation of gastroduodenal ulcers? First, the adherence of neutrophils to thevascular endothelium is accompanied by an activation of these cells, leading to therelease of proteases (e.g. elastase and collagenase) and oxygen-derived free radicals(e.g. superoxide anions). These substances may mediate much of the endothelial andepithelial injury caused by NSAIDs. This is supported by observations that the severityof NSAID-induced mucosal injury can be markedly diminished by compounds thatscavenge oxygen-derived free radicals62,63 and by inhibitors of neutrophil-derived

proteases.64,65

Second, neutrophil adherence to the endothelium, and the subsequentrecruitment of other elements of blood (e.g. platelets), could produce an obstructionof the capillaries, thereby reducing gastric mucosal blood ¯ow. In this respect, itshould be noted that the well-characterized ability of NSAIDs to reduce gastric blood¯ow37±39 has been shown to occur subsequent to the appearance of `white thrombi' inthe gastric microcirculation.38

INHIBITION OF RESTITUTION

Damage to the gastric epithelium probably occurs on a daily basis but does not usuallylead to deeper mucosal injury because of the ability of rapid (i.e. within minutes)repair to occur via the process of restitution. This process involves the rapid migrationof healthy cells from the gastric pits to re-establish an intact epithelial barrier.66 Thecells move along the denuded basement membrane, which acts as a template and hasbeen shown to be crucial to the restitution process.66±69 The basement membrane canbe damaged by acid, leading to an inhibition of restitution and the progression of necrosis to deeper layers of the mucosa.47,70,71 This does not, however, occur in normalcircumstances because of the formation over sites of injury (i.e. exposed basement

membrane) of a microenvironment in which the pH is maintained at near neutral,even in the presence of a signi®cant acid load in the lumen.47,70 A `mucoid cap'consisting of mucus, cellular debris and plasma proteins (particularly ®brin) formswithin seconds of gastric epithelial injury, trapping the plasma that leaks from theunderlying microcirculation.70 It is this plasma which accounts for the near-neutralpH within the protective mucoid cap, since even a very brief cessation of mucosalblood ¯ow results in a rapid decrease in the pH within the mucoid cap, which in turnresults in the formation of haemorrhagic erosions.41

As discussed above, NSAIDs can decrease mucosal blood ¯ow. Thus, NSAIDs cancause gastric injury by interfering with the appropriate function of the mucoid cap and

therefore the process of restitution. Indeed, we observed that, following the systemicadministration of an NSAID to an animal in which super®cial epithelial injury had beeninduced, the pH within the mucoid cap that had formed over the sites of epithelialdamage began to decline in parallel with the inhibition of prostaglandin synthesis.41

Within minutes thereafter, the formation of haemorrhagic erosions was clearlyevident. This eect could be prevented through the luminal delivery of exogenousprostaglandins, as could the formation of haemorrhagic erosions.41




REPAIR OF ULCERS

In addition to causing ulcer formation, NSAIDs can delay the healing of pre-existingulcers and promote their bleeding.72,73 The eects on ulcer healing are probablyrelated, once again, to the ability of NSAIDs to suppress prostaglandin synthesis. In

normal gastric mucosa, prostaglandin synthesis occurs mainly via the cyclo-oxygenase-1isoform. However, at a site of ulceration, and particularly around the ulcer margin,cyclo-oxygenase-2 appears to be the primary contributor to prostaglandin synthesis.Studies in mice and rats initially demonstrated the marked upregulation of cyclo-oxygenase-2 in ulcerated gastric tissue74,75, and this has recently been con®rmed inhumans.76 Moreover, the treatment of rats or mice with selective inhibitors of cyclo-oxygenase-2 results in a signi®cant delay of ulcer healing.74,75 These observations, andreports of selective cyclo-oxygenase-2 inhibitors exacerbating intestinal in¯ammationand ulceration77, suggest that caution should be exercised in regarding the new cyclo-

oxygenase-2 inhibitors as gastrointestinally safe.78,79

The ability of NSAIDs to promote the bleeding of pre-existing ulcers is mostprobably related to their inhibitory eects on platelet aggregation.80,81 The inhibitionof platelet aggregation by NSAIDs occurs as a consequence of the inhibition of thromboxane synthesis. It should be noted that, unlike other NSAIDs, aspirinproduces an irreversible inhibition of thromboxane synthesis in the platelet. Thus,even the low doses of aspirin used for the prophylaxis of myocardial infarction andstroke can signi®cantly increase the risk of gastrointestinal bleeding.82±84

ROLE OF ACID

The observation that NSAID-induced ulcers can develop in achlorhydric individ-uals29,30 has contributed to a widely held belief that acid is not involved in thepathogenesis of these lesions. Further reinforcing this hypothesis are several studiesdemonstrating that treatment with histamine H2-receptor antagonists did not reducethe incidence of NSAID-induced ulceration.85±87 However, many of these types of studies have demonstrated that H2-antagonists and proton pump inhibitors canprevent NSAID-induced gastric lesions, but not the formation of the clinically more

signi®cant ulcers, as well as ulcer complications. Recently, however, Taha et alreported that a high dose of famotidine (40 mg twice daily) was eective in preventingNSAID-induced ulcers61, and Hawkey et al88 demonstrated that omeprazole couldsigni®cantly reduce the incidence of NSAID-induced ulceration. These studiessuggested that a profound suppression of acid secretion, as is produced by omeprazoleor by a high dose of famotidine, was necessary in order to have a signi®cant impact onthe incidence of NSAID-induced ulcers.

Acid may contribute to NSAID-induced ulcer formation in several ways. First, acidcan exacerbate damage to the gastric mucosa induced by other agents. For example,acid can convert regions of ethanol-induced vascular congestion in the mucosa to

actively bleeding erosions.66 Second, acid will contribute to ulcer formation byinterfering with haemostasis. Platelet aggregation, for example, is inhibited at a pH of less than 4.89 Third, as outlined above, acid can convert super®cial injury to deepermucosal necrosis by interfering with the process of restitution. Fourth, acid caninactivate several growth factors (e.g. ®broblast growth factor) that are important forthe maintenance of mucosal integrity and for the repair of super®cial injury, sincethese growth factors are acid-labile.90

154 J. L. Wallace



It is important to note that NSAIDs can increase gastric acid secretion, although it isnot clear whether such eects have any impact on ulcer formation or healing.Prostaglandins exert inhibitory eects on parietal cells91, so the inhibition of theirsynthesis by NSAIDs can result in an increase in gastric acid secretion. 92

SUMMARY

A great deal has been learned about the pathogenesis of NSAID-induced gastric injuryover the past two decades. As a result, several new NSAIDs, which will have greatlyreduced gastrointestinal toxicity relative to current drugs, are in the process of beingintroduced to the marketplace. For example, selective inhibitors of cyclo-oxygenase-2,which will spare the major form of cyclo-oxygenase in the gastrointestinal tract,

produce substantially less injury to the stomach than do the current NSAIDs thatinhibit both cyclo-oxygenase-1 and -2.93 Whether or not these agents prove to be aseective for the treatment of the full range of in ammatory conditions currentlytreated with NSAIDs remains to be seen, and some experimental studies suggest thatthis may not be the case.94,95 Nitric oxide-releasing NSAIDs represent anotherapproach to reducing the adverse eects of this class of drug.96 The design of thesenew NSAIDs would not have been possible had it not been for an increased under-standing of the pathogenesis of NSAID-induced ulceration.

Acknowledgements

Dr Wallace is a Medical Research Council of Canada Senior Scientist and an Alberta HeritageFoundation for Medical Research Senior Scientist.

REFERENCES

1. Douthwaite AH & Lintott SAM. Gastroscopic observation of the eect of aspirin and certain othersubstances on the stomach. Lancet 1938; 2: 1222±1225.

2. Gabriel SE & Bombardier C. NSAID induced ulcers. An emerging epidemic? Journal of Rheumatology1990; 17: 1±4.

3. Singh G, Ramey DR, Morfeld D et al. Gastrointestinal tract complications of nonsteroidal anti-in¯ammatory drug treatment in rheumatoid arthritis. A prospective observation cohort study. Archivesof Internal Medicine 1996; 156: 1530±1536.

4. Bloom BS. Direct medical costs of disease and gastrointestinal side eects during treatment of arthritis.American Journal of Medicine 1988; 83 (supplement 2A): 20±24.

5. Davenport HW. Gastric mucosal hemorrhage in dogs. Eects of acid, aspirin, and alcohol.Gastroenterology 1969; 56: 439±449.

6. Fromm D. How do non-steroidal anti-in¯ammatory drugs aects gastric mucosal defenses? Clinical andInvestigative Medicine 1987; 10: 251±258.

7. Somasundaram S, Hayllar H, Ra® S et al. The biochemical basis of non-steroidal anti-in¯ammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis. Scandinavian Journal of Gastroenterology 1995; 30: 289±299.

8. Mahmud T, Wrigglesworth JM, Scott DL & Bjarnason I. Mitochondrial function and modi®cation of NSAID carboxyl moiety. In¯ammopharmacology 1996; 42: 189±194.

9. Estes LL, Fuhs DW, Heaton AH & Butwinick CS. Gastric ulcer perforation, associated with the use of injectable ketorolac. Annals of Pharmacotherapy 1993; 27: 42±43.

10. Henry D, Dobson A & Turner C. Variability in the risk of major gastrointestinal complications fromnonaspirin nonsteroidal anti-in¯ammatory drugs. Gastroenterology 1993; 10: 1078±1088.




11. Wallace JL & McKnight GW. Characterization of a simple animal model for nonsteroidal anti-in ammatory drug induced antral ulcer. Canadian Journal of Physiology and Pharmacology 1993; 71:447±452.

*12. Lichtenberger LM. The hydrophobic barrier properties of gastrointestinal mucus. Annual Review of Physiology 1995; 57: 565±583.

13. Goddard PJ, Hills BA & Lichtenberger LM. Does aspirin damage canine gastric mucosa by reducing its

hydrophobicity? American Journal of Physiology 1987; 252: G421±G430.14. Lichtenberger LM, Wang ZM, Romero JJ et al. Non-steroidal anti-in¯ammatory drugs (NSAIDs)

associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-inducedgastrointestinal injury. Nature Medicine 1995; 1: 154±158.

15. Lichtenberger LM, Wang ZM, Giraud MN et al. Eect of naproxen on gastric mucosal hydrophobicity.Gastroenterology 1995; 108: A149.

16. Graham DY, Smith JL, Holmes GI & Davies RO. Nonsteroidal anti-in ammatory eect of sulindacsulfoxide and sul®de on gastric mucosa. Clinical Pharmacology and Therapeutics 1985; 38: 65±70.

17. Carson JL, Strom BL, Soper KA et al. The relative gastrointestinal toxicity of the nonsteroidal anti-in¯ammatory drugs. Archives of Internal Medicine 1987; 147: 1054±1059.

18. Hawthorne AB, Mahida YR, Cole AT & Hawkey CJ. Aspirin-induced gastric mucosal damage: prevention

by enteric-coating and relation to prostaglandin synthesis. British Journal of Clinical Pharmacology 1991; 32:77±83.

19. Lichtenberger LM, Ulloa C, Vanous AL et al. Zwitterionic phospholipids enhance aspirin's therapeuticactivity, as demonstrated in rodent model systems. Journal of Pharmacology and Experimental Therapeutics1996; 277: 1221±1227.

20. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971;231: 232±235.

*21. Robert A, Schultz JR, Nezamis JE & Lancaster C. Gastric antisecretory and antiulcer properties of PGE2 ,15-methyl PGE2 , and 16,16-dimethyl PGE2. Gastroenterology 1976; 70: 359±370.

22. Lanza FL. A review of gastric ulcer and gastroduodenal injury in normal volunteers receiving aspirin andother nonsteroidal anti-in ammatory drugs. Scandinavian Journal of Gastroenterology 1989; 24(supplement 163): 24±31.

23. Rainsford KD & Willis C. Relationship of gastric mucosal damage induced in pigs by antiin ammatorydrugs to their eects on prostaglandin production. Digestive Diseases and Sciences 1982; 27: 624±635.

24. Whittle BJR. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclinbiosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 1981;80: 94±98.

25. Wallace JL, McCaerty D-M, Carter L et al. Tissue-selective inhibition of prostaglandin synthesis in rat bytepoxalin: anti-in¯ammatory without gastropathy. Gastroenterology 1993; 105: 1630±1636.

26. Wallace JL & Tigley AW. New insights into prostaglandins and mucosal defence. Alimentary Pharmacologyand Therapeutics 1995; 9: 227±235.

27. Langenbach R, Morham SG, Tiano HF et al. Prostaglandin synthase 1 gene disruption in mice reducesarachidonic acid-induced in ammation and indomethacin-induced gastric ulceration. Cell 1995; 83:

483±492.28. Whittle BJR. Mechanisms underlying gastric mucosal damage induced by indomethacin and bile salts, and

the actions of prostaglandins. British Journal of Pharmacology 1977; 60: 455±460.

29. Rashid F & Toolon EP. Misoprostol healed a benign nonsteroidal antiin¯ammatory drug-induced gastriculcer in a patient with pentagastrin-fast achlorhydria. Journal of Clinical Gastroenterology 1993; 16:219±221.

30. Janssen M, Dijkmans BAC, Vanderbroucke JP et al. Achlorhydria does not protect against benign uppergastrointestinal ulcers during NSAID use. Digestive Diseases and Sciences 1994; 39: 362±365.

31. Hogaboam CM, Bissonnette EY, Chin BC et al. Prostaglandins inhibit in¯ammatory mediator releasefrom rat mast cells. Gastroenterology 1993; 104: 122±129.

32. Rioux KP & Wallace JL. Mast cell activation increases gastric mucosal injury through peptido-leukotriene

release. American Journal of Physiology 1994; 266: G863±G869.33. Rosam AC, Wallace JL & Whittle BJR. Potent ulcerogenic actions of platelet-activating factor on thestomach. Nature 1986; 319: 54±56.

34. Rioux KP & Wallace JL. Mast cells do not contribute to NSAID-induced gastric mucosal injury inrodents. Alimentary Pharmacology and Therapeutics 1996; 10: 173±180.

35. Eastwood GL & Quimby GF. Eect of chronic aspirin ingestion on epithelial proliferation in rat fundus,antrum, and duodenum. Gastroenterology 1982; 82: 852±856.

36. Wallace JL & Granger DN. The cellular and molecular basis for gastroduodenal mucosal defense. FASEB Journal 1996; 10: 731±740.

156 J. L. Wallace



37. Ashley SW, Sonnenschein LA & Cheung LY. Focal gastric mucosal blood ¯ow at the site of aspirin-induced ulceration. American Journal of Surgery 1985; 149: 53±59.

38. Kitahora T & Guth PH. Eect of aspirin plus hydrochloric acid on the gastric mucosal microcirculation.Gastroenterology 1987; 93: 810±817.

39. Gana TJ, Huhlewych R & Koo J. Focal gastric mucosal blood ¯ow in aspirin-induced ulceration. Annals of Surgery 1987; 205: 399±403.

40. Rainsford KD. Microvascular injury during gastric damage by anti-in ammatory drugs in pigs and rats.Agents and Actions 1983; 13: 457±460.

*41. Wallace JL, Keenan CM & Granger DN. Gastric ulceration induced by nonsteroidal anti-in ammatorydrugs is a neutrophil-dependent process. American Journal of Physiology 1990; 259: G462±G467.

42. Granger DN, Kvietys PR & Perry MA. Leukocyte-endothelial cell adhesion caused by ischemia andreperfusion. Canadian Journal of Physiology and Pharmacology 1993; 71: 67±75.

43. Hernandez LA, Grisham MB, Twohig B et al. Granulocytes: the culprit in ischemic damage to theintestine. American Journal of Physiology 1987; 253: H669±H703.

44. Asako H, Kubes P, Wallace JL et al. Indomethacin-induced leukocyte adhesion in mesenteric venules: roleof lipoxygenase products. American Journal of Physiology 1992; 262: G903±G908.

45. Asako H, Kubes P, Wallace JL et al. Modulation of leukocyte adhesion to rat mesenteric venules by

aspirin and salicylate. Gastroenterology 1992; 103: 146±152.46. Wallace JL, McKnight W, Miyasaka M et al. Role of endothelial adhesion molecules in NSAID-induced

gastric mucosal injury. American Journal of Physiology 1993; 265: G993±G998.47. Wallace JL & McKnight GW. The mucoid cap over super®cial gastric damage in the rat. A high-

pH microenvironment dissipated by nonsteroidal antiin¯ammatory drugs and endothelin. Gastroenter-ology 1990; 99: 295±304.

48. Yoshida N, Takemura T, Granger DN et al. Molecular determinants of aspirin-induced neutrophiladherence to endothelial cells. Gastroenterology 1993; 105: 715±724.

49. Andrews FJ, Malcontenti-Wilson C & O'Brien PE. Eect of nonsteroidal anti-in¯ammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa. American Journal of Physiology 1994; 266: G657±G664.

50. Wallace JL, Arfors K-E & McKnight GW. A monoclonal antibody against the CD18 leukocyte adhesionmolecule prevents indomethacin-induced gastric damage in the rabbit. Gastroenterology 1991; 100:878±883.

51. McCaerty DM, Granger DN & Wallace JL. Indomethacin-induced gastric injury and leukocyteadherence in arthritic versus healthy rats. Gastroenterology 1995; 109: 1173±1180.

*52. Santucci L, Fiorucci S, Giansanti M et al. Pentoxifylline prevents indomethacin induced acute gastricmucosal damage in rats: role of tumour necrosis factor alpha. Gut 1994; 35: 909±915.

53. Kunkel SL, Wiggins RC, Chensue SW & Larrick J. Regulation of macrophage tumor necrosis factorproduction by prostaglandin E2. Biochemical and Biophysics Research Communications 1986; 137: 404±410.

54. Rothlein R, Czajkowski M, O'Neill MM et al. Induction of intercellular adhesion molecule 1 on primaryand continuous cell lines by pro-in ammatory cytokines. Regulation by pharmacologic agents andneutralizing antibodies. Journal of Immunology 1988; 141: 1665±1669.

55. Appleyard CB, McCaerty DM, Tigley AW et al. Tumour necrosis factor mediation of NSAID-induced

gastric damage: role of leukocyte adherence. American Journal of Physiology 1996; 270: G42±G48.56. Rainsford KD. The eects of 5-lipoxygenase inhibitors and leukotriene antagonists on the development

of gastric lesions induced by nonsteroidal antiin¯ammatory drugs in mice. Agents and Actions 1987; 21:316±319.

57. Pihan G, Rogers C & Szabo S. Vascular injury in acute gastric mucosal damage: mediatory role of leukotrienes. Digestive Diseases and Sciences 1988; 33: 625±632.

58. Vaananen PM, Keenan CM, Grisham MB & Wallace JL. A pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID-gastropathy. In¯ammation 1992; 16: 227±240.

59. Hudson N, Balsitis M, Everitt S & Hawkey CJ. Enhanced gastric mucosal leukotriene B4 synthesis inpatients taking non-steroidal anti-in¯ammatory drugs. Gut 1993; 34: 742±747.

60. Taha AS, Dahill S, Morran C et al. Neutrophils, Helicobacter pylori, and nonsteroidal anti-in¯ammatory

drug ulcers. Gastroenterology 1999; 116: 254±258.61. Taha AS, Hudson N, Hawkey CJ et al. Famotidine for the prevention of gastric and duodenal ulcerscaused by nonsteroidal antiin¯ammatory drugs. New England Journal of Medicine 1996; 334: 1435±1439.

62. Del Soldato P, Foschi D, Benoni G & Scarpignato C. Oxygen free radicals interact with indomethacin tocause gastrointestinal injury. Agents and Actions 1985; 17: 484±488.

63. Vaananen PM, Meddings JB & Wallace JL. Role of oxygen-derived free radicals in indomethacin-inducedgastric injury. American Journal of Physiology 1991; 261: G470±G475.

64. Yoshida N, Cepinskas G, Granger DN et al. Aspirin-induced, neutrophil-mediated injury to vascularendothelium. In¯ammation 1995; 19: 297±312.




65. Murakami K, Okajima K, Harada N et al. Plaunotol prevents indomethacin-induced gastric mucosalinjury in rats by inhibiting neutrophil activation. Alimentary Pharmacology and Therapeutics 1999; 13:521±520.

66. Morris GP & Wallace JL. The roles of ethanol and of acid in the production of gastric mucosal erosions inrats. Virchows Archives B (Cell Pathology) 1981; 38: 23±38.

67. Svanes K, Ito S, Takeuchi K & Silen W. Restitution of the surface epithelium of the in vitro frog gastric

mucosa after damage with hyperosmolar sodium chloride. Gastroenterology 1982; 82: 1409±1426.*68. Lacy ER & Ito S. Rapid epithelial restitution of the rat gastric mucosa after ethanol injury. Laboratory

Investigation 1984; 51: 573±583.

69. Moore R, Carlson S & Madara JL. Rapid barrier restitution in an in vitro model of intestinal epithelialinjury. Laboratory Investigation 1989; 60: 237±244.

70. Wallace JL & Whittle BJR. Role of mucus in repair of gastric epithelial damage in the rat. Inhibition of epithelial recovery by mucolytic agents. Gastroenterology 1986; 91: 603±611.

71. Black BA, Morris GP & Wallace JL. Eects of acid on the basal lamina of the rat stomach and duodenum.Virchows Archives B (Cell Pathology) 1985; 50: 109±118.

72. Armstrong CP & Blower AL. Non-steroidal anti-in¯ammatory drugs and life threatening complicationsof peptic ulceration. Gut 1997; 28: 527±532.

73. Stadler P, Armstrong D, Margalith D et al. Diclofenac delays healing of gastroduodenal mucosal lesions.Double-blind, placebo-controlled endoscopic study in healthy volunteers. Digestive Diseases and Sciences1991; 36: 594±600.

*74. Mizuno H, Sakamoto C & Matsuda K. Induction of cyclooxygenase-2 in gastric mucosal lesions and itsinhibition by the speci®c antagonist delays healing in mice. Gastroenterology 1997; 112: 387±397.

75. Schmassmann A, Peskar BM, Stettler C et al. Eects of inhibition of prostaglandin endoperoxidesynthase-2 in chronic gastro-intestinal ulcer models in rats. British Journal of Pharmacology 1998; 123:795±804.

76. Jackson LM, Wu KC, Mahida YR et al. Cyclooxygenase (COX)-1 and -2 in normal, in¯amed and ulceratedhuman gastric mucosa. Gut 1999; (in press).

77. Reuter BK, Asfaha S, Buret A et al. Exacerbation of in¯ammation-associated colonic injury in rat throughinhibition of cyclooxygenase-2. Journal of Clinical Investigation 1996; 98: 2076±2085.

78. Wallace JL. Selective COX-2 inhibitors: is the water becoming muddy? Trends in Pharmacological Sciences1999; 20: 4±6.

79. Wallace JL, McKnight W & Bak A. Selective inhibitors of COX-2: are they really eective? Are theyreally GI-safe? Journal of Clinical Gastroenterology 1998; 27: S28±S34.

80. Prichard PJ, Kitchingman GK, Walt RP et al. Human gastric mucosal bleeding induced by low doseaspirin, but not warfarin. British Medical Journal 1989; 298: 493±496.

81. Hawkey CJ, Hawthorne AB, Hudson N et al. Separation of the impairment of haemostasis by aspirinfrom mucosal injury in the human stomach. Clinical Science 1991; 81: 565±573.

82. The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondaryprophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345±1349.

83. Meade TW, Roderick PJ, Brennan PJ et al. Extracranial bleeding and other symptoms due to low dose

aspirin and low intensity oral anticoagulation. Thrombosis and Haemostasis 1992; 68: 1±6.84. Cryer B, Luk G & Feldman M. Eects of very low doses of aspirin (ASA) on gastric, duodenal & rectal

prostaglandins (PGs) & mucosal injury. Gastroenterology 1995; 108: A77.

85. Agrawal NM. Epidemiology and prevention of non-steroidal anti-in ammatory drug eects in thegastrointestinal tract. British Journal of Rheumatology 1995; 34 (supplement 1): 5±10.

86. Koch M, Capurso L, Dezi A et al. Prevention of NSAID-induced gastroduodenal mucosal injury: meta-analysis of clinical trials with misoprostol and H2-receptor antagonists. Digestive Diseases 1995; 13(supplement 1): 62±74.

87. Simon TJ, Berger ML, Hoover ME et al. A dose-ranging study of famotidine in prevention of gastroduodenal lesions associated with non-steroidal anti-in¯ammatory drugs (NSAIDs): results of a USmulticenter trial. American Journal of Gastroenterology 1994; 89: 1644 (abstract).

*88. Hawkey CJ, Karrasch JA, Szczepanski L et al. Omeprazole compared with misoprostol for ulcersassociated with nonsteroidal antiin ammatory drugs. New England Journal of Medicine 1998; 338: 727±734.

89. Green FW, Kaplan MM, Curtis LE & Levine PH. Eect of acid and pepsin on blood coagulation andplatelet aggregation: a possible contributor to prolonged gastroduodenal mucosal hemorrhage.Gastroenterology 1978; 74: 38±43.

90. Szabo S, Folkman J, Vattay P et al. Accelerated healing of duodenal ulcers by oral administration of a basic®broblast growth factor in rats. Gastroenterology 1994; 106: 1106±1111.

91. Soll AH. Mechanisms of action of antisecretory drugs: studies on isolated canine fundic mucosal cells.Scandinavian Journal of Gastroenterology 1986; 21: 1±6.

158 J. L. Wallace



92. Ligumsky M, Goto Y & Yamada T. Prostaglandins mediate inhibition of gastric acid secretion bysomatostatin in the rat. Science 1983; 219: 301±303.

*93. Xie W, Robertson DL & Simmons DL. Mitogen-inducible prostaglandin G/H synthase: a new target fornonsteroidal antiin¯ammatory drugs. Drug Development Research 1992; 25: 249±265.

*94. Wallace JL, Bak A, McKnight W et al. Cyclooxygenase-1 contributes to in ammatory responses in ratsand mice: implications for GI toxicity. Gastroenterology 1998; 115: 101±109.

95. Wallace JL, Chapman K & McKnight W. Limited anti-in ammatory ecacy of cyclooxygenase-2inhibition in carrageenan-airpouch in¯ammation. British Journal of Pharmacology 1999; 126: 1200±1204.

96. Wallace JL, Elliott SN, Del Soldato P et al. Gastrointestinal sparing anti-in ammatory drugs: thedevelopment of nitric oxide-releasing NSAIDs. Drug Development Research 1997; 42: 144±149.


Documents

Bagaimana NSAID dapat menyebabkan ulcer disease.pdf