Gastric Damage by Drugs and the Role of the Mucosal Barrier

Summary: There are six drugs usually implicated in peptic ulceration and these are adrenal corticosteroids, aspirin, phenylbutazone, indomethacin, ethanol and caffeine. The types of data upon which these conclusions rest follows three lines of evidence. First, the production of ulcers in experimental animals; all the drugs mentioned above can produce experimental ulcers. Second, the cause and effect relationship in man, i.e. epidemiological evidence; the epidemiological evidence is very weak except for aspirin. Third, a mechanism suspected of participating in the pathogenesis; the pathogenesis of drug ulceration is not fully understood but aspirin may be the only one with a body of data to support its ulcerogenic effect. The pathogenesis of peptic ulcer is usually considered in terms of the equation, acid-pepsin versus mucosal resistance. Caffeine is a moderately strong stimulus of acid secretion but corticosteroids, phenylbutazone, ethanol and indomethacin are very weak stimulants or have no effect. Aspirin decreases acid secretion. The lack of effect of these drugs on acid-pepsin secretion has led investigators to study the mucosal resistance. Mucosal resistance may be due to the gastric mucus barrier or the gastric mucosal barrier. The evidence for the mucus barrier rests on data indicating that mucus secretion is decreased and altered in composition by some of the drugs. It is difficult to know what this means since mucus has virtually no buffer capacity or neutralizing power and does not offer a barrier to the free diffusion of hydrogen ion. Thus, alteration of the composition and secretory rate of mucus may have no bearing on drug induced ulceration. The other parameter is the gastric mucosal barrier which prevents the acid in the lumen from diffusing into the blood down a high concentration gradient and similarly prevents sodium from diffusing from interstitial fluid into the lumen down its concentration gradient. The barrier is thought to depend upon the lipo-protein cellular lining. When the barrier is “broken”, acid rapidly leaves the lumen of the stomach, sodium enters the lumen of the stomach and the normal transmucosal potential difference (in man 40 mV, lumen negative to serosa) decreases. Unbuffered aspirin breaks the mucosal barrier but if buffered to pH 6–7 it has no effect. Indomethacin has variable effects in the dog but has no effect in man. Ethanol breaks the barrier in concentrations greater than 3 M (about 12%). Phenylbutazone, caffeine or adrenal corticosteroids have no effect. The effects of unbuffered aspirin and ethanol given together are additive. In 15 subjects on long term aspirin therapy (5.5 g/day for seven years) or long term prednisone therapy (20 mg/day for two months to six years) it was found that their electrical potential difference was normal and they behaved like normal subjects to a challenge with aspirin or prednisone. These studies suggest that aspirin causes episodes of acute damage which is potentially reversible. Of all the drugs, unbuffered aspirin is the most effective agent for breaking the barrier and causing erosions and occult bleeding. Limited studies with the other drugs indicate they usually do not cause erosions (except excessive ethanol ingestion) or occult bleeding (indomethacin causes a mild increase). These latter complications, i.e. erosions, occult bleeding, may be explained on the basis of the gastric mucosal barrier theory.