The methods of treatment of peptic ulcer have changed dramatically during the last 25 years. Numerous compounds having different modes of action have been used to treat upper gastrointestinal ulcers. Healing of ulcers may be achieved by at least three different modes. The first involves the stimulation of regeneration of cells surrounding the ulcer base, as postulated for licorice extracts. Second, the ulcer can be protected from gastric acid and pepsin by coating agents like sucralfate or bismuth. Third, the acidity of the gastric juice can be reduced, as can be achieved by inhibitors of gastric acid secretion or by antacids, which neutralize gastric acidity, and by prostaglandins which inhibit not only gastric acid secretion but additionally stimulate endogenous gastric bicarbonate secretion.

The most successful method to treat upper gastrointestinal ulcers has been the inhibition of gastric acid secretion. During the last 20 years, numerous clinical trials and clinical experience have demonstrated that inhibition of gastric acid secretion is superior in promoting ulcer healing and relieving ulcer symptoms to all the other possible methods mentioned above.

The era of gastric acid inhibitors started experimentally in the early 1970s with the histamine-H2-receptor antagonists. This was followed by gastric proton pump inhibitors about five years later.

Reversible inhibitors of the gastric proton pump differ from omeprazole like compounds in their chemical structure as well as in their mode of interference with the enzyme. Acid induced transformation is not necessary and their enzyme kinetics show that they bind competitively in a non-covalent manner to specific sites of the gastric proton pump.

SCH 28080 is the prototype of a reversible proton pump inhibitor. It was soon recognized that SCH 28080 has antisecretory properties in various in-vitro and in vivo assays and cytoprotective properties in different rat ulcer models. As early as 1983, it was suggested that the antisecretory effect might involve the gastric proton pump. The clinical development of SCH 28080 was discontinued because of liver toxicity in animals and elevated liver enzyme activity in the serum of human volunteers.

The cytoprotective effect of the follow-up compound SCH 32651 in rats was found four times more potent than the antisecretory potential. From results obtained in guinea pig isolated fundic mucosa, it has been suggested that the antisecretory effect of SCH 32651 is caused by a direct influence on the parietal cell at or near the site of the gastric proton pump.

SmithKline has done systematic synthesis to identify freely reversible, non-covalent inhibitors of the gastric proton pump with a mode of action comparable to SCH 28080.

Influenced by the appearance of carcinoids in long term studies in rats treated with omeprazole, it was expected that gastric proton pump inhibition with a shorter duration of action could be of therapeutic interest. This research is resulted in choosing compound SK&F 96067 and SK&F 97574 for further development.

Mechanism of action

SCH 28080 inhibits the enzyme activity in a concentration dependent manner with an IC50 in the micromolar range comparable to that of omeprazole.

The difference between omeprazole and SCH 28080 in their ability to inhibit gastric proton pump depends on the inhibition kinetics. In contrast to omeprazole, SCH 28080 in a competitive inhibitor of high affinity K+ site of the proton pump. Although it was not very specific for the gastric proton pump. It's effect on Na+/K+. ATPase activity is much less pronounced in comparison to its effect on gastric H+/K+ - ATPase activity. SCH 28080 is a protonatable weak base with pka-5.6. Therefore, like omeprazole and related compounds SCH 28080 accumulates in acidic compartments of the parietal cell in it's protonated from.

After protonation, SCH 28080 itself is active and does not need an acid-induced transformation which is required by omeprazole like irreversible inhibits. Therefore in proton transport studies SCH 28080 inhibits the initial rate of H+/K+ ATPase mediated H+ accumulation and the steady state proton concentration. Whereas, omeprazole needs accumulation of acid with in gastric resides to generate low pH for acid induced transformation. SCH 28080 finds to the lumenal side of proton pump. It's inhibitory effect cannot be prevented by addition of sulfhydryl reducing agents but can be reversed by dilution or washing. SK&F 96067 is also active in it's protonated form and finds competitively to the lumenal K+ binding site of the gastric proton pump.

Pharmacology :

As SCH 28080 inhibits the last enzymic step of acid formation, it can inhibit gastric acid secretion under basal conditions as well as during all kinds of stimulation. In isolated guinea pig fundic mucosa, SCH 28080 inhibits methacholine, histamine or dbc AMP stimulated acid secretion in a concentration dependent manner with IC50 values in the micromolar range. Similar results have been obtained in vivo. Pentagastrin, histamine and dimaprit induced gastric acid secretion in dogs is inhibited by similar doses. The antisecretory effect of SCH 28080 in human volunteers was first demonstrated in 1982 at a time when its unique mechanism of action had not been elucidated.

In rats and dogs SK&F 96067 causes a dose dependent inhibition of gastric acid secretion. Its duration of action is longer than that of cimetidine but much shorter than that of omeprazole. In human kinetic and pharmacological studies SK&F 96067 was well tolerated without serious adverse events.

A dose of 300mg twice daily led to an increase in gastric pH which was more effective than 150mg of ranitidine twice daily. At present the profile of acid inhibition by reversible proton-pump inhibitors resembles that of histamine H2-receptor antagonists.

In many clinical studies, predominantly in patients with Zollinger-Ellison syndrome, reflux oesophagitis, or complicated gastric and duodenal ulcers, the superiority of omeprazole-like irreversible gastric proton pump inhibitors above histamine-H2-receptor antagonists has clearly been demonstrated. Their clinically relevant advantages are related to their different mode and longer duration of action. The interference with the last enzymic step of acid formation is the most efficient method to block gastric acid secretion because the inhibitory effect is independent of the kind of acid stimulation. The longer duration of action ensures a more comfortable treatment scheme for patients given one tablet daily.

Reversible gastric proton pump inhibitors share the secretagogue independent mode of action with the irreversible inhibitors but show a duration of action that in comparable to that of histamine-H2-receptor antagonists. Their clinically relevant advantage over irreversible inhibitors has still to be proven. Other gastric proton pump inhibitors, such as Cl - channel blockers, are at present of experimental interest only.

At present the possible use of proton pump inhibitors in indications other than the treatment of acid-related disorders of the upper gastrointestinal tract is only of experimental status. One possible indication could be the specific inhibition of the H+/K+-ATPase-like proton pump in osteoclasts in the treatment of osteoporosis.

--- The authors B Ravinder Reddy is from Noorie College of Pharmacy; H S Basavaraja and S Shivaprasad LV J are from S.C.S. College of Pharmacy