SECTION 11 GASTROINTESTINAL DRUGS Drugs for Peptic Ulcer and Chapter 47 | Gastroesophageal Reflux | Disease ER Peptic ulcer occurs i tit part of the gastrointes- tinal tract (g.i.t.) wich is exposed to gastri acid and pepsin, i.e. the stomach and duodenum, The etiology of peptic ulcer is not clearly known. It results probably due to an imbalance between the aggressive (acid, pepsin, bile and H. pylori) and the defensive (gastric mucus and bicarbonate secretion, prostaglandins, nitric oxide, high mucosal blood flow, innate resistance of the mucosal cells) factors. A variety of psychosomatic, humoral and vascular derangements have been plicated and the causative role of Helico- bacter pylori infection in majority of duodenal uleers and many gastric uleers (which are not due to NSAIDs) has been realized. In gasiric ulcer, generally acid secretion is normal or low, while deficient mucosal defence (mostly impaired mucus and bicarbonate secre tion) plays a greater role. In duodenal ulcer, acid secretion is high in about half of the patients but normal in the rest. Notwithstanding Whether production of acid is normal or high, ation as an aggres- it does contribute to ulce : sive factor, reduction of which is the main approach to ulcer treatment. An understanding of the mechanism and control of gastric acid secretion will elucidate the targets of antisecre- tory drug action. Regulation of gastric acid secretion The mechanisms operating at the gastric parietal ectls are ‘summarized in Fig. 47.1. The terminal enzyme H'K*ATPase (proton pump) which seeretes H’ ions in the apical canaliculi of parietal cells ean be activated by hist ACh acting via their own receptors located fon the basolateral membrane of these cells, Out of the three physiological secretagogues, histamine, acting through H, receptors, plays the dominant role, because the other two, gastrin and ACh act partly direetly and to a greater extent indirectly by releasing histamine from paracrine centerochromaffin-like (ECL) cells called “histaminocytes” located in the oxyntic glands. While H, receptors activate H’K’ATPase by generating cAMP, muscarinic and gastrin’ cholecystokinin (CCK,) receptors appear fo function through the phospholipase C — IP,-DAG pathway that mobi- lizes intracellular Ca. The CAMP mediated proton pump ‘activation also involves Ca". The secretomotor response to ‘gastrin and cholinergic agonists is expressed fully only in the presence of cAMP generated by H, activation. As such, histamine participates in the acid response to gastrin and ‘ACh at more than one levels, and H, antagonists suppress not only histamine, but also ACh, pentagastrin and in fact any gastric acid secretory stimulus. Gastrin is secreted from the antrum in response t0 rise in antral pH, food constituents, especially peptides, and vagally mediated reflexes involving ganglion cells of the entetie nervous system (ENS). The postganglionic ENS neurones elicit gastrin release from gastrin secreting “G? cells by elaborating ACh as well as gastrin releasing peptide (GRP). The dominant muscarinic receptor mediating ‘vagal responses is of the M, subtype. Its location on the ‘ganglion cells ofthe intramural plexuses has been confirmed. ‘The parietal cell and ECL cell muscarinic receptors are of the M, subtype. 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