Biological basis of omeprazole therapy.

There are two means of reducing acid secretion. The best studied is inhibition of stimulation of the parietal cell. There are three major types of receptors that activate secretion by this cell and two classes of receptor antagonists, as well as at least two intracellular messenger pathways. The receptors are for histamine (H2 subtype), acetyl choline (M2 subtype) and gastrin. Antagonists of these receptors include the H2-antagonist class (Tagamet, Zantac and Pepcid), the M1 muscarinic antagonists (pirenzepine, telenzepine) and the gastrin antagonist, proglumide. The major pathway for stimulation appears to be the H2-receptor, since this is the only receptor that stimulates adenylate cyclase, and both acetyl choline and gastrin release histamine locally within the gastric mucosa. However, these agonists elevate intracellular calcium, which has a partially independent action on acid secretion. Accordingly, the most efficacious type of receptor antagonist will be of the H2 class, which is borne out by clinical experience. Prostaglandins of the E type prevent adenylate cyclase stimulation by histamine and are also effective antisecretory agents. It will be difficult to abolish acid secretion entirely by a single receptor antagonist, although longer-acting H2-antagonists should show clinical superiority to short-acting antagonists of this type. An alternative approach to acid suppression is to block the terminal step of acid secretion, the gastric proton pump (H+, K(+)-ATPase). This enzyme is virtually unique to the parietal cell and, when active, forms a very acidic space within the parietal cell called the secretory canaliculus. Activation of acid secretion involves several steps. The enzyme is present in cytosolic membranes when the cell is at rest and moves to the membrane of the secretory canaliculus when stimulated. Simultaneously, there is an increased permeability of potassium chloride (KCl), which allows presentation of K+ to the luminal surface of the pump and H+ for K+ exchange. The result is the secretion of HCl into the canaliculus, and hence into the gland lumen and then the stomach. There are two classes of pump inhibitors. One class is K+ competitive and relatively selective for the H+, K(+)-ATPase, as exemplified by SCH28080. This class has not yet been used in man. The other class is specific to the functioning H+, K(+)-ATPase in the stomach. It is exemplified by omeprazole (Losec). This compound is a weak base with a pKa of 4. In the unprotonated, uncharged form it will penetrate cell membranes and, at pH less than 4, it becomes protonated and therefore charged.(ABSTRACT TRUNCATED AT 400 WORDS)