Acid secretion

From a therapeutic point of view, selective agonists may become useful in the treatment of heart failure and catecholamine-insensitive cardiomyopathy, but only if compounds become available that do not stimulate gastric acid secretion or cause other unforeseen problems. 

Histamine H2 Receptor Antagonists. In 1972 a new class of histamine antagonists was described that was capable of antagonizing histamine-induced gastric acid secretion (6). The H2 antagonists are divided into five stmctural classes, some of which are shown in Table 3. A more complete review can be found in Reference 25. 

For control of gastric acid secretion, the H2 antagonists have encountered competition from the potent -ATPase inhibitors such as... 

Biologica.1 Activities a.ndAna.logues, The many pharmacological actions of neurotensin include hypotension, increased vascular permeabihty, hyperglycemia, increased intestinal motility, and inhibition of gastric acid secretion (120). In the brain, it produces analgesia at remarkably low doses (121). 

Bis(pyridiniumthio)quaternary compounds gastric acid secretion and, 2, 519 Bis(selenadiazoles) decomposition, 6, 349... 

Histamine is a biogenic amine that is widely distributed in the body and functions as a major mediator of inflammation and allergic reactions, as a physiological regulator of gastric acid secretion in the stomach, as a neurotransmitter in the central nervous system (CNS) and may also have a role in tissue growth and repair. 

The histamine H2-receptor (359 amino acids) is best known for its effect on gastric acid secretion. Histamine H2-receptor activation, in conjunction with gastrin and acetylcholine from the vagus, potently stimulate acid secretion from parietal cells. High concentrations of histamine are also present in cardiac tissues and can stimulate positive chronotropic and inotropic effects via H2-receptor stimulation and activation of adenylyl... 

It was known that the K+ -competitive imidazopyridine compound, SCH28080, inhibits acid secretion. Then, many reversible inhibitors were developed. These contain protonatable nitrogens but have a variety of core structures such as imidazopyiidines, piperidinopyr-idines, substituted 4-phenylaminoquinolines, pyrrolo [3,2-c]quinolines, guanidinothiazoles, and 2,4-diamino-pyrimidine derivatives. Several reversible inhibitors have been in clinical trials. 

The first compound of this class with inhibitory activity on the enzyme and on acid secretion was the 2-(pyridylmethyl)sulfinylbenzimidazole, timopra-zole, and the fust pump inhibitor used clinically was omeprazole, 2-[[3,5-dimethyl-4-methoxypyridin-2-yl] methylsulfinyl]-5-methoxy- lH-benzimidazole. Omeprazole is an acid-activated prodrug. Omeprazole and the other PPIs are accumulated in the acidic space of the parietal cell due to the pKa of the pyridine nitrogen and these are converted due to protonation of the benzimidazole nitrogen first to a thiol-reactive cationic sulfenic acid and then dehydrated to form the sulfenamide (Fig. 1). These thiophilic cations then bind to luminally... 

Fellenius E, Berglindh T, Sachs Getal(1981) Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ + K+)ATPase. Nature 290 159-161... 

Shin JM, Sachs G (2002) Restoration of acid secretion following treatment with proton pump inhibitors. Gastroenterology 123 1588-1597... 

Anticholinergics (cholinergic blocking drug) reduce gastric motility and decrease the amount of acid secreted by the stomach (see Chap. 25). Examples of anticholinergics used for GI disorders include propantheline (Pro-Banthine) and glycopyrrolate (Robinul). 

The proton pump inhibitors suppress gastric acid secretion by blocking the final step in the production of gastric acid by the gastric mucosa... 

Figure 3.1 A schematic representation of the control mechanism that stimulates gastric acid secretion, and the intervention points used to treat ulcers. The parietal cells and gastric cells form part of the epithelial cell lining of the stomach. Histamine release is usually triggered as part ofthe enteric nervous system response to distension of the stomach when food is eaten.

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