Control of gastric acid secretion. Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors.
Gastric acid secretion is regulated by an intricate interplay of neural (acetylcholine), hormonal (gastrin), and paracrine (histamine, somatostatin) mechanisms. Receptors for each of these agents and the signal transduction pathways to which these receptors are coupled have been identified on the parietal cell. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium, whereas that of histamine is mediated by activation of adenylate cyclase and generation of cAMP. Strong potentiation between histamine and either gastrin or acetylcholine reflects postreceptor interaction between the distinct pathways as well as the ability of acetylcholine and gastrin to release histamine from mucosal ECL cells. The inhibitory effects of somatostatin on acid secretion are mediated by receptors coupled by guanine nucleotide-binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H+K(+)-ATPase, the proton pump of the parietal cell. Precise information on the mechanisms involved in gastric acid secretion has led to the development of potent drugs capable of inhibiting acid secretion. These include competitive antagonists that interact with stimulatory receptors (e.g., histamine H2-receptor antagonists) as well as noncompetitive inhibitors of H+K(+)-ATPase (e.g., omeprazole). The histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, and nizatidine) continue as first-line therapy for peptic ulcer disease and are effective in preventing relapse. Although they are generally well tolerated, histamine H2-receptor antagonists may cause untoward CNS, cardiac, and endocrine effects as well as interference with the absorption, metabolism, and elimination of various drugs. Omeprazole is a weak base that reaches the parietal cell through the bloodstream, diffuses through the cytoplasm, and becomes activated and trapped as a sulfenamide in the acidic canaliculus of the parietal cell. It covalently binds to H+K(+)-ATPase, thereby irreversibly blocking acid secretion in response to all modes of stimulation. The main drawback to its use is its extreme potency, which leads to virtual anacidity, gastrin and ECL cell hyperplasia, hypergastrinemia, and, in rats, to the development of carcinoid tumors.
Medical College of Virginia, Richmond.
R D
RD
Shamburek
M L
ML
Schubert
D000042:Absorption; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D001562:Benzimidazoles / Q000378:metabolism / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000493:pharmacokinetics; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000201:enzymology; D017506:H(+)-K(+)-Exchanging ATPase; D006635:Histamine H2 Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009853:Omeprazole / Q000378:metabolism / Q000627:therapeutic use; D010437:Peptic Ulcer / Q000188:drug therapy
D001562:Benzimidazoles; D006635:Histamine H2 Antagonists; D003577:Cytochrome P-450 Enzyme System; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole