H 2 Blocker Dr. Raushanara Akter Assistant Professor, Department of Pharmacy BRACU

Physiological regulation of acid secretion by the parietal cell/ physiology of acid secretion: Gastric acid is secreted from parietal cells located mainly in the upper portion of the stomach and is stimulated by three endogenous substances: a) gastrin, b) acetylcholine and c) histamine. The parietal cell contains receptors for gastrin, acetylcholine  mascirinic, M3) and histamine  H2). When acetylcholine or gastrin bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+/K+ ATPase  the proton pump) on the canalicular surface. In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like  ECL) cells. ECL cells have receptors for gastrin and acetylcholine. It is thought that gastrin and acetylcholine act on ECL cells to release histamine.

Physiological regulation of acid secretion by the parietal cell/ physiology of acid secretion: Histamine then binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate  cAMP). cAMP activates protein kinases that stimulate acid secretion by the H+/K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation.

Figure: Schematic diagram of one model of the physiologic control of hydrogen ion secretion by the gastric parietal cell. ECL cell, enterochromaffin-like cell; G  CCK-B), gastrin-cholecystokinin-B receptor; H2 histamine; H2 histamine H2 receptor; M1, M3, muscarinic receptors; ST2, somatostatin2 receptor; ATPase, K+/H+ ATPase proton pump. Some investigators place histamine receptors- and possibly cholinoceptors- on nearby tissue cells rather than on the parietal cell itself.  Modified and redrawn from Sachs G, Prinz C: Gastric enterochromaffin-like cells and the regulation of acid secretion. News PhysioSci 1996; 11:57, and other sources)

Physiological regulation of acid secretion by the parietal cell/ physiology of acid secretion: Parietal Cell Acetylcholine or gastrin bind to the parietal call receptors Cause an increase in cytosolic Ca++ Stimulates acid secretion from H+/K+ ATPase  proton pump) on the canalicular surface Enterochromaffin like  ECL) cells Activates protein kinase Acetylcholine and gastrin bind to the ECL cell receptors  1) Release histamine Histamine binds to the H2 receptor on the parietal cell Activation of adenylyl cyclase Increases intracellular cyclic adenosine mono phosphate  cAMP) cAMP activates protein kinase Stimulates acid secretion by the H+/K+ ATPase Direct  Parietal)  30% Indirect  ECL)  70%

H2 receptor antagonists : H2 receptor antagonists are commonly referred to as H2 blockers. Chemistry: The H2 receptor antagonists in clinical use are histamine congeners that contain a bulky side chain in place of the ethylamine moiety. Early representatives of the group, such as burimamide and cimetidine  the first compound released for general use) retain the imidazole ring of histamine. This ring is replaced in more recently developd compounds by a furan  ranitidine) or a thiazole  famotidine, nizatidine). Structures of histamine and some H2 antagonists are given below: HistamineCimetidineRanitidineFamotidineNizatidine

Pharmacokinetics:  All these agents are rapidly absorbed from the intestine; peak concentrations in plasma are attained within 1 or 2 hours.  Ranitidine and famotidine undergo first pass hepatic metabolism resulting in a bioavailability of approximately 50%.  Nizatidine has little first pass metabolism and a bioavailability of 90%.  The serum half-lives of ranitidine and famotidine are 2 to 3 hours, while that of nizatidine is somewhat shorter about 1.3 hours; however duration of action depends on the dose given.  H2 antagonists are cleared by a combination of a) hepatic metabolism b) glomerular filtration and c) renal tubular secretion. Dose reduction is required in patients with moderate to severe renal  and possibly severe hepatic) insufficiency.

Pharmacodynamics/ Mechanism of action of H2 receptor antagonists:  The H2 receptor antagonists exhibit competitive inhibition at the parietal cell H2 receptor, and suppress basal  fasting), nocturnal and meal-stimulated acid secretion in a linear dose-dependent manner.  They are highly selective and do not affect H1 receptors.  H2 antagonists reduce acid secretion stimulated by histamine as well as by gastrin and cholinomimetic agents through two mechanisms: First histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H2 receptor. Second, direct stimulation of the parietal cell by gastrin or acetylcholine results in diminished acid secretion in the presence of H2 receptor blockade. It appears that reduced parietal cell cAMP levels attenuate the intracellular activation of protein kinase by gastrin or acetylcholine.

Synthesis of Ranitidine: REACTION: The reaction of 5- dimethylaminomethyl-2- furanylmethanol (I) with 2- mercaptoethylamine (II) by means of aqueous HCl gives 2-[[(5- dimethylamino-methyl-2- furanyl)methylthio]ethaneamine (III), which is then condensed with N- methyl-1-methylthio-2- nitrotheneamine (IV) by heating at 120 C. Compound (IV) is obtained by reaction of 1,1-bis(methylthio)-2- nitroethene (V) with methylamine in refluxing ethanol

Comparison between Ranitidine &Nizalidine: CharacteristicsRanitidineNizatidine Hepatic First Pass metabolism Undergoes moderate hepatic first pass metabolism Undergoes little hepatic first pass metabolism BioavailabilityApproximately 50%Approximately 90% Serum half life2 to 3 hoursAbout 1.3 hours Duration of actionlongershorter RingFuran/ thiazoleThiazole

Pharmacokinetics of Ranitidine:  Metabolism of Ranitidine: Rapidly absorbed from the intestine.  Peak concentration in plasma are attained within 1 to 2 hours  H2 antagonists are cleaned by: Excretion of the drug and its metabolites is largely in urine  30-40%) of dose is found unchanged in the urine and the S and N oxides and desmethylranitidine are detectable in urine within 24 hours of dosing. Ranitidine Ranitidine S- Oxide Ranitidine N- OxideDesmethylranitidine

Synthesis of Cimetidine:

Indications of Cimetidine/Ranitidine: Benign gastric and duodenal ulceration. Stomal ulcer. Reflux esophagitis. Zollinger- Ellison Syndrome. Other conditions where reduction of gastric acidity is beneficial

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