H2-receptor antagonists

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Chapter: Medicinal Chemistry : Antiulcer Agents

Antiulcer Agents - H2-receptor antagonists : i. Cimetidine (Tagamet) ii. Famotidine (Famocid, Famtac) iii. Ranitidine (Zantac) iv. Etintidine v. Oxmetidine vi. Nizatidine vii. Roxatidine (Rotane, Zorpex) - Synthesis and Drug Profile


SYNTHESIS AND DRUG PROFILE

H2-receptor antagonists

Mode of action: These drugs inhibit the acid production by reversibly competing with histamine for the binding with H2-receptor on the basolateral membrane of parietal cells. The most predominant effect of H2-receptor antagonist is on basal acid secretion. Histamine on H2-receptors produces cAMP-dependent protein kinase to elicit the response in the gastrointestinal tract (GIT). The H2-antagonists reversibly bind the H2-receptors and reduce the cAMP formation, which is responsible for the activation of proton pump and subsequently reduces the gastric acid formation in the GIT.

 

i. Cimetidine (Tagamet)


Synthesis

Route I. From: Ethyl-5-methyl-imidazole-4-carboxylate


Route II: From: Ethyl-2-chloro acetoacetate


Properties and uses: Cimetidine hydrochloride is a white crystalline powder, soluble in water, and sparingly soluble in ethanol. It is a H2-receptor antagonist that not only inhibits gastric acid secretion, but  also prevents other actions of histamine mediated by H2-receptors. It is used in the treatment of peptic ulceration. Cimetidine has a weak antiandrogenic effect. Gynaecomastia may occur in patients treated for a month or more.

Assay: Dissolve the substance in a mixture of 0.01 M HCl and alcohol (1:10) and titrate against 0.1 M sodium hydroxide. Determine the end point potentiometrically.

Dose: Oral dose is 200 mg thrice a day with meals and 400 mg at night.

 

ii. Famotidine (Famocid, Famtac)


Synthesis


Properties and uses: Famotidine is a white or yellowish-white crystalline powder or crystals, very slightly soluble in water, soluble in anhydrous ethanol and glacial acetic acid, but practically insoluble in ethyl acetate. It acts as a competitive, reversible H2-antagonist with a slow onset of equilibrium. This type of blockade is called nonequilibrium antagonism. It is used in the treatment of duodenal and gastric ulcers, Zollinger–Ellison syndrome, and heart burn.

Assay: Dissolve the sample in anhydrous acetic acid and titrate against 0.1 M perchloric acid. Determine the end-point potentiometrically.

Dose: The dose for gastric or duodenal ulcer is 40 mg at night for 4–8 weeks. The dose for prophylaxis or relapse is 20 mg at night. Not recommended for usage in children.

Dosage forms: Famotidine tablets B.P.

 

iii. Ranitidine (Zantac)


Synthesis


Metabolism of cimetidine, ranitidine, and fomotidine: Hydroxylation of the imidazole C-4 methyl group of cimitidine occurs. Ranitidine is excreted largely unchanged, but minor metabolic pathways include Ndemethylation as well as Nand S-oxidation. The metabolites are thought not as contributing to the therapeutic properties of parent drugs, with the exception of nizanidine, from which the N-demethyl metabolites retains H2-antihistamine activity.

Properties and uses: Ranitidine hydrochloride is a white or pale yellow crystalline powder, soluble in water, slightly soluble in anhydrous ethanol and methylene chloride. In Ranitidine, the imidazole ring of cimitidine was replaced by furan in conjugation with some rearrangement of the terminal functionality; the substituted guanidine group has been isosterically modified by utilizing a nitromethenyl moiety to basicity. It is used in the treatment of duodenal ulcer, gastric ulcer, and pathological hypersecretory conditions.

Assay: Dissolve the sample in water and titrate against 0.1 M sodium hydroxide. Determine the end point potentiometrically.

Dose: The dose is 150 mg (as the hydrochloride) two times a day.

Dosage forms: Ranitidine HCl injection I.P., Ranitidine HCl tablets I.P., Ranitidine injection B.P., Ranitidine oral solution B.P., Ranitidine tablets B.P.

 

iv. Etintidine


Synthesis


Uses: Used as antiulcer and it is twice as active as cimetidine.

 

v. Oxmetidine


Synthesis


Properties and uses: It shows a time dependent and slow onset of action, which differentiates it from ranitidine. It is reported to have histamine H2-receptor blocking activity.

 

vi. Nizatidine


Synthesis


Properties and uses: Nizatidine is a white or slightly brownish crystalline powder, sparingly soluble in water, and soluble in methanol. It is used as histamine H2-receptor antagonist in the treatment of peptic ulcer.

Assay: It is assayed by adopting liquid chromatography techniques.

Dosage forms: Nizatidine intravenous infusion B.P.

 

vii. Roxatidine (Rotane, Zorpex)


Synthesis


Dose and uses: Oral dose for peptic ulcer for adults is 150 mg at bedtime or 75 mg twice a day for 4–6 weeks; maintenance dose is 75 mg at bedtime. Dose for gastroesophageal reflux disease/oesophagitis, including erosions and ulcerations for adults is 75 mg twice a day or 150 mg at bedtime for 6–8 weeks. The dose for gastritis for adults is 75 mg once daily in the evening. For Zollinger–Ellison syndrome, the dose for adult is 75 mg twice a day. In anaesthetic premedication for adults, the dose is 75 mg in the evening on the day before surgery and repeated every 2 h before induction of anaesthesia, alternatively, 150 mg once on the night before surgery.

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