The Overview of Drugs Acting on H2 Receptors

THE OVERVIEW OF DRUGS ACTING ON H2 RECEPTORS

Drugs whose pharmacological action primarily involves antagonism of the action of histamine at its H2 receptors find therapeutic application in the treatment of acid-peptic disorders ranging from heartburn to peptic ulcer disease, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), acute stress ulcers, and erosions.

H2 receptor agonists were the first truly effective drugs for the treatment of acid-peptic disease

By competitively blocking the binding of histamine to H2 receptors, these agents reduce the intracellular concentrations of cyclic adenosine monophosphate and, thereby, secretion of gastric acid.

The secretion of gastric acid occurs at the level of parietal cells of the oxyntic gland in the gastric mucosa, producing 2-3 liters of gastric juice per day, pH 1 in hydrochloric acid.

Parietal cells contain a hydrogen ion pump, a unique H3O+/K+ - ATPse system that secretes H3O+ in exchange for the uptake of K+ ion.

The HCl acid is formed at the lumen of the canaliculi and then conducted through openings to the gastric lumen.

Secretions of acid by gastric parietal cell is regulated by the actions of various mediators at receptors located on the basolateral membrane, including Histamine agonsim of H2 receptors (cellular) Gastrin activity at G receptors (blood) Acetylcholine (Ach) at M1 Muscarinic

receptors (neuronal)

Histaminic pathway is cAMP dependentGastrin and Muscarinic receptors regulate the secretion through calcium ion dependent pathway

An H2 receptor antagonist must- be recongized by receptor bind more strongly than histamine not trigger acid secretion competitive antagonist

The H2 receptor antagonists in clinical use are histamine congeners that contain a bulky side chain in place of the ethylamine moiety (-CH2CH2NH2)

Imidazole ring

Early representatives of the group, such as Burimamide and Cimetidine retain the imidazole ring of histamine

This ring is replaced in more recently developed compounds by a furan (Ranitidine) or a thiazole ring (Famotidine, Nizatidine)

Ethyl amine side chain

CIMETIDINE (Imidazole ring)

RANITIDINE (Furan ring)

FAMOTIDINE (Thiazole ring)

NIZATIDINE (Thiazole ring)

STRUCTURES OF SOME H2 RECETOR ANTAGONIST

Drug Relative Potency

Dose to Achieve >50% Acid Inhibition for 10 Hours (mg)

Usual dose for Acute Gastric Ulcer (mg)

Usual dose for Gastroesophageal Reflux Disease (mg)

Bioavailability (F) (%)

Half Life (hr)

Cimetidine

1 400-800 800 HS or 400 bid

800 bid 60-70 2

Ranitidine

4-10x 150 300 HS or 150 bid

150 bid 50-60 2-3

Nizatidine

4-10x 150 300 HS or 150 bid

150 mg bid

90-100 1.6

Famotidine

20-50x 20 40 HS or 20 bid

20 mg bid 40-45 2.5-4

Cimetidine is the first discovered clinically used H2 antagonist

This product is obtained by undergoing a series of structural evolutions starting from the imidazole ring containing group of Histamine

HISTAMINE

H1 = H2 agonism

5-METHYL HISTAMINE

A highly selective H2 agonist (H2 > H1 agonism)

Methylation of the 5 position of the imidazole heterocyclic of histamine

5

Nα- Guanyl histamine

The Guanidine analogue of histamine

Partial H2 receptor agonist (weak antagonist)

Strongly basic Guanidine group

Burimamide

Increase in the length of the side chain from two to four carbon atomsCoupled with replacement of the strongly basic group Guanidine with the neutral methyl thiourea function

Full H2 Antagonist ; Low potency

Poor oral bioavailability

Toxic; Causes agranulocytosis (↓ leukocyte) because of the presence of thiourea

2-4 chain

extension

Methyl thioureaNeutral, non-charged

Metiamide

Insertion of an electronegative thioether group in the side chain in place of a methylene group (-CH2-)

Introduction of the 5-methyl group

Full H2 antagonist; Higher potency

Improved oral bioavailability

Toxic; Causes Bone marrow toxicity due to the presence of thiourea

5-methyl

5 Thioether group in place of methylene group

Cimetidine

Thiourea sulfur is replaced with a cyano- imino function

Toxicity related with the thiourea is eliminated

Full H2 antagonist, Higher potency

Improved oral bioavailability

Cyano- imino group in place of Thiourea sulfur

Short acting; hence required frequent doseProduces gynecomastia and impotence (due to

antiandrogen property)Inhibits cytochrome p-450 enzyme activity and thus

may interfare with the metabolism of drugs such as phenytoin, theophylin, phenobarbital, lidocaine, warfarin, imipramine, diazepam, and propranolol

May cause such hematological disorders such as thrombocytopenia, agranulocytosis, and aplastic anemia

Casues confusional states if patients are >60 years age or if the dosage is not adjusted for patients with decreased kidney or renal function

Trade Name Generic Name

Dose Dosage Form

Manufactured By

Neotack 150 Ranitidine 150 mg Tablet Square

Neotack 300 Ranitidine 300 mg Tablet Square

Neotack Ranitidine 50 mg/2 ml

Injection Square

Neotack Ranitidine 75 mg/5 ml

Syrup Square

Famotack 20 Famotidine 20 mg Tablet Square

Famotack 40 Famotidine 40 mg Tablet Square

Neoceptin R300

Ranitidine 300mg Tablet Beximco

Neocepton R Ranitidine 75 mg/5 ml

Syrup Beximco

Yamadin 20 Famotidine 20 mg Tablet Beximco

Yamadin 40 Famotidine 40 mg Tablet Beximco

Neofast Ranitidine 150 mg Tablet Incepta

Ranidin Ranitidine 50 mg/ 2 ml

Injection The ACME Ltd.

Gastroesophageal Reflux Disease (GERD): Patients with frequent heartburn or dyspepsia (fewer than 3 times per week) may take either antacids or H2 antagonists. However, the effect of antacids is short lived (1-2 hours) compared with H2 antagonists (6-10 hours)

Peptic Ulcer Disease: H2 antagonists are effective in promoting healing of duodenal and gastric ulcers. For patients with ulcers caused by aspirin or other NASIDs, H2 antagonists provide rapid ulcer healing so long as the NASIDs are discontinued. Though H2 antagonists are no longer used in patients with acute peptic ulcer caused by Helicobacter Pylori

Nonulcer Dyspepsia: H2 antagonists are commonly used as OTC agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer.

Prevention of Bleeding from Stress-Related Gastritis: H2 receptor antagonists significantly reduce the incidence of bleeding from stress-related gastritis in the serious patients in the intensive care unit. H2 antagonists are given intravenously, either as intermittent injections or continous infusions.

H2 antagonists are extremely safe drugs. Adverse effects occur in fewer than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation

Central Nervous System: Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H2 antagonists, especially in patients in the ICU who are elderly or who have renal or hepatic dysfunction. These events may be more common with Cimetidine

Endocrine Effects: Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidne and does not occur to other H2 antagonists.

Pregnancy and Nursing Mothers: Although there are no known harmful effects on the fetus, these agents cross the placenta. Therefore, should not be administered to pregnant women unless absolutely necessary. H2 antagonists are secreted into breast milk and may therefore affect nursing mothers.

Other effects: H2 antagonists may rarely cause blood dyscrasias, bradycardia, hypertension, reversible abnormalities in liver chemistry.

Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4. Hence, the half-lives of drugs metabolized may be prolonged

Ranitidine binds 4-10 times less avidly than cimetidine to cytochrome P450

Negligible interaction occurs with Famotidine and Nizatidine.

H2 antagonists only blocks the histaminic pathway of gastric acid secretion. Therefore, Acetyl-choline or Gastrin can act on parietal cell and stimulate parietal cell to secrete gastric acid

Long term treatment may develop tolerance or resistance

Activity of H2 antagonist is poor in some population when using for nocturnal gastric acid inhibition (Short Acting Therapy)

Acid Rebound (elevated acid secretary response) may occur after cessation of H2 antagonist therapy