Histamine H2 Receptor Antagonists
Gastroesophageal Reflux Disease,
Agents forGastric Antisecretory Drugs (GERD)
Astellas Pharma (Innovaator)Launched – 1985
|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Routes||Oral (tablet form)|
|Excretion||Renal (25-30% unchanged [Oral])|
|Mol. mass||337.449 g/mol|
Famotidine is an H2-histamine antagonist that was first launched by Astellas Pharma (formerly Yamanouchi) in Japan in 1985 as an injectable for the treatment of upper gastrointestinal hemorrhage and for the treatment of Zollinger-Ellison syndrome. In 1986, the drug was launched pursuant to a collaboration between Merck Sharp & Dohme and Sigma-Tau for the oral prevention and treatment of gastroesophageal reflux disease (GERD).
Famotidine (INN) /fəˈmɒtɪdiːn/ is a histamine H2-receptor antagonist that inhibits stomach acid production, and it is commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD/GORD). It is commonly marketed byJohnson & Johnson/Merck under the trade names Pepcidine and Pepcid and by Astellas under the trade name Gaster. Unlikecimetidine, the first H2 antagonist, famotidine has no effect on the cytochrome P450 enzyme system, and does not appear to interact with other drugs.
Certain preparations of famotidine are available over the counter (OTC) in various countries. In the US 20 or more mg, sometimes in combination with a more traditional antacid, are available OTC. Larger doses still require a prescription.
Famotidine is given to surgery patients before operations to prevent postoperative nausea and to reduce the risk of aspiration pneumonitis. Famotidine is also given to some patients taking NSAIDs, to prevent peptic ulcers. It serves as an alternative toproton-pump inhibitors.
It is also given to dogs and cats with acid reflux.
Famotidine was developed by Yamanouchi Pharmaceutical Co. It was licensed in the mid-80s by Merck & Co. and is marketed by a joint venture between Merck and Johnson & Johnson. The imidazole-ring of cimetidine was replaced with a 2-guanidinothiazole ring. Famotidine proved to be 30 times more active than cimetidine.
In the United States and Canada, a product called Pepcid Complete, which combines famotidine with an antacid in a chewable tablet to quickly relieve the symptoms of excess stomach acid, is available. In the UK, this product is known as Pepcidtwo.
Famotidine suffers from poor bioavailability (50%), as it is poorly soluble in the low pH of the stomach. Famotidine used in combination with antacids promotes local delivery of these drugs to the receptor of the parietal cell wall. Therefore, researchers are developing innovative formulations of tablets, such as gastroretentive drug delivery systems. Such tablets are retained in the stomach for a longer period of time, thereby improving the bioavailability of drugs. Local delivery also increases bioavailability at the stomach wall receptor site and increases the efficacy of drugs to reduce acid secretion.
Famotidine is also indicated in the treatment of duodenal and benign gastric ulcers, for the prevention of relapse of duodenal ulceration, for the treatment of gastric mucosal lesions associated with acute gastritis and acute exacerbation of chronic gastritis, for the treatment of heartburn associated with acid indigestion and sour stomach, for the prevention of meal-induced heartburn, and for the treatment of reflux esophagitis due to GERD, including ulcerative disease as diagnosed by endoscopy. The drug is currently marketed in tablet, film-coated tablet, orally-disintegrating tablet, powder, lyophilized powder for injection solution and injectable formulations. The compound had been in development for the treatment of non-erosive reflux disease (NERD), however, Astellas Pharma discontinued development for this indication in 2007.
Famotidine was developed by replacing the imidazole ring of GlaxoSmithKline’s cimetidine with a 2-guanidinothiazole ring, a modification proven to increase the activity of the drug 30-fold. Famotidine competitively inhibits the action of histamine at the histamine H2 receptors of the parietal cells. It suppresses the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid by two mechanisms: by blocking histamine released by enterochromaffin-like (ECL) cells in the stomach from binding to H2 receptors and stimulating acid secretion, and by reducing the effect that other compounds (such as gastrin, pentagastrin, caffeine, insulin and acetylcholine) have on the promotion of acid secretion due to H2 receptor blockade.
Famotidine was originally developed at Astellas Pharma. It was subsequently licensed in the U.S. to Merck & Co., known outside the U.S. and Canada as Merck Sharp & Dohme. In 2007, Salix acquired the U.S. rights to famotidine oral solution (Pepcid[R]) for the treatment of GERD and peptic ulcer. Sigma-Tau holds rights to the drug and is responsible for marketing activities in Italy. Famotidine is sold in over 110 countries worldwide, including France, Germany, Italy, Japan, the U.S. and the U.K.
The reaction ot S-(2-aminothiazol-4-ylmethyl)isothiourea (I) with 3-chloropropionitrile (II) by means of NaOH in ethanol – water gives 3-(2-aminothiazol-4-ylmethylthio)propionitrile (III), which is condensed with benzoyl isothiocyanate (IV) in refluxing acetone to afford 3-[2-(3-benzoylthioureido)thiazol-4-ylmethylthio]propionitrile (V). The hydrolysis of (V) with K2CO3 in acetone – methanol – water yields 3-(2-thioureidothiazonl-4-ylmethylthio)propionitrile (VI), which by methylation with methyl iodide in refluxing ethanol is converted into 3-[2-(S-methylisothioureido)thiazol-4-ylmethylthio]propionitrile hydroiodide (VII). The reaction of (VII) with NH3 and NH4Cl in methanol at 90 C in a pressure vessel affords 3-(2-guanidinothiazol-4-ylmethylthio)propionitrile (VIII), which by partial alcoholysis with methanol by means of dry HCl in CHCl3 is converted into methyl 3-(2-guanidinothiazol-4-ylmethylthio)propionimidate (IX). Finally, this compound is treated with sulfamide in refluxing methanol.
Drugs Fut 1983, 8, 1, 14
DOS 2 951 675 (Yamanouchi; appl. 21.12.1979; J-prior. 2.8.1979).
DOS 3 008 056 (Yamanouchi; appl. 3.3.1980; J-prior. 6.3.1979, 23.6.1979).
GB 2 052 478 (Yamanouchi; appl. 6.3.1980; J-prior. 6.3.1979, 23.6.1979).
GB 2 055 800 (Yamanouchi; appl. 20.12.1979; J-prior. 2.8.1979).
synthesis of S-[2-aminothiazol-4-ylmethyl]isothiourea:
Spragne, J.M.; Lund, A.H.; Ziegler, C.: J. Am. Chem. Soc. (JACSAT) 68, 2155 (1946).
FT IR OF FAMOTIDINE
[1H,13C] 2D NMR Spectrum
DSC OF FAMOTIDINE
WILL BE ADDED
|Conditions : Concentration – 1 mg / 100 ml|
|The solvent designation graphics||Methanol
|Maximum absorption||287 nm||–||265 nm||286 nm|
FIG WILL BE ADDED
|various generic drugs|
|Pepdin||Merck Sharp & Dohme-Chibret|
|Great Britain||Peptsid||Merck Sharp & Dohme|
|Gastridin||Merck Sharp & Dohme|
|United States||Peptsid||Merck, 1986|
|– “-||Johnson & Johnson; Merck|
|Ukraine||Ulfamid||Krka, dd, Novo mesto, Slovenia|
|Kvamatel||JSC “Gedeon Richter”, Hungary|
|Famasan||ABM. MED. CA AT Prague, Czech Republic|
|FamodinGeksal||Salyutas Pharma GmbH, Germany, venture hexane AG, Germany|
|various generic drugs|
ampoule 10 mg, 20 mg;
Tablets coated with 10 mg, 20 mg, 40 mg;
oral suspension, 40 mg / 5 ml;
2% powder, 10%;
10 mg tablets, 20 mg;
vials (lyophilisate) 20 mg
DOS 2,951,675 (Yamanouchi; appl. 21.12.1979; J-prior. 2.8.1979).
DOS 3,008,056 (Yamanouchi; appl. 3.3.1980; J-prior. 6.3.1979, 23.6.1979).
GB 2052478 (Yamanouchi; appl. 6.3.1980; J-prior. 6.3.1979, 23.6.1979).
GB 2055800 (Yamanouchi; appl. 20.12.1979; J-prior. 2.8.1979).
US 4,283,408 (Yamanouchi; 11.8.1981; J-prior. 2.8.1979).
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