Ranitidine Zantac

Ball-and-Stick Model

Space-filling Model h,c.

= Carbon = Hydrogen A = Oxygen A = Nitrogen ■ = Sulfur vV

h3c ch3

= Carbon = Hydrogen A = Oxygen A = Nitrogen ■ = Sulfur

Year of discovery: early 1970s (Glaxo); Year of introduction: 1981; Drug category: Histamine H2-receptor antagonist; Main uses: For the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease or prophylaxis; Related drugs: Cimetidine (Tagamet), Famotidine (Pepcid), Nizatidine (Axid) and Roxatidine.

Erosion of the mucosal lining of the stomach by an excess of the digestive enzyme pepsin and hydrochloric acid produces gastric (peptic) ulcers. Gastric ulcers occur as a consequence of insufficient protection against irritation by foreign agents (e.g., certain spices, histamine, medicines or microbes) and the corrosive action of stomach acid and pepsin. Ulcers affect more than 5 million people in the US alone and cause approximately 15,000 fatalities per year due to ulcer-related complications, such as perforation of the stomach wall, internal bleeding and infection.1

The search for substances that control the secretion of stomach acid began in the 1950s, but it was not until the early 1970s that James Black and coworkers at SmithKline used pharmacological evidence that the histamine H2-receptor is the important regulator of gastric acid production to guide the search for an antiulcer drug. Their research led to the discovery of cimetidine, an effective histamine H2-receptor antagonist.2 Cimetidine competitively inhibits the binding of histamine to H2-receptors on the surface of the acid-releasing parietal cells of the stomach. It selectively targets H2-receptors, and has almost no effect on Hrreceptors. The suppression of gastric acid secretion is dose-dependent. H2-receptor antagonists reduce both the concentration of gastric acid and the amount produced. Consequently, H2-receptor antagonists protect against gastric ulceration and help to promote healing.

Cimetidine (Tagamet™, see structure below) became the first billion-dollar drug during the 1980s.

Cimetidine is not an ideal antiulcer agent because it has a half-life of only 2 hours and can cause minor skin rash. It was succeeded by the longer-acting and more potent H2-receptor antagonist, ranitidine (Zantac™). Ranitidine is a very safe, twice-a-day medication (half-life 3 hours) that became the world's best-selling prescription drug by 1988. Both cimetidine and ranitidine are now available without a prescription in the US.

Other potent H2-receptor antagonists have been developed including nizatidine (Axid™, Eli Lilly) and famotidine (Pepcid™, Merck & Co.). The structures of these drugs are shown below.

Cimetidine (Tagamet )

Cimetidine (Tagamet )

Famotidine (Pepcid

1. Nat. Clin. Prac. Gastro. Hepat. 2006. 3, Disc. Dev. 2006, 7, 295-311, Refs. p. 107

Famotidine (Pepcid

1. Nat. Clin. Prac. Gastro. Hepat. 2006. 3, Disc. Dev. 2006, 7, 295-311, Refs. p. 107

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