Famotidine and nizatidine

The latter two results imply that the heterocyclic rings for cimetidine and ranitidine are not interacting in the same way with the H2 receptor. This is supported by the fact that a corresponding dimethylaminomethylene group attached to cimetidine leads to a drop in activity. 

Ranitidine was introduced to the market in 1981 and by 1988 was the world s biggest selling prescription drug. 

During 1985/87 two new antiulcer drugs were introduced to the market—famotidine and nizatidine. 

Famotidine (Pepcid) (Fig. 13.57) is 30 times more active than cimetidine in vitro. The side-chain contains a sulfonylamidine group while the heterocyclic imidazole ring of cimetidine has been replaced with a 2-guanidinothiazole ring. Structure-activity studies gave the following results  

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Traditional or Hj antihistamine drugs block many effects caused by histamine however, it turns out that they are not able to withstand events mediated by H2 receptors, in particular excess gastric juice secretion. In 1977 an H2-receptor antagonist, cimetidine, was proposed, which revolutionized stomach ulcer treatment. Later on, ranitidine was proposed, followed by drugs with minor structural and pharmacological differences such as famotidine and nizatidine. 

Ranitidine, famotidine, and nizatidine do not inhibit the cytochrome P450-linked oxygenase enzyme system in the liver. 

Drug/Food interactions Food may increase bioavailability of famotidine and nizatidine this is of no clinical consequence. Cimetidine and ranitidine are not affected. 

Histamine H2-receptor antagonists are the mainstay of prevention of Mendelson s syndrome at present. Probably the best protection is afforded by a combination of H2-receptor blockade by ranitidine and a single oral dose of sodium citrate or bicarbonate. Because of its longer duration of action, and relative lack of enzyme inhibition, ranitidine is preferred to cimetidine for this purpose, although there is a latent period of 1-2 hours before it takes effect. Famotidine and nizatidine are probably equally effective in blocking acid secretion. 

Inhibits hepatic microsomal drug-metabolizing enzymes. (Ranitidine, famotidine, and nizatidine do not appear to do so.) May inhibit the renal tubular secretion of weak bases. Purportedly reduces hepatic blood flow, thus reducing first-pass metabolism of highly extracted drugs. (However, the ability of cimetidine to affect hepatic blood... 

Actions The histamine H2-receptor antagonists—cimetidine, ranitidine, famotidine, and nizatidine—act on H2-receptors in the stomach, blood vessels, and other sites. They are competitive antagonists of histamine and are fully reversible. These agents completely inhibit gastric acid secretion induced by histamine, or gastrin. However, they only partially inhibit gastric acid secretion induced by acetylcholine or bethanechol. 

CIMETIDINE FAMOTIDINE NIZATIDINE, RANITIDINE BRONCHODILATORS -THEOPHYLLINE t efficacy and adverse effects, including seizures. There is conflicting information associated with ranitidine, famotidine and nizatidine Inhibition of metabolism via CYP1A2, cimetidine being the best known inhibitor Use alternative acid suppression, e.g. a proton pump inhibitor (not omeprazole or lansoprazole) or monitor closely considerable patient variation. Check levels on day 3 and then at 1 week. A 30-50% i dose of theophylline may be required. For doses <400 mg/day, the interaction may not be clinically significant... 

A. Oassification and Prototypes Four H, blockers are available cimetidine is the prototype. Ranitidine, famotidine, and nizatidine differ only in being slightly less toxic than cimetidine. These drugs do not resemble H, blockers structurally. They are orally active, with half-lives of 1-3 hours. Because they are relatively nontoxic, they can be given in large doses, so that the duration of action of a single dose may be 12-24 hours. 

Cimetidine reduces theophylline Cl by CYP1A2 inhibition dose-dependently up to 1200 mg/day2 Theophylline metabolism is hardly influenced by ranitidine at therapeutic doses, including high doses up to 4200 mg/day2° "< Similarly, famotidine and nizatidine do not alter theophylline... 

I. Pharmacology. Cimetidine, ranitidine, famotidine, and nizatidine are selective competitive inhibitors of histamine on Hj receptors. These receptors modulate smooth muscle, vascular tone, and gastric secretions and may be involved in clinical effects associated with anaphylactic and anaphylactoid reactions, as well as ingestion of histamine or histamine-like substances (eg, scombroid fish poisoning). Cimetidine, as an inhibitor of cytochrome P-450 enzymes, has been proposed or studied in animals as an agent to block the production of toxic intermediate metabolites (eg, acetaminophen, carbon tetrachloride, halothane. 

Shinn AF. Unrecognized drug interactions with famotidine and nizatidine. Arch Intern Med... 

Ranitidine, famotidine and nizatidine appear not to inhibit liver microsomal enzymes. There is some evidence that ranitidine increases the absorption of triazolam, and possibly other benzodiazepines, due to changes in gastric pH, ° although it has been suggested that this effect is negligi-ble. ° Cimetidine has been said to similarly affect the absorption of diazepam and lorazepam. ... 

The interactions with cimetidine are well established, well documented and of clinical importance. The incidence is uncertain hut most patients could be affected. Those taking amitriptyline, desipramine, doxepin, imi-pramine or nortriptyline who are given cimetidine should be warned that adverse effects such as mouth dryness, urine retention, blurred vision, constipation, tachycardia, postural hypotension may be more likely to occur. Other tricyclic antidepressants would be expected to be similarly affected. If symptoms are troublesome reduce the dosage of the antidepressant (33 to 50% has been suggested) or replace the cimetidine with ranitidine, which does not appear to interact. Other H2-ieceptor antagonists that do not cause enzyme inhibition (e.g. famotidine and nizatidine) would also not be expected to interact. 

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