H2Receptor Antagonists

The histamine receptor antagonists (H2 blockers) marketed in the United States are cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid). These agents bind to the H2-receptors on the cell membranes of parietal cells and prevent histamine-induced stimulation of gastric acid secretion. After prolonged use, down-regulation of receptor production occurs, resulting in tolerance to these agents. H2-blockers are approved for the treatment of gastroesophageal reflux disease, acute ulcer healing, and post-ulcer healing maintenance therapy. Although there are substantial differences in their relative potency, 70 to 85% of duodenal ulcers are healed during 4 to 6 weeks of therapy with any of these agents. The incidence of healing of gastric ulceration after 6 to 8 weeks of therapy approaches 60 to 80% with the use of cimetidine or raniti-dine. Since nocturnal suppression of acid secretion is particularly important in healing, nighttime-only dosing can be used. Most are available in low-dose over-the-counter formulations.

Cimetidine, the first released H2-blocker, like hista-mine, contains an imidazole ring structure. It is well absorbed following oral administration, with peak blood levels 45 to 90 minutes after drug ingestion. Blood levels remain within therapeutic concentrations for approximately 4 hours after a 300-mg dose. Following oral administration, 50 to 75% of the parent compound is excreted unchanged in the urine; the rest appears primarily as the sulfoxide metabolite.

Cimetidine may infrequently cause diarrhea, nausea, vomiting, or mental confusion. A rare association with granulocytopenia, thrombocytopenia, and pancy-topenia has been reported. Gynecomastia has been demonstrated in patients receiving either high-dose or long-term therapy. This occurs because cimetidine has a weak antiestrogen effect. Since cimetidine is partly metabolized by the cytochrome P450 system, coadminis-tered drugs such as the benzodiazepines, theophylline, and warfarin, which are also metabolized by this system, may accumulate if their dosage is not adjusted.

Ranitidine is well absorbed after oral administration, with a peak plasma level achieved 1 to 3 hours after ingestion. Elimination is by renal (25%) and hepatic (50%) routes. The half-life of elimination is 2.5 to 3.0 hours. Nizatidine is the newest H2-receptor antagonist. Similar to ranitidine, it has a relative potency twice that of cimetidine. About 90% of an oral dose is absorbed, with a peak plasma concentration occurring after 0.5 to 3 hours; inhibition of gastric secretion is present for up to 10 hours. The elimination half-life is 1 to 2 hours, and more than 90% of an oral dose is excreted in the urine. Famotidine has an onset of effect within 1 hour after oral administration, and inhibition of gastric secretion is present for the next 10 to 12 hours. It is the most potent H2-blocker. Elimination is by renal (65-70%) and hepatic (30-35%) routes. Ranitidine, famotidine, and niza-tidine do not alter the microsomal cytochrome P450 metabolism of other drugs, nor do they cause gyneco-mastia. A reduction in dosage of any of the H2-blockers is recommended in the presence of renal insufficiency.

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