Pharmacology of Histamine H2-Receptor Antagonists

Histamine H2-Receptor Antagonists
Th ere are two types of histamine receptors: histamine (H1) and histamine (H2). Th e second of these mediates the acid secretion from gastric parietal cells and is inhibited by the H2-receptor-blocking drugs. These drugs may be preferred to other antiulcer agents because of their convenience and lack of effect on GI motility. H2-receptor antagonists are listed in Table 15-2.

Mechanism of Action
Cimetidine was the fi rst H2-receptor antagonist approved for clinical use. It blocks the H2 receptor on the parietal cells of the stomach, thus decreasing gastric acid secretion.

Indications
H2-receptor antagonists are used to promote healing of gastric and duodenal ulcers, and hypersecretory states such as Zollinger-Ellison syndrome. Prototypes of H2-receptor antagonists include cimetidine, famotidine, nizatidine, and ranitidine. Th ey are a remarkably safe group of drugs.

• Cimetidine is available OTC for the treatment of acute gastric ulcer, duodenal ulcer, and gastroesophageal refux. It is also used in the treatment of Zollinger-Ellison syndrome. 

• Famotidine is the most potent H2-receptor antagonist. Aft er a 40-mg dose, mean nocturnal gastric acid secretion is reduced by 94 percent for up to 10 hours. It is recommended for the short-term treatment of mucosal ulcers of the GI tract. Famotidine is absorbed incompletely. It should be used in a lower dosage and at longer dosing intervals in patients with severe renal insuffi ciency. 

• The newest H2-receptor antagonist, nizatidine, may be used to treat and prevent recurrence of duodenal ulcers. It is also used for gastric ulcers, and gastroesophageal refl ux. More than 90 percent of an oral dose is excreted in the urine within 12 hours, and 60 percent as unchanged drug. Therefore, it should be used in reduced dosage in patients with severe renal insuffi ciency.

• Ranitidine is a more potent drug. It is fi ve to ten times more potent than cimetidine. Ranitidine requires a less frequent dosing schedule than cimetidine. It is an H2-receptor antagonist indicated for the short-term treatment of duodenal ulcers and the management of hypersecretory conditions such as Zollinger-Ellison syndrome. Th e pharmacokinetic profi le of ranitidine is similar to that of cimetidine.

Adverse Effects
The list of adverse reactions is long, but the incidence is low. Among the adverse eff ects associated with all four drugs are headache, dizziness, malaise, myalgia, nausea, diarrhea, constipation, rashes, pruritus, and impotence. Adverse effects, such as unusual bleeding, fever, sore throat, hallucinations, or skin rash should be reported promptly, and the therapy must be discontinued.

Contraindications and Precautions
Histamine H2 antagonists should be avoided in patients with a known hypersensitivity, and during lactation or pregnancy. Th ese agents are used cautiously in patients with hepatic or renal dysfunction. Cimetidine is used used cautiously in elderly patients because they may cause confusion, and a dosage reduction may be needed. Cimetidine, famotidine, and ranitidine are pregnancy category B drugs, while nizatidine is a pregnancy category C drug.

All of these drugs should be used cautiously during pregnancy and lactation.

Drug Interactions
Cimetidine increases the risk of decreased white blood cell counts with antimetabolites and alkylating agents. It also increases serum levels and risk of toxicity of warfarin-type anticoagulants, phenytoin, beta-adrenergic blocking agents, alcohol, quinidine, lidocaine, theophylline, chloroquine, and diazepam. Nizatidine increases serum salicylate levels with aspirin. Ranitidine also increases the eff ects of warfarin and toxicity of lidocaine. Ranitidine decreases the eff ectiveness of diazepam and its clearance.