Adverse Effects And Drug Interactions

Proton pump inhibitors generally cause remarkably few adverse effects. The most common are nausea, abdominal pain, constipation, flatulence, and diarrhea. Subacute myopathy, arthralgias, headaches, and rashes also have been reported. Proton pump inhibitors can interact with warfarin (esomeprazole, lansoprazole, omeprazole, and rabeprazole), diazepam (esomeprazole and omeprazole), and cyclosporine (omeprazole and rabeprazole). Omeprazole inhibits CYP2C19 (thereby decreasing the clearance of disulfiram, phenytoin, and other drugs) and induces the expression of CYP1A2 (thereby increasing the clearance of imipramine, several antipsychotic drugs, tacrine, and theophylline).

Loss of gastric acidity from chronic proton pump inhibitor treatment may affect the bioavailability of such drugs as ketoconazole, ampicillin esters, and iron salts. Chronic therapy, with proton pump inhibitors has been linked to increased frequency of hip fractures, possibly secondary to decreased absorption of calcium.

Hypergastrinemia is more frequent and more severe with proton pump inhibitors than with H2 receptor antagonists, and gastrin levels of >500 ng/L occur in ~5—10% of users with chronic omeprazole administration. This hypergastrinemia may predispose to rebound hypersecretion of gastric acid upon drug discontinuation (see below). The proton pump inhibitors have a long record of use worldwide without the emergence of major safety concerns.

THERAPEUTIC USES Proton pump inhibitors are used principally to promote healing of gastric and duodenal ulcers and to treat gastroesophageal reflux disease (GERD), including erosive esophagitis, that is either complicated or unresponsive to treatment with H2 receptor antagonists. Proton pump inhibitors also are the mainstay in the treatment of pathological hypersecretory conditions, such as the Zollinger-Ellison syndrome. Lansoprazole is FDA-approved for treatment and prevention of recurrence of nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers in patients who continue NSAID use and for reducing the risk of duodenal ulcer recurrence associated with H. pylori infections.

In children, omeprazole is safe and effective for treatment of erosive esophagitis and GERD. Younger patients generally have increased metabolic capacity, resulting in the need for higher dosages of omeprazole per kilogram in children compared to adults.

h2 receptor antagonists

The H2 receptor antagonists were the first truly effective drugs for the therapy of acid-peptic disease, and their long history of safety and efficacy with the eventually led to their availability without a prescription. Increasingly, proton pump inhibitors (some also available OTC) are replacing the H2 receptor antagonists in clinical practice.

CHEMISTRY; MECHANISM OF ACTION; PHARMACOLOGY The H2 receptor antagonists inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells. Four different H2 receptor antagonists, which differ mainly in their pharmacokinetics and propensity to cause drug interactions, are available in the U.S. (Figure 36-3): cimetidine (tagamet), ranitidine (Zantac), famotidine (pepcid), and nizatidine (axid). These drugs are less potent than proton pump inhibitors but still suppress 24-hour gastric acid secretion by ~70%. The H2 receptor antagonists predominantly inhibit basal acid secretion, which accounts for their efficacy in suppressing nocturnal acid secretion. Because the most important determinant of duodenal ulcer healing is the level of nocturnal acidity, evening dosing of H2 receptor antagonists is adequate therapy in most instances.

All four H2 receptor antagonists are available as prescription and over-the-counter formulations for oral administration. Intravenous and intramuscular preparations of cimetidine, ranitidine, and famotidine also are available. When the oral or nasogastric routes are not an option, these drugs can be given in intermittent intravenous boluses or by continuous intravenous infusion.

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