Chemistry, Mechanisms, and Effects

The structure of H₂ blockers is similar to that of histamine (Fig. 28-2), and this enables the drugs to compete with histamine for binding to H₂ receptors on gastric parietal cells (see Fig. 28-1). The H₂ blockers have been shown to be potent inhibitors of both meal-stimulated secretion and basal secretion of gastric acid. When they reduce the volume and concentration of gastric acid, they produce a proportionate decrease in the production of pepsin because gastric acid catalyzes the conversion of inactive pepsinogen to pepsin. The H₂ blockers also reduce the secretion of intrinsic factor, but not enough to significantly reduce vitamin B₁₂ absorption. They have no effect on gastric emptying time, esophageal sphincter pressure, or pancreatic enzyme secretion.

Pharmacokinetics

The H₂ blockers are well absorbed from the gut and undergo varying degrees of hepatic inactivation before being excreted in the urine. Although the half-life of most H₂ blockers is only 2 to 3 hours, their duration of action is considerably longer (Table 28-1), and these drugs are usually administered once or twice daily.

Indications

The H₂ blockers are used to treat conditions associated with excessive acid production, including dyspepsia, peptic ulcer disease, and gastroesophageal reflux disease (GERD). An H₂ blocker is also occasionally used in combination with an H₁ blocker for the treatment of allergic reactions that do not respond when an H₁ blocker is used alone.

Dyspepsia, or heartburn, is characterized by epigastric discomfort after meals. It is often associated with impaired digestion and excessive stomach acidity. Several low-dose formulations of H₂ receptor antagonists are available as nonprescription drugs for the prevention and treatment of dyspepsia. These formulations are most effective when taken 30 minutes before ingestion of a dyspepsia-provoking meal.

For the treatment of peptic ulcer disease, H₂ blockers are administered once or twice daily at doses that raise the gastric pH above 4 for at least 13 hours a day. Most authorities recommend giving a single daily dose at bedtime to ensure that acid secretion is suppressed all night. PPIs are usually preferred for treating peptic ulcer disease because they heal almost 90% of ulcers in 4 weeks (when used alone), whereas H₂ blockers require 6 to 8 weeks to achieve this level of efficacy.

Adverse Effects and Interactions

Cimetidine has weak antiandrogenic activity and can cause gynecomastia in elderly men, but this reaction is uncommon with other H₂ blockers. The fact that the H₂ blockers have proved remarkably nontoxic has led to their approval as nonprescription drugs.

Cimetidine is a well-known inhibitor of cytochrome P450 isozymes CYP2C9, CYP2D6, and CYP3A4. These isozymes are involved in the metabolism of numerous drugs, including alprazolam, carbamazepine, cisapride, disopyramide, felodipine, lovastatin, phenytoin, saquinavir, triazolam, and warfarin. The dosage of these drugs may need to be reduced in patients taking cimetidine. Other H₂ blockers do not inhibit P450 enzymes significantly and are preferred for patients receiving concomitant drug therapy.

Chemistry and Pharmacokinetics

The PPIs are acid-labile prodrugs that are administered orally as sustained-release, enteric-coated preparations. After they are absorbed from the gut, the drugs are distributed to the secretory canaliculi in the gastric mucosa and converted to active metabolites that bind to the proton pump. These drugs are eventually metabolized to inactive compounds in the liver, primarily by cytochrome P450 CYP2C19, and these compounds are excreted in the urine and feces. Persons with the CYP2C19 extensive (rapid) and ultrarapid metabolizer phenotypes may require higher doses of PPIs to cure peptic ulcer.

Mechanisms and Effects

The active metabolites of PPIs form a covalent disulfide link with a cysteinyl residue in the proton pump (H⁺,K⁺-ATPase) found in the luminal membrane of gastric parietal cells (see Fig. 28-1). The drugs irreversibly inhibit the proton pump and prevent the secretion of gastric acid for an extended period. The drugs can produce a dose-dependent inhibition of up to 95% of gastric acid secretion, and a single dose can inhibit acid secretion for 1 to 2 days. Hence the PPIs are more efficacious than the H₂ blockers for most conditions (see Table 28-1).

Indications

PPIs are highly effective in treating peptic ulcer disease. They typically heal 80% to 90% of peptic ulcers in 2 weeks or less when used in combination with antibiotics, whereas H₂-blocker combinations heal 70% to 80% in 4 weeks.

PPIs are the drugs of choice for patients with Zollinger-Ellison syndrome, a condition characterized by severe ulcers resulting from gastrin-secreting tumors (gastrinomas). Higher doses are required for treating patients with this condition than for treating patients with typical peptic ulcer disease.

PPIs are also the most effective drugs for treating GERD. Omeprazole is available without prescription for the treatment of dyspepsia and heartburn. Finally, PPIs can be used to prevent peptic ulcers and bleeding in persons receiving high-dose or long-term therapy with NSAIDs such as diclofenac.

Adverse Effects

PPIs are usually well tolerated. Minor gastrointestinal and central nervous system (CNS) side effects have occurred in some patients, and skin rash and elevated hepatic enzyme levels have also been reported. Many patients with GERD have been treated for several years without significant side effects. However, hypomagnesemia (low blood magnesium levels) has been reported in persons taking the drug for over a year.

Sucralfate

Misoprostol

As discussed in Chapter 26, misoprostol is a prostaglandin E₁ analogue. The drug exerts a cytoprotective effect by inhibiting gastric acid secretion and promoting the secretion of mucus and bicarbonate. It is primarily indicated for the prevention of gastric and duodenal ulcers in patients who are taking NSAIDs on a long-term basis for the treatment of arthritis and other conditions. Because misoprostol is expensive, it is usually reserved for patients at high risk of NSAID-induced ulcers, including the elderly and those with a history of peptic ulcer disease.

Misoprostol is administered orally four times daily with food for the duration of NSAID therapy. Diarrhea and intestinal cramping are the most common adverse effects, but other gastrointestinal reactions can also occur.

Misoprostol can stimulate uterine contractions and induce labor in pregnant women, so its use is contraindicated during pregnancy.