Drugs for Gastrointestinal Tract Disorders

Drugs for Gastrointestinal Tract Disorders

Classification of Drugs for Gastrointestinal Tract Disorders

aAlso cimetidine (TAGAMET), ranitidine (ZANTAC), and nizatidine (AXID).

bAlso rabeprazole (ACIPHEX), pantoprazole (PROTONIX), and esomeprazole (NEXIUM).

cAlso hyoscyamine (LEVSIN), dicyclomine (BENTYL), and scopolamine.

dAlso granisetron (KYTRIL), palonosetron (ALOXI), and dolasetron (ANZEMET).

eAlso promethazine (PHENERGAN) and dimenhydrinate (DRAMAMINE).

Drugs for Peptic Ulcer Disease

Peptic ulcer disease is characterized by epigastric pain, loss of appetite, and weight loss caused by inflamed excavations (ulcers) of the mucosa and underlying tissue of the upper gastrointestinal tract. The ulcers result from damage to the mucous membrane that normally protects the esophagus, stomach, and duodenum from gastric acid and pepsin. This damage is often caused by Helicobacter pylori infection, but nonsteroidal antiinflammatory drugs (NSAIDs) and other factors may cause or contribute to peptic ulcers.

In developed countries, the number of persons who harbor H. pylori increases from under 5% at birth to about 20% at the age of 45 years. Only a small proportion of persons harboring this bacterial organism, however, will develop peptic ulcer disease. Those at greatest risk include individuals who smoke, ingest excessive amounts of alcohol or NSAIDs, are elderly, or have gastrointestinal ischemia. Prolonged use of glucocorticoids can also be a risk factor for peptic ulcer disease.

H. pylori are found in the gastrointestinal tract of almost all patients with duodenal ulcers and about 80% of patients with gastric ulcers. H. pylori–induced gastritis is believed to precede the development of peptic ulcers in most persons. The organism attaches to epithelial cells and releases enzymes that damage mucosal cells and cause inflammation and tissue destruction. Eradication of H. pylori heals most peptic ulcers and significantly reduces the recurrence rate for gastric and duodenal ulcers.

The agents used to treat peptic ulcer disease include drugs that eliminate H. pylori, drugs that reduce gastric acidity, and drugs that exert a cytoprotective effect on the gastrointestinal mucosa.

Drugs That Reduce Gastric Acidity

The physiology of gastric acid secretion and sites of drug action are illustrated in Figure 28-1.

The principal physiologic stimulants of gastric acid secretion are gastrin, acetylcholine, and histamine. Gastrin is a hormone secreted by G cells in the gastric antrum, whereas acetylcholine is released from vagus nerve terminals. Gastrin and acetylcholine directly stimulate acid secretion by parietal cells, and they also stimulate the release of histamine from paracrine (enterochromaffin-like) cells. Histamine stimulates H2 receptors located on parietal cells and provokes acid secretion via cyclic adenosine monophosphate (cAMP) stimulation of the proton pump (H+,K+-ATPase).

The vagus nerve mediates the cephalic phase of gastric acid secretion evoked by the smell, taste, and thought of food. Gastrin mediates the gastric phase of acid secretion evoked by the presence of food in the stomach. Histamine contributes to the cephalic and gastric phases of acid secretion, and it also mediates basal acid secretion in the fasting state.

The level of gastric acidity can be reduced either by neutralizing gastric acid with antacids or by inhibiting gastric acid secretion with a histamine H2 receptor antagonist or a proton pump inhibitor (PPI).

Histamine H2 Receptor Antagonists

The H2 receptor antagonists, or H2 blockers, include cimetidine, famotidine, ranitidine, and nizatidine.

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.


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.


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.

Proton Pump Inhibitors

The PPIs include esomeprazole, omeprazole, pantoprazole, and rabeprazole.

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).


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.

Gastric Antacids

Gastric antacids chemically neutralize stomach acid. This raises the gastrointestinal pH sufficiently to relieve the pain of dyspepsia and acid indigestion and to enable peptic ulcers to heal. The most commonly used antacids are aluminum and magnesium hydroxides and calcium carbonate. These substances are available in chewable tablets and in liquid suspensions. When used alone, aluminum hydroxide can cause constipation, whereas magnesium hydroxide often causes diarrhea. For this reason, the combination of aluminum and magnesium hydroxides usually has a relatively neutral effect on gastrointestinal motility. Calcium carbonate can also cause constipation, and large doses of calcium carbonate can lead to a rebound in acid secretion.

Antacids are available without a prescription and are commonly used to treat acid indigestion and dyspepsia. Nonprescription products containing a low dose of a histamine H2 antagonist and an antacid are also available for this purpose. Antacids were formerly used to treat peptic ulcers, but they must be taken in large doses at frequent intervals for this purpose, and nocturnal acid secretion is particularly difficult to control with antacids. Hence, they are seldom used in treating peptic ulcer today.

Cytoprotective Drugs

Sucralfate and misoprostol both protect the gastrointestinal mucosa, but they do so by different means (see Fig. 28-1).



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.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Drugs for Gastrointestinal Tract Disorders

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