Drugs for peptic ulcer disease

The term peptic ulcer disease (PUD) refers to a group of upper GI disorders characterized by varying degrees of erosion of the gut wall. Severe ulcers can be complicated by hemorrhage and perforation. Although peptic ulcers can develop in any region exposed to acid and pepsin, ulceration is most common in the lesser curvature of the stomach and the duodenum. PUD is a common disorder that affects about 10% of Americans at some time in their lives. About 500,000 Americans get ulcers each year. Prior to the mid-1990s, PUD was considered a chronic, relapsing disorder of unknown cause and with no known cure; therapy promoted healing but did not prevent ulcer recurrence. Today, thanks to the pioneering work of two Australians—Barry J. Marshall and J. Robin Warren—we know that most cases of PUD are caused by infection with Helicobacter pylori, and that eradication of this bacterium not only promotes healing, but greatly reduces the chance of recurrence.

Pathogenesis of peptic ulcers

Peptic ulcers develop when there is an imbalance between mucosal defensive factors and aggressive factors (Fig. 78–1). The major defensive factors are mucus and bicarbonate. The major aggressive factors are H. pylori, nonsteroidal anti-inflammatory drugs (NSAIDs), gastric acid, and pepsin.

Figure 78–1 The relationship of mucosal defenses and aggressive factors to health and peptic ulcer disease.
When aggressive factors outweigh mucosal defenses, gastritis and peptic ulcers result. (NSAIDs = nonsteroidal anti-inflammatory drugs.)

Aggressive factors

Helicobacter pylori.

Helicobacter pylori is a gram-negative bacillus that can colonize the stomach and duodenum. By taking up residence in the space between epithelial cells and the mucus barrier that protects these cells, the bacterium manages to escape destruction by acid and pepsin. Once established, H. pylori can remain in the GI tract for decades. Although about half of the world’s population is infected with H. pylori, most infected people never develop symptomatic PUD.

Why do we think H. pylori causes PUD? First, between 60% and 75% of patients with PUD have H. pylori infection. Second, duodenal ulcers are much more common among people with H. pylori infection than among people who are not infected. Third, eradication of the bacterium promotes ulcer healing. And fourth, eradication of the bacterium minimizes ulcer recurrence. (One-year recurrence rates approach 80% when H. pylori remains present, compared with only 10% when the organism is gone.)

Although the mechanism by which H. pylori promotes ulcers has not been firmly established, likely possibilities are enzymatic degradation of the protective mucus layer, elaboration of a cytotoxin that injures mucosal cells, and infiltration of neutrophils and other inflammatory cells in response to the bacterium’s presence. Also, H. pylori produces urease, an enzyme that forms carbon dioxide and ammonia (from urea in gastric juice); both compounds are potentially toxic to the gastric mucosa.

In addition to its role in PUD, H. pylori appears to promote gastric cancer. In fact, the bacterium has been declared a type 1 carcinogen (a definite cause of human cancer) by the International Agency for Research on Cancer. There is a strong association between H. pylori infection and the presence of gastric mucosa-associated lymphoid tissue (MALT) lymphomas. Furthermore, among patients with localized MALT lymphoma, eradicating H. pylori produces tumor regression in 60% to 90% of cases. Whether treatment for H. pylori reduces the risk of gastric adenocarcinoma is unclear.

Nonsteroidal anti-inflammatory drugs.

NSAIDs are the underlying cause of many gastric ulcers and some duodenal ulcers. As discussed in Chapter 71, aspirin and other NSAIDs inhibit the biosynthesis of prostaglandins. By doing so, they can decrease submucosal blood flow, suppress secretion of mucus and bicarbonate, and promote secretion of gastric acid. Furthermore, NSAIDs can irritate the mucosa directly. NSAID-induced ulcers are most likely with long-term, high-dose therapy.

Gastric acid.

Gastric acid is an absolute requirement for peptic ulcer generation: In the absence of acid, no ulcer will form. Acid causes ulcers directly by injuring cells of the GI mucosa and indirectly by activating pepsin, a proteolytic enzyme. In most cases, acid hypersecretion, by itself, is insufficient to cause ulcers. In fact, in most patients with gastric ulcers, acid secretion is normal or reduced, and among patients with duodenal ulcers, only one-third produce excessive amounts of acid. From these observations, we can conclude that, in the majority of patients with peptic ulcers, factors in addition to acid must be involved.

Zollinger-Ellison syndrome is the primary disorder in which hypersecretion of acid alone causes ulcers. The syndrome is caused by a tumor that secretes gastrin, a hormone that stimulates gastric acid production. The amount of acid produced is so large that it overwhelms mucosal defenses. Zollinger-Ellison syndrome is a rare disorder that accounts for only 0.1% of duodenal ulcers.

Pepsin.

Pepsin is a proteolytic enzyme present in gastric juice. Like gastric acid, pepsin can injure unprotected cells of the gastric and duodenal mucosa.

Smoking.

Smoking delays ulcer healing and increases the risk of recurrence. Possible mechanisms include reduction of the beneficial effects of antiulcer medications, reduced secretion of bicarbonate, and accelerated gastric emptying, which would deliver more acid to the duodenum.

Summary

Infection with H. pylori is the most common cause of gastric and duodenal ulcers. However, among people whose PUD can be ascribed to H. pylori, additional factors must be involved. Why? Because more than 50% of the population harbors H. pylori, but only 10% develop ulcers. Factors that may increase the risk of PUD in people infected with H. pylori include smoking, increased acid secretion, and reduced bicarbonate production. The second most common cause of gastric ulcers is NSAIDs. Hypersecretion of acid underlies a few cases of PUD that are not caused by H. pylori or NSAIDs.

Overview of treatment

Drug therapy

The goal of drug therapy is to (1) alleviate symptoms, (2) promote healing, (3) prevent complications (hemorrhage, perforation, obstruction), and (4) prevent recurrence. With the exception of antibiotics, the drugs employed do not alter the disease process. Rather, they simply create conditions conducive to healing. Since nonantibiotic therapies do not cure ulcers, the relapse rate following their discontinuation is high. In contrast, the relapse rate following antibiotic therapy is low.

Classes of antiulcer drugs

As shown in Table 78–1, the antiulcer drugs fall into five major groups:

TABLE 78–1

Classification of Antiulcer Drugs

Class	Drugs	Mechanism of Action
Antibiotics	Amoxicillin [Amoxil]	Eradicate H. pylori
	Bismuth [Pepto-Bismol]
	Clarithromycin [Biaxin]
	Metronidazole [Flagyl]
	Tetracycline [Achromycin V]
	Tinidazole [Tindamax]
Antisecretory Agents
H₂ receptor antagonists	Cimetidine [Tagamet]	Suppress acid secretion by blocking H₂ receptors on parietal cells
	Famotidine [Pepcid]
	Nizatidine [Axid]
	Ranitidine [Zantac]
Proton pump inhibitors	Dexlansoprazole [Dexilant]	Suppress acid secretion by inhibiting H⁺, K⁺-ATPase, the enzyme that makes gastric acid
	Esomeprazole [Nexium]
	Lansoprazole [Prevacid]
	Omeprazole [Prilosec, Zegerid, Losec]
	Pantoprazole [Protonix, Pantoloc]
	Rabeprazole [Aciphex, Pariet]
Mucosal Protectant	Sucralfate [Carafate, Sulcrate]	Forms a barrier over the ulcer crater that protects against acid and pepsin
Antisecretory Agent That Enhances Mucosal Defenses	Misoprostol [Cytotec]	Protects against NSAID-induced ulcers by stimulating secretion of mucus and bicarbonate, maintaining submucosal blood flow, and suppressing secretion of gastric acid
Antacids	Aluminum hydroxide	React with gastric acid to form neutral salts
	Calcium carbonate
	Magnesium hydroxide

• Antibiotics

• Antisecretory agents (proton pump inhibitors, histamine₂ receptor antagonists)

• Mucosal protectants

• Antisecretory agents that enhance mucosal defenses

• Antacids

From this classification, we can see that drugs act in three basic ways to promote ulcer healing. Specifically, they can (1) eradicate H. pylori (antibiotics do this), (2) reduce gastric acidity (antisecretory agents, misoprostol, and antacids do this), and (3) enhance mucosal defenses (sucralfate and misoprostol do this).

Drug selection

Helicobacter pylori–associated ulcers.

In 1997, a National Institutes of Health Consensus Development Conference recommended that all patients with gastric or duodenal ulcers and documented H. pylori infection be treated with antibiotics. This recommendation applies to patients with newly diagnosed PUD, recurrent PUD, and PUD in which use of NSAIDs is a contributing factor. To hasten healing and relieve symptoms, an antisecretory agent should be given along with the antibiotics. By eliminating H. pylori, antibiotics can cure PUD, and can thereby prevent recurrence. Diagnosis of H. pylori infection and specific antibiotic regimens are discussed below under Antibacterial Drugs.

NSAID-induced ulcers.

Prophylaxis.

For patients with risk factors for ulcer development (eg, age over 60, history of ulcers, high-dose NSAID therapy), prophylactic therapy is indicated. Proton pump inhibitors (eg, omeprazole) are preferred. Misoprostol is also effective, but can cause diarrhea. Antacids, sucralfate, and histamine₂ receptor blockers are not recommended.

Treatment.

NSAID-induced ulcers can be treated with any ulcer medication. However, histamine₂ receptor blockers and proton pump inhibitors are preferred. If possible, the offending NSAID should be discontinued, so as to accelerate healing. If the NSAID cannot be discontinued, a proton pump inhibitor is the best choice to promote healing.

Evaluation

We can evaluate ulcer healing by monitoring for relief of pain and by radiologic or endoscopic examination of the ulcer site. Unfortunately, evaluation is seldom straightforward. Why? Because cessation of pain and disappearance of the ulcer rarely coincide: In most cases, pain subsides prior to complete healing. However, the converse may also be true: Pain may persist even though endoscopic or radiologic examination reveals healing is complete.

Eradication of H. pylori can be determined with several methods, including breath tests, serologic tests, stool tests, and microscopic observation of a stained biopsy sample. These methods are discussed below under Tests for Helicobacter pylori.

A note about the effects of drugs on pepsin

Pepsin is a proteolytic enzyme that can contribute to ulcer formation. The enzyme promotes ulcers by breaking down protein in the gut wall.

Like most enzymes, pepsin is sensitive to pH. As pH rises from 1.3 (the usual pH of the stomach) to 2, peptic activity increases by a factor of 4. As pH goes even higher, peptic activity begins to decline. At a pH of 5, peptic activity drops below baseline rates. When pH exceeds 6 to 7, pepsin undergoes irreversible inactivation.

Because the activity of pepsin is pH dependent, drugs that elevate gastric pH (eg, antacids, histamine₂ antagonists, proton pump inhibitors) can cause peptic activity to increase, thereby enhancing pepsin’s destructive effects. For example, treatment that produces a 99% reduction in gastric acidity will cause pH to rise from a base level of 1.3 up to 3.3. At pH 3.3, peptic activity will be significantly increased. To avoid activation of pepsin, drugs that reduce acidity should be administered in doses sufficient to raise gastric pH above 5.

Nondrug therapy

Optimal antiulcer therapy requires implementation of nondrug measures in addition to drug therapy.

Diet.

Despite commonly held beliefs, diet plays a minor role in ulcer management. The traditional “ulcer diet,” consisting of bland foods together with milk or cream, does not accelerate healing. Furthermore, there is no convincing evidence that caffeine-containing beverages (coffee, tea, colas) promote ulcer formation or interfere with recovery. A change in eating pattern may be beneficial: Consumption of five or six small meals a day, rather than three larger ones, can reduce fluctuations in intragastric pH, and may thereby facilitate recovery.

Other nondrug measures.

Smoking is associated with an increased incidence of ulcers and also retards recovery. Accordingly, cigarettes should be avoided. Because of their ulcerogenic actions, aspirin and other NSAIDs should be avoided by patients with PUD. The exception to this rule is use of aspirin to prevent cardiovascular disease; in the low doses employed, aspirin is only a small factor in PUD. There are no hard data indicating that alcohol contributes to PUD. However, if the patient notes a temporal relationship between alcohol consumption and exacerbation of symptoms, then alcohol use should stop. Many people feel that reduction of stress and anxiety may encourage ulcer healing; however, there is no good evidence that this is true.

Antibacterial drugs

Antibacterial drugs should be given to all patients with gastric or duodenal ulcers and confirmed infection with H. pylori. Antibiotics are not recommended for asymptomatic individuals who test positive for H. pylori.

Tests for helicobacter pylori

Several tests for H. pylori are available. Some are invasive; some are not. The invasive tests require an endoscopically obtained biopsy sample, which can be evaluated in three ways: (1) staining and viewing under a microscope to see if H. pylori is present; (2) assaying for the presence of urease (a marker enzyme for H. pylori); and (3) culturing and then assaying for the presence of H. pylori.

In the United States, three types of noninvasive tests are available: breath, serologic, and stool tests. In the breath test, patients are given radiolabeled urea. If H. pylori is present, the urea is converted to carbon dioxide and ammonia; radiolabeled carbon dioxide can then be detected in the breath. In the serologic test, blood samples are evaluated for antibodies to H. pylori. In the stool test, fecal samples are evaluated for the presence of H. pylori antigens.

Antibiotics employed

The antibiotics employed most often are clarithromycin, amoxicillin, bismuth, metronidazole, and tetracycline. None is effective alone. Furthermore, if these drugs are used alone, the risk of developing resistance is increased.

Clarithromycin.

Clarithromycin [Biaxin] suppresses growth of H. pylori by inhibiting protein synthesis. In the absence of resistance, treatment is highly effective. Unfortunately, the rate of resistance is rising, exceeding 20% in some areas. The most common side effects are nausea, diarrhea, and distortion of taste. The basic pharmacology of clarithromycin is presented in Chapter 86.

Amoxicillin.

Helicobacter pylori is highly sensitive to amoxicillin. The rate of resistance is low, only about 3%. Amoxicillin kills bacteria by disrupting the cell wall. Antibacterial activity is highest at neutral pH, and hence can be enhanced by reducing gastric acidity with an antisecretory agent (eg, omeprazole). The most common side effect is diarrhea. The basic pharmacology of amoxicillin is discussed in Chapter 84.

Bismuth.

Bismuth compounds—bismuth subsalicylate and bismuth subcitrate—act topically to disrupt the cell wall of H. pylori, thereby causing lysis and death. Bismuth may also inhibit urease activity and may prevent H. pylori from adhering to the gastric surface.

Bismuth can impart a harmless black coloration to the tongue and stool. Patients should be forewarned. Stool discoloration may confound interpretation of gastric bleeding. Long-term therapy may carry a risk of neurologic injury.

Tetracycline.

Tetracycline, an inhibitor of bacterial protein synthesis, is highly active against H. pylori. Resistance is rare (less than 1%). Because tetracycline can stain developing teeth, it should not be used by pregnant women or young children. The pharmacology of tetracycline is discussed in Chapter 86.

Metronidazole.

Metronidazole [Flagyl] is very effective against sensitive strains of H. pylori. Unfortunately, over 40% of strains are now resistant. The most common side effects are nausea and headache. A disulfiram-like reaction can occur if metronidazole is used with alcohol, and hence alcohol must be avoided. Metronidazole should not be taken during pregnancy. The basic pharmacology of metronidazole is discussed in Chapter 99.

Tinidazole.

Tinidazole [Tindamax] is very similar to metronidazole, and shares that drug’s adverse effects and interactions. Like metronidazole, tinidazole can cause a disulfiram-like reaction, and hence must not be combined with alcohol. The basic pharmacology of tinidazole is discussed in Chapter 99.

Antibiotic regimens

In 2007, the American College of Gastroenterology (ACG) issued updated guidelines for managing H. pylori infection. To minimize emergence of resistance, the guidelines recommend using at least two antibiotics, and preferably three. An antisecretory agent—proton pump inhibitor (PPI) or histamine₂ receptor antagonist (H₂RA)—should be included as well. Eradication rates are good with a 10-day course, and slightly better with a 14-day course.

Table 78–2 presents four ACG-recommended regimens. In regions where resistance to clarithromycin is low (below 20%), the preferred treatment is clarithromycin-based triple therapy, consisting of clarithromycin plus amoxicillin plus a PPI. For patients with penicillin allergy, metronidazole can be substituted for amoxicillin. In regions where resistance to clarithromycin is high (above 20%), the preferred regimen is bismuth-based quadruple therapy, consisting of bismuth subsalicylate plus metronidazole plus tetracycline, all three combined with a PPI or an H₂RA. For patients who can’t use triple therapy or quadruple therapy, sequential therapy is an option. This regimen consists of taking a PPI plus amoxicillin for 5 days, followed by a PPI plus clarithromycin plus tinidazole for 5 days. At this time, the efficacy of sequential therapy in North America has not been established.

TABLE 78–2

First-Line Regimens for Eradicating H. pylori

Drugs	Duration (days)	Eradication Rate (%)	Comments
Clarithromycin-Based Triple Therapy 1	10–14	70–85	Consider in non–penicillin-allergic patients who have not previously received clarithromycin or another macrolide
Standard-dose PPI*
Clarithromycin (500 mg twice daily)
Amoxicillin (1 gm twice daily)
Clarithromycin-Based Triple Therapy 2	10–14	70–85	Consider in penicillin-allergic patients who have not previously received a macrolide or are unable to tolerate bismuth quadruple therapy
Standard-dose PPI*
Clarithromycin (500 mg twice daily)
Metronidazole (500 mg twice daily)
Bismuth-Based Quadruple Therapy	10–14	75–90	Consider in penicillin-allergic patients, and in patients with clarithromycin-resistant H. pylori
Bismuth subsalicylate (525 mg 4 times daily)
Metronidazole (250 mg 4 times daily)
Tetracycline (500 mg 4 times daily)
Standard-dose PPI* or ranitidine (150 mg twice daily)
Sequential Therapy	10	Over 90	Efficacy in North America requires validation
Standard-dose PPI* + amoxicillin (1 gm twice daily) for 5 days, followed by:
Standard-dose PPI* + clarithromycin (500 mg once daily) + tinidazole (500 mg twice daily) for 5 days

^*Standard doses for PPIs are as follows: dexlansoprazole, 30 to 60 mg once daily; esomeprazole, 40 mg once daily; lansoprazole, 30 mg twice daily; omeprazole, 40 mg twice daily; pantoprazole, 40 mg twice daily; and rabeprazole 20 mg twice daily.

Adapted from Chey WD, Wong BCY, and Practice Parameters Committee of the American College of Gastroenterology: American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 102:1808–1825, 2007.

For several reasons, compliance with antibiotic therapy can be difficult. First, antibiotic regimens are complex, requiring the patient to ingest as many as 12 pills a day. Second, side effects—especially nausea and diarrhea—are common. Third, a course of treatment is somewhat expensive (about $200). However, it costs much less to eradicate H. pylori with antibiotics than it does to treat ulcers over and over again with traditional antiulcer drugs, which merely promote healing without eliminating the cause.

Histamine₂ receptor antagonists

The histamine₂ receptor antagonists (H₂RAs) are effective drugs for treating gastric and duodenal ulcers. These agents promote ulcer healing by suppressing secretion of gastric acid. Four H₂RAs are available: cimetidine, ranitidine, famotidine, and nizatidine. All four are equally effective. Serious side effects are uncommon.

Cimetidine

Cimetidine [Tagamet], introduced in 1977, was the first H₂RA available and will serve as our prototype for the group. At one time, cimetidine was the most frequently prescribed drug in the United States. Cimetidine was the first drug with sales over $1 billion, making it our first “blockbuster” drug.

Mechanism of action

As discussed in Chapter 70, histamine acts through two types of receptors, named H₁ and H₂. Activation of H₁ receptors produces symptoms of allergy. Activation of H₂ receptors, which are located on parietal cells of the stomach (Fig. 78–2), promotes secretion of gastric acid. By blocking H₂ receptors, cimetidine reduces both the volume of gastric juice and its hydrogen ion concentration. Cimetidine suppresses basal acid secretion and secretion stimulated by gastrin and acetylcholine. Because cimetidine produces selective blockade of H₂ receptors, the drug cannot suppress symptoms of allergy.