Defensive Factors
Defensive factors serve the physiologic role of protecting the stomach and duodenum from self-digestion. When defenses are intact, ulcers are unlikely. Conversely, when defenses are compromised, aggressive factors are able to cause injury. Two important agents that can weaken defenses are H. pylori and NSAIDs.
Mucus
Mucus is secreted continuously by cells of the GI mucosa, forming a barrier that protects underlying cells from attack by acid and pepsin.
Bicarbonate
Bicarbonate is secreted by epithelial cells of the stomach and duodenum. Most bicarbonate remains trapped in the mucus layer, where it serves to neutralize any hydrogen ions that penetrate the mucus. Bicarbonate produced by the pancreas is secreted into the lumen of the duodenum, where it neutralizes acid delivered from the stomach.
Blood Flow
Sufficient blood flow to cells of the GI mucosa is essential for maintaining mucosal integrity. If submucosal blood flow is reduced, the resultant local ischemia can lead to cell injury, thereby increasing vulnerability to attack by acid and pepsin.
Prostaglandins
Prostaglandins play an important role in maintaining defenses. These compounds stimulate secretion of mucus and bicarbonate, and they promote vasodilation, which helps maintain submucosal blood flow. They provide additional protection by suppressing secretion of gastric acid.
Aggressive Factors
Helicobacter pylori
H. 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. When 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 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. In one long-term study, treatment of H. pylori reduced the risk for gastric adenocarcinoma by 40% after 15 years.
Nonsteroidal Antiinflammatory Drugs
NSAIDs are the underlying cause of many gastric ulcers and some duodenal ulcers. As discussed in Chapter 55, 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 most 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 for 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 because more than 50% of the population harbors H. pylori but only 10% develop ulcers. Factors that may increase the risk for 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 goals of drug therapy are 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. Because nonantibiotic therapies do not cure ulcers, the relapse rate after their discontinuation is high. In contrast, the relapse rate after antibiotic therapy is low.
Classes of Antiulcer Drugs
As shown in Table 62.1, the antiulcer drugs fall into five major groups:
• Antisecretory agents (proton pump inhibitors [PPIs], histamine-2 [H2] receptor antagonists)
• Antisecretory agents that enhance mucosal defenses
TABLE 62.1
Classification of Antiulcer Drugs
| Class | Drugs | Availability | Usual Daily Adult Dosing | Mechanism of Action |
| Antibiotics | Amoxicillin [Amoxil] | 500-mg capsules | 2000 mg | Eradicate Helicobacter pylori |
| Bismuth [Pepto-Bismol] | 262.4-mg tablets | 3000 mg | ||
| Clarithromycin [Biaxin] | 500-mg tablets | 1000 mg | ||
| Metronidazole [Flagyl] | 125-mg tablets | 1000 mg | ||
| Tetracycline (generic only) | 125-mg tablets | 1500 mg | ||
| Tinidazole [Tindamax] | 500-mg tablets | 1000 mg | ||
| ANTISECRETORY AGENTS | ||||
| H2 receptor antagonists | Cimetidine [Tagamet] | 200-, 300-, 400-, 800-mg tablets 300-mg/mL solution | 800 mg Lower dose with renal impairment | Suppress acid secretion by blocking H2 receptors on parietal cells |
| Famotidine [Pepcid] | 20-, 40-mg tablets 20-, 40-mg orally disintegrating tablets | Ulcer treatment 40 mg GERD 20–40 mg | ||
| Nizatidine [Axid] | 75-, 150-, 300-mg capsules 15-mg/mL solution | 300 mg | ||
| Ranitidine [Zantac] | 75-, 150-, 300-mg tablets 150-, 300-mg capsules 15-mg/mL syrup | 300 mg | ||
| Proton pump inhibitors | Dexlansoprazole [Dexilant] | 30-, 60-mg capsules | Initial erosive esophagitis: 60 mg Maintenance: 30 mg | Suppress acid secretion by inhibiting H+,K+-ATPase, the enzyme that makes gastric acid |
| Esomeprazole [Nexium] | 20-, 40-mg delayed-release capsules 2.5-, 5-, 10-, 20-, 40-mg enteric-coated granules | 20 mg | ||
| Lansoprazole [Prevacid] | 15-, 30-mg delayed-release capsules 15-, 30-mg orally disintegrating delayed-release tablets | 30 mg | ||
Omeprazole [Prilosec, Zegerid, Losec  ] | 10-, 20-, 40-mg delayed-release capsules 20-, 40-mg delayed-release tablets 2.5-, 10-mg suspension 20-, 40-mg powder for reconstitution | 20 mg | ||
Pantoprazole [Protonix, Pantoloc  ] | 20-, 40-mg delayed-release tablets 40-mg enteric-coated granules | 40 mg | ||
Rabeprazole [Aciphex, Pariet  ] | 20-mg delayed-release tablets 5-, 10-mg delayed-release capsules | 20 mg | ||
| Mucosal protectant | Sucralfate [Carafate, Sulcrate  ] | 1-mg tablets 1-g/10 mL oral suspension | 4 g | Forms a barrier over the ulcer crater that protects against acid and pepsin |
| Antisecretory agent that enhances mucosal defenses | Misoprostol [Cytotec] | 100-, 200-mcg tablets | 800 mcg | 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 | Many forms | — | React with gastric acid to form neutral salts |
| Calcium carbonate | Many forms | — | ||
| Magnesium hydroxide | Many forms | — | ||
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 later under “Antibacterial Drugs.”
NSAID-Induced Ulcers
Prophylaxis.
For patients with risk factors for ulcer development (e.g., older than 60 years, history of ulcers, high-dose NSAID therapy), prophylactic therapy is indicated. PPIs (e.g., omeprazole) are preferred. Misoprostol is also effective but can cause diarrhea. Antacids, sucralfate, and H2 receptor blockers are not recommended.
Treatment.
NSAID-induced ulcers can be treated with any ulcer medication. However, H2 receptor blockers and PPIs are preferred. If possible, the offending NSAID should be discontinued, so as to accelerate healing. If the NSAID cannot be discontinued, a PPI 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 because cessation of pain and disappearance of the ulcer rarely coincide: in most cases, pain subsides before 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.
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 (e.g., antacids, H2 antagonists, PPIs) 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 delays 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.
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 for 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 71.
Amoxicillin
H. 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 (e.g., omeprazole). The most common side effect is diarrhea. The basic pharmacology of amoxicillin is discussed in Chapter 69.
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 for 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 71.
Metronidazole
Metronidazole [Flagyl] is very effective against sensitive strains of H. pylori. Unfortunately, more than 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 81.
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 81.
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—PPI or histamine-2 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 62.2 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 62.2
First-Line Regimens for Eradicating Helicobacter 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 g 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 | More than 90 | Efficacy in North America requires validation |
| Standard-dose PPI* + amoxicillin (1 g twice daily) for 5 days, followed by: | |||
| Standard-dose PPI* + clarithromycin (500 mg once daily) + tinidazole (500 mg twice daily) for 5 days |
