PHARMACOTHERAPY OF PEPTIC ULCER DISEASEVictor Nadler

Gastric Physiology

The stomach is an outpocket of the gastrointestinal tract in which ingested food undergoes mechanical and chemical changes that promote absorption in the small and large intestine. The gastric mucosa contains specialized structures known as oxyntic glands or gastric pits (which make up the fundus and corpus). This specialized mucosa produces acid (HCl) and intrinsic factor (in parietal cells); the proteolytic enzyme pepsin (in chief cells); mucus and bicarbonate (in mucous cells) and histamine (in enterochromaffin-like cells). The pyloric glands of the gastric mucosa contain G cells that produce gastrin. Acid is not absolutely required for digestion, because individuals with achlorhydria usually can digest food without malabsorption.

However, acid does serve to:1. solubilize food, in particular to extract metals from food2. activate pepsinogen to pepsin3. disinfect4. stimulate chemoreceptors on endocrine cells in the duodenum to promote release of the hormones: -gastric inhibitory peptide (GIP) increases activity of gastric smooth muscle and glands -cholecystokinin (CCK) - stimulates contraction of gall bladder and release of bile -secretin - stimulates pancreatic secretion

Pepsin, together with chymotrypsin in the duodenum, digests proteins to peptides. These peptides play a regulatory role and, by binding to receptors in the stomach, increase hormonal and neural input and gastric motility.

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Mucus (neutral fluid containing glycoproteins) and bicarbonate protect the gastric mucosa from both mechanical and chemical damage.

Ulcers – Clinical Characteristics and Historical Views

Ulcers are lesions of the gastroduodenal mucosa 3 mm in diameter that extend through the muscularis mucosa. In North America, ~90% occur in the duodenum. This percentage varies dramatically in different parts of the world; in Asia, the great majority of ulcers are in the gastric mucosa. About 4.5 million Americans suffer from peptic ulcer disease in an average year. Ulcers affect 11-14% of men and 8-11% of women at some time in their lives. It is important to confirm that an ulcer is present, by either endoscopy or an upper GI radiographic series, before treatment is initiated. In the case of gastric ulcers, roughly 5% are malignant, and treatment may need to be directed toward the malignancy (see below). In addition, one needs to demonstrate that healing has occurred after treatment in order to exclude a malignant cause of the ulcer.

The symptom of an ulcer is a burning pain felt anywhere between the navel and the sternum. The pain may last from a few minutes to many hours at a time, and it comes and goes over a period of a few days to a few weeks. The pain is worse when the stomach is empty and is relieved temporarily by eating, taking an antacid, or taking an acid-suppressing drug. Pain characteristically flares at night.

The historical view of ulcers was that there was a balance of powers in the gastric mucosa between acid production and mucosal defenses and that ulcers resulted from subtle shifts in this balance. This idea retains some validity. However, there is little evidence of increased acid production in gastric ulcers and only in a minority of duodenal ulcers. Gastric acid is required for ulcer formation. Hence blocking acid production pharmacologically can heal the ulcer. If that is all that is done, however, another ulcer forms in 50-90% of cases.

Several factors were believed to contribute to enhanced acid production, reduced mucosal defense, or both. These factors were thought to include smoking, alcohol, stress, spicy food, and genetics. Some of these certainly can exacerbate ulcers, and thus eliminating them can improve healing. Therapies included alterations in lifestyle to reduce smoking, drinking, and stress and to introduce blander diets. Gastroduodenal surgery, freeze lesion, and vagotomy were standard therapies until the first effective pharmacotherapy was introduced in the 1970s. Even with a variety of different lifestyle changes and pharmacological interventions, many ulcers continued to recur to plague patients for years.

In the 1980s, a revolution in thinking about the causes of ulcers began and focused attention on the role of an infectious agent, the bacterium Helicobacter pylori, in ulcer formation. The role for H. pylori in gastroduodenal disease, including ulcers and cancer, is now well established and treatment of this infection usually cures the disease.

Ulcers – Etiology

Infection with H. pylori is the leading cause of peptic ulcer disease. When this association was originally confirmed in the 1980s, H. pylori infection accounted for 90% of duodenal ulcers and 70% of gastric ulcers. Today, at least in North America, these numbers are lower. Only about 60-65% of both duodenal and gastric ulcers can be attributed to mucosal infection with H. pylori. H. pylori is thought to be spread by contaminated food and water and by the exchange of GI fluids with a carrier of the infection. The decline in the infection rate is attributed to improved sanitation and the eradication of the bacterium in persons with peptic ulcer disease. Nevertheless, about half the American population 50 years of age or older is infected with H. pylori and one out of six will develop symptomatic peptic ulcer disease. It is not entirely clear why most people infected with the bacterium never develop symptomatic disease. There are many strains of H. pylori, however, and some are more infectious than others. Treatment of ulcers caused by H. pylori is intended to cure the ulcer.

Chronic use of NSAIDs is the second most important known cause of peptic ulcer disease. The increasing incidence of arthritis as the population ages and the regular use of aspirin by persons over 50

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years of age as prophylaxis against thrombotic events (no longer recommended in most cases) assures that NSAID-induced ulcers will be an increasing problem in the years ahead. Treatment of NSAID-induced ulcers is intended to prevent an ulcer from developing.

Zollinger-Ellison syndrome results from a non-beta cell tumor of the pancreatic islets or duodenum that secretes gastrin. Excessive production and release of gastrin causes hypersecretion of gastric acid, leading to many small ulcers. Other GI diseases, such as Crohn’s disease, are also associated with the production of ulcers. However, these causes together account for no more than 1% of all ulcers. Treatment for ulcers caused by other GI diseases is usually directed at the underlying disease.

An increasing percentage of ulcers occurs in the absence of detectable H. pylori infection, NSAID use, or other concomitant GI diseases. It is estimated that about 30% of all ulcers currently diagnosed in North America fall into this class. In part, this may be explained by the decline in H. pylori infections. However, there does seem to be an absolute increase in ulcers of unknown origin. Persons presenting with an idiopathic ulcer are typically older, sicker, and suffer more bleeding episodes than those with ulcers of known cause. Many of these persons were previously “cured” of an H. pylori-induced or NSAID-induced ulcer. It is thought that H. pylori and NSAIDs can damage the mucosa to such a degree that it remains vulnerable to changes in the balance between acid secretion and protective factors even years after healing. The aging gastric mucosa may also be relatively vulnerable. Treatment of idiopathic ulcers is intended to heal the ulcer, but most will recur.

Helicobacter pylori

H. pylori is a spiral Gram-negative microaerophilic (thrives in a low oxygen environment) rod first reported in gastric tissue in 1892. The initial reports were dismissed as being due to contamination of the tissue sample, because it was believed impossible for bacteria to survive in stomach acid for any length of time. H. pylori was first shown to be specific for persons with peptic ulcer disease and chronic gastritis by Warren 1979-1982. It was first cultured from gastric biopsies by Marshall in 1982. Treatment of patients with antibiotics and bismuth began in the early 1980s. A central question was whether the bacterium causes inflammation and ulceration of the gastroduodenal mucosa or simply lives there after the fact. Two human subjects who voluntarily swallowed H. pylori cultures suffered inflammation of the gastric mucosa. One spontaneously resolved, the other developed chronic gastritis. This unique experiment proved that H. pylori does indeed cause disease in humans.

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H. pylori produces a hyperactive form of the enzyme urease, which catalyzes conversion of urea to NH3 and CO2. The expression of this enzyme allows the bacterium to raise the pH of the gastroduodenal fluid that surrounds it. This property and its microaerophilic nature allow it to survive the

harsh conditions in the human stomach.H. pylori infection damages the mucosa through the release of cytokines, lipopolysaccharides,

and other toxic substances. Release of these substances by the bacterium initiates an inflammatory cascade. H. pylori-induced inflammation also involves the proliferation of parietal cells, with an accompanying increase in acid secretion and pepsin production. Hypersecretion of acid and high levels of pepsin further erode the gastroduodenal mucosa.

Diagnostic Tests

– Biopsy (demonstrate breakdown of urea by H. pylori urease in the sample). Most accurate test for diagnosis; seldom used for monitoring therapy. Does not work if blood is present.

– Breath test (ingest 13C-urea, exhale 13C-CO2). Accurate for diagnosis and monitoring therapy, but expensive.

– Serology (detect circulating antibody to H. pylori). Most cost effective test for diagnosis, but not as accurate as others. Not useful for monitoring therapy.

– Stool antigen (detect H. pylori in feces with an antibody-based test). Useful for diagnosis and monitoring therapy. More cost effective than the breath test and more accurate than serology.

Eradication of H. pylori

There are several important principles. (1) Many H. pylori isolates exhibit considerable resistance to once-effective antibiotics. Furthermore, resistant strains emerge rapidly. Therefore treatment must involve at least two antibiotics that work by different mechanisms, such that the combination produces a synergistic kill. (2) The microaerophilic nature of the bacterium allows the use of metronidazole, which is very effective if the strain of H. pylori is not excessively resistant. H. pylori expresses the electron transport proteins required to transform metronidazole to free radicals that then damage DNA structure. (3) Bismuth salts are toxic to H. pylori. This is the major mechanism of action of Pepto-Bismol, an emulsion of bismuth subsalicylate. Bismuth is not effective enough to substitute for

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one of the conventional antibiotics. However, it may be added to the pharmacotherapeutic regimen to improve efficacy. (4) Suppression of gastric acid secretion speeds healing and improves the stability of amoxicillin, one of the standard antibiotics used. Proton pump inhibitors (PPIs) also have some toxicity toward H. pylori. For this reason and because they reduce gastric acid secretion to a greater extent than other drugs, PPIs are included in all protocols for the eradication of H. pylori.

Triple Therapy – First-Line (where H. pylori is more likely to be metronidazole-resistant than clarithromycin-resistant)

• Amoxicillin– Cell wall inhibitor. Only modest efficacy when used by itself.

• Clarithromycin– Protein synthesis inhibitor. Normally a bacteriostatic drug, but amoxicillin damages the

bacterial cell wall allowing a bactericidal concentration of clarithromycin to accumulate intracellularly.

• PPI• Continue for 14 days• Note: Substitute metronidazole (source of intracellular free radicals in anaerobic and

microaerophilic bacteria) for amoxicillin in patients with penicillin allergy.

Quadruple Therapy – Backup (first-line in areas where H. pylori is more likely to be clarithromycin-resistant than metronidazole-resistant)

• Tetracycline– Protein synthesis inhibitor

• Metronidazole– Source of intracellular free radicals

• Bismuth subsalicylate (Pepto-Bismol) or bismuth citrate– Toxic to H. pylori and protects stomach lining from acid

• PPI• Continue for 14 days

H. pylori-associated Tumors

Gastric carcinoma. H. pylori infection leads to chronic gastritis, epithelial cell hyperplasia, and increased risk of malignant transformation. Thus the risk of developing gastric carcinoma is increased 3 to 5-fold.

MALT (mucosa-associated lymphoid tissue) lymphoma. This form of cancer is directly associated with H. pylori infection; it does not occur in the absence of the bacterium. It is a low-grade type of B cell non-Hodgkin lymphoma (aka extranodal marginal zone B cell lymphoma). Lymphoid tissue is normally absent from the stomach. Inflammation of gastric tissue by H. pylori causes the development of MALT-type lymphoid tissue. B lymphocytes are stimulated to proliferate by the constant presence of bacteria. In some people, the lymphocytes undergo malignant transformation. In the low-grade form of MALT lymphoma, eradication of H. pylori with antibiotics by itself induces tumor regression in 50-70% of cases. Transformation to a more aggressive form of MALT lymphoma occurs in <10% of cases. These cases require treatment with surgery and conventional chemotherapy.

Gastric Acid Production

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Parietal cells contain a modified smooth endoplasmic reticulum, called the tubulovesicular and canalicular structures. Pumps in the apical membrane secrete H+ ions, derived from dissociation of carbonic acid into H+ and HCO3

-, in exchange for K+ ions. ATP to drive these pumps is supplied by abundant mitochondria. Cl- ions from the circulation are exchanged for HCO3

- in the basolateral membrane. Cl- and K+ flow through specific channels in the apical membrane. After the countertransport of H+ and K+, the secretory product of the parietal cell is HCl. The pH in the canaliculi is very acid, pH 0.8.

Gastric acid secretion is regulated in a complex fashion. Some of these regulatory mechanisms are modified by drugs. Neural signals via the vagus nerve impinge on parasympathetic ganglion cells in the stomach. The postganglionic fibers release acetylcholine onto the basolateral membrane of parietal cells to stimulate gastric acid production and onto enterochromaffin-like cells to enhance histamine release. Acetylcholine works through M3 receptors. Histamine is the most important regulator of gastric acid secretion. When released by enterochromaffin-like cells, it activates H2 receptors on the basolateral membrane of parietal cells and stimulates gastric acid production. Other local paracrine factors include prostaglandin E2, which inhibits acid production. Lastly, G cells release gastrin into the circulation in response to stretch (presence of food in the stomach) and chemoreceptors. Gastrin activates CCKB receptors on the basolateral membrane of parietal cells and enterochromaffin-like cells to increase the release of gastric acid and histamine, respectively. Other endocrine cells secrete somatostatin, which counteracts the stimulatory effects of gastrin.

In the parietal cell, histamine and prostaglandins act via G-proteins to increase or decrease, respectively, cAMP production by adenylate cyclase. In contrast, gastrin and acetylcholine increase the cytoplasmic Ca2+ concentration via synthesis of IP3. Thus (1) prostaglandins inhibit histamine action, but not isolated acetylcholine or gastrin signals and (2) gastrin and acetylcholine potentiate histamine action (by enhancing histamine release and activating a second intracellular signalling pathway). Activation of the histamine and acetylcholine or histamine and gastrin pathways together increases gastric acid secretion synergistically. The second messengers cAMP and Ca2+ activate protein kinases. Although the final steps in the enhancement of gastric acid secretion are not entirely clear, one effect is phosphorylation of cytoskeletal proteins involved in the transport of H+/K+-ATPase from the cytoplasm to the apical membrane. Thus more proton pumps are inserted into the membrane.

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PHARMACOLOGIC APPROACHES TO REDUCE GASTRODUODENAL ACIDITY

Proton Pump Inhibitors (PPIs)

Gastric acid is secreted from the apical surface of parietal cells by the action of H +/K+-ATPase (the proton pump). Several substituted benzimidazoles, such as omeprazole (Prilosec®) and esomeprazole (Nexium®), inhibit this pump. They are referred to as proton pump inhibitors or PPIs. PPIs are very potent and efficacious irreversible inhibitors of gastric acid secretion. They suppress gastric acid secretion by 95%.

PPIs have an unusual mechanism of action. Although they are administered orally, they cannot inhibit the proton pump from the lumen of the stomach or duodenum. In fact, these drugs are destroyed by acid. They must therefore be formulated in enteric-coated capsules that remain intact until reaching the small intestine. The drug is absorbed into the circulation from the small intestine and reaches the parietal cells from the basolateral membrane. PPIs enter the parietal cell and accumulate in the canaliculi because they are weak bases. The highly acidic condition in the canaliculi protonates the PPI, leading to the formation of reactive sulfenic acid and sulfenamide intermediates. The reactive intermediates bind irreversibly to cysteine residues from the extracellular surface of the proton pump. As the pump is blocked, the canalicular pH rises. When the pH reaches 4-5 (depending on the PPI), conversion of the PPI to its active intermediate ceases.

PPIs suppress gastric acid secretion more effectively than any other drugs. They are also remarkably well tolerated when used for a relatively short period of time, such as the two-week course of therapy needed to eradicate H. pylori and heal an ulcer. Therefore PPIs have become the first-line acid-suppression therapy for all the common upper GI diseases: to promote healing of duodenal and gastric ulcers, to treat Zollinger-Ellison syndrome, and for symptomatic therapy of gastroesophageal reflux disease (GERD). Because omeprazole is available over the counter and in generic form, PPI therapy is also cost effective and convenient.

Unfortunately, the suppression of gastric acid secretion with PPIs necessarily eliminates the benefits of producing gastric acid. Furthermore, some clinical uses, including prevention of NSAID-induced ulcers, symptomatic treatment of GERD, symptomatic treatment of idiopathic ulcers, and

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treatment of Zollinger-Ellison syndrome, may require a PPI to be taken for years. Increasing reports document that chronic suppression of gastric acid secretion can lead to infection of the stomach and duodenum by agents normally confined to the intestines (e.g., E. coli), infection with Clostridium difficile, increased risk of nosocomial pneumonia, and an increased risk of fractures. The increased risk of fractures is related to the hypocalcemia produced by failure to absorb enough calcium. Apparently, gastric acid is more important for extracting calcium from food than was thought. This adverse effect of PPIs can be addressed by increasing calcium intake, preferably through increased consumption of dairy products.

H2 Receptor Antagonists

Histamine plays a central role in acid production by parietal cells. The H2 receptor antagonists block acid production in response to food, gastrin, or vagal input.

The most commonly used H2 blockers are cimetidine (Tagamet®) and ranitidine (Zantac®). These agents competitively inhibit the histamine-receptor interaction and decrease acid and pepsin production. They are less effective than the PPIs, reducing gastric acid production by 60%. They are more effective in reducing basal secretion than feeding-induced secretion. They reduce nocturnal gastric acid secretion effectively if taken during the evening. Because gastric acid secretion is high during the night, this is an important capability. H2 blockers are most useful to treat less serious symptoms of peptic ulcer disease or GERD or where one might not want to use a PPI for chronic therapy. Their use has declined in favor of the PPIs.

Sucralfate

This is a coating agent (complex of sucrose octasulfate and polyaluminum hydroxide) that acts locally on the mucosal surface to protect it from acid and pepsin. It is most effective when given prior to, rather than after, meals. At pH values below 4 (i.e., in the stomach), sucralfate polymerizes into a highly viscous gel that adheres to the mucosa and especially to ulcer craters. You can think of this as something like super-mucus that forms where it is needed. Sucralfate is about as effective as an H2 blocker in promoting ulcer healing. The indications for its use are the same as for H2 blockers.

Antacids

Antacids have been used in various forms for centuries to treat GERD, chronic gastritis, and ulcers. Although more effective and much longer-acting agents are available for ulcer therapy today, antacids still have a place in providing cheap and effective symptomatic relief when PPI therapy is inadequate. Considerations are buffering capacity, sodium content, and side effects (diarrhea, constipation).

Common over-the-counter antacids include Mg(OH)2, which is an effective antacid but can cause an osmotic diarrhea. For this reason, it is usually combined with Al(OH)3 which, although less effective in neutralizing acid, has a counteracting constipating effect. (To remember this, think of the name Maalox = magnesium + aluminum + oxide, in which magnesium comes first because it is more effective and causes diarrhea).

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Pharmacotherapy of NSAID-induced ulcers

NSAID-induced ulcers are diagnosed mainly in persons who use large doses to treat arthritis and other chronic inflammatory conditions. Even those who take low doses of NSAID for prophylaxis of thrombotic events are at risk, however. Overall, 3-4.5% of chronic NSAID users experience clinically-significant upper GI events.

NSAIDs inhibit the enzymes (COX-1 and COX-2) responsible for the biosynthesis of prostaglandins and thromboxanes. Accordingly, NSAIDs eliminate the beneficial effects of these lipids in the stomach. The major prostaglandin produced in the stomach is prostaglandin E2. Prostaglandin E2

inhibits gastric acid secretion (by reducing cAMP production in the parietal cell) and promotes the production of mucus and bicarbonate by mucous cells. Prostaglandin E2 and prostacyclin (PGI2) produced by vascular endothelial cells increase mucosal blood flow through vasodilation. Finally, thromboxane A2 derived from platelets promotes clotting, thereby attenuating or preventing gastroduodenal bleeding. Obviously, the loss of these functions promotes mucosal injury.

The first approach to preventing NSAID-induced ulcers is to use the lowest effective dose of the drug. Avoid using aspirin (except for thrombotic prophylaxis), due to its irreversible inhibition of COX-1 and COX-2.

The most effective way to prevent NSAID-induced ulcers is to combine NSAID therapy with a PPI. This approach is effective in 80-90% of patients.

Alternatively, one could combine NSAID therapy with misoprostol. Misoprostol is a more stable analog of prostaglandin E1. It has the same actions in the stomach and the vasculature as the natural prostaglandin E2. Combination therapy with misoprostol is less successful (60-75%) than combination therapy with a PPI. Side effects may include diarrhea, cramping, and uterine contractions that can lead to abortion during pregnancy. Therefore misoprostol should never be given to pregnant or potentially pregnant women. Misoprostol is used mainly in persons for whom chronic PPI therapy may be too risky.

A final alternative is to use a specific COX-2 inhibitor instead of a conventional NSAID. COX-2 inhibitors were developed because it was believed that only COX-1 is responsible for producing

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beneficial prostaglandins in the stomach and that expression of COX-2 is only induced in regions of inflammation. Thus COX-2 inhibitors were expected to have anti-inflammatory and analgesic activities, but not to promote the development of an ulcer. The only such drug that remains on the market in the USA today is celecoxib (Celebrex®). The others, including rofecoxib (Vioxx), were withdrawn due to reports of increased thrombotic events. COX-2 inhibitors are thought to increase the risk of such events by inhibiting COX-2 constitutively expressed by vascular endothelial cells. Endothelial cells synthesize the anti-thrombotic and vasodilatory prostaglandins E2 and I2 with use of both COX-1 and COX-2. Platelets utilize only COX-1 for the synthesis of the proaggregant vasoconstrictor thromboxane A2. Thus thromboxane A2 gains the upper hand when COX-2 is inhibited. The result can be a symptomatic clot, especially in an artery already narrowed by atherosclerosis. Celecoxib appears to present a lower risk of clotting than other COX-2 inhibitors, probably owing to its being the least specific for COX-2 as opposed to COX-1. However, the clotting risk is still greater than that of conventional NSAIDs (all NSAID packaging is required to display a warning about increased risk of thrombotic events). Moreover, the use of celecoxib (or any other COX-2 inhibitor) does not eliminate the risk of NSAID-induced ulcer, it only reduces the risk. Combining a conventional NSAID with a PPI is probably as efficacious in preventing NSAID-induced ulcer as using celecoxib and it may be cheaper. The ultimate protection against NSAID-induced peptic ulcer is to combine celecoxib with a PPI.

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