Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VI
Drugs Affecting Gastrointestinal Function

chapter 45
Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease

The treatment and prevention of acid-related disorders are accomplished by decreasing gastric acidity and enhancing mucosal defense. The appreciation that an infectious agent,Helicobacter pylori, plays a key role in the pathogenesis of acid-peptic diseases has stimulated new approaches to prevention and therapy.


Gastric acid secretion is a complex and continuous process: neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors all regulate the secretion of H+ by parietal cells (Figure 45–1).


Figure 45–1 Pharmacologist’s view of gastric secretion and its regulation: the basis for therapy of acid-peptic disorders. Shown are the interactions among an enterochromaffin-like (ECL) cell that secretes histamine, a ganglion cell of the enteric nervous system (ENS), a parietal cell that secretes acid, and a superficial epithelial cell that secretes mucus and bicarbonate. Physiological pathways, shown in solid black, may be stimulatory (+) or inhibitory (–). 1 and 3 indicate possible inputs from postganglionic cholinergic fibers; 2 shows neural input from the vagus nerve. Physiological agonists and their respective membrane receptors include acetylcholine (ACh), muscarinic (M), and nicotinic (N) receptors; gastrin, cholecystokinin receptor 2 (CCK2); histamine (HIST), H2 receptor; and prostaglandin E2 (PGE2), EP3receptor. A red indicates targets of pharmacological antagonism. A light blue dashed arrow indicates a drug action that mimics or enhances a physiological pathway. Shown in red are drugs used to treat acid-peptic disorders. NSAIDs are nonsteroidal anti-inflammatory drugs, which can induce ulcers via inhibition of cyclooxygenase.

Specific receptors (M3, H2, and CCK2, respectively) are on the basolateral membrane of parietal cells in the body and fundus of the stomach. Some of these receptors are also present on enterochromaffin-like (ECL) cells, where they regulate the release of histamine. The H2 receptor is a GPCR that activates the Gs–adenylyl cyclase–cyclic AMP–PKA pathway. ACh and gastrin signal through GPCRs that couple to the Gq–PLC-IP3–Ca2+ pathway in parietal cells. In parietal cells, the cyclic AMP and the Ca2+-dependent pathways activate H+, K+-ATPase (the proton pump), which exchanges H+ and K+ across the parietal cell membrane. This pump generates the largest ion gradient known in vertebrates, with an intracellular pH of ~7.3 and an intracanalicular pH of ~0.8.

ACh release from postganglionic vagal fibers directly stimulates gastric acid secretion through muscarinic M3 receptors on the basolateral membrane of parietal cells. The CNS predominantly modulates the activity of the enteric nervous system via ACh, stimulating gastric acid secretion in response to the sight, smell, taste, or anticipation of food (the “cephalic” phase of acid secretion). ACh also indirectly affects parietal cells by increasing the release of histamine from the ECL cells and of gastrin from G cells. ECL cells, the source of gastric histamine, usually are in close proximity to parietal cells. Histamine acts as a paracrine mediator, diffusing from its site of release to nearby parietal cells, where it activates H2 receptors to stimulate gastric acid secretion.

Gastrin, produced by antral G cells, is the most potent inducer of acid secretion. Multiple pathways stimulate gastrin release, including CNS activation, local distention, and chemical components of the gastric contents. Gastrin stimulates acid secretion indirectly by inducing the release of histamine by ECL cells; a direct effect on parietal cells also plays a lesser role. Somatostatin (SST), which is produced by antral D cells, inhibits gastric acid secretion. Acidification of the gastric luminal pH to <3 stimulates SST release, which in turn suppresses gastrin release in a negative feedback loop. SST-producing cells are decreased in patients with H. pylori infection, and the consequent reduction of SST’s inhibitory effect may contribute to excess gastrin production.

GASTRIC DEFENSES AGAINST ACID. The extremely high concentration of H+ in the gastric lumen requires robust defense mechanisms to protect the esophagus and the stomach. The primary esophageal defense is the lower esophageal sphincter, which prevents reflux of acidic gastric contents into the esophagus. The stomach protects itself from acid damage by a number of mechanisms that require adequate mucosal blood flow. One key defense is the secretion of a mucus layer that helps to protect gastric epithelial cells by trapping secreted bicarbonate at the cell surface. Gastric mucus is soluble when secreted but quickly forms an insoluble gel that coats the mucosal surface of the stomach, slows ion diffusion, and prevents mucosal damage by macromolecules such as pepsin. Mucus production is stimulated by prostaglandins E2 and I2, which also directly inhibit gastric acid secretion by parietal cells. Thus, drugs that inhibit prostaglandin formation (e.g., NSAIDs, ethanol) decrease mucus secretion and predispose to the development of acid-peptic disease. Figure 45–1 outlines the rationale and pharmacological basis for the therapy of acid-peptic diseases. The proton pump inhibitors are used most commonly, followed by the histamine H2 receptor antagonists.


The most potent suppressors of gastric acid secretion are inhibitors of the gastric H+, K+-ATPase (proton pump) (Figure 45–2). These drugs diminish the daily production of acid (basal and stimulated) by 80-95%.

Figure 45–2 Activation of prodrug proton pump inhibitor. Omeprazole is converted to a sulfenamide in the acidic secretory canaliculi of the parietal cell. The sulfenamide interacts covalently with sulfhydryl groups in the proton pump, thereby irreversibly inhibiting its activity. Lansoprazole, rabeprazole, and pantoprazole undergo analogous conversions.


CHEMISTRY; MECHANISM OF ACTION; PHARMACOLOGY. Six proton pump inhibitors are available for clinical use: omeprazole (PRILOSEC, others) and its S-isomer, esomeprazole (NEXIUM),lansoprazole (PREVACID) and its R-enantiomer, dexlansoprazole (KAPIDEX), rabeprazole (ACIPHEX), and pantoprazole (PROTONIX, others). All proton pump inhibitors have equivalent efficacy at comparable doses.

Proton pump inhibitors (PPIs) are prodrugs that require activation in an acid environment. After absorption into the systemic circulation, the prodrug diffuses into the parietal cells of the stomach and accumulates in the acidic secretory canaliculi. Here, it is activated by proton-catalyzed formation of a tetracyclic sulfenamide (see Figure 45–2), trapping the drug so that it cannot diffuse back across the canalicular membrane. The activated form then binds covalently with sulfhydryl groups of cysteines in the H+, K+-ATPase, irreversibly inactivating the pump molecule. Acid secretion resumes only after new pump molecules are synthesized and inserted into the luminal membrane, providing a prolonged (up to 24- to 48-h) suppression of acid secretion, despite the much shorter plasma t1/2 ~ 0.5-2 h of the parent compounds.

To prevent degradation of PPIs by acid in the gastric lumen and improve oral bioavailability, oral dosage forms are supplied in different formulations:

• Enteric-coated drugs contained inside gelatin capsules (omeprazole, dexlansoprazole, esomeprazole, and lansoprazole)

• Enteric-coated granules supplied as a powder for suspension (lansoprazole)

• Enteric-coated tablets (pantoprazole, rabeprazole, and omeprazole)

• Powdered omeprazole combined with sodium bicarbonate (ZEGERID) contained in capsules and formulated for oral suspension

Patients for whom the oral route of administration is not available can be treated parenterally with esomeprazole, pantoprazole, or lansoprazole. The FDA-approved dose of intravenous pantoprazole for gastroesophageal reflux disease is 40 mg daily for up to 10 days. Higher doses (e.g., 160-240 mg in divided doses) are used to manage hypersecretory conditions such as the Zollinger-Ellison syndrome.

ADME. Because an acidic pH in the parietal cell acid canaliculi is required for drug activation and food stimulates acid production, these drugs ideally should be given ~30 min before meals. Concurrent administration of food may reduce somewhat the rate of absorption of PPIs. Once in the small bowel, PPIs are rapidly absorbed, highly protein bound, and extensively metabolized by hepatic CYPs, particularly CYP2C19 and CYP3A4. Asians are more likely than whites or African Americans to have the CYP2C19 genotype that correlates with slow metabolism of PPIs (23% vs. 3%, respectively), which may contribute to heightened efficacy and/or toxicity in this ethnic group.

Because not all pumps and all parietal cells are active simultaneously, maximal suppression of acid secretion requires several doses of the PPIs. For example, it may take 2-5 days of therapy with once-daily dosing to achieve the 70% inhibition of proton pumps that is seen at steady state. More frequent initial dosing (e.g., twice daily) will reduce the time to achieve full inhibition but is not proven to improve patient outcome. The resulting proton pump inhibition is irreversible; thus, acid secretion is suppressed for 24-48 h, or more, until new proton pumps are synthesized and incorporated into the luminal membrane of parietal cells. Chronic renal failure does not lead to drug accumulation with once-a-day dosing of the PPIs. Hepatic disease substantially reduces the clearance of esomeprazole and lansoprazole.

ADVERSE EFFECTS AND DRUG INTERACTIONS. PPIs generally cause remarkably few adverse effects. The most common side effects are nausea, abdominal pain, constipation, flatulence, and diarrhea. Subacute myopathy, arthralgias, headaches, and skin rashes also have been reported. As noted earlier, PPIs are metabolized by hepatic CYPs and therefore may interfere with the elimination of other drugs cleared by this route. PPIs have been observed to interact with warfarin (esomeprazole, lansoprazole, omeprazole, and rabeprazole), diazepam (esomeprazole and omeprazole), and cyclosporine (omeprazole and rabeprazole). Among the PPIs, only omeprazole inhibits CYP2C19 (thereby decreasing the clearance of disulfiram, phenytoin, and other drugs) and induces the expression of CYP1A2 (thereby increasing the clearance of imipramine, several antipsychotic drugs, tacrine, and theophylline). There is emerging evidence that omeprazole can inhibit conversion of clopidogrel (at the level of CYP2C19) to the active anticoagulating form. Pantoprazole is less likely to result in this interaction; concurrent use of clopidogrel and PPIs (mainly pantoprazole) significantly reduces GI bleeding without increasing adverse cardiac events (see Chapter 30).

Chronic treatment with omeprazole decreases the absorption of vitamin B12, but the clinical relevance of this effect is not clear. Loss of gastric acidity also may affect the bioavailability of such drugs as ketoconazole, ampicillin esters, and iron salts. Chronic use of PPIs has been reported to be associated with an increased risk of bone fracture and with increased susceptibility to certain infections (e.g., hospital-acquired pneumonia, community-acquired Clostridium difficile). Hypergastrinemia is more frequent and more severe with PPIs than with H2 receptor antagonists. This hypergastrinemia may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and also may promote the growth of GI tumors.

Therapeutic Uses. Prescription PPIs are used to promote healing of gastric and duodenal ulcers and to treat gastroesophageal reflux disease (GERD), including erosive esophagitis, which is either complicated or unresponsive to treatment with H2 receptor antagonists. Over-the-counter omeprazole is approved for the self-treatment of heartburn. PPIs also are the mainstay in the treatment of pathological hypersecretory conditions, including the Zollinger-Ellison syndrome. Lansoprazole and esomeprazole are approved for treatment and prevention of recurrence of NSAID-associated gastric ulcers in patients who continue NSAID use. It is not clear if PPIs affect the susceptibility to NSAID-induced damage and bleeding in the small and large intestine. All PPIs are approved for reducing the risk of duodenal ulcer recurrence associated with H. pylori infections. Therapeutic applications of PPIs are further discussed later under “Specific Acid-Peptic Disorders and Therapeutic Strategies.”


The H2 receptor antagonists inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells.


Four different H2 receptor antagonists are available in the U.S.: cimetidine (TAGAMET, others), ranitidine (ZANTAC, others), famotidine (PEPCID, others), and nizatidine (AXID, others). These drugs are less potent than PPIs but still suppress 24-h gastric acid secretion by ~70%. Because the most important determinant of duodenal ulcer healing is the level of nocturnal acidity, evening dosing of H2 receptor antagonists is adequate therapy in most instances. All 4 H2 receptor antagonists are available as prescription and over-the-counter formulations for oral administration. Intravenous and intramuscular preparations of cimetidine, ranitidine, and famotidine also are available.

ADME. The H2 receptor antagonists are rapidly absorbed after oral administration, with peak serum concentrations within 1-3 h. Absorption may be enhanced by food or decreased by antacids, but these effects probably are unimportant clinically. Therapeutic levels are achieved rapidly after intravenous dosing and are maintained for 4-5 h (cimetidine), 6-8 h (ranitidine), or 10-12 h (famotidine). Only a small percentage of H2 receptor antagonists are protein bound. Small amounts (from <10% to ~35%) of these drugs undergo metabolism in the liver, but liver disease per se is not an indication for dose adjustment. The kidneys excrete these drugs and their metabolites by filtration and renal tubular secretion, and it is important to reduce drug doses in patients with decreased creatinine clearance. Neither hemodialysis nor peritoneal dialysis clears significant amounts of these drugs.

ADVERSE REACTIONS AND DRUG INTERACTIONS. H2 receptor antagonists generally are well tolerated, with a low (<3%) incidence of adverse effects. Side effects are minor and include diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation. Less common side effects include those affecting the CNS (confusion, delirium, hallucinations, slurred speech, and headaches), which occur primarily with intravenous administration of the drugs or in elderly subjects. Several reports have associated H2 receptor antagonists with various blood dyscrasias, including thrombocytopenia. H2 receptor antagonists cross the placenta and are excreted in breast milk. Although no major teratogenic risk has been associated with these agents, caution is warranted when they are used in pregnancy.

All agents that inhibit gastric acid secretion may alter the rate of absorption and subsequent bioavailability of the H2 receptor antagonists (see “Antacids” section). Drug interactions with H2 receptor antagonists occur mainly with cimetidine, and its use has decreased markedly. Cimetidine inhibits CYPs (e.g., CYP1A2, CYP2C9, and CYP2D6), and thereby can increase the levels of a variety of drugs that are substrates for these enzymes. Ranitidine also interacts with hepatic CYPs, but with an affinity of only 10% of that of cimetidine. Famotidine and nizatidine are even safer in this regard. Slight increases in blood-alcohol concentration may result from concomitant use of H2 receptor antagonists.

Therapeutic Uses. The major therapeutic indications for H2 receptor antagonists are to promote healing of gastric and duodenal ulcers, to treat uncomplicated GERD, and to prevent the occurrence of stress ulcers. For more information about the therapeutic applications of H2 receptor antagonists, see below, “Specific Acid-Peptic Disorders and Therapeutic Strategies.”


Tolerance to the acid-suppressing effects of H2 receptor antagonists may develop within 3 days of starting treatment and may be resistant to increased doses of the medications. Diminished sensitivity to these drugs may result from the effect of the secondary hypergastrinemia to stimulate histamine release from ECL cells. PPIs do not cause this phenomenon; however, rebound increases in gastric acidity can occur when either of these drug classes is discontinued.



Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are the major prostaglandins synthesized by the gastric mucosa. Contrary to their cyclic AMP-elevating effects on many cells via EP2 and EP4 receptors, these prostanoids bind to the EP3 receptor on parietal cells and stimulate the Gi pathway, thereby decreasing intracellular cyclic AMP and gastric acid secretion. PGE2 also can prevent gastric injury by cytoprotective effects that include stimulation of mucin and bicarbonate secretion and increased mucosal blood flow. Acid suppression appears to be the most important effect clinically.

Because NSAIDs diminish prostaglandin formation by inhibiting cyclooxygenase, synthetic prostaglandin analogs offer a logical approach to counteract NSAID-induced damage. Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC, others) is a synthetic analog of PGE1 that is FDA-approved to prevent NSAID-induced mucosal injury. The degree of inhibition of gastric acid secretion by misoprostol is directly related to dose; oral doses of 100-200 μg significantly inhibit basal acid secretion (up to 85-95% inhibition) or food-stimulated acid secretion (up to 75-85% inhibition). The usual recommended dose for ulcer prophylaxis is 200 μg 4 times a day.

ADME. Misoprostol is rarely used because of its side effects. The drug is rapidly absorbed after oral administration and is rapidly and extensively de-esterified to form misoprostol acid, the principal and active metabolite of the drug. A single dose inhibits acid production within 30 min; the therapeutic effect peaks at 60-90 min and lasts for up to 3 h. Food and antacids decrease the rate of misoprostol absorption. The free acid is excreted mainly in the urine, with an elimination t1/2 of 20-40 min.

ADVERSE EFFECTS. Diarrhea, with or without abdominal pain and cramps, occurs in up to 30% of patients who take misoprostol. Apparently dose related, it typically begins within the first 2 weeks after therapy is initiated and often resolves spontaneously within a week; more severe cases may necessitate drug discontinuation. Misoprostol can cause clinical exacerbations of inflammatory bowel disease(see Chapter 47). Misoprostol also is contraindicated during pregnancy because it can increase uterine contractility.


In the presence of acid-induced damage, pepsin-mediated hydrolysis of mucosal proteins contributes to mucosal erosion and ulcerations. This process can be inhibited by sulfated polysaccharides. Sucralfate (CARAFATE, others) consists of the octasulfate of sucrose to which Al(OH)3 has been added. In an acid environment (pH <4), sucralfate undergoes extensive cross-linking to produce a viscous, sticky polymer that adheres to epithelial cells and ulcer craters for up to 6 h after a single dose. In addition to inhibiting hydrolysis of mucosal proteins by pepsin, sucralfate may have additional cytoprotective effects, including stimulation of local production of prostaglandins and EGF. Sucralfate also binds bile salts; thus, some clinicians use sucralfate to treat individuals with the syndromes of biliary esophagitis or gastritis (the existence of which is controversial).

Therapeutic Uses. The use of sucralfate to treat peptic acid disease has diminished in recent years. Nevertheless, because increased gastric pH may be a factor in the development of nosocomial pneumonia in critically ill patients, sucralfate may offer an advantage over PPIs and H2 receptor antagonists for the prophylaxis of stress ulcers. Sucralfate also has been used in conditions associated with mucosal inflammation/ulceration that may not respond to acid suppression, including oral mucositis (radiation and aphthous ulcers) and bile reflux gastropathy. Administered by rectal enema, sucralfate also has been used for radiation proctitis and solitary rectal ulcers. Because it is activated by acid, sucralfate should be taken on an empty stomach 1 h before meals. The use of antacids within 30 min of a dose of sucralfate should be avoided. The dose of sucralfate is 1 g 4 times daily (for active duodenal ulcer) or 1 g twice daily (for maintenance therapy).

ADVERSE EFFECTS. The most common side effect of sucralfate is constipation (~2%). Sucralfate should be avoided in patients with renal failure who are at risk for aluminum overload. Likewise, aluminum-containing antacids should not be combined with sucralfate in these patients. Sucralfate forms a viscous layer in the stomach that may inhibit absorption of other drugs, including phenytoin, digoxin, cimetidine, ketoconazole, and fluoroquinolone antibiotics. Sucralfate therefore should be taken at least 2 h after the administration of other drugs. The “sticky” nature of the viscous gel produced by sucralfate in the stomach also may be responsible for the development of bezoars in some patients.


There are more effective and persistent agents than antacids, but their price, accessibility, and rapid action make them popular with consumers. Many factors, including palatability, determine the effectiveness and choice of antacid. Although sodium bicarbonate effectively neutralizes acid, it is very water soluble and rapidly absorbed from the stomach, and the alkali and sodium loads may pose a risk for patients with cardiac or renal failure. CaCO3 rapidly and effectively neutralizes gastric H+, but the release of CO2 from bicarbonate- and carbonate-containing antacids can cause belching, nausea, abdominal distention, and flatulence. Calcium also may induce rebound acid secretion, necessitating more frequent administration. Combinations of Mg2+ (rapidly reacting) and Al3+ (slowly reacting) hydroxides provide a relatively balanced and sustained neutralizing capacity and are preferred by most experts. Magaldrate, a hydroxymagnesium aluminate complex, is converted rapidly in gastric acid to Mg(OH)2 and Al(OH)3, which are absorbed poorly and thus provide a sustained antacid effect. Although fixed combinations of magnesium and aluminum theoretically counteract the adverse effects of each other on the bowel (Al3+ can relax gastric smooth muscle, producing delayed gastric emptying and constipation; Mg2+ exerts the opposite effects), such balance is not always achieved in practice. Simethicone, a surfactant that may decrease foaming and hence esophageal reflux, is included in many antacid preparations. However, other fixed combinations, particularly those with aspirin, that are marketed for “acid indigestion” are potentially unsafe in patients predisposed to gastroduodenal ulcers, and should not be used.

For uncomplicated ulcers, antacids are given orally 1 and 3 h after meals and at bedtime. For severe symptoms or uncontrolled reflux, antacids can be given as often as every 30-60 min. In general, antacids should be administered in suspension form because this probably has a greater neutralizing capacity than powder or tablet dosage forms. Antacids are cleared from the empty stomach in ~30 min. However, the presence of food is sufficient to elevate gastric pH to ~5 for ~1 h and to prolong the neutralizing effects of antacids for ~2-3 h.

Antacids vary in the extent to which they are absorbed, and hence in their systemic effects. In general, most antacids can elevate urinary pH by ~1 pH unit. Antacids that contain Al3+, Ca2+, or Mg2+ are absorbed less completely than are those that contain NaHCO3. With renal insufficiency, absorbed Al3+ can contribute to osteoporosis, encephalopathy, and proximal myopathy. About 15% of orally administered Ca2+ is absorbed, causing a transient hypercalcemia. The hypercalcemia from as little as 3-4 g of CaCO3 per day can be problematic in patients with uremia. In the past, when large doses of NaHCO3 and CaCO3 were administered commonly with milk or cream for the management of peptic ulcer, the milk-alkali syndrome (alkalosis, hypercalcemia, and renal insufficiency) occurred frequently. Today, this syndrome is rare and generally results from the chronic ingestion of large quantities of Ca2+ (five to forty 500-mg tablets per day of calcium carbonate) taken with milk.

By altering gastric and urinary pH, antacids may affect a number of drugs (e.g., thyroid hormones, allopurinol, and imidazole antifungals, by altering rates of dissolution and absorption, bioavailability, and renal elimination). Al3+ and Mg2+ antacids also are notable for their propensity to chelate other drugs present in the GI tract and thereby decrease their absorption. Most interactions can be avoided by taking antacids 2 h before or after ingestion of other drugs.

OTHER ACID SUPPRESSANTS AND CYTOPROTECTANTS. The M1 muscarinic receptor antagonists pirenzepine and telenzepine (see Chapter 9) can reduce basal acid production by 40-50%. The ACh receptor on the parietal cell itself is of the M3 subtype, and these drugs are believed to suppress neural stimulation of acid production via actions on M1 receptors of intramural ganglia (see Figure 45–1). Because of their relatively poor efficacy, significant and undesirable anticholinergic side effects, and risk of blood disorders (pirenzepine), they rarely are used today.

Rebamipide is used for ulcer therapy in parts of Asia. Its cytoprotective effects are exerted by increasing prostaglandin generation in gastric mucosa and by scavenging reactive oxygen species. Ecabet(GASTROM), which appears to increase the formation of PGE2 and PGI2, also is used for ulcer therapy, mostly in Japan. Carbenoxolone, a derivative of glycyrrhizic acid found in licorice root, has been used with modest success for ulcer therapy in Europe. Unfortunately, carbenoxolone inhibits the type I isozyme of 11β-hydroxysteroid dehydrogenase, which protects the mineralocorticoid receptor from activation by cortisol in the distal nephron; it therefore causes hypokalemia and hypertension due to excessive mineralocorticoid receptor activation (see Chapter 42). Bismuth compounds (see Chapter 46) are frequently prescribed in combination with antibiotics to eradicate H. pylori and prevent ulcer recurrence. Bismuth compounds bind to the base of the ulcer, promote mucin and bicarbonate production, and have significant antibacterial effects.



Although most cases of heartburn or gastroesophageal regurgitation follow a relatively benign course, these symptoms, often referred to as GERD, can be associated with severe erosive esophagitis; stricture formation and Barrett metaplasia (replacement of squamous by intestinal columnar epithelium), in turn, is associated with a small but significant risk of adenocarcinoma. The goals of GERD therapy are complete resolution of symptoms and healing of esophagitis. PPIs clearly are more effective than H2 receptor antagonists in achieving these goals (see Figure 45–3).


Figure 45–3 Comparative success of therapy with proton pump inhibitors and H2 receptor antagonists. Data show the effects of a proton pump inhibitor (given once daily) and an H2 receptor antagonist (given twice daily) in elevating gastric pH to the target ranges (i.e., pH 3 for duodenal ulcer, pH 4 for GERD, and pH 5 for antibiotic eradication of H. pylori).

In general, the optimal dose for each patient is determined based on symptom control. Strictures associated with GERD also respond better to PPIs than to H2 receptor antagonists. One of the complications of GERD, Barrett esophagus, appears to be more refractory to therapy because neither acid suppression nor antireflux surgery has been shown convincingly to produce regression of metaplasia.

Regimens for the treatment of GERD with PPIs and histamine H2 receptor antagonists are listed in Table 45–1. Although some patients with mild GERD symptoms may be managed by nocturnal doses of H2 receptor antagonists, twice-daily dosing usually is required. Antacids are recommended only for the patient with mild, infrequent episodes of heartburn. In general, prokinetic agents (see Chapter 46) are not particularly useful for GERD, either alone or in combination with acid-suppressant medications.

Table 45–1

Antisecretory Drug Regimens for Treatment and Maintenance of GERD


SEVERE SYMPTOMS AND NOCTURNAL ACID BREAKTHROUGH. In patients with severe symptoms or extraintestinal manifestations of GERD, twice-daily dosing with a PPI may be needed. However, it is difficult if not impossible to render patients achlorhydric and two-thirds or more of subjects will continue to make acid, particularly at night. This phenomenon, called nocturnal acid breakthrough, has been invoked as a cause of refractory symptoms in some patients with GERD. However, decreases in gastric pH at night while on therapy generally are not associated with acid reflux into the esophagus, and the rationale for suppressing nocturnal acid secretion remains to be established. Patients with continuing symptoms on twice-daily PPIs are often treated by adding an H2 receptor antagonist at night. Although this can further suppress acid production, the effect is short lived, probably due to the development of tolerance.

THERAPY FOR EXTRAINTESTINAL MANIFESTATIONS OF GERD. Acid reflux has been implicated in a variety of atypical symptoms, including noncardiac chest pain, asthma, laryngitis, chronic cough, and other ear, nose, and throat conditions. PPIs (at higher doses) have been used with some success in certain patients with these disorders.

GERD AND PREGNANCY. Heartburn is estimated to occur in 30-50% of pregnancies, with an incidence approaching 80% in some populations. In the vast majority of cases, GERD ends soon after delivery and thus does not represent an exacerbation of a preexisting condition. Because of its high prevalence and the fact that it can contribute to the nausea of pregnancy, treatment often is required. Treatment choice in this setting is complicated by the paucity of data for the most commonly used drugs. In general, most drugs used to treat GERD fall in FDA Category B, with the exception of omeprazole (FDA Category C). Mild cases of GERD during pregnancy should be treated conservatively; antacids or sucralfate are considered the first-line drugs. If symptoms persist, H2 receptor antagonists can be used, with ranitidine having the most established track record in this setting. PPIs are reserved for women with intractable symptoms or complicated reflux disease. In these situations, lansoprazole is considered the preferred choice.


Peptic ulcer disease is best viewed as an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, NO, and other peptides and growth factors) and injurious factors (acid and pepsin). On average, patients with duodenal ulcers produce more acid than do control subjects, particularly at night (basal secretion). Although patients with gastric ulcers have normal or even diminished acid production, ulcers rarely if ever occur in the complete absence of acid. Presumably, a weakened mucosal defense and reduced bicarbonate production contribute to the injury from the relatively lower levels of acid in these patients. H. pylori and exogenous agents such as NSAIDs interact in complex ways to cause an ulcer. Up to 60% of peptic ulcers are associated with H. pylori infection of the stomach. This infection may lead to impaired production of somatostatin by D cells and, in time, decreased inhibition of gastrin production, resulting in increased acid production and reduced duodenal bicarbonate production.

Table 45–2 summarizes current recommendations for drug therapy of gastroduodenal ulcers. PPIs relieve symptoms of duodenal ulcers and promote healing more rapidly than do H2 receptor antagonists, although both classes of drugs are very effective in this setting (see Figure 45–3). Peptic ulcer represents a chronic disease, and recurrence within 1 year is expected in the majority of patients who do not receive prophylactic acid suppression. With the appreciation that H. pylori plays a major etiopathogenic role in the majority of peptic ulcers, prevention of relapse is focused on eliminating this organism from the stomach. Intravenous pantoprazole or lansoprazole is the preferred therapy in patients with acute bleeding ulcers. The theoretical benefit of maximal acid suppression in this setting is to accelerate healing of the underlying ulcer. In addition, a higher gastric pH enhances clot formation and retards clot dissolution.

Table 45–2

Recommendations for Treatment of Gastroduodenal Ulcers


NSAIDs also are very frequently associated with peptic ulcers and bleeding. The effects of these drugs are mediated systemically; in the stomach, NSAIDS suppress mucosal prostaglandin synthesis (particularly PGE2 and PGI2) and thereby reduce mucous production and cytoprotection (see Figure 45–1). Thus, minimizing NSAID use is an important adjunct to gastroduodenal ulcer therapy.

TREATMENT OF HELICOBACTER PYLORI INFECTION. H. pylori, a gram-negative rod, has been associated with gastritis and the subsequent development of gastric and duodenal ulcers, gastric adenocarcinoma, and gastric B-cell lymphoma. Because of the critical role of H. pylori in the pathogenesis of peptic ulcers, to eradicate this infection is standard care in patients with gastric or duodenal ulcers. Provided that patients are not taking NSAIDs, this strategy almost completely eliminates the risk of ulcer recurrence. Eradication of H. pylori also is indicated in the treatment of mucosa-associated lymphoid tissue lymphomas of the stomach, which can regress significantly after such treatment.

Five important considerations influence the selection of an eradication regimen (Table 45–3).

Table 45–3

Therapy of Helicobacter pylori Infection


• Single-antibiotic regimens are ineffective in eradicating H. pylori infection and lead to microbial resistance. Combination therapy with 2 or 3 antibiotics (plus acid-suppressive therapy) is associated with the highest rate of H. pylori eradication.

• A PPI or H2 receptor antagonist significantly enhances the effectiveness of H. pylori antibiotic regimens containing amoxicillin or clarithromycin (see Figure 45–3).

• A regimen of 10-14 days of treatment appears to be better than shorter treatment regimens.

• Poor patient compliance is linked to the medication-related side effects experienced by as many as half of patients taking triple-agent regimens, and to the inconvenience of 3 or 4 drug regimens administered several times per day. Packaging that combines the daily doses into 1 convenient unit is available and may improve patient compliance.

• The emergence of resistance to clarithromycin and metronidazole increasingly is recognized as an important factor in the failure to eradicate H. pylori. In the presence of in vitro evidence of resistance to metronidazole, amoxicillin should be used instead. In areas with a high frequency of resistance to clarithromycin and metronidazole, a 14-day quadruple-drug regimen (3 antibiotics combined with a PPI) generally is effective therapy.

NSAID-RELATED ULCERS. Chronic NSAID users have a 2-4% risk of developing a symptomatic ulcer, GI bleeding, or perforation. Ideally, NSAIDs should be discontinued in patients with an ulcer if at all possible. Healing of ulcers despite continued NSAID use is possible with the use of acid-suppressant agents, usually at higher doses and for a considerably longer duration than standard regimens (e.g., ≤8 weeks). PPIs are superior to H2 receptor antagonists and misoprostol in promoting the healing of active ulcers, and in preventing recurrence of gastric and duodenal ulcers in the setting of continued NSAID administration.

STRESS-RELATED ULCERS. Stress ulcers are ulcers of the stomach or duodenum that occur in the context of a profound illness or trauma requiring intensive care. The etiology of stress-related ulcers differs somewhat from that of other peptic ulcers, involving acid and mucosal ischemia. Because of limitations on the oral administration of drugs in many patients with stress-related ulcers, intravenous H2receptor antagonists have been used extensively to reduce the incidence of GI hemorrhage due to stress ulcers. Now that intravenous preparations of PPIs are available, it is likely that they will prove to be equally beneficial. However, there is some concern over the risk of pneumonia secondary to gastric colonization by bacteria in an alkaline milieu. In this setting, sucralfate appears to provide reasonable prophylaxis against bleeding without increasing the risk of aspiration pneumonia.

ZOLLINGER-ELLISON SYNDROME. Patients with this syndrome develop pancreatic or duodenal gastrinomas that stimulate the secretion of very large amounts of acid, sometimes in the setting of multiple endocrine neoplasia, type I. This can lead to severe gastroduodenal ulceration and other consequences of uncontrolled hyperchlorhydria. PPIs are the drugs of choice, usually given at twice the routine dosage for peptic ulcers with the therapeutic goal of reducing acid secretion to 1-10 mmol/h.

NONULCER DYSPEPSIA. This term refers to ulcer-like symptoms in patients who lack overt gastroduodenal ulceration. It may be associated with gastritis (with or without H. pylori) or with NSAID use, but the pathogenesis of this syndrome remains controversial.