Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease | Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e | AccessBiomedical Science

Gastric acid secretion is a complex, continuous process in which multiple central and peripheral factors contribute to a common end point: the secretion of H⁺ by parietal cells. Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors all regulate acid secretion (Figure 45–1). Their 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 cells (ECL), where they regulate the release of histamine. The H₂ receptor is a GPCR (Chapters 3 and 32) that activates the G_s–adenylyl cyclase–cyclic AMP–PKA pathway. ACh and gastrin signal through GPCRs that couple to the G_q–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 hydrogen and potassium ions 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.

Figure 45–1.

Physiological and pharmacological regulation of gastric secretion: 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), EP₃ receptor. 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.

The most important structures for CNS stimulation of gastric acid secretion are the dorsal motor nucleus of the vagal nerve, the hypothalamus, and the solitary tract nucleus. Efferent fibers originating in the dorsal motor nuclei descend to the stomach via the vagus nerve and synapse with ganglion cells of the enteric nervous system. 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 in the fundus of the stomach and of gastrin from G cells in the gastric antrum.

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. The critical role of histamine in gastric acid secretion is dramatically demonstrated by the efficacy of H₂ receptor antagonists in decreasing gastric acid secretion.

Gastrin, which is 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, perhaps because of the high metabolic activity and oxygen requirements of the gastric mucosa. 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.

PROTON PUMP INHIBITORS

Chemistry; Mechanism of Action; Pharmacology. The most potent suppressors of gastric acid secretion are inhibitors of the gastric H⁺, K⁺-ATPase (proton pump) (Figure 45–2). In typical doses, these drugs diminish the daily production of acid (basal and stimulated) by 80-95%. 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). These drugs have different substitutions on their pyridine and/or benzimidazole groups but are remarkably similar in their pharmacological properties (Appendix II). Omeprazole is a racemic mixture of R- and S-isomers; the S-isomer, esomeprazole (S-omeprazole), is eliminated less rapidly than R-omeprazole, which theoretically provides a therapeutic advantage because of the increased t_1/2. Despite claims to the contrary, all proton pump inhibitors have equivalent efficacy at comparable doses.

Figure 45–2.

Proton pump inhibitors. A. Inhibitors of gastric H⁺, K⁺-ATPase (proton pump). B. Conversion of omeprazole 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. The other three proton pump inhibitors undergo analogous conversions.

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 (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-hour) suppression of acid secretion, despite the much shorter plasma half-lives (0.5-2 hours) of the parent compounds. Because they block the final step in acid production, the proton pump inhibitors are effective in acid suppression regardless of other stimulating factors.

To prevent degradation of proton pump inhibitors by acid in the gastric lumen, 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 oralsuspension

The delayed-release and enteric-coated tablets dissolve only at alkaline pH, whereas admixture of omeprazole with sodium bicarbonate simply neutralizes stomach acid; both strategies substantially improve the oral bioavailability of these acid-labile drugs. Until recently, the requirement for enteric coating posed a challenge to the administration of proton pump inhibitors in patients for whom the oral route of administration is not available (Freston et al., 2003). These patients and those requiring immediate acid suppression now can be treated parenterally with esomeprazole, pantoprazole, or lansoprazole, which are approved for intravenous administration in the U.S. A single intravenous bolus of 80 mg of pantoprazole inhibits acid production by 80-90% within an hour, and this inhibition persists for up to 21 hours, permitting once-daily dosing to achieve the desired degree of hypochlorhydria. 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.

Pharmacokinetics. 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 minutes before meals. Concurrent administration of food may reduce somewhat the rate of absorption of proton pump inhibitors, but this effect is not thought to be clinically significant. Concomitant use of other drugs that inhibit acid secretion, such as H₂ receptor antagonists, might be predicted to lessen the effectiveness of the proton pump inhibitors, but the clinical relevance of this potential interaction is unknown.

Once in the small bowel, proton pump inhibitors are rapidly absorbed, highly protein bound, and extensively metabolized by hepatic CYPs, particularly CYP2C19 and CYP3A4. Several variants of CYP2C19 have been identified. Asians are more likely than whites or African Americans to have the CYP2C19 genotype that correlates with slow metabolism of proton pump inhibitors (23% vs. 3%, respectively), which has been suggested to contribute to heightened efficacy and/or toxicity in this ethnic group (Dickson and Stuart, 2003). Although the CYP2C19 genotype is correlated with the magnitude of gastric acid suppression by proton pump inhibitors in patients with gastroesophageal reflux disease, there is no evidence that the CYP2C19 genotype predicts clinical efficacy of these drugs (Chong and Ensom, 2003).

Because not all pumps or all parietal cells are active simultaneously, maximal suppression of acid secretion requires several doses of the proton pump inhibitors. 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 (Wang and Hunt, 2008). More frequent initial dosing (e.g., twice daily) will reduce the time to achieve full inhibition but is not proven to improve patient outcome. Because the proton pump inhibition is irreversible, acid secretion will be suppressed for 24-48 hours, 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 proton pump inhibitors. Hepatic disease substantially reduces the clearance of esomeprazole and lansoprazole. Thus, in patients with severe hepatic disease, dose reduction is recommended for esomeprazole and should be considered for lansoprazole.

Adverse Effects and Drug Interactions. Proton pump inhibitors 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, proton pump inhibitors are metabolized by hepatic CYPs and therefore may interfere with the elimination of other drugs cleared by this route. Proton pump inhibitors have been observed to interact with warfarin (esomeprazole, lansoprazole, omeprazole, and rabeprazole), diazepam (esomeprazole and omeprazole), and cyclosporine (omeprazole and rabeprazole). Among the proton pump inhibitors, 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 interact adversely with the anticlotting agent, clopidogrel, at the level of CYP2C19, for which both are substrates; thus, omeprazole can inhibit conversion of clopidogrel to the active anticoagulating form. Pantoprazole is less likely to result in this interaction (Ferreiro and Angiolillo, 2009; Norgard et al., 2009); concurrent use of clopidogrellarry and PPIs (mainly pantoprazole) significantly reduced GI bleeding without increasing adverse cardiac events (Ray et al., 2010). For the pharmacological issues involved in the concurrent use of dual antiplatelet therapy and proton pump inhibitors, see Chapter 30, "Regulation of Blood Coagulation."

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 proton pump inhibitors 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) (Coté and Howden, 2008). Hypergastrinemia is more frequent and more severe with proton pump inhibitors than with H₂ receptor antagonists, and gastrin levels of >500 ng/L occur in ~5-10% of users with chronic omeprazole administration. This hypergastrinemia may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and also may promote the growth of gastrointestinal (GI) tumors. In rats, long-term administration of proton pump inhibitors causes hyperplasia of enterochromaffin-like cells and the development of gastric carcinoid tumors. Although the gastrin levels observed in rats are ~10-fold higher than those seen in human beings, this finding has raised concerns about the possibility of similar complications of proton pump inhibitors in humans, for which there is no unequivocal evidence.

Therapeutic Uses. Prescription proton pump inhibitors 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. Proton pump inhibitors also are the mainstay in the treatment of pathological hypersecretory conditions, including the Zollinger-Ellison syndrome. Lansoprazole and esomeprazole are FDA approved for treatment and prevention of recurrence of nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers in patients who continue NSAID use. It is not clear if proton pump inhibitors affect the susceptibility to NSAID-induced damage and bleeding in the small and large intestine. In addition, all proton pump inhibitors are approved for reducing the risk of duodenal ulcer recurrence associated with H. pylori infections. Therapeutic applications of proton pump inhibitors are further discussed later under "Specific Acid-Peptic Disorders and Therapeutic Strategies."

Use in Children. In children, omeprazole is safe and effective for treatment of erosive esophagitis and GERD. Younger patients generally have increased metabolic capacity, which may explain the need for higher dosages of omeprazole per kilogram in children compared with adults.

H₂ RECEPTOR ANTAGONISTS

The description of selective histamine H₂ receptor blockade was a landmark in the treatment of acid-peptic disease (Black, 1993). Before the availability of the H₂ receptor antagonists, the standard of care was simply acid neutralization in the stomach lumen, generally with inadequate results. The long history of safety and efficacy with the H₂ receptor antagonists eventually led to their availability without a prescription. Increasingly, however, proton pump inhibitors are replacing the H₂ receptor antagonists in clinical practice.

Chemistry; Mechanism of Action; Pharmacology. 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, which differ mainly in their pharmacokinetics (Appendix II) and propensity to cause drug interactions, are available in the U.S. (Figure 45–3): cimetidine (tagamet, others), ranitidine (zantac, others), famotidine (pepcid, others), and nizatidine (axid, others). These drugs are less potent than proton pump inhibitors but still suppress 24-hour gastric acid secretion by ~70%. The H₂ receptor antagonists predominantly inhibit basal acid secretion, which accounts for their efficacy in suppressing nocturnal acid secretion. 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. Ranitidine and nizatidine also may stimulate GI motility, but the clinical importance of this effect is unknown.

All four 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. When the oral or nasogastric routes are not an option, these drugs can be given in intermittent intravenous boluses or by continuous intravenous infusion (Table 45–1). The latter provides better control of gastric pH but is not proven to be more effective in preventing significant bleeding in critically ill patients.

Pharmacokinetics. The H₂ receptor antagonists are rapidly absorbed after oral administration, with peak serum concentrations within 1-3 hours. 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 hours (cimetidine), 6-8 hours (ranitidine), or 10-12 hours (famotidine). Unlike proton pump inhibitors, 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 doses of H₂ receptor antagonists in patients with decreased creatinine clearance. Neither hemodialysis nor peritoneal dialysis clears significant amounts of the drugs.

Adverse Reactions and Drug Interactions. Like the proton pump inhibitors, the H₂ receptor antagonists generally are well tolerated, with a low (<3%) incidence of adverse effects. Side effects usually 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. Long-term use of cimetidine at high doses—seldom used clinically today—decreases testosterone binding to the androgen receptor and inhibits a CYP that hydroxylates estradiol. Clinically, these effects can cause galactorrhea in women and gynecomastia, reduced sperm count, and impotence in men. 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 nevertheless 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; thus, ranitidine interferes only minimally with hepatic metabolism of other drugs. Famotidine and nizatidine are even safer in this regard, with no significant drug interactions mediated by inhibiting hepatic CYPs. Slight increases in blood-alcohol concentration may result from concomitant use of H₂ receptor antagonists, but this is unlikely to be clinically significant.

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. More information about the therapeutic applications of H₂ receptor antagonists is provided in the section "Specific Acid-Peptic Disorders and Therapeutic Strategies."

Figure 45–3.

Histamine and H₂ receptor antagonists.

Table 45-1Intravenous Doses of H₂ Receptor Antagonists

Table 45-1 Intravenous Doses of H₂ Receptor Antagonists

CIMETIDINE

RANITIDINE

FAMOTIDINE

Intermittent bolus

300 mg every 6-8 hours

50 mg every 6-8 hours

20 mg every 12 hours

Continuous infusion

37.5-100 mg/hour

6.25-12.5 mg/hour

1.7-2.1 mg/hour

TOLERANCE AND REBOUND WITH ACID-SUPPRESSING MEDICATIONS

Tolerance to the acid-suppressing effects of H₂ receptor antagonists is well described and may account for a diminished therapeutic effect with continued drug administration (Sandevik et al., 1997). Tolerance can 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. Proton pump inhibitors, despite even greater elevations of endogenous gastrin, do not cause this phenomenon, probably because their site of action is distal to the action of histamine on acid release. However, rebound increases in gastric acidity can occur when either of these drug classes is discontinued, possibly reflecting changes in function and justifying a gradual drug taper or the substitution of alternatives (e.g., antacids) in at-risk patients.

AGENTS THAT ENHANCEMUCOSAL DEFENSE

Prostaglandin Analogs: Misoprostol

Chemistry; Mechanism of Action; Pharmacology. 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 (Chapters 33 and 34) and stimulate the G_i 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. Although smaller doses than those required for acid suppression can protect the gastric mucosa in laboratory animals, this has not been convincingly demonstrated in humans; acid suppression appears to be the most important effect clinically (Wolfe and Sachs, 2000).

Because NSAIDs diminish prostaglandin formation by inhibiting cyclooxygenase, synthetic prostaglandin analogs offer a logical approach to reducing NSAID-induced mucosal damage. Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE₁; cytotec, others) is a synthetic analog of PGE₁. Structural modifications include an additional methyl ester group at C1 that increases potency and duration of antisecretory effect, and transfer of a hydroxyl group from C15 to C16 and addition of a methyl group that increases oral bioactivity, duration of antisecretory action, and safety. 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 four times a day.

Pharmacokinetics. Misoprostol is rapidly absorbed after oral administration and then is rapidly and extensively de-esterified to form misoprostol acid, the principal and active metabolite of the drug. Some of this conversion may occur in the parietal cells. A single dose inhibits acid production within 30 minutes; the therapeutic effect peaks at 60-90 minutes and lasts for up to 3 hours. Food and antacids decrease the rate of misoprostol absorption, resulting in delayed and decreased peak plasma concentrations of the active metabolite. The free acid is excreted mainly in the urine, with an elimination t_1/2 of 20-40 minutes.

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 or protracted cases may necessitate drug discontinuation. Misoprostol can cause clinical exacerbations of inflammatory bowel disease (Chapter 47) and should be avoided in patients with this disorder. Misoprostol is contraindicated during pregnancy because it can increase uterine contractility.

Therapeutic Use. Misoprostol is FDA-approved to prevent NSAID-induced mucosal injury. However, it rarely is used because of its adverse effects and the inconvenience of four-times-daily dosing.

SUCRALFATE

Chemistry; Mechanism of Action; Pharmacology. 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 hours 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 epidermal growth factor. 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 proton pump inhibitors and H₂ receptor antagonists for the prophylaxis of stress ulcers. Due to its unique mechanism of action, sucralfate also has been used in several other 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 hour before meals. The use of antacids within 30 minutes of a dose of sucralfate should be avoided. The usual dose of sucralfate is 1 g four 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%). Because some aluminum can be absorbed, 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 hours 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, particularly in those with underlying gastroparesis.

ANTACIDS

Although hallowed by tradition, the antacids largely have been replaced by more effective and convenient drugs. Nevertheless, they continue to be used by patients for a variety of indications, and some knowledge of their pharmacology is important for the medical professional (Table 45–2 compares some commonly used antacid preparations).

Table 45-2Composition and Acid Neutralizing Capacities of Popular Antacid Preparations

Table 45-2 Composition and Acid Neutralizing Capacities of Popular Antacid Preparations

PRODUCT

Al(OH)₃^a

Mg(OH)₂^a

CaCO₃^a

SIMETHICONE^a

ACID NEUTRALIZING CAPACITY^b

Tablets

Gelusil

200

0

25

10.5

Maalox Quick Dissolve

0

600

0

12

Mylanta Double Strength

400

0

40

23

Riopan Plus Double Strength

Magaldrate, 1080

20

30

Calcium Rich Rolaids

80

412

0

11

Tums EX

0

750

0

15

Liquids

Maalox TC

600

300

0

28

Milk of Magnesia

0

400

0

14

Mylanta Maximum Strength

400

0

40

25

Riopan

Magaldrate, 540

0

15

^aContents, milligrams per tablet or per 5 ml.

^bAcid neutralizing capacity, milliequivalents per tablet or per 5 ml.

The U.S. marketplace for antacids is fluid. The current trend of "reusing" well-known brand names to introduce new products that contain an active ingredient different from expected is a source of confusion that can present a danger to patients. Medication safety experts encourage clinical practitioners to refer to the active ingredient(s) in conjunction with the proprietary (brand) name when selecting OTC products.

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. Depending on particle size and crystal structure, 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 is a hydroxymagnesium aluminate complex that 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 irrational choices, are potentially unsafe in patients predisposed to gastroduodenal ulcers, and should not be used.

The relative effectiveness of antacid preparations is expressed as milliequivalents of acid-neutralizing capacity (defined as the quantity of 1N HCl, expressed in milliequivalents, that can be brought to pH 3.5 within 15 minutes); according to FDA requirements, antacids must have a neutralizing capacity of at least 5 mEq per dose. Due to discrepancies between in vitro and in vivo neutralizing capacities, antacid doses in practice are titrated simply to relieve symptoms. For uncomplicated ulcers, antacids are given orally 1 and 3 hours after meals and at bedtime. This regimen, providing ~120 mEq of a Mg-Al combination per dose, may be almost as effective as conventional dosing with an H₂ receptor antagonist. For severe symptoms or uncontrolled reflux, antacids can be given as often as every 30-60 minutes. In general, antacids should be administered in suspension form because this probably has a greater neutralizing capacity than powder or tablet dosage forms. If tablets are used, they should be thoroughly chewed for maximum effect.

Antacids are cleared from the empty stomach in ~30 minutes. However, the presence of food is sufficient to elevate gastric pH to ~5 for ~1 hour and to prolong the neutralizing effects of antacids for ~2-3 hours.

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 normal renal function, the modest accumulations of Al³⁺ and Mg²⁺ do not pose a problem; with renal insufficiency, however, absorbed Al³⁺ can contribute to osteoporosis, encephalopathy, and proximal myopathy. About 15% of orally administered Ca²⁺ is absorbed, causing a transient hypercalcemia. Although this is not a problem in normal patients, 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. Patients may be asymptomatic or may present with the insidious onset of hypercalcemia, reduced secretion of parathyroid hormone, retention of phosphate, precipitation of Ca²⁺ salts in the kidney, and renal insufficiency.

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, forming insoluble complexes that pass through the GI tract without absorption. Thus it generally is prudent to avoid concurrent administration of antacids and drugs intended for systemic absorption. Most interactions can be avoided by taking antacids 2 hours before or after ingestion of other drugs.

Other Acid Suppressants and Cytoprotectants

The M₁ muscarinic receptor antagonists pirenzepine and telenzepine (Chapter 9) can reduce basal acid production by 40-50% and long have been used to treat patients with peptic ulcer disease in countries other than the U.S. 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 (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.

In the hope of providing more rapid onset of action and sustained acid suppression, reversible inhibitors of the gastric H⁺, K⁺-ATPase (e.g., the pyrrolopyridazine derivative AKU517) are being developed for clinical use. Antagonists of the CCK2 gastrin receptor on parietal cells also are under study. The precise role that these agents will play in the therapy of acid-peptic disorders in the future is yet to be determined.

Rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]-propionic acid) is used for ulcer therapy in parts of Asia. It appears to exert a cytoprotective effect both by increasing prostaglandin generation in gastric mucosa and by scavenging reactive oxygen species. Ecabet (gastrom; 12-sulfodehydroabietic acid monosodium), 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. Its exact mechanism of action is not clear, but it may alter the composition and quantity of mucin. 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 (Chapter 42). Bismuth compounds (Chapter 46) may be as effective as cimetidine in patients with peptic ulcers and 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. Bismuth compounds are an important component of many anti-Helicobacter regimens; however, given the availability of more effective drugs, bismuth compounds seldom are used alone as cytoprotective agents.

SPECIFIC ACID-PEPTIC DISORDERS AND THERAPEUTIC STRATEGIES

The success of acid-suppressing agents in a variety of conditions is critically dependent on their ability to keep intragastric pH above a certain target, generally pH 3-5; this target varies to some extent with the disease being treated (Figure 45–4).

Figure 45–4.

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).

Gastroesophageal Reflux Disease

In the U.S., it is estimated that one in five adults has symptoms of heartburn or gastroesophageal regurgitation at least once a week. Although most cases follow a relatively benign course, these symptoms, often referred to as "gastroesophageal reflux disease" (GERD), can be associated with severe erosive esophagitis; stricture formation and Barrett's metaplasia (replacement of squamous by intestinal columnar epithelium), in turn, is associated with a small but significant risk of adenocarcinoma. Most of the symptoms of GERD reflect injurious effects of the refluxed acid-peptic content on the esophageal epithelium, providing the rationale for suppression of gastric acid. The goals of GERD therapy are complete resolution of symptoms and healing of esophagitis. Proton pump inhibitors clearly are more effective than H₂ receptor antagonists in achieving these goals. Healing rates after 4 weeks and 8 weeks of therapy with protein pump inhibitors are ~80% and 90%, respectively; the corresponding healing rates with H₂ receptor antagonists are 50% and 75%, respectively. Indeed, proton pump inhibitors are so effective that their empirical use is advocated as a therapeutic trial in patients in whom GERD is suspected to play a role in the pathogenesis of symptoms.

Because of the wide clinical spectrum associated with GERD, the therapeutic approach is best tailored to the level of severity in the individual patient (Figure 45–5). In general, the optimal dose for each patient is determined based on symptom control, and routine measurement of esophageal pH to guide dosing is not recommended. Strictures associated with GERD also respond better to proton pump inhibitors than to H₂ receptor antagonists; indeed, the use of proton pump inhibitors reduces the requirement for esophageal dilation. Unfortunately, one of the other complications of GERD, Barrett's esophagus, appears to be more refractory to therapy because neither acid suppression nor antireflux surgery has been shown convincingly to produce regression of metaplasia or to decrease the incidence of tumors.

Regimens for the treatment of GERD with proton pump inhibitors and histamine H₂ receptor antagonists are listed in Table 45–3. 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 (Chapter 46) are not particularly useful for GERD, either alone or in combination with acid-suppressant medications.

GERD is a chronic disorder that requires long-term therapy. Some experts advocate "stepdown" approaches that attempt to maintain symptomatic remission by either decreasing the dose of the proton pump inhibitor or switching to an H₂ receptor antagonist. Other experts have advocated intermittent, "on-demand" therapy with proton pump inhibitors for symptomatic relief in patients who have responded initially but continue to have symptoms. However, many patients will maintain their requirement for proton pump inhibitors, and several studies suggest that these drugs are better than H₂ receptor antagonists for maintaining remission in GERD.

Severe Symptoms and Nocturnal Acid Breakthrough. In patients with severe symptoms or extraintestinal manifestations of GERD, twice-daily dosing with a proton pump inhibitor may be needed. However, it is difficult if not impossible to render patients achlorhydric—even on twice-daily doses of proton pump inhibitors—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 (even if feasible) remains to be established. Nevertheless, patients with continuing symptoms on twice-daily proton pump inhibitors 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, as described earlier (Fackler et al., 2002).

Therapy for Extraintestinal Manifestations of GERD. With varying levels of evidence, 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. Proton pump inhibitors have been used with some success in certain patients with these disorders, generally in higher doses and for longer periods of time than those used for patients with more classic symptoms of GERD.

GERD and Pregnancy. Heartburn is estimated to occur in 30-50% of pregnancies, with an incidence approaching 80% in some populations (Richter, 2003). In the vast majority of cases, GERD ends soon after delivery and thus does not represent an exacerbation of a preexisting condition. Nevertheless, 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 among the proton pump inhibitors, based on animal data and available experience in pregnant women.

Figure 45–5.

General guidelines for the medical management of gastroesophageal reflux disease (GERD). Only medications that suppress acid production or that neutralize acid are shown. (Adapted from Wolfe and Sachs, 2000, with permission from Elsevier. Copyright © Elsevier.)

Table 45-3Antisecretory Drug Regimens for Treatment and Maintenance of GERD

Table 45-3 Antisecretory Drug Regimens for Treatment and Maintenance of GERD

DRUG

DOSAGE

H₂ Receptor Antagonists

Cimetidine

400^*/800^* mg bid

Famotidine

20/40 mg bid

Nizatidine

150^*/300^* mg bid

Ranitidine

150/300 mg bid

Proton Pump Inhibitors

Esomeprazole

20/40 mg daily/40^* mg bid

Lansoprazole

30^*/60^* mg daily/30^* mg bid

Omeprazole

20/40^* mg daily/20^* mg bid

Pantoprazole

40/80^* mg daily/40^* mg bid

Rabeprazole

20/40^* mg daily/20^* mg bid

bid, twice daily.

^*Indicates unlabeled use.

PEPTIC ULCER DISEASE

The pathophysiology of 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.

NSAIDs also are very frequently associated with peptic ulcers and bleeding. Topical injury by the luminal presence of the drug appears to play a minor role in the pathogenesis of these ulcers, as evidenced by the fact that ulcers can occur with very low doses of aspirin (10 mg) or with parenteral administration of NSAIDs (Wallace, 2008). The effects of these drugs are instead mediated systemically; the critical element is suppression of mucosal prostaglandin synthesis (particularly PGE₂ and PGI₂). Most of the mucosal prostaglandin synthesis occurs via the constitutively expressed cyclooxygenase-1 (COX-1), but COX-2, which can be very rapidly induced, also contributes significantly to the generation of mucosal-protective prostaglandins. Thus suppression of COX-1 and COX-2 by NSAIDs contributes to the induction of mucosal injury. COX-2-derived prostaglandins are particularly important in repair of mucosal injury (Wallace, 2008).

Table 45–4 summarizes current recommendations for drug therapy of gastroduodenal ulcers. Proton pump inhibitors 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. 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. Chronic acid suppression, once the mainstay of ulcer prevention, now is used mainly in patients who are H. pylori–negative or, in some cases, for maximum prevention of recurrence in patients who have had life-threatening complications.

Intravenous pantoprazole or lansoprazole clearly 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 45-4Recommendations for Treatment of Gastroduodenal Ulcers

Table 45-4 Recommendations for Treatment of Gastroduodenal Ulcers

DRUG

ACTIVE ULCER

MAINTENANCE THERAPY

H₂ Receptor Antagonists

Cimetidine

800 mg at bedtime/400 mg twice daily

400 mg at bedtime

Famotidine

40 mg at bedtime

20 mg at bedtime

Nizatidine/ranitidine

300 mg after evening meal or at bedtime/150 mg twice daily

150 mg at bedtime

Proton Pump Inhibitors

Lansoprazole

15 mg (DU; NSAID risk reduction) daily

30 mg (GU including NSAID-associated) daily

Omeprazole

20 mg daily

Rabeprazole

20 mg daily

Prostaglandin Analog

Misoprostol

200 μg four times daily (NSAID-associated ulcer prevention)^*

DU, duodenal ulcer; GU, gastric ulcer.

^*Only misoprostol 800 μg/day has been directly shown to reduce the risk of ulcer complications such as perforation, hemorrhage, or obstruction (Rostom et al., 2009).

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 (Suerbaum and Michetti, 2002). 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.

Many regimens for H. pylori eradication have been proposed. Evidence-based literature review suggests that the ideal regimen in this setting should achieve a cure rate of at least 80%. Five important considerations influence the selection of an eradication regimen (Chey and Wong, 2007; Graham, 2000) (Table 45–5). First, single-antibiotic regimens are ineffective in eradicating H. pylori infection and lead to microbial resistance. Combination therapy with two or three antibiotics (plus acid-suppressive therapy) is associated with the highest rate of H. pylori eradication. Second, a proton pump inhibitor or H₂ receptor antagonist significantly enhances the effectiveness of H. pylori antibiotic regimens containing amoxicillin or clarithromycin. Third, a regimen of 10-14 days of treatment appears to be better than shorter treatment regimens; in the U.S., a 14-day course of therapy generally is preferred. Fourth, 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 three- or four-drug regimens administered several times per day. Packaging that combines the daily doses into one convenient unit is available and may improve patient compliance (Table 45–5). Finally, the emergence of resistance to clarithromycin and metronidazole increasingly is recognized as an important factor in the failure to eradicate H. pylori. Clarithromycin resistance is related to mutations that prevent binding of the antibiotic to the ribosomes of the pathogen and is an all-or-none phenomenon. In contrast, metronidazole resistance is relative rather than absolute and may involve several adaptations by the bacteria. 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 (three antibiotics combined with a proton pump inhibitor) generally is effective therapy.

Table 45-5Therapy of Helicobacter pylori Infection

Table 45-5 Therapy of Helicobacter pylori Infection

Triple therapy × 14 days: Proton pump inhibitor + clarithromycin 500 mg plus metronidazole 500 mg or amoxicillin 1 g twice a day (tetracycline 500 mg can be substituted for amoxicillin or metronidazole)

Quadruple therapy × 14 days: Proton pump inhibitor twice a day + metronidazole 500 mg three times daily plus bismuth subsalicylate 525 mg + tetracycline 500 mg four times daily

or

H₂ receptor antagonist twice a day plus bismuth subsalicylate 525 mg + metronidazole 250 mg + tetracycline 500 mg four times daily

Dosages:

Proton pump inhibitors: H₂ receptor antagonists:

Omeprazole: 20 mg Cimetidine: 400 mg

Lansoprazole: 30 mg Famotidine: 20 mg

Rabeprazole: 20 mg Nizatidine: 150 mg

Pantoprazole: 40 mg Ranitidine: 150 mg

Esomeprazole: 40 mg

See Chey and Wong, 2007.

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. If continued therapy is needed, selective COX-2 inhibitors may be considered, although this does not eliminate the risk of subsequent ulcer formation and the possible association of these drugs with adverse cardiovascular events mandates caution (Chapter 34). Moreover, any GI benefit of selective COX-2 inhibitors is lost if the patient is also taking low-dose aspirin. 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). Again, proton pump inhibitors are superior to H₂ receptor antagonists and misoprostol in promoting the healing of active ulcers (healing rates of 80-90% for proton pump inhibitors vs. 60-75% for the H₂ receptor antagonists), and in preventing recurrence of gastric and duodenal ulcers in the setting of continued NSAID administration (Lanas and Hunt, 2006; Rostom et al., 2009).

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 H₂ receptor antagonists have been used extensively to reduce the incidence of GI hemorrhage due to stress ulcers. Now that intravenous preparations of proton pump inhibitors 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. This approach also appears to provide reasonable prophylaxis against bleeding, but it is less convenient (Cook et al., 1998).

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. Proton pump inhibitors clearly 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/hour.

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. Although empirical treatment with acid-suppressive agents is used routinely in patients with nonulcer dyspepsia, there is no convincing evidence of their benefit in controlled trials.

CLINICAL SUMMARY

The control of acid-peptic disease represents a major triumph for modern pharmacology. Proton pump inhibitors are considered superior for acid suppression in most clinically significant acid-peptic diseases, including gastroesophageal reflux disease, peptic ulcers, and NSAID-induced ulcers. Proton pump inhibitors also are employed in combination with antibiotics to eradicate infection with H. pylori and thereby play a role in preventing recurrent peptic ulcers. These agents largely have replaced the use of misoprostol and sucralfate, although the latter still is a low-cost alternative for prophylaxis against stress ulcers. The delay in maximal inhibition of acid secretion with the proton pump inhibitors (3-5 days) makes them less suited for use on an as-needed basis for symptom relief. In this setting, H₂ receptor antagonists, although less effective than proton pump inhibitors in suppressing acid secretion, have a more rapid onset of action that makes them useful for patient-directed management of mild or infrequent symptoms.

BIBLIOGRAPHY