SECTION VI - DRUGS AFFECTING GASTROINTESTINAL FUNCTION
CHAPTER 36. PHARMACOTHERAPY OF GASTRIC ACIDITY, PEPTIC ULCERS, AND GASTROESOPHAGEAL REFLUX DISEASE - Willemijntje A. Hoogerwerf and Pankaj Jay Pasricha
PHARMACOTHERAPY OF GASTRIC ACIDITY, PEPTIC ULCERS, AND GASTROESOPHAGEAL REFLUX DISEASE: INTRODUCTION
The acid-peptic diseases are those disorders in which gastric acid and pepsin are necessary, but usually not sufficient, pathogenic factors. While inherently caustic, acid and pepsin in the stomach normally do not produce damage or symptoms because of intrinsic defense mechanisms. Barriers to the reflux of gastric contents into the esophagus comprise the primary esophageal defense. If these protective barriers fail and reflux occurs, dyspepsia and/or erosive esophagitis may result. Therapies are directed at decreasing gastric acidity, enhancing the lower esophageal sphincter, or stimulating esophageal motility (see Chapter 37). In the stomach, mucus and bicarbonate, stimulated by the local generation of prostaglandins, protect the gastric mucosa. If these defenses are disrupted, a gastric or duodenal ulcer may form. The treatment and prevention of these acid-related disorders are accomplished either by decreasing the level of gastric acidity or by enhancing mucosal protection. 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.
PHYSIOLOGY OF GASTRIC SECRETION
Gastric acid secretion is a complex, continuous process in which multiple central and peripheral factors contribute to a common endpoint: the secretion of H+ by parietal cells. Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors all regulate acid secretion (Figure 36-1). Their specific receptors (M3, H2, and CCK2 receptors, respectively) are on the basolateral membrane of parietal cells in the body and fundus of the stomach. The H2 receptor is a GPCR that activates the Gs-adenylylcyclase-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 hydrogen and potassium ions across the parietal cell membrane. This pump generates the largest known ion gradient in vertebrates, with an intracellular pH of about 7.3 and an intracanalicular pH of about 0.8.
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 enterochromaffin-like (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 secretion, 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 (see below).
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 protects gastric epithelial cells. 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, alcohol, aspirin, and other drugs that inhibit prostaglandin formation decrease mucus secretion and predispose to the development of acid-peptic disease. A second important part of the normal mucosal defense is the secretion of bicarbonate ions by superficial gastric epithelial cells. Bicarbonate neutralizes the acid in the region of the mucosal cells, thereby raising pH and preventing acid-mediated damage.
Figure 36-1 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 36-2A). In typical doses, these drugs diminish the daily production of acid (basal and stimulated) by 80% to 95%. Five proton pump inhibitors are available for clinical use: omeprazole (PRILOSEC, RAPINEX, ZEGERID) and its S-isomer, esomeprazole (NEXIUM), lansoprazole (PREVACID), rabeprazole (ACIPHEX), and pantoprazole (PROTONIX). These drugs have different substitutions on their pyridine and/or benzimidazole groups but are remarkably similar in their pharmacological properties (see 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 half-life. Despite claims to the contrary, all proton pump inhibitors have equivalent efficacy at comparable doses.
Proton pump inhibitors 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 36-2), 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 to 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: (1) enteric-coated drugs contained inside gelatin capsules (omeprazole, esomeprazole, and lansoprazole); (2) enteric-coated granules supplied as a powder for suspension (lansoprazole); (3) enteric-coated tablets (pantoprazole, rabeprazole, and omeprazole); and (4) powdered drug combined with sodium bicarbonate (omeprazole). The delayed-release and enteric-coated tablets dissolve only at alkaline pH, while 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 pantoprazole or lansoprazole, both of which are approved for intravenous administration in theUnited States United States
Pharmacokinetics. Since an acidic pH in the parietal cell acid canaliculi is required for drug activation, and since food stimulates acid production, these drugs ideally should be given about 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 Caucasians 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 to 5 days of therapy with once-daily dosing to achieve the 70% inhibition of proton pumps that is seen at steady state (Wolfe and Sachs, 2000). More frequent initial dosing (e.g., twice daily) will reduce the time to achieve full inhibition but is not proven to improve patient outcome. Since the proton pump inhibition is irreversible, acid secretion will be suppressed for 24 to 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 above, 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).
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.
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 approximately 5% to 10% of users with chronic omeprazole administration. This hypergastrinemia may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy (see below) and also may promote the growth of gastrointestinal 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 about tenfold 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. The proton pump inhibitors have a track record of approximately 25 years of use worldwide without the emergence of major safety concerns (Klinkenberg-Knol et al., 1994; Kuipers and Meuwissen, 2000).
Therapeutic Uses. Proton pump inhibitors are used principally 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. Proton pump inhibitors also are the mainstay in the treatment of pathological hypersecretory conditions, including the Zollinger-Ellison syndrome. Lansoprazole is FDA approved for treatment and prevention of recurrence of nonsteroidal antiinflammatory drug (NSAID)-associated gastric ulcers in patients who continue NSAID use. In addition, all proton pump inhibitors are FDA approved for reducing the risk of duodenal ulcer recurrence associated with H. pylori infections. Therapeutic applications of proton pump inhibitors are further discussed below 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 to 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 (see Appendix II) and propensity to cause drug interactions, are available in the United States (Figure 36-3): cimetidine (TAGAMET), ranitidine (ZANTAC), famotidine (PEPCID), and nizatidine (AXID). These drugs are less potent than proton pump inhibitors but still suppress 24-hour gastric acid secretion by about 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 36-1). The latter provides better control of gastric pH, but is not proven to be more effective in preventing clinically significant bleeding in critically ill patients.
Pharmacokinetics. The H2-receptor antagonists are rapidly absorbed after oral administration, with peak serum concentrations within 1 to 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 to 5 hours (cimetidine), 6 to 8 hours (ranitidine), or 10 to 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 doses¾seldom used clinically today¾decreases 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 (see below).
All agents that inhibit gastric acid secretion may alter the rate of absorption and subsequent bioavailability of the H2-receptor antagonists (see "Antacids," below). 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 below under "Specific Acid-Peptic Disorders and Therapeutic Strategies."
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. On the other hand, 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 ENHANCE MUCOSAL DEFENSE
Prostaglandin Analogs: Misoprostol
Chemistry; Mechanism of Action; Pharmacology. Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are the major prostaglandins synthesized by the gastric mucosa. They bind to the EP3 receptor on parietal cells (see Chapter 26) 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. 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). Since NSAIDs diminish prostaglandin formation by inhibiting cyclooxygenase, synthetic prostaglandin analogs offer a logical approach to reducing NSAID-induced mucosal damage (see below). Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC) is a synthetic analog of prostaglandin E1. 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 to 200 mg significantly inhibit basal acid secretion (up to 85% to 95% inhibition) or food-stimulated acid secretion (up to 75% to 85% inhibition). The usual recommended dose for ulcer prophylaxis is 200 mg 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 to 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 half-life of about 20 to 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 (see Chapter 38) 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. The proton pump inhibitors and H2-receptor antagonists also are used to diminish the gastrointestinal side effects of NSAIDs, but only lansoprazole holds an FDA approved indication for this purpose.
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) 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 (see below). 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.
Since 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 (about 2%). As 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 (see Table 36-2 for a comparison of some commonly used antacid preparations).
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, while 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 about 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 to 60 minutes. In general, antacids should be administered in suspension form, as this probably has a greater neutralizing capacity than do 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 about 30 minutes. However, the presence of food is sufficient to elevate gastric pH to about 5 for approximately 1 hour and to prolong the neutralizing effects of antacids for about 2 to 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 about one 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 to 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 (see Chapter 7) can reduce basal acid production by 40% to 50% and long have been used to treat patients with peptic ulcer disease in countries other than the United States. 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 36-1). 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 ofAsia . 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 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 11b-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 59). Bismuth compounds (see Chapter 37) 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 (see below); however, given the availability of more effective drugs, bismuth compounds seldom are used alone as cytoprotective agents.
SPECIFIC ACID-PEPTIC DISORDERS AND THERAPEUTIC STRATEGIES
Introduction
The success of acid-suppressing agents in a variety of conditions is critically dependent upon their ability to keep intragastric pH above a certain target, generally pH 3 to 5; this target varies to some extent with the disease being treated (Figure 36-4).
Gastroesophageal Reflux Disease
In theUnited States
Regimens for the treatment of GERD with proton pump inhibitors and histamine H2-receptor antagonists are listed in Table 36-3. 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 (see Chapter 37) 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 "step-down" 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 achlorhydric¾even on twice-daily doses of proton pump inhibitors¾and 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. While this can further suppress acid production, the effect is short-lived, probably due to the development of tolerance, as described above (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% to 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. Proton pump inhibitors 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.
Peptic Ulcer Disease
The pathophysiology of peptic ulcer disease is best viewed as an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, 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 nonsteroidal antiinflammatory drugs (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 (in up to 60% of patients, particularly those with complications such as 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. The effects of these drugs are instead mediated systemically; the critical element is suppression of the constitutive form of cyclooxygenase-1 (COX-1) in the mucosa and decreased production of the cytoprotective prostaglandins PGE2 and PGI2.
Table 36-4 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 (see below), 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.
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 (Graham, 2000) (Table 36-5). 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 to 14 days of treatment appears to be better than shorter treatment regimens; in theUnited States
NSAID-Related Ulcers. Chronic NSAID users have a 2% to 4% risk of developing a symptomatic ulcer, gastrointestinal 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 (see Chapter 25). 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 or longer). Again, proton pump inhibitors are superior to H2-receptor antagonists and misoprostol in promoting the healing of active ulcers (healing rates of 80% to 90% for proton pump inhibitors versus 60% to 75% for the H2-receptor antagonists), and in preventing recurrence of gastric and duodenal ulcers in the setting of continued NSAID administration (Lanza, 1998).
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 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 to 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. 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 to 5 days) makes them less suited for use on an as-needed basis for symptom relief. In this setting, H2-receptor antagonists, while 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.
CHAPTER 36. PHARMACOTHERAPY OF GASTRIC ACIDITY, PEPTIC ULCERS, AND GASTROESOPHAGEAL REFLUX DISEASE - Willemijntje A. Hoogerwerf and Pankaj Jay Pasricha
PHARMACOTHERAPY OF GASTRIC ACIDITY, PEPTIC ULCERS, AND GASTROESOPHAGEAL REFLUX DISEASE: INTRODUCTION
The acid-peptic diseases are those disorders in which gastric acid and pepsin are necessary, but usually not sufficient, pathogenic factors. While inherently caustic, acid and pepsin in the stomach normally do not produce damage or symptoms because of intrinsic defense mechanisms. Barriers to the reflux of gastric contents into the esophagus comprise the primary esophageal defense. If these protective barriers fail and reflux occurs, dyspepsia and/or erosive esophagitis may result. Therapies are directed at decreasing gastric acidity, enhancing the lower esophageal sphincter, or stimulating esophageal motility (see Chapter 37). In the stomach, mucus and bicarbonate, stimulated by the local generation of prostaglandins, protect the gastric mucosa. If these defenses are disrupted, a gastric or duodenal ulcer may form. The treatment and prevention of these acid-related disorders are accomplished either by decreasing the level of gastric acidity or by enhancing mucosal protection. 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.
PHYSIOLOGY OF GASTRIC SECRETION
Gastric acid secretion is a complex, continuous process in which multiple central and peripheral factors contribute to a common endpoint: the secretion of H+ by parietal cells. Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors all regulate acid secretion (Figure 36-1). Their specific receptors (M3, H2, and CCK2 receptors, respectively) are on the basolateral membrane of parietal cells in the body and fundus of the stomach. The H2 receptor is a GPCR that activates the Gs-adenylylcyclase-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 hydrogen and potassium ions across the parietal cell membrane. This pump generates the largest known ion gradient in vertebrates, with an intracellular pH of about 7.3 and an intracanalicular pH of about 0.8.
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 enterochromaffin-like (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 secretion, 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 (see below).
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 protects gastric epithelial cells. 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, alcohol, aspirin, and other drugs that inhibit prostaglandin formation decrease mucus secretion and predispose to the development of acid-peptic disease. A second important part of the normal mucosal defense is the secretion of bicarbonate ions by superficial gastric epithelial cells. Bicarbonate neutralizes the acid in the region of the mucosal cells, thereby raising pH and preventing acid-mediated damage.
Figure 36-1 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 36-2A). In typical doses, these drugs diminish the daily production of acid (basal and stimulated) by 80% to 95%. Five proton pump inhibitors are available for clinical use: omeprazole (PRILOSEC, RAPINEX, ZEGERID) and its S-isomer, esomeprazole (NEXIUM), lansoprazole (PREVACID), rabeprazole (ACIPHEX), and pantoprazole (PROTONIX). These drugs have different substitutions on their pyridine and/or benzimidazole groups but are remarkably similar in their pharmacological properties (see 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 half-life. Despite claims to the contrary, all proton pump inhibitors have equivalent efficacy at comparable doses.
Proton pump inhibitors 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 36-2), 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 to 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: (1) enteric-coated drugs contained inside gelatin capsules (omeprazole, esomeprazole, and lansoprazole); (2) enteric-coated granules supplied as a powder for suspension (lansoprazole); (3) enteric-coated tablets (pantoprazole, rabeprazole, and omeprazole); and (4) powdered drug combined with sodium bicarbonate (omeprazole). The delayed-release and enteric-coated tablets dissolve only at alkaline pH, while 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 pantoprazole or lansoprazole, both of which are approved for intravenous administration in the
Pharmacokinetics. Since an acidic pH in the parietal cell acid canaliculi is required for drug activation, and since food stimulates acid production, these drugs ideally should be given about 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 Caucasians 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 to 5 days of therapy with once-daily dosing to achieve the 70% inhibition of proton pumps that is seen at steady state (Wolfe and Sachs, 2000). More frequent initial dosing (e.g., twice daily) will reduce the time to achieve full inhibition but is not proven to improve patient outcome. Since the proton pump inhibition is irreversible, acid secretion will be suppressed for 24 to 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 above, 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).
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.
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 approximately 5% to 10% of users with chronic omeprazole administration. This hypergastrinemia may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy (see below) and also may promote the growth of gastrointestinal 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 about tenfold 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. The proton pump inhibitors have a track record of approximately 25 years of use worldwide without the emergence of major safety concerns (Klinkenberg-Knol et al., 1994; Kuipers and Meuwissen, 2000).
Therapeutic Uses. Proton pump inhibitors are used principally 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. Proton pump inhibitors also are the mainstay in the treatment of pathological hypersecretory conditions, including the Zollinger-Ellison syndrome. Lansoprazole is FDA approved for treatment and prevention of recurrence of nonsteroidal antiinflammatory drug (NSAID)-associated gastric ulcers in patients who continue NSAID use. In addition, all proton pump inhibitors are FDA approved for reducing the risk of duodenal ulcer recurrence associated with H. pylori infections. Therapeutic applications of proton pump inhibitors are further discussed below 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 to 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 (see Appendix II) and propensity to cause drug interactions, are available in the United States (Figure 36-3): cimetidine (TAGAMET), ranitidine (ZANTAC), famotidine (PEPCID), and nizatidine (AXID). These drugs are less potent than proton pump inhibitors but still suppress 24-hour gastric acid secretion by about 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 36-1). The latter provides better control of gastric pH, but is not proven to be more effective in preventing clinically significant bleeding in critically ill patients.
Pharmacokinetics. The H2-receptor antagonists are rapidly absorbed after oral administration, with peak serum concentrations within 1 to 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 to 5 hours (cimetidine), 6 to 8 hours (ranitidine), or 10 to 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 doses¾seldom used clinically today¾decreases 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 (see below).
All agents that inhibit gastric acid secretion may alter the rate of absorption and subsequent bioavailability of the H2-receptor antagonists (see "Antacids," below). 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 below under "Specific Acid-Peptic Disorders and Therapeutic Strategies."
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. On the other hand, 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 ENHANCE MUCOSAL DEFENSE
Prostaglandin Analogs: Misoprostol
Chemistry; Mechanism of Action; Pharmacology. Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are the major prostaglandins synthesized by the gastric mucosa. They bind to the EP3 receptor on parietal cells (see Chapter 26) 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. 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). Since NSAIDs diminish prostaglandin formation by inhibiting cyclooxygenase, synthetic prostaglandin analogs offer a logical approach to reducing NSAID-induced mucosal damage (see below). Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC) is a synthetic analog of prostaglandin E1. 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 to 200 mg significantly inhibit basal acid secretion (up to 85% to 95% inhibition) or food-stimulated acid secretion (up to 75% to 85% inhibition). The usual recommended dose for ulcer prophylaxis is 200 mg 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 to 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 half-life of about 20 to 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 (see Chapter 38) 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. The proton pump inhibitors and H2-receptor antagonists also are used to diminish the gastrointestinal side effects of NSAIDs, but only lansoprazole holds an FDA approved indication for this purpose.
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) 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 (see below). 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.
Since 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 (about 2%). As 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 (see Table 36-2 for a comparison of some commonly used antacid preparations).
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, while 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 about 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 to 60 minutes. In general, antacids should be administered in suspension form, as this probably has a greater neutralizing capacity than do 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 about 30 minutes. However, the presence of food is sufficient to elevate gastric pH to about 5 for approximately 1 hour and to prolong the neutralizing effects of antacids for about 2 to 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 about one 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 to 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 (see Chapter 7) can reduce basal acid production by 40% to 50% and long have been used to treat patients with peptic ulcer disease in countries other than the United States. 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 36-1). 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
SPECIFIC ACID-PEPTIC DISORDERS AND THERAPEUTIC STRATEGIES
Introduction
The success of acid-suppressing agents in a variety of conditions is critically dependent upon their ability to keep intragastric pH above a certain target, generally pH 3 to 5; this target varies to some extent with the disease being treated (Figure 36-4).
Gastroesophageal Reflux Disease
In the
Regimens for the treatment of GERD with proton pump inhibitors and histamine H2-receptor antagonists are listed in Table 36-3. 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 (see Chapter 37) 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 "step-down" 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 achlorhydric¾even on twice-daily doses of proton pump inhibitors¾and 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. While this can further suppress acid production, the effect is short-lived, probably due to the development of tolerance, as described above (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% to 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. Proton pump inhibitors 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.
Peptic Ulcer Disease
The pathophysiology of peptic ulcer disease is best viewed as an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, 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 nonsteroidal antiinflammatory drugs (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 (in up to 60% of patients, particularly those with complications such as 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. The effects of these drugs are instead mediated systemically; the critical element is suppression of the constitutive form of cyclooxygenase-1 (COX-1) in the mucosa and decreased production of the cytoprotective prostaglandins PGE2 and PGI2.
Table 36-4 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 (see below), 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.
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 (Graham, 2000) (Table 36-5). 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 to 14 days of treatment appears to be better than shorter treatment regimens; in the
NSAID-Related Ulcers. Chronic NSAID users have a 2% to 4% risk of developing a symptomatic ulcer, gastrointestinal 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 (see Chapter 25). 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 or longer). Again, proton pump inhibitors are superior to H2-receptor antagonists and misoprostol in promoting the healing of active ulcers (healing rates of 80% to 90% for proton pump inhibitors versus 60% to 75% for the H2-receptor antagonists), and in preventing recurrence of gastric and duodenal ulcers in the setting of continued NSAID administration (Lanza, 1998).
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 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 to 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. 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 to 5 days) makes them less suited for use on an as-needed basis for symptom relief. In this setting, H2-receptor antagonists, while 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.
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