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Treatment advances in acid secretory disorders: the promise of rapid symptom relief with disease resolution
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 1999 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 94, No. 11, Suppl., 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00658-9
Treatment Advances in Acid Secretory Disorders: The Promise of Rapid Symptom Relief With Disease Resolution David L. Earnest, M.D., F.A.C.P., F.A.C.G., and Malcolm Robinson, M.D., F.A.C.P., F.A.C.G. The University of Arizona Health Sciences Center, Tucson, Arizona; and University of Oklahoma College of Medicine, and Oklahoma Foundation for Digestive Research, Oklahoma City, Oklahoma
ABSTRACT Gastric acid–related disorders are common clinical problems associated with a wide range of symptoms. Important advances have occurred over the last 20 yr that have improved our understanding of these disorders as well as our approach to treatment. Today, control of gastric acid secretion represents the cornerstone of effective management of both peptic ulcer disease and gastroesophageal reflux disease (GERD). A variety of acid-reducing strategies are now available to clinicians to manage symptoms and control or resolve disease. Antacids offer rapid symptomatic relief but probably have little effect on overall disease progression. Histamine-2 receptor antagonists can also provide good initial symptomatic treatment in peptic ulcer disease and in mild to moderate GERD. However, problems with postmeal acid control and tachyphylaxis may detract from their longterm usefulness. The availability of proton pump inhibitors (PPIs), which block the final process in H⫹ ion secretion, has revolutionized our approach to the management of patients with acid secretory disorders. The currently available PPIs, omeprazole and lansoprazole, enable us to control symptoms effectively and safely, hasten healing, and minimize disease recurrence. New PPIs, such as rabeprazole and pantoprazole, will further expand our treatment options and may offer even greater possibilities with regard to rapid symptomatic relief and disease resolution. (Am J Gastroenterol 1999;94(Suppl.):S17–S24. © 1999 by Am. Coll. of Gastroenterology)
cation. Gastric acid also plays a pivotal causative role in the development of GERD. Control of gastric pH, therefore, remains the cornerstone of effective management of these disorders. Research during the past decade has demonstrated that gastric acid suppression resulting in sustained elevation of gastric pH above 3 greatly accelerates healing of peptic ulcer disease; a pH greater than 4 facilitates healing of GERD, and a pH greater than 5 promotes eradication of H. pylori (Fig. 1) (1). The development of agents that effectively suppress gastric acid secretion to achieve these pH levels represents an important milestone in the management of these diseases. Numerous clinical trials have documented the evolving safety and efficacy of these drugs in providing rapid symptom relief and dramatically improving healing of peptic ulcer disease and erosive GERD. This article reviews some of the critical developments that have occurred over the last 2 decades in the management of acid-related disorders. It also examines how improved understanding and new insights have contributed to the evolution of drug therapy from antacids and histamine-2 (H2) receptor antagonists to proton pump inhibitors (PPIs). Finally, we briefly review the PPIs and examine some of the subtle differences among them. The newest PPIs, rabeprazole and pantoprazole, appear to provide some additional benefits for patients who require acid suppressive therapy. These advances will be discussed.
INTRODUCTION
BEYOND ANTACIDS TO H2-RECEPTOR ANTAGONISTS FOR PEPTIC ULCER DISEASE
Gastric acid–related disorders, including peptic ulcer disease and gastroesophageal reflux disease (GERD), are common clinical problems associated with a wide range of symptoms. Important advances have occurred over the last 20 yr that have improved our understanding of these disorders as well as our approach to treatment. We now know that although Helicobacter pylori plays a critical role in the pathogenesis and relapse of peptic ulcer disease, effective suppression of gastric acid is required in addition to antibiotic therapy for prompt ulcer healing and H. pylori eradi-
In the mid-1970s, the standard treatment for peptic ulcer disease was a large dose of liquid antacid, administered 1 and 3 h after meals and at bedtime. Although this was considered an effective way to relieve symptoms and promote ulcer healing, the antacids did nothing to permanently suppress secretion of gastric acid or otherwise modify pathophysiology. The treatment of peptic ulcer disease changed dramatically with the introduction of H2-receptor antagonists such as cimetidine, ranitidine, famotidine, and nizatidine. Once considered appropriate only for difficult-
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Figure 1. Level and duration of intragastric pH elevation needed for optimal treatment of duodenal ulcer, GERD, and H. pylori infection. H2RA ⫽ H2-receptor antagonist (1).
to-treat patients or unusual cases, H2-receptor antagonists block one of the key receptors on the parietal cell that triggers acid secretion. The result is suppression of gastric acid secretion and an increase in the pH of the gastric contents for several hours after dosing. Meal-stimulated acid secretion responds only partially to H2-receptor antagonists. Suppression of nocturnal acid secretion is notable with evening administration, an effect that enhances healing of peptic ulcer disease. Dosing Adjustments In an effort to increase patient compliance with H2-receptor antagonists, investigators studied different dosage regimens. Although b.i.d. dosing with H2-receptor antagonists was effective, once-a-day bedtime dosing resulted in better patient compliance for ulcer healing. The relatively high nocturnal gastric pH led to ulcer healing nearly equal to that with the b.i.d. regimens. The improvements in managing peptic ulcer disease with H2-receptor antagonists initially seemed quite dramatic. Over time, however, the H2-receptor antagonists proved to have some shortcomings as therapeutic agents for acid control. Because these drugs remain at therapeutic blood levels for only 4 – 8 h, they had minimal effects on meal-related or other daytime gastric acid secretion when administered at bedtime. It also became clear that even asymptomatic ulcer patients often relapsed when H2receptor antagonist treatment was discontinued. When gastric pH returned to pretreatment levels, the ulcer frequently recurred.
Helicobacter pylori Clearly, the discovery of the role of H. pylori in the pathogenesis and recurrence of peptic ulcer disease has significantly altered the treatment and outcome of peptic ulcer disease. Although antibiotics to eradicate H. pylori have become an important component of modern ulcer therapy, it is well recognized that gastric acid suppression remains a critical factor in the successful management of the disease. The degree of acid suppression needed to facilitate eradication of H. pylori, however, is greater than that required to heal peptic ulcers or GERD (Fig. 1). High doses of PPIs provide nearly complete acid suppression and are recommended in combination with two antibiotics for H. pylori eradication (2). Interestingly, follow-up studies among patients with peptic ulcer disease who had recurrent symptoms and in whom H. pylori had been eradicated showed that many of these patients did not have a recurrent ulcer but, in fact, had GERD-related heartburn or nonulcer dyspepsia. Additional studies subsequently showed that GERD developed or seemed to become more severe with the greater gastric acid production that can occur after successful eradication of H. pylori (3, 4).
H2-RECEPTOR ANTAGONISTS FOR GERD As with peptic ulcers, control of acid secretion became recognized as a critical component in the management of GERD and in some cases of reflux-like dyspepsia. Patients
AJG – November, Suppl., 1999
with GERD, for example, seldom awaken in the middle of the night with acid-provoked epigastric pain. Instead, their symptoms generally occur after meals. Early studies demonstrated that patients with GERD had a significantly greater number of postprandial acid reflux events compared with individuals without GERD. However, these episodes of acidic reflux were not due to a weak lower esophageal sphincter, as had been thought, but were usually related to inappropriate relaxation of the lower esophageal sphincter—a phenomenon that occurred with gastric distention (5). Attention thus shifted away from nocturnal acid control to postmeal acid control. Conventional doses of H2-receptor antagonists do not overcome the integrated stimuli to acid secretion produced by a meal and thus do not effectively suppress postmeal acid secretion and postprandial esophageal acid exposure (6). Thus, for clinical and pharmacological reasons, new therapeutic strategies were sought for the treatment of GERD. Dosing Adjustments A study by Sabesin et al. (7) showed that the standard peptic ulcer disease healing dose of the H2-receptor antagonist famotidine was more effective in GERD when it was given as b.i.d. therapy than when administered as a single daily dose. The b.i.d. regimen improved control of both postmeal and nocturnal acid secretion. Increasing each of the two daily doses also improved treatment success. Euler et al. (8) demonstrated similar improvements in ranitidine efficacy when frequent dosing was used for erosive esophagitis. In a multicenter, double-blind, placebo-controlled study, ranitidine 150 mg or 300 mg four times daily resulted in significantly higher endoscopic healing rates than placebo at 12 weeks. The four-times-daily dose was also effective in relieving symptoms (8). Results from this high-dose H2receptor antagonist therapy were numerically similar to the results subsequently attained with PPI therapy. Treatment Shortcomings Although H2-receptor antagonists provided GERD sufferers dramatic therapeutic benefit in comparison with antacids, significant shortcomings were apparent, especially for patients with severe disease. Individuals with fairly mild disease could be managed with H2-receptor antagonists twice daily or more frequent treatment at standard or higher dosing levels, and many studies demonstrated acceptable healing of mild to moderate disease. However, as the severity of the erosive disease increased, healing became more difficult or less complete (9). More frequent doses of H2-receptor antagonists were thus apparently required for adequate gastric acid control, but this approach would have impaired compliance and increased cost. In addition, daytime acid suppression was suboptimal for many patients. This was not surprising because H2-receptor antagonists affect only one of the parietal-cell receptors that stimulate meal-related acid secretion. Furthermore, studies showed that acid reduction might not be sustained over time.
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In fact, most H2-receptor antagonist studies, especially those done with PPI comparators, have demonstrated incomplete symptom relief, prolonged time to healing, and relatively high GERD relapse rates during maintenance therapy (10). The problem of tachyphylaxis occurring with H2-receptor antagonists was first observed in the 1980s among patients receiving H2-receptor antagonists i.v. for the treatment of stress ulcers. Subsequently, Decktor et al. (11) examined this problem by comparing three different H2-receptor antagonists in patients with GERD. Although all three agents effectively reduced distal esophageal acid exposure after 24 h, all ceased to be differentiable from placebo after 4 wk of daily therapy, suggesting that pharmacological tolerance to these agents could reduce their long-term effectiveness (Fig. 2). It became clear that despite good early effects with H2-receptor antagonists, some patients with GERD could not be well managed over the long term with this class of agents. In fact, no studies of H2-receptor antagonists for GERD have shown either the acid suppression or the sustained healing levels achievable with standard regimens of PPIs (10).
DRAMATIC ADVANCE: PROTON PUMP INHIBITORS The introduction of PPIs, beginning with omeprazole in the late 1980s, represented a significant advance in the management of all acid-related disorders. PPIs work by blocking the final process in H⫹ ion secretion. This eliminates the problem created by multiple meal-related stimuli for parietal-cell acid secretion and the difficulties inherent in blocking a single parietal-cell receptor. In addition, the time required for parietal cells to synthesize new acid pumps to replace those inactivated by PPIs results in more prolonged gastric acid suppression than that achievable by clinical H2-receptor antagonist dosing. H2-Receptor Antagonists Versus PPIs Studies in gastric acid–related disorders have shown that healing is directly related to the degree and duration of acid suppression (10). Thus, in patients with GERD, if the pH in the esophagus can be maintained above 4.0 for extended periods, high levels of healing can be anticipated. The H2-receptor antagonists accomplish less complete elevation of esophageal pH than PPIs, and consequently the H2receptor antagonists achieve relatively lower levels of healing and symptom control (12). Standard doses of omeprazole, which can provide 12–15 h of acid control, result in improved healing compared with H2-receptor antagonists. When higher or more frequent doses of omeprazole are given, effective acid control is possible for most of the day, even in individuals with resistant disease. Data from individual studies show the superiority of PPIs to H2-receptor antagonists in healing duodenal ulcers and erosive esophagitis and in improving symptoms (13–15). Furthermore, a recent meta-analysis by Chiba et al. (10),
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Figure 2. Effects of 1 and 28 d of treatment with standard doses of H2-receptor antagonists on percentage of 24 h that esophageal pH was ⬍4. All three H2-receptor antagonists demonstrated tolerance, or tachyphylaxis, after 28 d of continuous treatment (11).
combining data from a large number of GERD treatment studies using both H2-receptor antagonists and PPIs, demonstrated an advantage for PPIs in producing more rapid and complete heartburn relief (Fig. 3) and in healing erosive esophagitis (Fig. 4). In addition, PPIs have proved useful in treating patients with reflux esophagitis refractory to H2receptor antagonists (16). Two PPIs, omeprazole and lansoprazole, are currently available in the United States for clinical use. Two additional agents in this class, rabeprazole and pantoprazole, are available in Asia and Europe and are in the final stages of evaluation in the United States. Both will increase the options for disease management. Data show that all four PPIs are extremely effective for acute and chronic treatment of acid-related disorders. In addition, all of the PPIs appear to have minimal side effects, demonstrate favorable safety profiles, and have had good tolerability throughout longterm use (1, 17). As more PPIs become clinically available, it is important to recognize and evaluate the differences among their specific actions to maximize their potential therapeutic advantage in individual patients. Clinical experience with PPIs has already revealed subtle differences among them that can affect such factors as potency, time to maximum effectiveness, pharmacodynamic predictability, adequacy of noctur-
nal acid suppression, and the potential for clinically significant adverse drug interactions related to cytochrome P450 metabolism. Comparative Studies A recent study by Besancon et al. (18) compared the rate of inhibition of H⫹, K⫹, –ATPase activity and acid transport in isolated proton pumps by PPIs. The enzyme inhibition rates for lansoprazole and omeprazole were very similar; pantoprazole was significantly slower; and rabeprazole was significantly faster than the other drugs, achieving full inhibition of the enzyme at 5 min. The rate of inhibition of acid transport was fastest with rabeprazole, equal with omeprazole and lansoprazole, and slowest with pantoprazole (Fig. 5), correlating with their relative rates of acid inhibition in this model. Rabeprazole’s faster rate of inhibition of gastric acid secretion in vitro has been confirmed in normal volunteers, in whom it caused significantly greater suppression of gastric acid, leading to increased pH, compared with omeprazole on day 1 of dosing (Fig. 6) (19). Other studies comparing omeprazole with lansoprazole show that lansoprazole is more potent than omeprazole and demonstrates superior bioavailability (20). A study comparing lansoprazole and pantoprazole also demonstrated that lansoprazole was significantly more potent than pantopra-
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Figure 3. Relief of heartburn with PPI treatment. A dramatic shift is seen in the number of patients who are completely symptom free, particularly early in the course of treatment. After 8 weeks, few patients have any residual heartburn. Reproduced with permission from (10).
Figure 4. Healing time curves for esophagitis treated with either a proton pump inhibitor (PPI), an H2-receptor antagonist (H2RA), or placebo. Note that by week 4, PPIs have healed more patients than any other class of drug; maximum healing is usually achieved by week 6 – 8. Reproduced with permission from (10).
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Figure 5. Comparative rates (t1/2) of inhibition of acid transport by isolated proton pumps induced by lansoprazole, omeprazole, pantoprazole, and rabeprazole. The lower values represent faster inhibition. Reproduced with permission from (18).
Figure 6. Intragastric pH in 23 normal volunteers on day 1 after the first dose of rabeprazole, omeprazole, or placebo. A marked increase in intragastric pH was seen on day 1 only with rabeprazole. Adapted with permission from (19).
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zole based on 24-h pH profiles (21). Results from welldesigned studies are not yet available between pantoprazole or lansoprazole and rabeprazole for the important clinical indications. Although it has not been studied as extensively yet because it is the newest PPI, rabeprazole shows promise in a number of specific features, including very rapid onset of action with dramatic and prolonged reduction of gastric acid secretion, effectiveness in healing peptic ulcer disease and erosive or ulcerative GERD (22–24), rapid relief of peptic ulcer disease and GERD pain (22–24), dosing flexibility, safety, and tolerability (25, 26). The safety and efficacy of rabeprazole in GERD maintenance therapy has also been shown in early clinical trials (27, 28). Maintenance of GERD Healing Long-term maintenance of esophagitis healing in GERD patients is especially important given the high rates of relapse associated with this disease. There is a need for sustained symptom relief and, perhaps most important, the prevention of serious pathological esophageal mucosal changes such as stricture and Barrett’s esophagus. In particular, Barrett’s epithelium, which has an increased risk of malignant change, is present in up to 15% of patients with chronic GERD (4). It is thought to develop in part as a result of chronically increased exposure of the distal esophagus to acidic gastric contents. Adequate control of gastric acid secretion by PPIs may be important in decreasing the formation of Barrett’s epithelium and in preventing its subsequent malignant transformation. Several maintenance trials for GERD healing are under way that may provide answers to this question as well as additional information regarding the ideal management of chronic GERD.
CONCLUSIONS As we have observed throughout this review, the control of gastric acid secretion remains the cornerstone of effective management of both peptic ulcer disease and GERD. Greater and sustained control of gastric acid secretion and esophageal pH results in better symptom relief and more rapid disease resolution for many patients. Clinicians today have a variety of acid-reducing strategies available to them. Antacids are good for quick symptomatic relief, but they presumably have little long-term effect on overall disease progression. The H2-receptor antagonists are effective for healing peptic ulcer disease and mild GERD, and they can provide good symptom control and disease management initially in appropriately selected patients. However, problems with daytime and postmeal acid control as well as tachyphylaxis may detract from their utility in severe acidrelated disorders and long-term disease suppression. Finally, the ability to control the acid pump has revolutionized our approach to the treatment of patients with acid secretory disorders. PPIs now enable us to control symptoms safely and effectively, hasten disease resolution, and
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minimize disease recurrence. Drugs in this class such as omeprazole and lansoprazole are available for clinical use in the United States. Additional new agents such as rabeprazole and pantoprazole will likely become available soon. Selection of the appropriate PPI will depend on the profile of the specific drug and the individual needs of the patient. Given this expanding range of treatment options, the outlook is excellent for effective acute and long-term control of these common and potentially serious disorders. Reprint requests and correspondence: David L. Earnest, M.D., F.A.C.P., F.A.C.G., Gastroenterology Section, The University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724. Received Mar. 29, 1999; accepted Aug. 3, 1999.
REFERENCES 1. Modlin IM, Sachs G. Acid related diseases: Biology and treatment. Milan: Schnetztor-Verlag GmbH Konstanz, 1998. 2. Stack WA, Knifton A, Thirlwell D, et al. Safety and efficacy of rabeprazole in combination with four antibiotic regimens for the eradication of Helicobacter pylori in patients with chronic gastritis with or without peptic ulceration. Am J Gastroenterol 1998;93:1909 –13. 3. Labenz J, Blum AL, Bayerdo¨rffer E, et al. Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997;112:1442–7. 4. Labenz J, Tillenburg B, Peitz U, et al. Efficacy of omeprazole one year after cure of Helicobacter pylori infection in duodenal ulcer patients. Am J Gastroenterol 1997;92:576 – 81. 5. Freston JW, Malagelada JR, Petersen H, et al. Critical issues in the management of gastroesophageal reflux disease. Eur J Gastroenterol Hepatol 1995;7:577– 86. 6. Merki HS, Wilder-Smith CH, Walt RP, et al. The cephalic and gastric phases of gastric acid secretion during H2-antagonist treatment. Gastroenterology 1991;101:599 – 606. 7. Sabesin SM, Berlin RG, Humphries TJ, et al. Famotidine relieves symptoms of gastroesophageal reflux disease and heals erosions and ulcerations. Results of a multicenter, placebo-controlled, dose-ranging study. Arch Intern Med 1991; 151:2394 – 400. 8. Euler AR, Murdock RH Jr, Wilson TH, et al. Ranitidine is effective therapy for erosive esophagitis. Am J Gastroenterol 1993;88:520 – 4. 9. Bate CM, Keeling PWN, O’Morain C, et al. Comparison of omeprazole and cimetidine in reflux oesophagitis: Symptomatic, endoscopic, and histological evaluations. Gut 1990;31: 968 –72. 10. Chiba N, De Gara CJ, Wilkinson JM, et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: A meta-analysis. Gastroenterology 1997;112:1798 – 810. 11. Decktor DL, Robinson M, Maton PN, et al. H2-receptor antagonist tolerance and gastroesophageal reflux disease: A comparison of nizatidine, ranitidine and famotidine on esophageal and gastric pH over 28 days of standard therapy. Am J Gastroenterol 1993;88:1487 (abstract). 12. Klinkenberg-Knol EC, Festen HPM, Meuwissen SGM. Pharmacological management of gastro-oesophageal reflux disease. Drugs 1995;49:695–710. 13. Humphries TJ, Spera A, Breiter J, et al. Rabeprazole sodium once daily is superior to ranitidine 150 mg bid in the healing
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16. 17. 18. 19.
20. 21.
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of active duodenal ulcer. Gastroenterology 1997;112:A154 (abstract). Klinkenberg-Knol EC, Festen HPM, Jansen JMBJ, et al. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet 1987;1:349 –51. Humphries TJ, Spera A, Breiter J, et al. Rabeprazole sodium (E3810) once daily is superior to ranitidine 150 mg qid in the healing of erosive or ulcerative gastroesophageal reflux disease. Gastroenterology 1996;110:A139 (abstract). Klinkenberg-Knol EC. Eleven years’ experience of continuous maintenance treatment with omeprazole in GERD-patients. Gastroenterology 1998;114:A180 (abstract). Klinkenberg-Knol EC, Festen HPM, Jansen JBMJ, et al. Longterm treatment with omeprazole for refractory reflux esophagitis: Efficacy and safety. Ann Intern Med 1994;121:161–7. Besancon M, Simon A, Sachs G, et al. Sites of reaction of the gastric H, K-ATPase with extracytoplasmic thiol reagents. J Biol Chem 1997;272:22438 – 46. Williams MP, Sercombe J, Hamilton MI, et al. A placebocontrolled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther 1998;12:1079 – 89. Sanders SW. Pathogenesis and treatment of acid peptic disorders: Comparison of proton pump inhibitors with other antiulcer agents. Clin Ther 1996;18:2–34. Florent C, Forestier S. Twenty-four-hour monitoring of intragastric acidity: Comparison between lansoprazole 30 mg and pantoprazole 40 mg. Eur J Gastroenterol Hepatol 1997;9:195– 200.
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22. Cloud ML, Enas N, Humphries TJ, et al. Rabeprazole in treatment of acid peptic diseases. Results of three placebocontrolled dose-response clinical trials in duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease (GERD). Dig Dis Sci 1998;43:993–1000. 23. Dekkers CPM, Beker JA, Thjodleifsson B, et al. Double-blind, placebo-controlled comparison of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of erosive or ulcerative gastrooesophageal reflux disease. Aliment Pharmacol Ther 1999;13: 49 –57. 24. Dekkers CPM, Beker JA, Thjodleifsson B, et al. Comparison of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of active gastric ulcer—a European multicentre study. The European Rabeprazole Study Group. Aliment Pharmacol Ther 1998;12:789 –95. 25. Humphries T, Merritt J, Hoyumpa A, et al. Rabeprazole 20 mg does not appear to require dosage adjustment in elderly patients or those with mild to moderate hepatic disease. Am J Gastroenterol 1998;93:1638 (abstract). 26. Humphries TJ, Keane WF, St Peter JV, et al. Rabeprazole: Safety, tolerance, and pharmacokinetics in patients with renal dysfunction. Am J Gastroenterol 1998;93:1638 (abstract). 27. Humphries TJ, Dekkers CPM, Beker JA, et al. Rabeprazole vs omeprazole for maintenance therapy of healed erosive GERD: Results of a 1-year multicenter trial. Am J Gastroenterol 1998;93:1616 (abstract). 28. Birbara C, Breiter J, Collins D, et al. Rabeprazole: Preventing endoscopic and symptomatic relapse in erosive or ulcerative GERD. Am J Gastroenterol 1998;93:1630 (abstract).
Vol. 94, No. 11, Suppl., 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00658-9
Treatment Advances in Acid Secretory Disorders: The Promise of Rapid Symptom Relief With Disease Resolution David L. Earnest, M.D., F.A.C.P., F.A.C.G., and Malcolm Robinson, M.D., F.A.C.P., F.A.C.G. The University of Arizona Health Sciences Center, Tucson, Arizona; and University of Oklahoma College of Medicine, and Oklahoma Foundation for Digestive Research, Oklahoma City, Oklahoma
ABSTRACT Gastric acid–related disorders are common clinical problems associated with a wide range of symptoms. Important advances have occurred over the last 20 yr that have improved our understanding of these disorders as well as our approach to treatment. Today, control of gastric acid secretion represents the cornerstone of effective management of both peptic ulcer disease and gastroesophageal reflux disease (GERD). A variety of acid-reducing strategies are now available to clinicians to manage symptoms and control or resolve disease. Antacids offer rapid symptomatic relief but probably have little effect on overall disease progression. Histamine-2 receptor antagonists can also provide good initial symptomatic treatment in peptic ulcer disease and in mild to moderate GERD. However, problems with postmeal acid control and tachyphylaxis may detract from their longterm usefulness. The availability of proton pump inhibitors (PPIs), which block the final process in H⫹ ion secretion, has revolutionized our approach to the management of patients with acid secretory disorders. The currently available PPIs, omeprazole and lansoprazole, enable us to control symptoms effectively and safely, hasten healing, and minimize disease recurrence. New PPIs, such as rabeprazole and pantoprazole, will further expand our treatment options and may offer even greater possibilities with regard to rapid symptomatic relief and disease resolution. (Am J Gastroenterol 1999;94(Suppl.):S17–S24. © 1999 by Am. Coll. of Gastroenterology)
cation. Gastric acid also plays a pivotal causative role in the development of GERD. Control of gastric pH, therefore, remains the cornerstone of effective management of these disorders. Research during the past decade has demonstrated that gastric acid suppression resulting in sustained elevation of gastric pH above 3 greatly accelerates healing of peptic ulcer disease; a pH greater than 4 facilitates healing of GERD, and a pH greater than 5 promotes eradication of H. pylori (Fig. 1) (1). The development of agents that effectively suppress gastric acid secretion to achieve these pH levels represents an important milestone in the management of these diseases. Numerous clinical trials have documented the evolving safety and efficacy of these drugs in providing rapid symptom relief and dramatically improving healing of peptic ulcer disease and erosive GERD. This article reviews some of the critical developments that have occurred over the last 2 decades in the management of acid-related disorders. It also examines how improved understanding and new insights have contributed to the evolution of drug therapy from antacids and histamine-2 (H2) receptor antagonists to proton pump inhibitors (PPIs). Finally, we briefly review the PPIs and examine some of the subtle differences among them. The newest PPIs, rabeprazole and pantoprazole, appear to provide some additional benefits for patients who require acid suppressive therapy. These advances will be discussed.
INTRODUCTION
BEYOND ANTACIDS TO H2-RECEPTOR ANTAGONISTS FOR PEPTIC ULCER DISEASE
Gastric acid–related disorders, including peptic ulcer disease and gastroesophageal reflux disease (GERD), are common clinical problems associated with a wide range of symptoms. Important advances have occurred over the last 20 yr that have improved our understanding of these disorders as well as our approach to treatment. We now know that although Helicobacter pylori plays a critical role in the pathogenesis and relapse of peptic ulcer disease, effective suppression of gastric acid is required in addition to antibiotic therapy for prompt ulcer healing and H. pylori eradi-
In the mid-1970s, the standard treatment for peptic ulcer disease was a large dose of liquid antacid, administered 1 and 3 h after meals and at bedtime. Although this was considered an effective way to relieve symptoms and promote ulcer healing, the antacids did nothing to permanently suppress secretion of gastric acid or otherwise modify pathophysiology. The treatment of peptic ulcer disease changed dramatically with the introduction of H2-receptor antagonists such as cimetidine, ranitidine, famotidine, and nizatidine. Once considered appropriate only for difficult-
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Figure 1. Level and duration of intragastric pH elevation needed for optimal treatment of duodenal ulcer, GERD, and H. pylori infection. H2RA ⫽ H2-receptor antagonist (1).
to-treat patients or unusual cases, H2-receptor antagonists block one of the key receptors on the parietal cell that triggers acid secretion. The result is suppression of gastric acid secretion and an increase in the pH of the gastric contents for several hours after dosing. Meal-stimulated acid secretion responds only partially to H2-receptor antagonists. Suppression of nocturnal acid secretion is notable with evening administration, an effect that enhances healing of peptic ulcer disease. Dosing Adjustments In an effort to increase patient compliance with H2-receptor antagonists, investigators studied different dosage regimens. Although b.i.d. dosing with H2-receptor antagonists was effective, once-a-day bedtime dosing resulted in better patient compliance for ulcer healing. The relatively high nocturnal gastric pH led to ulcer healing nearly equal to that with the b.i.d. regimens. The improvements in managing peptic ulcer disease with H2-receptor antagonists initially seemed quite dramatic. Over time, however, the H2-receptor antagonists proved to have some shortcomings as therapeutic agents for acid control. Because these drugs remain at therapeutic blood levels for only 4 – 8 h, they had minimal effects on meal-related or other daytime gastric acid secretion when administered at bedtime. It also became clear that even asymptomatic ulcer patients often relapsed when H2receptor antagonist treatment was discontinued. When gastric pH returned to pretreatment levels, the ulcer frequently recurred.
Helicobacter pylori Clearly, the discovery of the role of H. pylori in the pathogenesis and recurrence of peptic ulcer disease has significantly altered the treatment and outcome of peptic ulcer disease. Although antibiotics to eradicate H. pylori have become an important component of modern ulcer therapy, it is well recognized that gastric acid suppression remains a critical factor in the successful management of the disease. The degree of acid suppression needed to facilitate eradication of H. pylori, however, is greater than that required to heal peptic ulcers or GERD (Fig. 1). High doses of PPIs provide nearly complete acid suppression and are recommended in combination with two antibiotics for H. pylori eradication (2). Interestingly, follow-up studies among patients with peptic ulcer disease who had recurrent symptoms and in whom H. pylori had been eradicated showed that many of these patients did not have a recurrent ulcer but, in fact, had GERD-related heartburn or nonulcer dyspepsia. Additional studies subsequently showed that GERD developed or seemed to become more severe with the greater gastric acid production that can occur after successful eradication of H. pylori (3, 4).
H2-RECEPTOR ANTAGONISTS FOR GERD As with peptic ulcers, control of acid secretion became recognized as a critical component in the management of GERD and in some cases of reflux-like dyspepsia. Patients
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with GERD, for example, seldom awaken in the middle of the night with acid-provoked epigastric pain. Instead, their symptoms generally occur after meals. Early studies demonstrated that patients with GERD had a significantly greater number of postprandial acid reflux events compared with individuals without GERD. However, these episodes of acidic reflux were not due to a weak lower esophageal sphincter, as had been thought, but were usually related to inappropriate relaxation of the lower esophageal sphincter—a phenomenon that occurred with gastric distention (5). Attention thus shifted away from nocturnal acid control to postmeal acid control. Conventional doses of H2-receptor antagonists do not overcome the integrated stimuli to acid secretion produced by a meal and thus do not effectively suppress postmeal acid secretion and postprandial esophageal acid exposure (6). Thus, for clinical and pharmacological reasons, new therapeutic strategies were sought for the treatment of GERD. Dosing Adjustments A study by Sabesin et al. (7) showed that the standard peptic ulcer disease healing dose of the H2-receptor antagonist famotidine was more effective in GERD when it was given as b.i.d. therapy than when administered as a single daily dose. The b.i.d. regimen improved control of both postmeal and nocturnal acid secretion. Increasing each of the two daily doses also improved treatment success. Euler et al. (8) demonstrated similar improvements in ranitidine efficacy when frequent dosing was used for erosive esophagitis. In a multicenter, double-blind, placebo-controlled study, ranitidine 150 mg or 300 mg four times daily resulted in significantly higher endoscopic healing rates than placebo at 12 weeks. The four-times-daily dose was also effective in relieving symptoms (8). Results from this high-dose H2receptor antagonist therapy were numerically similar to the results subsequently attained with PPI therapy. Treatment Shortcomings Although H2-receptor antagonists provided GERD sufferers dramatic therapeutic benefit in comparison with antacids, significant shortcomings were apparent, especially for patients with severe disease. Individuals with fairly mild disease could be managed with H2-receptor antagonists twice daily or more frequent treatment at standard or higher dosing levels, and many studies demonstrated acceptable healing of mild to moderate disease. However, as the severity of the erosive disease increased, healing became more difficult or less complete (9). More frequent doses of H2-receptor antagonists were thus apparently required for adequate gastric acid control, but this approach would have impaired compliance and increased cost. In addition, daytime acid suppression was suboptimal for many patients. This was not surprising because H2-receptor antagonists affect only one of the parietal-cell receptors that stimulate meal-related acid secretion. Furthermore, studies showed that acid reduction might not be sustained over time.
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In fact, most H2-receptor antagonist studies, especially those done with PPI comparators, have demonstrated incomplete symptom relief, prolonged time to healing, and relatively high GERD relapse rates during maintenance therapy (10). The problem of tachyphylaxis occurring with H2-receptor antagonists was first observed in the 1980s among patients receiving H2-receptor antagonists i.v. for the treatment of stress ulcers. Subsequently, Decktor et al. (11) examined this problem by comparing three different H2-receptor antagonists in patients with GERD. Although all three agents effectively reduced distal esophageal acid exposure after 24 h, all ceased to be differentiable from placebo after 4 wk of daily therapy, suggesting that pharmacological tolerance to these agents could reduce their long-term effectiveness (Fig. 2). It became clear that despite good early effects with H2-receptor antagonists, some patients with GERD could not be well managed over the long term with this class of agents. In fact, no studies of H2-receptor antagonists for GERD have shown either the acid suppression or the sustained healing levels achievable with standard regimens of PPIs (10).
DRAMATIC ADVANCE: PROTON PUMP INHIBITORS The introduction of PPIs, beginning with omeprazole in the late 1980s, represented a significant advance in the management of all acid-related disorders. PPIs work by blocking the final process in H⫹ ion secretion. This eliminates the problem created by multiple meal-related stimuli for parietal-cell acid secretion and the difficulties inherent in blocking a single parietal-cell receptor. In addition, the time required for parietal cells to synthesize new acid pumps to replace those inactivated by PPIs results in more prolonged gastric acid suppression than that achievable by clinical H2-receptor antagonist dosing. H2-Receptor Antagonists Versus PPIs Studies in gastric acid–related disorders have shown that healing is directly related to the degree and duration of acid suppression (10). Thus, in patients with GERD, if the pH in the esophagus can be maintained above 4.0 for extended periods, high levels of healing can be anticipated. The H2-receptor antagonists accomplish less complete elevation of esophageal pH than PPIs, and consequently the H2receptor antagonists achieve relatively lower levels of healing and symptom control (12). Standard doses of omeprazole, which can provide 12–15 h of acid control, result in improved healing compared with H2-receptor antagonists. When higher or more frequent doses of omeprazole are given, effective acid control is possible for most of the day, even in individuals with resistant disease. Data from individual studies show the superiority of PPIs to H2-receptor antagonists in healing duodenal ulcers and erosive esophagitis and in improving symptoms (13–15). Furthermore, a recent meta-analysis by Chiba et al. (10),
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Figure 2. Effects of 1 and 28 d of treatment with standard doses of H2-receptor antagonists on percentage of 24 h that esophageal pH was ⬍4. All three H2-receptor antagonists demonstrated tolerance, or tachyphylaxis, after 28 d of continuous treatment (11).
combining data from a large number of GERD treatment studies using both H2-receptor antagonists and PPIs, demonstrated an advantage for PPIs in producing more rapid and complete heartburn relief (Fig. 3) and in healing erosive esophagitis (Fig. 4). In addition, PPIs have proved useful in treating patients with reflux esophagitis refractory to H2receptor antagonists (16). Two PPIs, omeprazole and lansoprazole, are currently available in the United States for clinical use. Two additional agents in this class, rabeprazole and pantoprazole, are available in Asia and Europe and are in the final stages of evaluation in the United States. Both will increase the options for disease management. Data show that all four PPIs are extremely effective for acute and chronic treatment of acid-related disorders. In addition, all of the PPIs appear to have minimal side effects, demonstrate favorable safety profiles, and have had good tolerability throughout longterm use (1, 17). As more PPIs become clinically available, it is important to recognize and evaluate the differences among their specific actions to maximize their potential therapeutic advantage in individual patients. Clinical experience with PPIs has already revealed subtle differences among them that can affect such factors as potency, time to maximum effectiveness, pharmacodynamic predictability, adequacy of noctur-
nal acid suppression, and the potential for clinically significant adverse drug interactions related to cytochrome P450 metabolism. Comparative Studies A recent study by Besancon et al. (18) compared the rate of inhibition of H⫹, K⫹, –ATPase activity and acid transport in isolated proton pumps by PPIs. The enzyme inhibition rates for lansoprazole and omeprazole were very similar; pantoprazole was significantly slower; and rabeprazole was significantly faster than the other drugs, achieving full inhibition of the enzyme at 5 min. The rate of inhibition of acid transport was fastest with rabeprazole, equal with omeprazole and lansoprazole, and slowest with pantoprazole (Fig. 5), correlating with their relative rates of acid inhibition in this model. Rabeprazole’s faster rate of inhibition of gastric acid secretion in vitro has been confirmed in normal volunteers, in whom it caused significantly greater suppression of gastric acid, leading to increased pH, compared with omeprazole on day 1 of dosing (Fig. 6) (19). Other studies comparing omeprazole with lansoprazole show that lansoprazole is more potent than omeprazole and demonstrates superior bioavailability (20). A study comparing lansoprazole and pantoprazole also demonstrated that lansoprazole was significantly more potent than pantopra-
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Figure 3. Relief of heartburn with PPI treatment. A dramatic shift is seen in the number of patients who are completely symptom free, particularly early in the course of treatment. After 8 weeks, few patients have any residual heartburn. Reproduced with permission from (10).
Figure 4. Healing time curves for esophagitis treated with either a proton pump inhibitor (PPI), an H2-receptor antagonist (H2RA), or placebo. Note that by week 4, PPIs have healed more patients than any other class of drug; maximum healing is usually achieved by week 6 – 8. Reproduced with permission from (10).
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Figure 5. Comparative rates (t1/2) of inhibition of acid transport by isolated proton pumps induced by lansoprazole, omeprazole, pantoprazole, and rabeprazole. The lower values represent faster inhibition. Reproduced with permission from (18).
Figure 6. Intragastric pH in 23 normal volunteers on day 1 after the first dose of rabeprazole, omeprazole, or placebo. A marked increase in intragastric pH was seen on day 1 only with rabeprazole. Adapted with permission from (19).
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zole based on 24-h pH profiles (21). Results from welldesigned studies are not yet available between pantoprazole or lansoprazole and rabeprazole for the important clinical indications. Although it has not been studied as extensively yet because it is the newest PPI, rabeprazole shows promise in a number of specific features, including very rapid onset of action with dramatic and prolonged reduction of gastric acid secretion, effectiveness in healing peptic ulcer disease and erosive or ulcerative GERD (22–24), rapid relief of peptic ulcer disease and GERD pain (22–24), dosing flexibility, safety, and tolerability (25, 26). The safety and efficacy of rabeprazole in GERD maintenance therapy has also been shown in early clinical trials (27, 28). Maintenance of GERD Healing Long-term maintenance of esophagitis healing in GERD patients is especially important given the high rates of relapse associated with this disease. There is a need for sustained symptom relief and, perhaps most important, the prevention of serious pathological esophageal mucosal changes such as stricture and Barrett’s esophagus. In particular, Barrett’s epithelium, which has an increased risk of malignant change, is present in up to 15% of patients with chronic GERD (4). It is thought to develop in part as a result of chronically increased exposure of the distal esophagus to acidic gastric contents. Adequate control of gastric acid secretion by PPIs may be important in decreasing the formation of Barrett’s epithelium and in preventing its subsequent malignant transformation. Several maintenance trials for GERD healing are under way that may provide answers to this question as well as additional information regarding the ideal management of chronic GERD.
CONCLUSIONS As we have observed throughout this review, the control of gastric acid secretion remains the cornerstone of effective management of both peptic ulcer disease and GERD. Greater and sustained control of gastric acid secretion and esophageal pH results in better symptom relief and more rapid disease resolution for many patients. Clinicians today have a variety of acid-reducing strategies available to them. Antacids are good for quick symptomatic relief, but they presumably have little long-term effect on overall disease progression. The H2-receptor antagonists are effective for healing peptic ulcer disease and mild GERD, and they can provide good symptom control and disease management initially in appropriately selected patients. However, problems with daytime and postmeal acid control as well as tachyphylaxis may detract from their utility in severe acidrelated disorders and long-term disease suppression. Finally, the ability to control the acid pump has revolutionized our approach to the treatment of patients with acid secretory disorders. PPIs now enable us to control symptoms safely and effectively, hasten disease resolution, and
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minimize disease recurrence. Drugs in this class such as omeprazole and lansoprazole are available for clinical use in the United States. Additional new agents such as rabeprazole and pantoprazole will likely become available soon. Selection of the appropriate PPI will depend on the profile of the specific drug and the individual needs of the patient. Given this expanding range of treatment options, the outlook is excellent for effective acute and long-term control of these common and potentially serious disorders. Reprint requests and correspondence: David L. Earnest, M.D., F.A.C.P., F.A.C.G., Gastroenterology Section, The University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724. Received Mar. 29, 1999; accepted Aug. 3, 1999.
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22. Cloud ML, Enas N, Humphries TJ, et al. Rabeprazole in treatment of acid peptic diseases. Results of three placebocontrolled dose-response clinical trials in duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease (GERD). Dig Dis Sci 1998;43:993–1000. 23. Dekkers CPM, Beker JA, Thjodleifsson B, et al. Double-blind, placebo-controlled comparison of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of erosive or ulcerative gastrooesophageal reflux disease. Aliment Pharmacol Ther 1999;13: 49 –57. 24. Dekkers CPM, Beker JA, Thjodleifsson B, et al. Comparison of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of active gastric ulcer—a European multicentre study. The European Rabeprazole Study Group. Aliment Pharmacol Ther 1998;12:789 –95. 25. Humphries T, Merritt J, Hoyumpa A, et al. Rabeprazole 20 mg does not appear to require dosage adjustment in elderly patients or those with mild to moderate hepatic disease. Am J Gastroenterol 1998;93:1638 (abstract). 26. Humphries TJ, Keane WF, St Peter JV, et al. Rabeprazole: Safety, tolerance, and pharmacokinetics in patients with renal dysfunction. Am J Gastroenterol 1998;93:1638 (abstract). 27. Humphries TJ, Dekkers CPM, Beker JA, et al. Rabeprazole vs omeprazole for maintenance therapy of healed erosive GERD: Results of a 1-year multicenter trial. Am J Gastroenterol 1998;93:1616 (abstract). 28. Birbara C, Breiter J, Collins D, et al. Rabeprazole: Preventing endoscopic and symptomatic relapse in erosive or ulcerative GERD. Am J Gastroenterol 1998;93:1630 (abstract).