THE YALE JOURNAL OF BIOLOGY AND MEDICINE 65 (1992), 649-657
`Progress with Proton Pump Inhibition
`
`NICHOLAS J.V. BELL, M.A., F.R.C.S.,
`AND RICHARD H. HUNT, F.R.C.P., F.R.C.P.(C)
`
`Division of Gastroenterology, McMaster University Medical Centre,
`Hamilton, Ontario, Canada
`Received May 11, 1992
`
`The proton pump, a H+/K+-ATPase located on the secretory canalicular membrane of the
`parietal cell, forms the final pathway for gastric acid secretion. Omeprazole is concentrated in
`the secretory canaliculus, where it is converted to its active form, which binds covalently with
`the H+ /K+-ATPase, thus inhibiting acid secretion arising from any stimulus.
`Meta-analysis has defined the primary determinants for peptic ulcer healing as the degree of
`acid suppression, the duration of suppression over 24 hours, and the length of treatment. The
`longer duration of acid suppression with omeprazole, particularly during the day, when food is
`ingested and H2-receptor antagonists are less effective, is reflected in the clinical superiority for
`symptom relief and ulcer healing and especially for the treatment of erosive esophagitis.
`Extensive clinical experience has proved omeprazole to be safe, and concerns over hypergas-
`trinemia, ECL-cell hyperplasia, and carcinoid formation have not been substantiated in
`humans. Recent evidence has shown that omeprazole suppresses Helicobacter pylori and, in
`combination with antibiotics, can eradicate this organism in a substantial proportion of
`patients. This effect may result from enhancement of antibiotic bioavailability and optimizing
`host defense mechanisms.
`
`The gastric parietal cell is regulated by a complex interaction of neural, endocrine,
`and paracrine factors. These act on muscarinic M3, gastrin, and histamine H2
`receptors, respectively. Ligand binding to all three receptors initiates a cascade
`involving the release of intracellular calcium, while the binding of histamine to the
`H2 receptor also activates adenylate cyclase, causing an increase in cellular cyclic
`AMP [1]. Transduction via these pathways results in activation of the "proton
`pump," a H+/K+-ATPase, which is active only at the secretory canalicular mem-
`brane of the parietal cell. Whereas blockade of the cholinergic, histamine, or gastrin
`receptors can modulate or reduce acid secretion, only inhibition of this H+/K+-
`ATPase, which is the final common pathway to acid secretion, can abolish the
`secretory response to all known secretagogues.
`Omeprazole is the first of a new class of substituted benzimidazole compounds
`that can specifically block the parietal cell H+/K+-ATPase and thus inhibit gastric
`acid secretion.
`Omeprazole is a lipophilic weak base. It is absorbed from the proximal small
`intestine, distributed throughout the body with a plasma half-life of about one hour,
`and concentrated in the parietal cells. Within the parietal cells, omeprazole is
`concentrated and trapped in the highly acidic compartment of the secretory canalic-
`ulus. Here, it is converted to its active sulfenamide form, which binds covalently to
`the H+/K+-ATPase, inactivating the pump, and thus inhibiting acid secretion. From
`649
`MIC: minimum inhibitory concenration
`Abbreviation:
`Copyright © 1992 by The Yale Journal of Biology and Medicine, Inc.
`All rights of reproduction in any form reserved.
`
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`BELL AND HUNT
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`its mechanism of action, one may see that omeprazole can only be trapped and
`converted in an actively secreting parietal cell. This fact may partly explain why
`morning dosing, when the parietal cells are secreting in response to meal stimulation,
`has a greater effect on intragastric acidity than evening dosing [2,3].
`As omeprazole is acid-labile, it is formulated as enteric-coated granules dispensed
`in a gelatine capsule. The granules release at an alkaline pH, allowing absorption of
`intact omeprazole into the circulation. Peak plasma levels occur about three hours
`after an oral dose [4]. The plasma half-life is short, and the drug is undetectable by
`about 11 hours after dosing. As the active form of omeprazole binds covalently to the
`H+ /K+-ATPase enzyme, the plasma drug levels at any one time do not correlate with
`the degree of acid inhibition, which can be detected for three to four days after a
`single dose. The initial degree of acid inhibition does, however, correlate with the
`area under the plasma concentration time curve, which represents the amount of
`drug available to the parietal cells [5]. The bioavailability of omeprazole increases
`with repeated dosing, from 35 percent after a single dose to 60 percent after one
`week's administration, possibly due to increased absorption secondary to reduced
`intragastric acidity [2,6].
`Omeprazole dose-dependently inhibits basal and stimulated gastric acid secretion
`[7] and also lowers 24-hour acidity, omeprazole, 30 mg daily, for one week, resulting
`in a 97 percent reduction in median 24-hour intragastric acidity [8].
`Lansoprazole is the second agent in the class of substituted benzimidazoles to be
`developed for clinical use. It has a mechanism of action similar to that of omeprazole
`and also produces a dose-dependent decrease in basal and pentagastrin stimulated
`acid output. The effect on stimulated acid output increases with repeated dosing,
`from 81 percent reduction on day 2 to 90 percent reduction on day 8 of dosing with 30
`mg daily [9]. Basal and stimulated acid outputs return to pre-treatment levels one
`week after cessation of treatment.
`Another substituted benzimidazole, pantoprazole, which also profoundly reduced
`gastric acid secretion, has been withdrawn from further development due to toxicol-
`ogy problems.
`All of these drugs bind covalently to the H+/K+-ATPase and thus act in a
`non-competitive manner. A new agent, a semi-naphthoquinone, derived from Strep-
`tomyces aculeolatus, acts competitively on the proton pump to inhibit acid secretion
`[10]. Development of this compound may lead to a new class of reversible proton
`pump inhibitors available for clinical use.
`APPROPRIATE LEVELS OF ACID SUPPRESSION
`Acid is considered central to the pathophysiology of duodenal and gastric ulcer
`and reflux esophagitis, and Schwartz's dictum, "no acid-no ulcer," still holds true.
`Meta-analysis allows pooling of the results of clinical trials to assess the signifi-
`cance of any relationship or trend that might not be evident from any single smaller
`study. Predetermined criteria of eligibility, which have to be met in order for a study
`to be included in the pooling, are established. Such methods have been used to
`determine the degree of acid inhibition necessary for the optimal healing of acid
`peptic disorders. Initial analysis of various doses of H2-receptor antagonists showed a
`clear linear relationship between nocturnal acid suppression and duodenal ulcer
`healing [11]. This finding reflects the predominant effect of these drugs on basal
`nighttime acid secretion. When omeprazole, which extends the period of acid
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`
`suppression into the daytime, was added to the analysis, healing was better corre-
`lated to suppression of 24-hour intragastric acidity.
`A further extensive analysis of raw pH data from 490 individual patients utilized
`polynomial regression and response surface methodology [12]. This process defined
`the three primary determinants for duodenal ulcer healing to be the degree of acid
`suppression, the duration of suppression over the 24-hour period, and the length of
`treatment. Suppression to increase the intragastric pH to above 3.0 was not, however,
`found to increase ulcer healing further. Additional benefit was obtained by extending
`the duration of antisecretory effect or increasing the length of treatment. This model
`predicts 100 percent healing of duodenal ulcers at four weeks if the intragastric pH
`can be maintained at or above 3.0 for 18 hours of the 24. A similar approach has been
`applied to gastric ulcer [13,14], and the same three variables predict gastric ulcer
`healing, although the length of treatment is a more important variable than that for
`duodenal ulcer healing.
`The healing of erosive esophagitis at eight weeks also correlates with the duration
`in hours that the intragastric pH is maintained above 4.0 (r = 0.87;p < 0.05) [15]. A
`close association also exists between healing at eight weeks and the reduction in
`esophageal acid exposure (r = 0.83). This fact is not surprising, since there is a close
`relationship between the duration of suppression of intragastric acidity to above pH
`4.0 and the reduction in esophageal acid exposure. We have constructed a model for
`reflux esophagitis using polynomial regression similar to that performed for duode-
`nal and gastric ulcers [16]. Stepwise regression shows that the same three determi-
`nants of duration and degree of acid suppression and length of treatment are of
`approximately equal importance; however, the intragastric pH threshold above
`which further suppression has minimal effect on healing rates appears to be 4.0.
`Maintaining the intragastric pH at or above this threshold for 21 hours of each 24
`predicts 100 percent healing of esophagitis at eight weeks.
`Conventional doses of H2-receptor antagonists act best at suppressing basal acid
`output and exert most effect during the nighttime period of prolonged unstimulated
`acid secretion. They cannot overcome the integrated stimulus to acid production
`resulting from a meal, and this difficulty limits their duration of action [17,18]. Proton
`pump inhibition effectively blocks the acid secretory response to all stimuli and thus
`maintains a raised intragastric pH for prolonged periods throughout the full 24 hours
`(Fig. 1).
`
`THERAPEUTIC EFFICACY
`
`The long duration of acid inhibition achieved by omeprazole translates into more
`rapid symptom relief and healing than is obtained with other therapeutic agents. A
`meta-analysis of pain relief in studies comparing omeprazole and ranitidine for the
`treatment of duodenal ulcer showed that 71 percent of patients treated with
`omeprazole, 20 mg daily, had complete relief of symptoms within two weeks,
`compared with only 58 percent of patients being symptom-free on treatment with
`ranitidine, 300 mg at night [19]. This result confirmed a significant therapeutic gain in
`favor of omeprazole. Omeprazole was as effective as ranitidine in the relief of
`nocturnal pain but was significantly more effective in relieving daytime pain
`(p < 0.001). A similar advantage in favor of omeprazole was noted for gastric ulcer
`(65 percent of patients being pain-free on omeprazole, 20 mg, at two weeks,
`compared with 56 percent on ranitidine, 150 mg twice daily) and reflux esophagitis
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`pH>3
`pH >4
`
`652
`
`24 Hours
`
`20-
`
`16-
`
`12
`
`8 4
`
`020
`060
`030
`R3N
`C8N
`C4Q
`R150
`F40
`C4B
`ClG
`ANT
`FIG. 1. Duration (hours) of the total 24-hour day that the intragastric pH is raised above the
`ANT, antacid, 150 mmol,
`thresholds of pH 3 and 4 required for optimal healing of acid peptic diseases.
`seven times a day; C1G, cimetidine, 200 mg, three times a day, and 400 mg at bedtime; C4B, cimetidine,
`400 mg, twice a day; C4Q, cimetidine, 400 mg, four times a day; C8N, cimetidine, 800 mg, at bedtime; F40,
`famotidine, 40 mg, at bedtime; R150, ranitidine, 150 mg, twice a day; R3N, ranitidine, 300 mg, at bedtime;
`020, omeprazole, 20 mg, once a day; 030, omeprazole, 30 mg, once a day; 040, omeprazole, 40 mg, once a
`day.
`
`(64 percent of omeprazole-treated patients achieving relief of symptoms at four
`weeks, compared with 31 percent of ranitidine-treated patients) [19].
`Omeprazole also produces more rapid healing of duodenal ulcers than ranitidine.
`Omeprazole, 20 mg daily, gives a two-week healing rate of 69 percent, compared with
`53 percent for ranitidine, 300 mg daily [19]. The healing rates at four weeks were 93
`percent for omeprazole and 83 percent for ranitidine. These differences were
`significant at both time periods (p < 0.001). A similar therapeutic advantage is
`observed for omeprazole when compared with other drugs commonly used to treat
`duodenal ulcer, including sucralfate, colloidal bismuth, prostaglandin analogs, and
`the newer H2-receptor antagonists, nizatidine and famotidine [20]. The new proton
`pump inhibitor, lansoprazole, has also been shown to result in faster healing than
`H2-receptor antagonists. In comparative studies with ranitidine, lansoprazole, 30 mg,
`healed 93-95 percent of duodenal ulcer patients in four weeks, compared with 82-89
`percent healing in those taking ranitidine, 300 mg, at night [21,22]. In a trial with
`famotidine, two-week healing rates of 54 percent were achieved with lansoprazole,
`30 mg, compared with 39 percent of patients taking famotidine, 40 mg, at night. The
`healing rates at four weeks were 91 percent and 83 percent, respectively [23].
`Omeprazole is also superior to H2-receptor antagonists for the treatment of gastric
`ulcer, although healing takes longer than for duodenal ulcer [19]. Healing rates of 73
`percent at four weeks are obtained with omeprazole, 20 mg daily, increasing to 91
`percent at eight weeks. In comparison, ranitidine, 150 mg twice daily, healed 62
`percent at four weeks and 85 percent at eight weeks (p < 0.01).
`The leftward shift of the healing time curve noted with omeprazole is particularly
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`PROGRESS WITH PROTON PUMP INHIBITION
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`653
`
`%0X HEALING
`100 %HEALING
`
`omeprazole 40 mg
`
`80
`
`60-
`
`40 -
`
`~~~~~~ranitidine 300 mg nocte
`
`20~~~~~~~~~~~~~0
`/
`, ' -
`20
`
`.. ..............................................................
`pirenzepine 50 mg bid
`
`.
`
`cimetidine 400 mg qid
`
`2
`
`4
`
`0
`
`8
`6
`WEEKS OF TREATMENT
`FIG. 2. Rate of healing of erosive esophagitis according to class of agent used.
`
`10
`
`12
`
`evident in reflux esophagitis (Fig. 2). In comparative trials, omeprazole in doses of
`20-60 mg healed 67-92 percent of patients with erosive esophagitis within four
`weeks. Ranitidine, 300 mg at night, healed only 27-45 percent of patients in the same
`time period [19,24]. Better healing rates are achieved with lower grades of esophagi-
`tis; 90-100 percent of patients with grade I-II disease healing within four weeks'
`treatment with omeprazole, compared with 53-55 percent of those treated with
`ranitidine. More severe grades of esophagitis also heal with omeprazole but require a
`longer time, 70 percent of those with grade III disease healing in four weeks and 90
`percent at eight to 12 weeks. Even grade IV esophagitis responds to omeprazole
`treatment, 48 percent healing rates being seen at four weeks, rising to 62 percent at
`eight weeks [25]. Lansoprazole has also been shown to be superior to ranitidine in
`the short-term treatment of erosive esophagitis [26]. Once healed, omeprazole, 20
`mg, is effective in preventing relapse of esophagitis, with 89 percent remaining in
`remission at 12 months, compared with 25 percent of those taking ranitidine, 150 mg
`twice daily [27].
`
`CLINICAL SAFETY
`More than 19,000 patients have been studied in clinical trials of omeprazole, the
`majority in comparative trials with ranitidine, and over 25 million patient treatments
`given worldwide. The incidence of adverse events reported by patients taking
`omeprazole is low and of a similar spectrum and severity to those patients receiving
`ranitidine or placebo [28]. Indeed, the incidence of severe adverse events in these
`trials was 1.1 percent compared to 4 percent among those taking placebo, and none
`of the serious adverse events was considered attributable to omeprazole. There is no
`increase in adverse events in elderly patients compared to those under 65 years of
`age, and omeprazole is safe in patients with renal or hepatic insufficiency. Extensive
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`post-marketing surveillance and data from the compassionate use program, in which
`patients have now been studied for up to seven years, have not revealed any
`significant adverse effects.
`Concerns have been raised about the rise in plasma gastrin levels seen with
`omeprazole treatment and the potential for the development of ECL-cell carcinoid
`formation. Female rats treated over a lifetime with very high doses of omeprazole in
`toxicology studies show an increased incidence of gastric ECL-cell hyperplasia and
`carcinoid tumors [29]. Similar findings have been reported with short- and long-
`acting H2-receptor antagonists such as ranitidine and loxtidine, the hypolipidemic
`compound ciprofibrate, and after partial gastric corpectomy [30-32]. This effect
`appears to be related to the hypergastrinemia associated with acid suppression
`achieved by a variety of means rather than a direct effect of any specific drug or class
`of drug.
`Omeprazole treatment does produce a rise in plasma gastrin in man, related to the
`degree of acid suppression [33]. This effect is similar in extent to the rise in gastrin
`occurring after proximal gastric vagotomy and is approximately sixfold less than that
`seen in patients with pernicious anemia [34]. Furthermore, the plasma gastrin does
`not continue to rise with long-term treatment but plateaus out at approximately four
`times normal levels after four months' treatment with omeprazole, 40 mg daily [35].
`No further rise was observed even after five years' treatment. No dysplasia of the
`gastric enterochromaffin-like cells occurred during the five years of follow-up. In
`another study of 122 patients treated with long-term omeprazole, gastric biopsies
`were studied to evaluate any possible changes in gastric endocrine cells [36].
`Hyperplasia of a simple, linear, and/or micronodular type was noted in 11-19
`percent of patients, but no dysplasia or neoplastic changes were seen. The mild
`changes of hyperplasia appeared to be related to interstitial or subatrophic gastritis
`and probably arise independently from omeprazole treatment [36].
`ECL-cell changes similar to those observed in rats have not been seen in man
`despite extensive investigation, and omeprazole appears safe for short- and long-
`term use.
`
`PROTON PUMP INHIBITION AND HELICOBACTER PYLORI
`
`Epidemiological evidence suggests a close association between infection with
`Helicobacter pyloni and peptic ulcer disease. A causal link has been proven with
`chronic active gastritis, but a similar role in the etiology of duodenal ulcer disease has
`not yet been confirmed [37]. The healing of duodenal ulcers is not dependent upon
`eradication of the organism nor is the ability to maintain remission with antisecretory
`therapy. Ulcer relapse rates are greatly reduced, however, by eradication of H. pyloni
`and may even approach zero [37-39].
`In clinical trials, omeprazole achieves temporary suppression of H. pylori in 50-90
`percent of cases but fails to eradicate the organism [40-45]; however, the combina-
`tion of omeprazole with amoxycillin, in doses of 750-2,000 mg per day, improves the
`eradication rate variably to about 30 percent with omeprazole, 20 mg, and 60-82
`percent with omeprazole, 40 mg daily [46-51].
`The mechanism of effect of omeprazole on H. pyloni is uncertain. In vitro, both
`lansoprazole and omeprazole show direct toxicity against the organism with mini-
`mum inhibitory concentrations (MICs) similar to that of bismuth [52-54]. Lansopra-
`zole is four times more potent than omeprazole in killing H. pylori in vitro. In
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`comparison, none of the H2-receptor antagonists tested showed any significant
`activity [54]. It is not known what concentration of omeprazole exists in the mucus
`layer and at the mucus layer-epithelial cell interface where H. pylon is found.
`Although rapidly converted in an acid environment, parent drug could conceivably
`be found in the mucus layer, due to the alkalinizing action of H. pyloni urease, or
`under conditions of low acidity resulting from inhibition of acid secretion. This
`theory might explain the apparent redistribution of the organism during omeprazole
`treatment away from the gastric antrum, which might be at a relatively neutral pH
`toward the corpus, which is the site of acid production [45]. Interestingly, two
`acid-converted forms of lansoprazole are also bactericidal to H. pylon in vitro, with
`potencies two to four times that of lansoprazole alone [54].
`Omeprazole might act simply by its effect on gastric acid secretion. Whether this
`effect would alter the bioavailability of antibiotics is unknown. The peak systemic
`concentrations achieved after oral dosing with amoxycillin and bacampicillin are
`reduced with omeprazole treatment, although the areas under the plasma concentra-
`tion curves are unaltered [55]. Whether this effect might increase the local antibiotic
`bioavailability in the gastric lumen and mucus layer is unknown.
`It has been suggested that increasing the intragastric pH might lead to overgrowth
`of competitive bacteria such as is seen in pernicious anemia, which is associated with
`a very low prevalence of H. pylon. It is, however, uncommon for omeprazole to cause
`complete anacidity throughout the 24 hours, and gastric juice is bactericidal below
`pH 4.0 within ten minutes [56]. A further hypothesis proposes that elevation of the
`pH removes the neutralizing action of acid on local ammonia produced by bacterial
`urease. This process results in bacterial "suicide from overalkalinization."
`Clearly, larger controlled trials to investigate the action of proton pump inhibition
`with and without antibiotic co-therapy as a cure for duodenal ulcer disease are
`urgently required.
`
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