Journal of Pediatric Gastroenterology & Nutrition:
Omeprazole and Other Proton Pump Inhibitors: Pharmacology, Efficacy, and Safety, with Special Reference to Use in Children
Israel, David M.; Hassall, Eric
British Columbia Children's Hospital, Vancouver, British Columbia, Canada
Received August 28, 1997; first revision March 6, 1998; second revision April 29, 1998; accepted May 1, 1998.
Address correspondence and reprint requests to Eric Hassall, Associate Professor, Division of Gastroenterology, B.C. Children's Hospital, 4480 Oak Street, Vancouver, British Columbia, Canada V6H3V4.
Our current approaches to acid-related disorders stem from many major landmark discoveries and trials of therapies, including acid buffering, surgery, and more recently, acid suppression by H2-receptor antagonists (H2RA) (1,2).
The latest major development was the recognition of the so-called "proton pump" or "acid pump" by Dr. George Sachs et al. in 1976 (3,4). Soon thereafter, the Hässle Research Laboratories in Mölndal, Sweden, developed a substituted benzimidazole, H149/94, which covalently bound the molecule of the pump to block its action (5). H149/94 was the first "proton pump inhibitor" (PPI) to be tested in humans (6), but omeprazole was the first to be studied extensively in humans. Omeprazole was first approved in Sweden in 1988 for treatment of duodenal ulcer. It was approved in Canada and in the United States in 1989, for treatment of duodenal ulcer, gastric ulcers, reflux esophagitis, and Zollinger-Ellison syndrome. As of 1998, approximately 280 million treatment courses of omeprazole have been prescribed, equivalent to 23 million treatment years.
The proton pump inhibitors are a class of substances that offer a much greater potency of acid inhibition than H2RA and that have revolutionized the management of acid-related disorders. Recently, newer proton pump inhibitors lansoprazole and pantoprazole have been introduced.
Proton pump inhibitors block acid at the final common pathway of secretion-that is, at the proton pump-regardless of the stimulus of acid secretion, and thereby offer by far the most potent suppression of gastric acid.
There are two classes of PPI, covalent and competitive. Drugs in the competitive class of PPI bind to a three-dimensional site on the extracellular surface of the proton pump and cause reversible inhibition (7). Those in the covalent class inhibit the pump by irreversibly binding to cysteines in the pump. Only the covalent group are in clinical use. They consist of the substituted benzimidazoles omeprazole, lansoprazole, and pantoprazole, which act as "prodrugs," that is, they require modification of their structure to become active.
The irreversibility of the covalent bond results in inhibition of acid secretion until more enzyme is synthesized. It is this factor that accounts for the long duration (more than 24 hours) of the antisecretory effect of PPIs (8).
At present, omeprazole is available in most countries as a capsule containing approximately 170 enteric-coated (acid-protected) granules of omeprazole, each 1 to 2 mm in diameter (see Administration of Omeprazole section). The hard gelatin capsule remains intact during its brief transit through the esophagus and dissolves in the acid stomach to release granules of the prodrug omeprazole. The granules' polymer coating dissolves only at a pH of more than 6, allowing release of omeprazole in the alkaline duodenum. Theoretically, if the prodrug omeprazole were released into an acidic stomach, it would convert to the active sulfenamide form in the gastric lumen, where reaction with proton pumps is not possible (7).
The prodrug omeprazole is rapidly and almost completely absorbed, with peak plasma levels occurring 1 to 3 hours after ingestion. It is highly (95%) protein-bound and rapidly distributed in plasma (9). The prodrug is rapidly metabolized by hepatic cytochrome P-450 isoenzyme CYP2C19, resulting in a very short plasma half-life of 40 to 60 minutes, although it is as long as 2 hours in 3% to 5% of whites who do not have the specific isoenzyme (9). The pharmacokinetics of omeprazole are unaltered in renal failure, although renal excretion of metabolites is slowed. However, this seems to be compensated by greater biliary excretion. In hepatic cirrhosis, however, metabolism is delayed, with a half-life of as long as 3 hours. The healthy elderly also metabolize omeprazole more slowly, probably because of decreased hepatic blood flow. Although there are no published data on the pharmacokinetics of orally administered omeprazole in children, our own as yet unpublished data indicate that omeprazole is metabolized more rapidly by children between the ages of 1 and 8 to 9 years or so than by older children or adults. We did not study children less than 1 year of age. During a once-daily dose regimen, the bioavailability of omeprazole is approximately 60% and increases with doses of more than 20 mg.
Despite the usual short half-life of omeprazole, the covalent bond with the pump provides sustained inhibition of acid. Thus, the antisecretory effect of omeprazole is not dependent on its plasma concentration at any given time but is directly proportional to the area under the plasma concentration curve (AUC).
Because omeprazole can inhibit only active pumps- that is, those that are exposed on the canalicular surface, and because H+, K+-ATPase pumps are maximally exposed at the canalicular surface of meal-stimulated parietal cells, the ideal time to administer omeprazole is with the first meal of the day after an overnight fast. Omeprazole will inhibit daytime and nocturnal acid secretion whether administered in the morning or the evening; however, morning administration results in higher median 24-hour pH values (10). This may be in part because morning administration results in a greater AUC than does evening administration, for reasons that are unclear. A period of approximately 3 days is required for steadystate inhibition to occur in a single daily dose regimen (11,12), suggesting a half-life of the pump of approximately 36 hours. A once-daily dose of a PPI usually results in transient return of acid secretion at approximately 15 hours after the dose, suggesting the possible presence of a circadian rhythm of synthesis and processing of pumps. Even with administration of 20 mg omeprazole twice daily or 30 mg lansoprazole twice daily in healthy volunteers or in patients with gastroesophageal reflux disease (GERD), nocturnal acid break-through to intragastric pH of less than 4 occurs for at least 60 minutes in at least half of subjects (13).
Potent gastric acid suppression may cause elevated levels of serum gastrin, change in the microbial flora of the gastrointestinal tract, and altered absorption of hematinics. Drug interaction is another safety concern.
However, that omeprazole is a safe medication is evident from the scarcity of adverse effects in spite of extensive use. In addition to vast clinical experience with the drug, the use of omeprazole has been studied in more than 40,000 patients enrolled in manufacturer-sponsored clinical trials.
Hypergastrinemia and Morphologic Changes
Hypochlorhydria induces hypergastrinemia. By this mechanism, hypergastrinemia may occur during treatment with PPIs, high dose H2RAs, or after vagotomy. In those circumstances, mean gastrin levels are usually less than 200 pmol/l. In pernicious anemia, mean plasma gastrin levels are much higher, approximately 500 to 600 pmol/l (14); peak gastrin levels are usually considerably higher. Gastrin, in addition to its effect on acid secretion, is trophic for some gastrointestinal cells. For example, sustained hypergastrinemia results in increased weight and thickness of oxyntic mucosa (15). Gastrin is also trophic for gastric enterochromaffin-like (ECL) cells. Thus, concerns have been raised that PPI therapy may result in ECL cell carcinoid tumors. The increasing degrees of ECL cell hyperplasia are categorized as simple, linear, micronodular, and adenomatoid, all benign. The next stage, carcinoid, may or may not be benign (16).
An early concern regarding PPI therapy was related to the finding of gastric ECL cell carcinoids in aged rats with PPI-induced hypergastrinemia caused by very high-dose omeprazole. These rats were bred for longevity, and carcinoids have occurred without PPI in such animals; furthermore, the rat ECL response is species-specific and does not reflect that of humans (17). In more than 10 years of omeprazole use in clinical practice, gastric carcinoids have not been described in humans during long-term PPI therapy.
It is hypochlorhydria rather than achlorhydria that occurs with PPI therapy, and the degree of hypergastrinemia in pernicious anemia is uncommon, even with high-dose omeprazole therapy (14,18,19). The gastrin response is also highly variable (20,21): During long-term treatment with high-dose ranitidine (450-600 mg daily), or 40 mg omeprazole daily, fasting gastrin levels may be normal, 2 to 4 times normal, occasionally 10 times normal. Gastrin levels that rise during omeprazole treatment may return to normal despite continued treatment (21,22).
Benign ECL hyperplasia occurs in patients treated for as long as 5 years with omeprazole, as in some patients with peptic ulcer disease never treated with H2RAs or PPIs (23). These changes correlate with the severity of corpus gastritis and the presence of Helicobacter pylori and are probably disease- rather than drug-related (20).
Adults with Barrett's esophagus (BE) receiving long-term omeprazole in doses of 20 to 40 mg/day, may have development of parietal cell hyperplasia, lingular projections of parietal cells (pseudohypertrophy), and fundic gland cysts (24). These changes occur within 6 months of beginning high-dose (80 mg) omeprazole therapy, and remain during therapy with 40 mg daily (25). The hyperplasia and associated gastric acid hypersecretion revert toward normal by 3 months after withdrawal of high-dose omeprazole (26).
Gastric polyps develop in some patients during omeprazole maintenance therapy (27-29). These polyps usually develop in the gastric corpus, may be single or multiple, and are hyperplastic or benign fundic gland cysts. The parietal cell hyperplasia and fundic gland cysts within the lamina propria may be forerunners of such polyps (27,28).
Hypergastrinemia (21,22), changes in the parietal cell layer similar to those above (30), and occasionally, gastric polyps (31) have also been described in children receiving long-term omeprazole therapy. As in adults, the histologic changes are benign. Although it is tempting to ascribe the morphologic changes to the trophic effect of hypergastrinemia on oxyntic mucosa, fasting serum gastrin levels were often normal in patients with such changes. In adults (25,28,29) and children (30,31) there was no correlation between the degree or duration of hypergastrinemia, when present, or between the dose of omeprazole and the presence of polyps or parietal cell changes. Adults in whom gastric polyps developed tended to be the more elderly, and there did not appear to be an association with H. pylori infection (29). In our experience, most children receiving omeprazole for 2 to 3 months or more had parietal cell hyperplasia. The two children with fundic gland polyps had received omeprazole for a mean of 24 months (range, 10-48 months) (31).
Recently, Kuipers et al. (32,33) reported that patients treated long-term with omeprazole for reflux esophagitis were at increased risk of development of chronic atrophic gastritis involving the gastric corpus, which manifested during a 3- to 8-year follow-up (mean, 5 years). These changes were found only in patients who were determined by histology to be positive for H. pylori and not in those who were negative. The investigators concluded that patients receiving long-term omeprazole should first receive treatment to eradicate H. pylori. The study subjects were older and from a different country than the control subjects and may have differed in other respects. The data from this important study require confirmation. More recently, results in a controlled study of patients with GERD randomized to omeprazole or anti-reflux surgery showed no predilection toward development of atrophic gastritis in the omeprazole-treated patients. No patients in either group had intestinal metaplasia in the stomach (34).
Investigators in a recent study (35) suggested that in H. pylori-infected patients with GERD treated with omeprazole for 61 ± 25 months, development of atrophic gastritis was associated with decreased serum vitamin B12 levels, without clinical B12 deficiency. These data are preliminary and require confirmation. The implications are unclear at present. Because body stores of cobalamin are large, it is likely that clinically significant cobalamin deficiency would not occur before 20 years or so of acid suppression (36,37). Also, there is a theoretical risk that marked or prolonged acid suppression may cause iron-deficiency anemia, but so far this has not been reported (36).
Rare Adverse Effects
Possible adverse effects are described in case reports in which it is difficult to separate the effects of concomitant therapies and the underlying conditions from those of omeprazole. Minimal transient elevations of amino-transferases have been described, with no known morbidity or mortality. In one case report, fulminant hepatic failure developed in a 62-year-old man after 17 days of treatment with omeprazole (38). He was concurrently treated for hypertension with atenolol, diltiazem, and aspirin. Other rare adverse effects are described elsewhere (39-42).
The theoretical risk of bacterial overgrowth occurring in the upper GI tract due to acid suppression is not considered clinically relevant (43).
Omeprazole appears to interact with only one P-450 isoenzyme, CYP2C19 (9,44). Thus, it is expected to have a narrow spectrum of interaction limited to drugs that are metabolized by this enzyme. Interactions with diazepam, phenytoin, warfarin, digoxin, or methotrexate are not clinically significant (44-49). There was no effect of omeprazole on the metabolism of several other drugs tested: theophylline (50,51), propranolol (52), or cyclosporine (53).
ADMINISTRATION OF DRUG
Omeprazole should be administered with or just before the first meal of the day. In patients in whom nocturnal reflux persists despite a morning dose of 40 mg omeprazole or more, the dose can be split and a second dose provided with the evening meal to maximize proton pump exposure.
Ideally, the intact capsule (or enteric-coated tablet, available in Canada only) is administered orally, without crushing or chewing. For those unable to swallow capsules or tablets-for example, patients with neurologic impairment or swallowing disorders-the granules may be removed from the intact capsule, and suspended in a slightly acidic medium such as apple, orange, or cranberry juice or yogurt (pH 4), to prevent dissolution of the protective coating. The suspension is then administered through a large-bore gastrostomy or nasogastric tube. When using tubes for instillation, 5 to 10 ml juice should be used to flush all the granules out of the tube. When using gastrostomy buttons, a straight connecting tube is preferred to a right-angle connecting tube, in which granules may lodge. With these measures, granules are less likely to coalesce and block the tube. Tubes with flap valves, such as button gastrostomy tubes, are more likely to become obstructed than those without. Administration of lansoprazole has been studied in adults with difficulty swallowing intact capsules. When lansoprazole granules in applesauce were administered orally, the time to peak plasma levels and the bioavailability of drug were no different than for drug administered in intact capsules (54). Similarly, when nonencapsulated, intact omeprazole granules were administered by gastrostomy tubes in adults, the degree of acid suppression was comparable to that achieved using intact omeprazole capsules by mouth in other studies (55).
In two studies (56,57), a simplified omeprazole suspension (SOS) was prepared by mixing, in a 50-ml syringe, the granules from two 20-mg capsules of omeprazole with 20 ml 8.4% sodium bicarbonate, making a 2-mg/ml suspension. The enteric-coated granules in bicarbonate were agitated for approximately 30 minutes to produce a partially dissolved, partially suspended preparation, milky white with a fine sediment. It was shaken, then administered through a nasogastric tube, followed by 5 to 10 ml tap water. The subjects were adults receiving ventilatory support and taking nothing by mouth in a surgical-burn intensive care unit with multiple risk factors for gastrointestinal bleeding. Of particular interest was the control of gastric pH, in that a pH of more than 5.5 was maintained. Each 10 ml SOS contains 10 mEq bicarbonate, sufficient to provide 40 minutes to 3 hours of buffering, with early intragastric pH of more than 7. The subsequent pH control is probably caused by omeprazole absorption and effect. The theoretical concern with this approach is that dissolution of omeprazole in alkali releases active drug, which may be destroyed in the acid stomach. The success of the approach may be because of protection of active drug in the stomach by bicarbonate, then gastric emptying of active drug and its rapid absorption in the duodenum. Previous concepts notwithstanding, the same investigators showed, by measuring omeprazole levels in blood, that some omeprazole is absorbed from the stomach when drug is administered to patients with a blind-ending stomach (J. O. Phillips, personal communication, 1997). Most is absorbed from the duodenum.
In children, administration of omeprazole or lansoprazole is sometimes difficult or impossible. In young children unable to swallow intact capsules or tablets, suspension of granules in applesauce or yogurt and swallowing without chewing is recommended. However, most children find it difficult to swallow a semiliquid without some chewing. The chewing of even a few granules produces a bitter alkaloid- or quininelike taste, resulting in poor compliance and a subsequent distaste for the vehicle itself. When omeprazole or lansoprazole granules, mixed in cranberry or other juices, are administered through a nasogastric or gastrostomy tube, they will often block the tube or the flap valve of the tube. Because of their tendency to float, many granules stick to the plunger of the administering syringe and never exit the syringe. Potential problems with administration in children of an omeprazole-in-bicarbarbonate solution are the sodium load, the liberation of CO2 in the stomach causing belching, and the bitter taste. Phillips et al. (56) have minimized the quantity of bicarbonate by making a pediatric SOS solution of 5 mg/ml omeprazole-bicarbonate solution and flavoring it with root beer or other flavors. For adults (and children), they now have a premade SOS that is stable and retains more than 90% potency for 7 days unrefrigerated and for at least 30 days refrigerated. It is stored in amber bottles, because omeprazole is light-sensitive. The use of this suspension overcomes the problems of administration of omeprazole to children by mouth or by tube. (J. O. Phillips, personal communication). Pharmacodynamic studies to prove efficacy of this suspension in children are necessary.
For patients with duodenal or jejunal tubes, the drug will be delivered directly into an alkaline environment. Because jejunal tubes usually are of small caliber and can be blocked by particulate matter, the granules should be well dissolved before injection into the tube and should be flushed with 5 ml of water. A randomized crossover study of SOS in this setting is underway, and preliminary results show rapid absorption and excellent pH control when compared with administration by nasogastric tube (J. O. Phillips, personal communication, 1997).
Just recently, a new formulation of omeprazole has been introduced in Europe. Known as Losec MUPS (Astra, Sweden) (meaning multiple unit pellet system), each 20-mg tablet contains some 1000 acid-protected micropellets, approximately 0.5 mm in diameter. These are rapidly dispersed in the stomach and pass into the alkaline duodenum where the coating dissolves, releasing prodrug omeprazole. The MUPS tablet is dispersed in water or slightly acidic fluids, such as some fruit juices, producing a solution easy to drink if prepared 30 minutes or so before administration. It can also be administered by nasogastric or gastrostomy tube. The tablets can be cut or broken. The new formulation is bioequivalent to the capsule form and has important potential advantages for children, perhaps obviating the need for preparation of the SOS.
Intravenous administration of omeprazole is significantly more effective for acid suppression than ranitidine (58). Repeated intravenous administration of omeprazole every 6 hours for 24 hours (in doses of 80, 20, 20, and 20 mg) significantly increases gastric pH, but there is marked unpredictability in response between subjects, and persistent elevation of pH above 4 was reached in only 2 of 10 subjects. The doses of intravenous omeprazole in children were adapted from adult data, 60 to 80 mg/1.73 m2 loading dose followed by 40 mg/1.73 m2 at 12-hour intervals administered as a slow infusion over 15 minutes (59). Pharmacokinetic studies of intravenous omeprazole in children (59) yielded results similar to those reported in adults, although many of the children studied were critically ill and receiving other medications.
At present, the intravenous form of omeprazole is available only as an investigational drug on an individual basis for critically ill patients who cannot take oral omeprazole and who are refractory to or cannot tolerate alternative commercially available intravenous therapy (e.g., high-dose intravenous ranitidine or cimetidine). The intravenous drug has been used mainly for acute treatment of gastrointestinal bleeding.
TREATMENT OF SPECIFIC DISORDERS
Reflux esophagitis is usually a chronic, relapsing condition. Although studies in adults have shown relapse rates of more than 80% within 6 months of the cessation of medical treatment (60), no relapse rate data are available for the pediatric age group. However, it is well recognized that erosive esophagitis in children is usually a chronic relapsing condition, as it is in adults.
The outcome of medical treatment of esophagitis is often dependent on its severity (60,61). An objective grading system of esophagitis (60,62) is therefore fundamental to our ability to understand and compare the efficacy of different treatment protocols. The use of histologic criteria to quantitate severity of esophagitis is fraught with problems, including sampling error and inconsistency of quantitation of severity between observers (63). For these reasons, endoscopic assessments have been used to quantify esophagitis at baseline and during treatment in most studies in adults, and increasingly so in studies in children.
Mechanisms of Healing
There are different mechanisms by which acid suppression effects healing of esophagitis. Gastric acid suppression causes an increase in the pH of refluxate, thereby decreasing the corrosive and inflammatory processes initiated by chronic or repeated contact between acid and esophageal epithelium (64).
The presence of acid reflux into the esophagus is also a prerequisite for the development of bile-induced reflux esophagitis, because acid is necessary to break intercellular tight junctions of squamous epithelium, which then facilitates and allows the corrosive and inflammatory actions of bile to occur (65). Thus, even when pathologic bile reflux is present, effective acid suppression will result in healing of esophagitis.
Suppression of gastric acid secretion also results in decrease of 24-hour intragastric volumes, facilitating emptying of gastric contents, decreasing the volume of gastric contents available to reflux and thereby decreasing both acid and bile reflux (66).
Thus, potent acid suppression, such as that effected by proton pump inhibitors, heals esophagitis by changing intraesophageal pH and by decreasing gastric residual volumes.
Esophagitis in Adults
Most studies of the efficacy of omeprazole in esophagitis fall into one of three categories: short-term treatment of erosive esophagitis, long-term maintenance of remission, and prevention of peptic strictures. For the former two, omeprazole has long been shown to be superior to H2RAs (60,67-70).
For the treatment of esophagitis with benign peptic stricture, 20 mg omeprazole daily was significantly superior to 150 mg ranitidine twice daily for preventing stricture recurrence over a 12-month period (71), in terms of the number of patients requiring redilatation (30% vs. 46%) and the number of redilatations required (0.48 vs. 1.08). See also PPIs Other Than Omeprazole).
Also in esophagitis with benign peptic stricture, 20 mg omeprazole daily produced a higher rate of esophagitis healing and relief of dysphagia and a less need for dilatation than 150 mg ranitidine twice daily or 20 mg famotidine twice daily (72). This was the first controlled study to show that medical antireflux treatment could affect the natural history of peptic stricture disease, and in doing so, it was 40% to 50% more cost effective than H2RAs. Investigators in a more recent study (73) confirmed these findings, emphasizing the need for vigorous treatment of esophagitis in patients with peptic strictures.
Esophagitis in Children
The mechanisms of pathologic reflux in children are summarized elsewhere (74). Of course, children with severe esophagitis are those of most concern and greatest challenge, in that it is this group who are most likely to require long-term therapy with proton pump inhibitors or antireflux surgery.
Compared with adults, there is a relative paucity of data on the use of proton pump inhibitors in children. The first study to examine the efficacy and safety of long-term omeprazole use in children was that of Gunasekaran and Hassall (21). The study subjects were 15 children aged 0.8 to 17 years (mean, 8.1 years) in whom medical therapy with H2RAs and prokinetic agents had failed; in addition, 4 had had at least one Nissen fundoplication with unsuccessful outcome. Most had grade 3 or 4 esophagitis before treatment with omeprazole. The dose of omeprazole was titrated to achieve a normal 24-hour intraesophageal pH study-that is, the dose used was increased until the reflux index was less than 6% of a 24-hour study. After 2 to 3 months of omeprazole treatment (at first follow-up endoscopy), 10 of the 15 patients had a normal-appearing esophageal mucosa (grade 0 or 1). At the second follow-up endoscopy after 4 to 6 months of treatment, esophagitis had healed in all patients, and symptoms and signs of GERD and esophagitis had resolved or markedly improved in all patients. The effective total dose of omeprazole was 10 to 60 mg daily, equal to 0.7 to 3.3 mg/kg per day. These patients were maintained on omeprazole for periods of 5.5 to 26 months. In all, 11 patients had hypergastrinemia during omeprazole therapy, and 4 had normal gastrin levels. In 6 of the patients with hypergastrinemia, fasting gastrin levels of 400 to 700 ng/l were present (upper limit of normal, 130 ng/ml).
In a study by Karjoo and Kane reported in 1995 (75), 129 children aged 6 to 18 years had esophagitis; 31% of these had grade 1 "esophagitis,"-erythema, which most investigators consider to be within normal limits. The remaining 69% had erosive esophagitis, and two-thirds of these had grade 2 esophagitis. All patients were developmentally normal and had no history of esophageal or gastric surgery. Patients were initially treated with 8 mg/kg ranitidine per day, which was increased to 12 mg/kg per day if no symptomatic improvement was observed after 2 weeks. In those still symptomatic after 4 weeks of treatment, ranitidine was considered a failed therapy, and all were then treated with the same dose of omeprazole, 20 mg daily. Symptomatic response to ranitidine was present in 90% of those with grade 1 esophagitis, in 74% of those with grade 2, but in only 37% of those with grade 3 and 50% of those with grade 4. Eighty-seven percent of those who did not respond to ranitidine had a symptomatic improvement after 2 weeks of omeprazole therapy. Although these results show the superiority of omeprazole over ranitidine for relief of symptoms, many of the patients did not have erosive esophagitis, and endoscopic follow-up to document healing was not performed. Many of those with erosive esophagitis may have been undertreated and may not have healed.
In a study by Cucchiara et al. reported in 1993 (76), 25 children aged 6 months to 13.4 years had esophagitis that was unresponsive to 8 mg/kg per day ranitidine and 0.8 mg/kg per day cisapride for 8 weeks. These children were randomly assigned to treatment with 40 mg/1.73 m sup 2 per day omeprazole or 20 mg/kg per day ranitidine for 8 weeks. The parameters studied were endoscopic findings, histologic scores, and a clinical scoring system for symptoms of GERD. Follow-up endoscopy showed similar numbers of children in each group with normal mucosa, erythema, or erosions of the esophagus. The investigators concluded that ranitidine was comparable to omeprazole for treatment of esophagitis. This claim seems unsupported. Failure to find a difference between the two treatment groups in the study was probably because of small sample size and several other factors. First, very high-dose ranitidine was compared with a dose of omeprazole that was generally low for the pediatric age group, compared with doses in pediatric studies in which omeprazole has been uniformly successful in treating refractory esophagitis (21). Second, histologic and clinical scoring systems are less reliable than endoscopic grading systems (63). It may well be that in the study group chosen, there was a high percentage of children with mild esophagitis (nonerosive or grade 2 only), which may have skewed the results. Finally, a duration of treatment of 8 weeks is often insufficient for more severe grades of esophagitis in children.
Recently, De Giacomo et al. (77) treated erosive esophagitis in 10 children 2 to 9 years of age with 20 mg omeprazole for those weighing less than 30 kg, and 40 mg for those more than 30 kg. In 9 of 10, erosive esophagitis healed. Not surprisingly, histologic parameters did not correlate well with healing or symptomatic relief. Doses of omeprazole used were 0.87 to 1.94 mg/kg, and the authors recommend their dose regimen. However, of note are the small number of patients treated and the presence of mild erosive esophagitis (grade 2) in the majority of those treated.
Most recently, the doses of omeprazole required to heal chronic erosive esophagitis in children were determined in a prospective, multicenter study (78). The entry criteria were age 1 to 16 years, and the presence of chronic erosive esophagitis and intraesophageal pH of 4 or more for more than 6% of the duration of a 24-hour study. The initial omeprazole dose of 0.7 mg/kg per day was increased in increments until the reflux index on intraesophageal pH study was normal. Follow-up endoscopy was performed after 3 months of therapy with this healing dose, and healing was defined as the presence of macroscopically normal esophageal mucosa: grade 0 or 1. Of 57 patients, 27 were less than 7 years old, 19 were 7 to 12 years, 11 were 12 years and older. Sixty-seven percent of patients had esophagitis grade 3 or 4. Only 24 were previously untreated; in the remainder, H2RAs, pro-kinetics, or surgery had failed. Half of the patients had no underlying disease, the remainder were neurologically impaired or had repaired esophageal atresia, and almost half of the patients had hiatal hernias. Fifty-four of the 57 patients completing the healing phase of the study successfully healed, although 3 required a second course of treatment to heal. The absolute healing doses of omeprazole ranged from less than 10 mg to 80 mg. A healing dose of 0.7 mg/kg per day was effective in 45% of children, whereas a dose of 1.4 mg/kg per day promoted healing another almost 30% of patients. Gastric biopsy specimens were evaluated for changes in ECL cells, gastritis and H. pylori status. There were no changes in these parameters, and no adverse events occurred that were attributable to omeprazole. In general, on a per kilogram basis, the doses of omeprazole required in children are higher than those required in adults, perhaps because of the pharmacokinetics of the drug in children.
Several children in an earlier study (21) have now been observed for almost 9 years on omeprazole therapy (E. Hassall, personal experience). They have not had adverse effects other than parietal cell hyperplasia in some (30) and benign fundic gland polyps in two (31). Thus, effective and safe medical therapy in the form of long-term use of omeprazole is now a viable alternative to antireflux surgery for children.
Although antireflux surgery may be the treatment of choice for documented GERD in selected patients, children have often undergone antireflux surgery without clearly documented indications, and the morbidity and failure rate of antireflux surgery is high in certain high-risk groups (74). Ironically, the perioperative morbidity, failure, and even mortality rates are highest in those groups of children most at risk for severe reflux: those with neurologic impairment, repaired esophageal atresia, and chronic lung disease.
There are many factors to be considered in the choice of long-term therapy with PPIs versus antireflux surgery; these are discussed in more detail elsewhere (74,79). Cost is one factor. The high initial costs of antireflux surgery can be justified when there are no ongoing costs for morbidity, further investigations, repeated operations, and the cost of repeated hospital admissions, in addition to the psychosocial costs of absences from school and family. These costs must be weighed against the substantial costs of use of expensive PPIs for long periods. A recent study in the United States (80) showed that in adults, even when antireflux surgery was performed laparoscopically, the costs of medical therapy equaled those of surgery only 10 years after surgery. Thus, much hinges on maintenance of the long-term antireflux effect of surgery-that is, its long-term success. In this regard, most pediatric studies offer data regarding only short-term follow-up (74). In adults, a sobering study was that of Luosterinen et al. (81) in which antireflux surgery failed in 30% of adults followed up for 20 years. Of relevance to pediatrics is that these adults did not have the same high-risk factors as do certain children.
In considering the treatment of BE without dysplasia or cancer, aspects to consider are firstly the treatment of esophagitis, erosions, and ulcers that may be present, and secondly treatment of the Barrett's mucosa itself. For severe esophagitis with ulcers present in BE, 40 mg/day omeprazole in adults resulted in healing rates of only 41% after 4 weeks of treatment and only 56% after 8 weeks (60). Severe erosive esophagitis in BE is clearly more refractory to treatment than is squamous esophagitis. More recent studies (82,83) have shown that high-dose PPIs can heal the erosions and ulcers in Barrett's mucosa if used for 3 to 6 months. In the study by Sharma et al. (82), high doses of lansoprazole (60 mg daily) for as long as 3 years healed the erosive esophagitis in all 13 patients treated, although that study was primarily focused on regression of Barrett's mucosa, and it was not clear whether patients required the full 3 years of treatment to heal esophagitis. In the author's (EH) experience with a small number of children BE treated with omeprazole, although the esophageal erosions healed in some patients in 2 to 4 months, in others, doses of 40 to 80 mg omeprazole daily were required for as long as 6 to 8 months before the deepest Barrett's ulcers had completely healed. When indolent ulcers are present, malignant disease should be ruled out.
The second issue in BE is that of regression. The term regression in BE refers to the (possible) event in which the columnar mucosa of the esophagus reverts to squamous mucosa, once the chronic insult of reflux is removed. The regression that occurs is most often in the form of the new appearance of squamous white islands and buried Barrett's specialized mucosa. To date, there has not been a well-documented case of complete regression of BE after medical or surgical therapy (85,86). We have seen partial regression also in children treated with PPIs.
Thus, it is well established that antireflux surgery and high doses of PPIs can result in healing of severe erosive esophagitis and partial regression of Barrett's mucosa itself. Regression of Barrett's mucosa would carry clinical significance only if it resulted in a risk of cancer that was decreased or eliminated. Unfortunately, this has never been shown (86,87). It is possible that young patients without dysplasia at the time effective antireflux therapy is initiated may not progress to malignant disease, but this remains to be shown.
Peptic Ulcer Disease
In adults, peptic ulcer disease is common (88). Several 2-week treatment regimens including three antimicrobial drugs or combinations of acid suppression plus antimicrobial drugs can achieve H. pylori eradication rates of 80% to 90% (89). Studies are ongoing to determine whether 7- or 10-day therapy is as effective as longer regimens and comparing results of PPI-antibiotic regimens with those of H2RA-antibiotic regimens.
Omeprazole on its own does not eradicate H. pylori (90), but PPIs have some anti-H. pylori properties, in vivo and in vitro (91), although not by a urease-dependent mechanism (92). The actual mechanism for this effect is not clear. The increase in gastric pH with omeprazole therapy also preserves acid-labile antibiotics such as amoxicillin, with corresponding decrease in their minimum inhibitory concentration (MIC)90 (92,93). Higher gastric pH may also serve to protect specific anti-H. pylori immunoglobulins from proteolytic destruction. Of clinical importance is that acid suppression affects the accuracy of the urea breath test, resulting in equivocal or false-negative urea breath test results in as many of as 61% of patients, an effect that resolves within 5 days of drug cessation (92,94).
Eradication of H. pylori infection may sometimes have surprising consequences. Recently, Labenz et al. showed that reflux esophagitis ensued after H. pylori eradication in adults with duodenal ulcers (95). Elsewhere, they showed that in duodenal ulcer patients, cure of H. pylori infection resulted in a marked rapid and persistent decrease of the pH-increasing effect of omeprazole 1 year later (96). Others have shown that H. pylori-negative GERD patients tend to have more severe disease than H. pylori-positive GERD patients (97). Gillen et al. (98) demonstrated that inhibition of gastric acid secretion by PPI therapy is much more profound in H. pylori-positive than in H. pylori-negative adults, and that marked rebound hypersecretion of gastric acid occurs after PPI therapy in H. pylori-negative, but not in H. pylori-positive adults (99). These studies all indicate that H. pylori infection increases gastric pH. Some suggest that the apparent increase in gastric acid output during omeprazole therapy after cure of the infection is caused by the abolition of H. pylori-derived ammonia production and not by increase in basal or gastrin-releasing peptide secretion (100). Others suggest that it is the H. pylori corpus gastritis developing during omeprazole therapy that impairs acid secretion and augments the effect of the drug (98). These investigators speculate that this suppression of acid may have the deleterious effects of facilitating gastric bacterial colonization and predisposing to atrophic gastritis, but they did not study this (98) (see the earlier section, Atrophic Gastritis).
Peptic ulcer disease is much less prevalent in children than in adults. Treatment studies are therefore far fewer and tend to be open rather than controlled. Six weeks of therapy with two or three antibiotics without acid suppressors resulted in eradication of H. pylori and healing of duodenal ulcers in complaint children, but not in non-compliant children (101,102). In the search for shorter regimens, 2 weeks of omeprazole and amoxicillin therapy had poor results in children (103,104), but metronidazole, omeprazole, and clarithromycin (MOC) therapy for 2 weeks resulted in an overall 93% H. pylori eradication rate (105). A regimen of 2 weeks omeprazole, amoxicillin, and clarithromycin (OAC) plus 4 weeks of omeprazole in those with ulcers, produced a 92% eradication rate of H. pylori in children with H. pylori gastritis with or without ulcer; all seven active ulcers healed (104).
Of importance in children and adults in recognition that not all primary ulcer disease is H. pylori-related (106-109). True non-H. pylori duodenal ulcer disease is a distinct entity, perhaps accounting for as much as 15% to 20% of duodenal ulcers in children (106). In such cases, acid suppression alone is the preferred effective treatment. Recently, guidelines for an approach to diagnosis and treatment of children with peptic ulcer disease were published as part of a Canadian Consensus document (110).
Antral G cell hyperplasia or hyperfunction and the gastrinomas of Zollinger-Ellison syndrome are characterized by hypergastrinemia-driven, marked acid hypersecretion and peptic ulcer disease refractory to H2RAs. Omeprazole has been used with success in G-cell disorders in children (111).
An association between GERD and pulmonary disease has long been recognized (the reader is referred to a comprehensive review of the topic by Sontag ). In established pulmonary disease there is a high prevalence of GERD ranging from 47% to 64% in children, and from 33% to 90% in adults, depending largely on the criterion used to establish the presence of pathologic GERD (112). Gastroesophageal reflux disease may cause or exacerbate pulmonary diseases such as asthma, bronchitis, pneumonia, and pulmonary fibrosis.
Conversely, the cough and tachypnea of pulmonary disease may cause GERD by mechanisms of increased negativity of intrathoracic pressure and increased positive intraabdominal pressure. Other factors reported to promote GERD in pulmonary disease are bronchodilator therapy, the supine position, and the presence of hiatal hernia.
Methods used to clarify the association between GERD and pulmonary disease include sputum microscopy for lipid-laden macrophages, scintigraphy reflux scans, intraesophageal pH monitoring, acid infusion into the esophagus to provoke bronchoconstriction, and surveys on the prevalence of GERD symptoms. Unfortunately, none can reliably prove GERD as the cause of pulmonary disease. A more reliable indicator has been examination of the effects of antireflux treatment of pulmonary disease-that is, the use of antireflux measures for both treatment and diagnosis.
Sontag has reported highly beneficial results of anti-reflux surgery in adults with GERD and long-standing duration (113). Subsequent studies (114,115) showed that even relatively low doses of omeprazole (20 to 40 mg daily) in patients with asthma and heartburn or esophagitis resulted in significant improvement in asthma, despite relatively short durations of treatment. The response of heartburn and erosive esophagitis to omeprazole treatment strongly predicted the response of cough or hoarseness. From results in several studies in adults, it can be concluded that patients most likely to benefit from omeprazole or antireflux surgery are those with nocturnal acid reflux, symptoms of esophagitis, erosive esophagitis, normal esophageal motility and acid clearance, and asthma rather than chronic unexplained respiratory disease (113-116).
There are relatively few studies in pediatrics on this topic. Results in some studies have suggested that use of cisapride resolved nocturnal coughing episodes in infants and children aged 3 months to 10 years (117); improved apnea, cough, irritability, and disrupted sleep patterns in infants aged 4 to 26 weeks (118); and decreased requirements for medication in patients with uncontrolled asthma aged 18 months to 15 years (119). Although the studies in children have shown potential benefit, they are uncontrolled. Their use of short durations of treatment (2 weeks-3 months) allows for an early placebo effect, and durations are too short to determine durability of response. Unlike the subjects in most of the adult studies, these children were at the milder end of the spectrum of GERD, with few or no gastrointestinal symptoms and no endoscopic findings reported. Omeprazole has also been used with success in the management of reflux laryngitis (120).
Omeprazole or lansoprazole administered 3 to 12 hours before surgery can significantly reduce gastric residual volume and increase gastric pH (121,122). Administration of a single dose of 1 mg/kg omeprazole the night before surgery was more effective in increasing gastric pH than a dose administered 3 hours before surgery. Omeprazole therapy in an adult with congenital chloridorrhea resulted in control of his diarrhea and hypokalemia, by reducing gastric chloride secretion (123).
PPIs OTHER THAN OMEPRAZOLE
Lansoprazole (Prevacid, TAP Pharmaceuticals, USA) and pantoprazole (Pantolic BYK Gulden, Germany) are substituted benzimidazoles structurally and pharmacologically related to omeprazole. They, too, have a short half-life (1-2 hours), but a prolonged (>24-hour) antisecretory effect (8,10,124). In hepatic cirrhosis, all three PPIs have decreased clearance and prolonged half-life, whereas in renal failure, clearance and half-life are unchanged. Although all three PPIs share the same cytochrome P-450 isoenzymes for the first step in metabolism of the drug, unlike omeprazole and lansoprazole, pantoprazole is further metabolized by nonsaturable, noncytochrome P-450-dependent reactions. Thus, pantoprazole is said to have less potential for drug interaction than omeprazole or lansoprazole (124).
At this time, in adults, there appear to be no major differences between the efficacy of 20 mg omeprazole, 30 mg lansoprazole, and 40 mg pantoprazole for healing of erosive esophagitis or treatment of peptic ulcers (124,125). In the treatment of erosive esophagitis, 30 mg lansoprazole daily may produce slightly earlier symptomatic relief of nocturnal heartburn than 20 mg omeprazole, but healing rates were equivalent (126). When 30 mg lansoprazole was compared with 40 mg omeprazole, both drugs were equally efficacious for symptom relief and healing of all grades of esophagitis (127). In erosive esophagitis with severe heartburn, 60 mg lansoprazole may be superior to 30 mg for symptom relief (128).
However, there may be differences between the drugs for maintenance of remission. In a recent study, double standard doses of PPI (40 mg omeprazole daily, lansoprazole 60 mg daily and pantoprazole 80 mg daily) were compared for maintenance treatment of grade 4 esophagitis with stricture (129), which had been healed in all patients by an initial course of 40 mg omeprazole daily. Although esophagitis healed in all patients, omeprazole was significantly more effective in preventing relapse of esophagitis and strictures. This may suggest that only omeprazole effects a dose-related acid suppression, whereas increasing doses of lansoprazole and pantoprazole do not seem to have an advantage over the standard dose. These findings require confirmation. For H. pylori-associated ulcer disease, most recent triple therapy regimens that include omeprazole or lansoprazole result in an H. pylori eradication rate of more than 85% to 90%.
At the time of writing these is little, if any, published experience with lansoprazole and pantoprazole in children, whereas dose regimens, efficacy, and safety have been established for omeprazole use in children with erosive esophagitis.
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