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Abstract

After completing this article, readers should be able to: Proton pump inhibitors (PPIs) have become the mainstay of treatment for acid-related gastrointestinal disease in adults since their introduction in 1989. There are several inherent advantages of PPIs compared with the older medication classes of antacids or histamine2-receptor antagonists (H2-RAs). H2-RAs reduce acid secretion only by competing with histamine receptors located in the parietal cell membrane; other cellular receptors that respond to endocrine (gastrin) and neuroendocrine (vagal stimulation) pathways are not affected. As a consequence, H2-RAs do not completely block gastric parietal cell acid production.Unlike H2-RAs, PPIs demonstrate consistent gastric pH control and do not develop tachyphylaxis with repeated dosing. The pharmacology of every PPI involves targeting the gastric acid or proton pump (H+-K+ ATPase), which is situated in parietal cell membranes. After extensive first-pass metabolism in the liver, prodrug accumulates in the canalicular space of the parietal cell and is converted to an active metabolite through an acid-catalyzed reaction. Active drug then irreversibly binds to cysteine residues within the H+-K+ ATPase via a covalent bond. Consequently, PPIs inhibit the final step of gastric acid secretion by blocking proton production.PPIs require an acidic environment within the canalicular space for activation, and proton pumps are maximally exposed on the surfaces of meal-stimulated parietal cells. As a result, administration optimally should occur in a fasting state 30 minutes prior to the first meal of the day. In general, most PPIs are manufactured as capsules that remain intact until they reach the stomach, at which time gastric acid dissolves the capsules and releases prodrug granules. The granules’ polymer coating dissolves only at a pH of 6, which allows for release of medication in the duodenum. Currently, five PPIs are available in the United States (Table), including omeprazole (Prilosec™, Astra Zeneca, Wilmington, DE), lansoprazole (Prevacid™, TAP Pharmaceuticals, Deerfield, IL), rabeprazole (Aciphex™, Janssen Pharmaceutica, Titusville, NJ), pantoprazole (Protonix™, Wyeth-Ayerst Laboratories, Philadelphia, PA), and esomeprazole (Nexium™, Astra Zeneca, Wilmington, DE). The relative cost of each PPI has been demonstrated in several review articles (see Suggested Reading).There appears to be a minimal risk of adverse effects in humans with long-term PPI administration. When high-dose PPIs were administered to rats, hypergastrinemia, endocrine cell hyperplasia, and carcinoid tumors developed. Elevated gastrin levels have been observed in patients receiving omeprazole, but serum gastrin normalized once the drug was discontinued. In addition, enterochromaffinlike cell hyperplasia and gastric polyps have been observed in adults receiving long-term PPI therapy, but no carcinoid tumor formation ever has been reported in humans. Pashankar and associates followed six children receiving long-term omeprazole therapy (4 to 7 y) and found an increase in the number of G cells (gastrin-secreting cells) as well as an increase in the G-cell-to-D-cell (somatostatin-secreting cell) ratio. The clinical significance of this finding is unclear. Children have been observed for several years while receiving PPI therapy with no major adverse effects noted, but the relative safety of prolonged PPI usage in children is still unknown.The clinical spectrum for PPI usage within the pediatric population has increased remarkably, with most of the research in children involving gastroesophageal reflux disease (GERD). Gastroesophageal reflux (GER), or the passage of stomach contents into the esophagus, is a normal physiologic occurrence that normally decreases significantly in the first few months of life. GER must be differentiated from GERD, which is defined as the passage of stomach contents into the esophagus with associated symptoms such as irritability, vomiting, hematemesis, esophagitis, failure to thrive, apnea, recurrent respiratory problems, or dysphagia due to esophageal stricture. The causes of GERD are complex and multiple, including an increase in transient lower esophageal sphincter relaxation episodes, decreased competence of the lower esophageal sphincter, and increased acid secretion. The cycle of excessive acid secretion and protracted sphincter relaxation ultimately results in pathology.In this article, we discuss the current recommendations for PPI usage for treatment of GERD in children. However, these drugs have a potential benefit for a variety of other conditions that affect children, including peptic ulcer disease, Helicobacter pylori infection, and nonulcer dyspepsia.Omeprazole, the first PPI used in the United States, was also the first PPI to be studied in the pediatric population. However, its safety and effectiveness in children have not been established in large controlled studies. Omeprazole is currently available in 10-, 20-, and 40-mg delayed-release capsule formulations that contain enteric-coated granules. For patients who cannot take capsules or for those requiring gastrostomy tube feeding, four preparations of omeprazole are recommended. These include mixing intact granules with water, acidic fruit juices, or solid foods such as applesauce and yogurt to prevent removal of the prodrug’s protective coating. Additionally, omeprazole can be placed in a sodium bicarbonate suspension, which allows the granules to dissolve. This method of delivery is ideal for situations where enteric access is limited to the alkaline environment of the small bowel (eg, jejunostomy tube). Although the various methods have been shown to have equal efficacy in acid suppression, dissolving granules in a bicarbonate suspension can make administration of omeprazole via a gastrostomy or jejunostomy tube ideal by preventing clogging of tubing. As with any administration of medication through a tube, flushing with 5 to 10 mL water afterwards prevents clogging of the feeding apparatus.Omeprazole’s serum level is not altered in patients who have underlying renal disease, although dosages may need to be adjusted in cases of hepatic dysfunction. Drugs metabolized through the cytochrome P-450 system, such as phenytoin, carbamazapine, diazepam, and warfarin, may have decreased clearance and require dosing adjustments if administered with omeprazole.Omeprazole appears to be safe to use even in infants. Alliët and colleagues evaluated 12 infants (mean age, ∼ 3 mo) who had erosive esophagitis that did not respond to a combination of cisapride, aluminum hydroxide, and positioning. Omeprazole, added at a dosage of 0.5 mg/kg per day for 6 weeks, resulted in a marked improvement of GERD symptoms and intragastric acidity. Repeat endoscopy revealed complete resolution of esophagitis after treatment in most of the patients. Omeprazole also is an effective therapy for esophagitis in older children. Hassall and associates demonstrated that omeprazole administered in a dose range of 0.7 to 3.5 mg/kg per day improved the grade of esophagitis in 54 of 57 patients (95%) studied (age range, 1 to 16 y).Omeprazole may be superior to H2-RAs and prokinetic agents for esophagitis in children. Karjoo and Kane followed 129 pediatric patients between 6 and 18 years of age who had endoscopically proven esophagitis. As the severity of esophagitis increased, approximately 50% of the patients treated with high-dose ranitidine responded to therapy. However, patients refractory to ranitidine therapy who were treated with omeprazole 20 mg/d experienced a significant improvement in symptoms (87% improved after 2 wk of treatment). Gunasekaran and Hassall evaluated 15 children who presented with severe esophagitis unresponsive to both H2-RAs and prokinetic agents. Omeprazole was titrated to achieve an intraesophageal pH greater than 4.0; the mean dose required to reach this desired endpoint was 1.9 mg/kg per day. Signs and symptoms of GERD were absent in all patients within 6 months of initiating treatment, and the majority of responding patients who required repeat endoscopy at 6 months had an improvement in esophagitis. Similarly, Strauss and colleagues found that omeprazole at a mean dose of 0.7 mg/kg per day led to a significant improvement of symptoms among 18 pediatric patients who had refractory esophagitis despite H2-RA and prokinetic therapy.Omeprazole has been compared directly with H2-RAs for treatment of GERD in children. Cucchiara and associates randomized 32 patients who had esophagitis (age range, 6 mo to 13 y) to receive either omeprazole (40 mg/1.73m2 per day) or high-dose ranitidine (20 mg/kg per day) for 8 weeks. Patients receiving omeprazole had a greater improvement in both endoscopically proven esophageal healing and symptom relief at the end of therapy compared with ranitidine, although the difference was not significant.These studies, which generally involved small numbers of patients, demonstrate that omeprazole is safe for the treatment of GERD in children and possibly is a more effective treatment than H2-RAs or prokinetic medications.Lansoprazole is pharmacologically similar to omeprazole. It has been tested extensively in adult patients, and the following brief review of its pharmacology provides insight into its use for the pediatric population. Lansoprazole is available as capsules (15 mg and 30 mg) and a liquid suspension formulation (15 mg and 30 mg). The capsules may be opened and their contents given either by mouth or by tube in a manner similar to omeprazole, although the liquid suspension formulation often obviates this need. Lansoprazole has an increased plasma concentration in patients who have cirrhosis and renal insufficiency, which may necessitate a dosage reduction.Few data are available regarding the use of lansoprazole in the pediatric population. Franco and coworkers evaluated its use in 35 children who had GERD refractory to H2-RA therapy. An initial dose of 1.3 to 1.5 mg/kg per day was sufficient to inhibit gastric acid secretion in 12 patients (34%). However, 23 patients (66%) treated at a lower initial dose of 0.8 to 1.0 mg/kg per day required a dose increase because of inadequate acid suppression. Most patients had complete esophageal healing, as demonstrated by repeat endoscopy and symptom assessment, and the drug was well tolerated by all. The authors suggested using an initial lansoprazole dose of 1.5 mg/kg per day for treatment of esophagitis in children, noting that a dosage increase may be warranted if symptoms persist. Similarly, Faure and associates demonstrated that lansoprazole was extremely effective in the treatment of endoscopically documented GERD in children and recommended a dosage of 1.4 mg/kg per day.Rabeprazole is similar to other PPIs in its pharmacologic profile. One limitation is that it is only available as a 20-mg tablet that cannot be crushed or chewed. Because the drug is metabolized exclusively in the liver, dosing adjustments are required for patients who have severe hepatic insufficiency. Drugs metabolized through the cytochrome P-450 system can reach increased serum levels when coadministered with rabeprazole because of rabeprazole’s extensive clearance in the liver. On the other hand, rabeprazole is not affected by renal function and can be given to patients who have end-stage kidney disease. Presently, there are no pediatric studies of this medication.Pantoprazole is a unique PPI that has been approved in the United States for both oral and intravenous administration. It differs from other PPIs by exclusive binding to cysteine residues 813 and 822 of the proton pump, which allows for more direct inhibition of acid secretion. Pantoprazole is available as a 40-mg tablet and in an intravenous formulation. The oral and intravenous preparations are equivalent on a milligram-to-milligram basis, and studies evaluating 24-hour intragastric pH demonstrate excellent acid suppression after either route of administration. The intravenous formulation requires a filter during administration to prevent potential precipitate from infusing into the patient.Obviously, the intravenous formulation makes pantoprazole an attractive drug for patients who cannot take an oral PPI (such as in the intensive care unit). Pantoprazole has a low affinity for the cytochrome P-450 system, and dosage adjustments are not required for patients who have renal or hepatic impairment. No pediatric studies have evaluated the use of pantoprazole for acid-related disease, including GERD.Esomeprazole is the newest PPI used in the clinical setting and is the first developed as a single optical isomer (the S-isomer) of omeprazole. The liver metabolizes the S- and R-isomers of omeprazole differently, and esomeprazole was developed because the S-isomer (esomeprazole) was shown to achieve higher plasma levels in vivo. The clinical significance of this finding, however, is not entirely clear. Esomeprazole is available in 20- and 40-mg delayed-release capsules containing enteric-coated pellets. Dosage adjustments based on renal insufficiency are not necessary. Patients who have cirrhosis require a lower dose because of the drug’s hepatic metabolism. Clinical studies comparing esomeprazole with other PPIs are ongoing, although no current published pediatric clinical data are available.There is much potential for PPI usage in pediatrics because of the effectiveness of the drug class in reducing acid secretion. The North American Society of Pediatric Gastoenterology, Hepatology, and Nutrition guidelines for treatment of GERD in children recommend omeprazole as a potential treatment for esophagitis at a dosage of 1 mg/kg per day administered once or divided twice daily.Unfortunately, pediatric clinical studies evaluating PPI usage are available only for omeprazole and lansoprazole. Both drugs can be made into a suspension to ease intake and compliance in young patients. Additional studies are required for the remaining PPIs, although they probably are equally safe and efficacious and have minimal risks of adverse effects. The primary care clinician should feel comfortable using the PPI in short-term treatment of gastric acid-related disease. However, because peptic disease can be mimicked by other disorders and can be serious in children, prolonged use of PPIs is recommended under the consultative supervision of a pediatric gastroenterologist.