Experience with antacids is limited in infants. Their efficacy in buffering gastric acidity in infants is strongly influenced by the time of administration, and requires multiple administrations.
Alginate-antacids form a viscous fluid with surface-active properties, floating as a raft on the surface of the gastric contents, and hence forming an artificial protective barrier against reflux.142 Their efficacy as monotherapy or in combination with prokinetics for reflux is not convincing. Important drug interactions with antacids include the prevention of the absorption of antibacterials such as tetracycline, azithromycin and quino-lones.143 Antacid ingestion decreased the bioavail-ability of famotidione, ranitidine and cimetidine by 20-25%, and the bioavailability of nizatidine by 12%.144 Gaviscon® contains a considerable amount of sodium carbonate, so that its administration may increase the sodium content of the feeds to an undesirable degree (1g of Gaviscon contains 46mg of sodium and the suspension contains twice this amount). Algicon®, having a better taste than Gaviscon, has a lower sodium load, but a higher aluminium content.142 Occasional formation of large bezoar-like masses of agglutinated intragastric material has been reported in association with Gaviscon. Side-effects include diarrhea with magnesium-rich preparations, and excessive absorption of aluminium in infants.142 Dimethicone is used in some regions for regurgitation, although there are no reliable studies demonstrating its efficacy in the treatment of GER in infants. Although often classified as an antacid, it acts more as a feed thickener, as it contains more than 50% of bean gum and has hardly any acid-neutralizing properties.
Acid-suppressant therapy is recommended in severe esophagitis, but this does not rectify primary disordered motility, a major pathophysio-logical mechanism underlying GERD in children. Historically, cimetidine was the first H2RA that became available. Ranitidine and nizatidine are the most popular and best studied (although quite poorly) H2RAs in children.145,146 Experience with other H2RAs such as roxatidine or ebrotidine is very limited or non-existent in children. In general, H2RAs are considered to be quite safe. Adverse events reported in clinical trials with rani-tidine include headache, tiredness and mild gastrointestinal disturbances, but the incidence is not higher than that for placebo.146 A high dose of cimetidine can cause reversible impotence and gynecomastia.146 The endocrinological side-effects associated with long-term administration of cimetidine in adults essentially preclude its long-term use in children.147 Fatigue, dizziness, headache, dyspepsia, nausea, abdominal pain, flatulence, constipation and diarrhea occur in 1-6% of patients.148 H2RAs have been reported to provoke central nervous system dysfunction, but these are poorly documented in children. Ranitidine enhances ischemic neuronal damage.148 Raniti-dine has occasionally been associated with acute interstitial nephritis in native and transplanted kidneys.149 While ranitidine exhibits no clinically significant drug-drug interactions, cimetidine interacts with many drugs metabolized by cytochrome P450. Theophylline plasma levels were 25-32% higher if cimetidine was administered, compared to ranitidine. Neither ranitidine nor nizatidine increased theophylline levels.144,150 H2RAs, PPIs and prokinetic agents undergo metabolism by the cytochrome P450 system present in the liver and gastrointestinal tract.143 Cimetidine is an inhibitor of CYP3A and it may cause significant interactions with drugs of narrow therapeutic range and low bioavailability that are metabolized by those enzymes.143
Whether ranitidine may exceptionally cause QT prolongation or not, is still debated.151 If ranitidine is administered intravenously after autonomic blockade, the sinus cycle length is prolonged, and the systolic and diastolic blood pressures are decreased.152 Thus, ranitidine has to be administered by a slow intravenous infusion in patients with sinus node dysfunction.152 The altered cardiac sympathovagal balance after oral administration of the H2RA ranitidine indicates a shift towards sympathetic predominance in the heart rate control.153 Ranitidine modulates high-frequency power of heart rate, and this may be the underlying mechanism of cardiovascular side-effects.154 Since H2 receptors are present in the stomach and the heart, they have a trend towards decreasing the heart rate and cardiac contractility.
Nizatidine and ranitidine are susceptible to metabolism by colonic bacteria, but famotidine and cimetidine are not (see also the section on PPIs, below).155 Ranitidine alters the gastrointestinal flora156 and causes significantly more pneumonias in patients in intensive care units.157 In the majority of patients on H2RAs, there is a relatively important nocturnal breakthrough of acid secretion, sometimes limiting therapeutic efficacy, but on the other hand minimizing side-effects related to long-term blockade of acid secretion as with PPIs. There is a rapid development of tachyphylaxis or tolerance to H2RAs, limiting their long-term clinical use.158
The combination of ranitidine and pirenzipine, a muscarinic receptor antagonist, does not aid the healing of reflux esophagitis, but does improve symptom relief after 4 weeks.159 However, side-effects were reported in nine of 75 patients in the ranitidine group and 19 of 76 patients in the ranitidine and pirenpizine group.159
The suppression of gastric acid secretion achieved with H2RAs has, however, proved to be subopti-mal.158 In this regard, the advent of the PPIs has been a major breakthrough. Drugs of this category have in fact been shown to be more effective than H2RAs.96 Esomeprazole seems to be the most effective PPI commercialized today.160 Step-down treatment is recommended in adults.161 Failure to control symptoms with high-dose PPI treatment raises the likelihood of non-acid-related causes for the symptoms.
The pharmacokinetics and tolerance of pantopra-zole were similar in patients with moderate and severe hepatic impairment.162 These were also evaluated for famotidine in 150 children.163 Recent studies with lansoprazole showed its efficacy in reducing symptoms and healing esophagitis in children.164 The availability of a syrup facilitates the use of this drug in children.164 Zimmermann and colleagues reviewed the literature on the use and administration of omeprazole in children.165 In uncontrolled trials and case reports, omeprazole was used at a dosage of 0.2-3.5mg/kg per day for periods ranging from 14 days to 36 months, and found to be effective and well tolerated for the acute and chronic treatment of esophageal and peptic ulcer disease in children aged 2 months to 18 years.165
The following side-effects of PPI have been reported: headache (about 3%); neurological and psychiatric side-effects, especially fatigue, dizziness and confusion in patients with hepatic diseases and/or advanced age; cutaneous reactions, generally rash and urticaria; hemolytic anemia, leukopenia and agranulocytosis; gyneco-mastia; subacute myopathy; gastrointestinal side-effects such as flatulence, constipation, diarrhea (about 4%), dyspepsia and nausea (about 2%), vomiting and abdominal pain; hepatic disorders, especially moderate elevation of amino-transferases; and excessive urinary sodium loss.97,142,166,167 The high cost of PPIs can also be considered an important albeit not medical 'side-effect'.
Omeprazole, esomeprazole, lansoprazole, rabepra-zole and pantaprazole rarely exhibit clinically important interactions with other hepatically metabolized medications or pH-dependent drugs.168 The absorption of drugs that are pH sensitive, as is the case with digoxin and keto-conazole, will be influenced by PPIs.169
The gastroparietal PPIs lansoprazole, omeprazole and pantoprazole are all primarily metabolized by a genetically polymorphic enzyme, CYP2C19, that is absent in approximately 3% of Caucasians and 20% of Asians.143 These drugs may also interact with CYP3A, but to a lesser extent. Esomeprazole has the potential to interact with CYP2C19. The slightly altered metabolism of cisapride was also suggested to be the result of inhibition of a minor metabolic pathway for cisapride mediated by CYP2C19. Esomeprazole did not interact with the CYP3A4 substrates clarithromycin and quini-dine.169 Overall, the potential for drug-drug interactions with esomeprazole is low, and similar to that reported for omeprazole.169 Salivary secretion is decreased with omeprazole. Prolonged use of PPIs can result in vitamin B12 deficiency as a consequence of impaired release of vitamin B12 from food in a non-acid environment. However, cystic fibrosis patients treated for at least 2 years with a PPIs and cystic fibrosis patients without PPI had higher vitamin B12 levels than healthy controls.170
The safety of long-term administration of acid-blocking medication needs to be considered in relation to potential consequences of prolonged acid suppression, including the risk of proliferation of gastric flora and the risk of developing ente-rochromaffin-like cell hyperplasia, which could, in turn, theoretically, lead to gastric malignancy. Hypergastrinemia occurs in nearly all patients treated with omeprazole, causing hyperplasia and pseudohypertrophy of the parietal cells, as recently shown in 93% of adult patients on long-term omeprazole. Patients on omeprazole therapy for 5-8 years remained without evidence of significant enterochromaffin cell hyperplasia, gastric atrophy, intestinal metaplasia, dysplasia or neoplastic changes.171 Because of the excellent efficacy profile, these drugs tend to be overused.172 Since PPIs could delay the diagnosis of gastric cancer, the long-term uncontrolled and unnecessary use of these drugs should be avoided. Bacterial proliferation in the gastric content may not only change colonic flora, but may also be a risk factor for the patient to develop nosocomial pneumonia.
Sucralfate causes bezoars, especially when given to patients in intensive care units, and diarrhea. Patients with renal failure treated with sucralfate are exposed to aluminium toxicity.173-175 Other anti-emetic drugs such as batanopride also have a QTc-prolonging effect.176 Octeotride is a long-acting somatostatin, that induces a phase 3-like migrating motor complex response, which is not inhibited by meals (differing from normal), and has an inhibitory effect on the gastric antrum (and is therefore indicated in dumping syndrome). Motilin agonists have been studied with inconsistent results in adults, and are not yet available for pediatric use.177
During recent years, new endoscopic techniques intending to improve the function of the antireflux barrier have been developed. The first results of endoscopic gastroplasty (Endocinch® system), radiofrequency delivery at the cardia (Stretta® system) and injection therapy (Enteryx® procedure) in adults have been reported.178-181 The first series in adolescents have been performed. Although experience is too limited to recommend broad use, the theoretical concept of these procedures is interesting. Further improvements to the techniques are still being introduced.
While anti-reflux surgery in certain groups of children may be of considerable benefit, it also has a mortality and a failure rate.184-187 Ninety per cent of patients remained free from significant reflux symptoms after a laparoscopic Nissen operation, although side-effects occurred in up to 22%.186 After a median follow-up of 16 years, the Nissen-Rosetti procedure in 24 consecutive children without congenital or acquired anomalies of the esophagus except GERD showed a result that was considered excellent in only 75%, good in 21% and poor in 4%.187 Failure rates of 5-20% have been found after objective postoperative follow-up.187 A protective anti-reflux surgical procedure in neuro-logically impaired children needing a gastrostomy increased the morbidity and mortality rate of the gastrostomy procedure itself.188
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Gastroesophageal reflux disease is the medical term for what we know as acid reflux. Acid reflux occurs when the stomach releases its liquid back into the esophagus, causing inflammation and damage to the esophageal lining. The regurgitated acid most often consists of a few compoundsbr acid, bile, and pepsin.