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  • Downloaded from ep.bmj.com on 26 August 2008 Update on drugs for gastro-oesophageal reflux disease Simon Keady Arch. Dis. Child. Ed. Pract. 2007;92;ep114-ep118 doi:10.1136/adc.2006.106328 Updated information and services can be found at: http://ep.bmj.com/cgi/content/full/92/4/ep114 These include: References This article cites 46 articles, 10 of which can be accessed free at: http://ep.bmj.com/cgi/content/full/92/4/ep114#BIBL Rapid responses One rapid response has been posted to this article, which you can access for free at: http://ep.bmj.com/cgi/content/full/92/4/ep114#responses You can respond to this article at: http://ep.bmj.com/cgi/eletter-submit/92/4/ep114 Email alerting service Receive free email alerts when new articles cite this article - sign up in the box at the top right corner of the article Notes To order reprints of this article go to: http://journals.bmj.com/cgi/reprintform To subscribe to Archives of Disease in Childhood - Education and Practice go to: http://journals.bmj.com/subscriptions/
  • Downloaded from ep.bmj.com on 26 August 2008 PHARMACY UPDATE UPDATE ON DRUGS FOR GASTROOESOPHAGEAL REFLUX DISEASE Simon Keady ep114 Arch Dis Child Educ Pract Ed 2007; 92:ep114–ep118. doi: 10.1136/adc.2006.106328 G astro-oesophageal reflux (GOR) is a common and usually self-limiting condition involving the regurgitation of gastric contents into the oesophagus. It causes symptoms (table 1) such as heartburn, oesophagitis, acute life-threatening events and respiratory disease,1–3 at which point it is defined as gastro-oesophageal reflux disease (GORD). The prevalence of GOR and GORD in infants is between 20–40%, higher than that in children and adults. This high number is associated with the transient immaturity of the oesophagus and the stomach. Features include a short abdominal oesophagus (,1 cm), increased oesophageal clearance, increased number of transient lower oesophageal sphincter relaxations coupled with delayed gastric emptying.4–6 Methods of detection include oesophageal pH monitoring, especially with respiratory manifestations,1 3 7–9 or multiple intraluminal impedance.10–12 The latter allows detection of continued postprandial reflux despite a neutralisation of gastric contents by milk formula. However, there continues to be a wide variation in diagnostic and management strategies even across major neonatal intensive care units in the UK, requiring further work to evaluate appropriateness and effectiveness.13 TREATMENT OF GOR AND GORD IN INFANTS, CHILDREN AND YOUNG PEOPLE The principal aims of treatment are to alleviate symptoms, allow healing of the oesophageal mucosa if indicated, manage and prevent any complications and to maintain long-term remission. Treatment strategies and options depend upon the severity of the GORD and may include lifestyle changes or pharmacological and surgical interventions. Older children and young people should be counselled on specific lifestyle changes such as weight reduction if obese and the avoidance of smoking and drinking alcohol if necessary. For the purpose of this article, the focus will primarily be on drug management of this condition (table 2). TREATMENT OF GOR OR MILD GORD Normal steps in the management of mild conditions are usually non-pharmacological and may involve reassurance of parents/carers, thickening of feeds and placing the infant in a supine position. The latter, while often suggested, has few data to support its recommendation.14 FEED THICKENERS Carob-based thickeners can be used in infants under one to thicken feeds. For those infants being breast fed, the thickener can be given as a paste prior to feeds. Starch-based thickeners can be used in feeds and liquids for children over the age of 1. Caesin-based infant formula is a pre-thickened formula that contains small quantities of pregelatinised starch. It is primarily recommended for those infants with mild GOR. The formula is prepared in the same way as a normal infant formula and is able to flow through a standard teat. The feed does not thicken on standing but does so in the stomach when it is exposed to an acidic environment. ANTACIDS (INCLUDING ALGINATE FORMULATIONS) __________________________ Correspondence to: Mr S Keady, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK; simon.keady@uclh.nhs.uk __________________________ www.archdischild.com Initial pharmacological intervention is usually with antacid therapy which neutralises gastric acid and reduces the symptoms of indigestion and oesophagitis. The major advantage of antacids is their rapid onset of action in providing relief. An intragastric pH above 3.5 can be achieved within minutes. Their limitation, however, is maintaining this pH in the presence of continued acid secretion and the gastric emptying rate. Alginate-containing antacids (for example, Gaviscon Infant) form a ‘‘raft’’ that floats on the surface of the stomach contents which should reduce reflux and afford some protection to the oesophageal mucosa. However, recent assessment of Gaviscon Infant on GOR by combined intraluminal impedance/pH questions its efficacy at preventing reflux.15
  • Downloaded from ep.bmj.com on 26 August 2008 PHARMACY UPDATE Table 1 Symptoms of gastro-oesophageal reflux disease (GORD) Usual manifestations Specific manifestations Nausea Vomiting Regurgitation Symptoms related to GORD complications Symptoms related to iron deficiency anaemia Dysphagia (direct symptom of oesophagitis or from stricture formation) Weight loss and/or failure to thrive Epigastric or retrosternal pain Non-cardiac angina-like chest pain Belching, postprandial fullness General irritability Irritable oesophagus Unusual presentations GORD related to chronic respiratory disease (bronchitis, asthma, laryngitis, etc) Sandifer–Sutcliffe syndrome Apnoeas, apparent life-threatening event and sudden infant death syndrome Congenital and/or central nervous system abnormalities Intracranial tumours, cerebral palsy, psychomotor retardation Those alginate preparations containing aluminium should be avoided in chronic use wherever possible, especially in neonates, infants and children with renal impairment, because of accumulation leading to an increased plasma-aluminium concentration. Gaviscon Infant should not be used when excessive water loss is likely—such as pyrexia, diarrhoea or vomiting or where there is a risk of intestinal obstruction. The prescribing and co-administration of alginates and thickening agents should be undertaken with caution because of the risk of agglutinated intragastric materials being formed which can lead to possible intestinal obstruction. To avoid confusion in the use of Gaviscon Infant, each half of the dual sachet is identified as ‘‘one dose’’. The prescription should be in terms of dual sachets when prescribing a dose— that is, two doses (one dual sachet). MANAGEMENT OF MODERATE TO SEVERE GORD Drug treatment in this group of patients usually combines a prokinetic agent with an appropriate acid suppressant. With the withdrawal of cisapride and the adverse effects associated with Table 2 Summary of drugs used to treat GOR and GORD Drug Available formulations Aluminium hydroxide Maalox Mucogel Gaviscon Infant Liquid Liquid Sachets Suspension Tablets Domperidone Liquid, tablets Erythromycin Metoclopramide Liquid, tablets Liquid, tablets Ranitidine Liquid, tablets Lansoprazole Capsules, FastTabs (disp tabs), suspension Capsules, tablets Omeprazole Frequency Licensed (Y/N) 14–18 years: 10–20 ml 12–18 years: 10–20 ml Neonate under 4.5 kg: 1 dose with feeds/water when required Neonate over 4.5 kg: 2 doses with feeds/water when required 1 mo–12 years: 2 doses with feeds/water when required 2–12 years: 2.5–5 ml 12–18 years: 5–10 ml 6–12 years: 1 tablet 12–18 years: 1–2 tablets Neonate: 100–300 mg/kg 1 mo–12 years: 200–400 mg/kg (max 20 mg) 12–18 years: 10–20 mg Neonate – 18 years: 3 mg/kg Neonate: 100 mg/kg 1 mo–1 year and body-weight up to 10 kg: 100 mg/kg 1–3 year and body-weight 10–14 kg: 1 mg 3–5 year and body-weight 15–19 kg: 2 mg 5–9year and body-weight 20–29 kg: 2.5 mg 9–18 year and body-weight 30–60 kg: 5 mg 15–18 year and body-weight over 60 kg: 10 mg Neonate: 2 mg/kg (up to max 3 mg/kg) 1 mo–6 mo: 1 mg/kg (up to max 3 mg/kg) 6 mo–12 year: 2–4 mg/kg (max 150 mg) 12–18 year: 150 mg Child under 30 kg: 0.5–1 mg/kg (max 15 mg) Child over 30 kg: 15 mg–30 mg After meals and at bedtime After meals and at bedtime Max 6 times in 24 h N (not ,14 years) N (not ,12 years) Y Max 6 times in 24 h Y Max 6 times in 24 h After meals and at bedtime After meals and at bedtime After meals and at bedtime After meals and at bedtime 4–6 times daily before feeds 3–4 times daily before feeds 3–4 times daily before food Four times a day Every 6–8 h Twice daily 2–3 times daily 2–3 times daily Three times daily Three times daily Three times daily Three times daily Three times daily Twice daily Twice daily Once daily in the morning Once daily in the morning Y N Y N Y N N N N N N N N N N N N N N N N N Neonate: 700 mg/kg increasing to 1.4 mg/kg after 7–14 days. Some neonates may require 2.8 mg/kg Once daily Y (for children >1 year with severe ulcerating reflux oesophagitis) 1 mo–2 year: 700 mg/kg increased to 3 mg/kg if necessary (max 20 mg) Body weight 10–20 kg: 10 mg initially increasing to 20 mg if necessary Body weight over 20 kg: 20 mg once daily increasing to 40 mg if necessary Gaviscon Advance Dose Once daily (not ,12 years) (not ,12 years) (not (not (not (not (not (not (not (not (not (not (not (not (not (not (not for for for for for for for for for for for for for for for GORD) GORD) GORD) GORD) GORD) GORD) GORD) GORD) GORD) GORD) GORD) GORD) GORD) GORD) GORD) Once daily Once daily Doses based on recommendations from the British National Formulary for Children 2006. www.archdischild.com ep115
  • Downloaded from ep.bmj.com on 26 August 2008 KEADY metoclopramide, the common prokinetic agents include domperidone and erythromycin. PROKINETIC DRUGS ep116 Domperidone Domperidone is a peripheral D2 receptor antagonist that increases motility and gastric emptying and decreases the postprandial reflux time. Since the suspension of the marketing authorisation of cisapride in 2000 and the company’s subsequent withdrawal of the product in 2005, domperidone has become increasingly used. Clinical trials assessing domperidone use in infants or children with GORD are limited. Four randomised clinical trials identified showed very little efficacy in the reduction of symptoms in both GOR and GORD.16–19 The immaturity of the nervous system and the blood/brain barrier in premature infants, infants and children may make these patients more susceptible to neurological symptoms (extrapyramidal and oculo-gyric crisis)20 21 associated with domperidone. However, in all four trials, no adverse events were documented. Erythromycin Erythromycin is a macrolide antibiotic which has demonstrated an increase in GI motility by acting directly upon motilin receptors in the GI tract. Motilin is a hormone secreted into the GI tract during times of fasting and has a function on smooth muscle contractions. Trials involving erythromycin have mainly focused on its use in neonates and infants and although there is some evidence of its efficacy in older children, none is supported by prospective clinical trials.22–30 Both the oral and intravenous routes have been used while doses have ranged from 1.5–12.5 mg/kg every 6 h. However, erythromycin’s effects appear to be dose dependent and side effects can be minimised without diminishing motility at doses of 1–3 mg/kg.31 Adverse effects at these doses, although rare, can be severe. They include GI upset, hepatotoxicity, anaphylaxis, arrhythmias and infantile hypertrophic pyloric stenosis. As with all antibiotics, especially for non-infectious conditions, the potential for resistance should be considered prior to initiating therapy. Metoclopramide Metoclopramide is a dopamine antagonist which increases motility and accelerates gastric emptying by enhancing the GI tract’s response to acetylcholine. It also increases the lower oesophageal sphincter tone. Although it may appear to have the ideal combination of properties to treat GORD, studies have shown it to be little better than placebo.32 It is also associated with a number of serious adverse effects including drowsiness, restlessness, galactorrhoea as well as extrapyramidal reactions such as dystonia and tardive dysknesia.33 34 Other prokinetic agents available now limit its use. Withdrawal of cisapride In 2000 when the Committee on the Safety of Medicines (CSM) withdrew the product license for cisapride, it had been used in 140 million patient treatments with 37.8 million of these in patients up to 20 years of age. Of these, 25.2 million were in the under 1s.35 www.archdischild.com The CSM cited concerns over cisapride’s potential to prolong the QT interval, which could lead to adverse events such as torsades des pointes or a clinically significant degree of heartblock.36 With no agreed method for quantifying a normal QTc interval, it makes a definitive description of a QTc prolongation difficult. All the reported cases of torsades des pointes involved the concomitant administration of cisapride with a macrolide antibiotic, an overdose of cisapride or both.36 37 Post-marketing experience showed that doses up to 800 mg/kg/ day could be used safely. Recommendations were made in an attempt to ensure the continued availability of cisapride.38 These included a strict maximum dose limit, ECG monitoring, correction of relevant electrolyte discrepancies prior to initiation of therapy and awareness of drugs to avoid while on cisapride therapy. Despite this, in 2005 the company terminated its product license and ceased production of cisapride. GASTRIC ACID SUPPRESSANTS Histamine-2-receptor antagonists Rantidine is the drug of choice in this group of drugs. It works by inhibiting the H2 receptors of the gastric parietal cells. Side effects, although rare, can include fatigue, dizziness, diarrhoea and other gastrointestinal disturbances.39–41 Unsurprisingly, efficacy is greater in cases of mild oesophagitis than in severe ones where a proton pump inhibitor maybe of more benefit. Oral ranitidine given 2–3 times a day provides symptomatic and endoscopic symptom improvement in erosive oesophagitis. In infants, a three times a day regime is often required as intragastric pH returns to its baseline level within 5 h. Rises in gastric pH have been associated with bacterial overgrowth in infants.42 Tolerance to the antisecretory effect of histamine-2-receptor antagonists develops quickly and the possible occurrence of rebound hypersecretion must be taken into account upon discontinuation of the drug and a reduction in a stepwise manner is recommended.43 The long-term effects of gastric acid blockade have yet to be determined especially in infants. It is therefore still unclear as to whether total acid suppression is an appropriate target or whether small periods of gastric acid secretion through the day are warranted. However, with the introduction of proton pump inhibitors and their demonstrated superiority over histamine-2-receptor antagonists, this question may never be answered. Proton pump inhibitors Lansoprazole and omeprazole are proton pump inhibitors (PPIs) that inactivate the H(+)/K(+) –ATPase pump in parietal cells inhibiting gastric acid secretion and increasing the intragastric pH. This series of events involves the protonation of the drug molecule and through a variety of reactions, turns it into an active form. Gastric acid secretion only returns once the parietal cells synthesise new H+/K+ ATPase supplies. PPIs are often well tolerated by patients with the commonest side effects including mild to moderate headaches, abdominal pain, vomiting and diarrhoea. Occasional electrolyte disturbances and minor reversible elevation of transaminase levels have also been reported.
  • Downloaded from ep.bmj.com on 26 August 2008 PHARMACY UPDATE Prolonged periods of hypochlorhydria have been identified in neonates as well as adults, resulting in bacterial overgrowth. The effects of this overgrowth still remain unclear but increases in respiratory infections in critically ill patients have been reported.44 Approximately 40% of children prescribed omeprazole will respond to a dosage of 0.73 mg/kg/day, a further 26% to an increase to 1.44 mg/kg/day while approximately 35% will fail at this dose.45 Pharmacokinetic studies of omeprazole in children have shown a significant difference in the half life of the drug in children less than 7 years of age and those over 7. The younger cohort of patients appears to metabolise the drug quicker and this higher metabolic rate suggests that these patients may benefit from a twice daily regime instead of a single morning dose. PPIs are metabolised by the hepatocyte cytochrome P450 isoforms CYP2C19 and CYP3A4 to inactive metabolites. The CYP2C19 is the predominant enzyme with an affinity to the PPI 10 times that of the CYP3A4. CYP2C19 displays a known genetic polymorphism which can lead to large variations in the kinetic disposition of the PPI. The phenotype is present in approximately 3–5% of the Caucasian and African-American population but rises to 15–20% in the Asian population. This variation of genetic polymorphism related to these enzymes will further lead to differences in the kinetic disposition of PPIs. The ‘‘poor metabolisers’’, that is, reduced enzymatic activity, can have plasma concentrations and area under the concentration curve up to 5 times greater than ordinary metabolisers. It would therefore be prudent to consider the impact of the CYP2C19 genotype when researchers evaluate the pharmacokinetic and pharmacodynamic data of PPIs in the paediatric population. Current treatment options involving PPIs can be limited due to a lack of suitable ‘‘child friendly’’ formulations. There is no licensed liquid PPI available in the UK and granules and tablets are not able to be crushed because of their gastro-protective coat. Inadvertent crushing will lead to a significant change in the drugs pharmacokinetic and pharmacodynamic properties due to altered absorption and metabolism. This requires manipulation of the solid dosage forms into a more suitable version. Extemporaneous liquid formulations therefore have limited information with regards to stability and bioavailability. An extemporaneous liquid formulation of omeprazole in sodium bicarbonate 8.4% can be made46 but there can still be variations in absorption etc when compared to the administration of a tablet or capsule. The lansoprazole FasTab is able to be administered down enteral feeding tubes if necessary, which makes it a viable choice in those infants requiring feed through nasogastric tubes. The lansoprazole suspension should be avoided in this group of patients because of its tendency to block the tube. Future treatment options In order to achieve a more rapid, potent and sustained degree of remission, several other drugs have been tried. Baclofen, a GABAB receptor agonist has been used as an add-on therapy with PPIs, particularly in cases where there is persisting reflux symptoms. It has been shown to inhibit transient lower oesophageal sphincter pressure relaxations as well as possibly increasing the basal lower oesophageal sphincter pressure. Further work is required to determine optimum doses required because of the variability in the volume of distribution of the drug due to evolving body composition.47 Histamine receptor agonists continue to be viewed with interest despite the withdrawal of cisapride. Prucalopride (a highly specific 5-HT4 receptor agonist) demonstrated a stimulation of the peristaltic reflex and a decrease in colonic transit time. However, its association with possible carcinogenicity48 led to its development being reduced and interest turning to Tegaserod instead. Tegaserod is a partial 5-HT4 agonist but with a high potency and specificity licensed in the USA by the Food and Drug Administration (FDA) for the treatment of chronic constipation in patients under 65 years of age. Advantages in using this drug included increasing the peristaltic reflex, decreasing visceral sensitivity and providing a reliable prokinetic activity in the colon. This was seen in the UK as a possible option where current conventional therapy had failed or had not fully resolved symptoms. In March 2007, the FDA withdrew Tegaserod from the US market due to concerns relating to increased incidences of cardiac chest pain and stroke.49 Side-effect profiles of other groups of drugs which may be of benefit—that is, anticholinergics, opioid mu receptor agonists and nitric oxide synthase inhibitors—have so far prevented indepth study.50 Surgical management Surgery can play an important role in GORD but for the purpose of this article will only be covered briefly. Surgical interventions such as Nissens fundoplication have usually been reserved for those patients who are resistant to drug therapy or who may require long-term medical management. However, recent advances in surgical techniques, such as endoscopic fundoplication which can be performed on a day case basis, may well allow a surgical intervention to be considered at a much earlier stage of the disease process. To date, no studies have compared medical to surgical treatments and all information reported is retrospective. Current results looking at a surgical intervention suggest that any surgery of this type should be delayed if possible until the child is 2 years of age. CONCLUSION GORD is a condition which undoubtedly benefits from pharmaceutical intervention. However, the majority of drugs used have limited robust data supporting their use. Further work is needed in this field to identify optimal treatment regimes through large, well designed, multicentre studies and to assess pharmacokinetic and bioavailability of formulations to ensure that not only can the best care be delivered but also that the treatments become licensed for this specific indication. Until this is achieved, clinicians and pharmacists will continue to work with limited choices. Competing interests: None. REFERENCES 1 Thomson M. Disorders of the oesophagus and stomach in infants. Baillieres Clin Gastroenterol 1997;11:547–72. 2 Thomson M, Esophagitis. In:, Walker A, Goulet O, Kleinman R, et al, eds. Pediatric gastrointestinal diseases. Fourth edition. Hamilton, Ontario: BC Decker, 2004. 3 Vandenplas Y, Goyvaerts H, Helven R, et al. Gastresophageal reflux, as measured by 24 hour pH monitoring, in 509 healthy infants screened for risk of sudden infant death syndrome. Pediatrics 1991;88:834–40. www.archdischild.com ep117
  • Downloaded from ep.bmj.com on 26 August 2008 KEADY ep118 4 Silny J. Intraluminal multiple electric impedance procedure for measurement of gastrointestinal motility. Journal of Gastrointestinal Motility 1991;3:151–62. 5 Wenzl TG, Silny J, Schenke S, et al. Gastro-esophageal reflux and respiratory phenomena in infants—status of the intraluminal impedance technique. J Pediatr Gastroenterol Nutr 1999;28:423–8. 6 Wenzl TG, Moroder C, Trachterna M, et al. Esophageal pH monitoring and impedance measurement: a comparison of two diagnostic tests for gastroesophageal reflux. J Pediatr Gastroenterol Nutr 2002;34:519–23. 7 Newell SJ, Sarkar PK, Durbin GM, et al. Maturation of the lower oesophageal sphincter in the preterm baby. Gut 1988;29:167–172. 8 Omari TI, Miki K, Fraser R, et al. Esophageal body and lower oesophageal sphincter function in healthy premature infants. Gastroenterology 1995;109:1757–64. 9 Vandenplas Y, Hassall E. 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