This document provides an update on drugs used to treat gastroesophageal reflux disease (GORD) in infants, children, and young people. It discusses non-pharmacological treatments like thickening feeds and positioning. For mild GORD, antacids like alginate formulations are often used. For moderate to severe GORD, treatment typically combines a prokinetic agent to increase motility (such as domperidone or erythromycin) with an acid suppressant like ranitidine or a proton pump inhibitor like lansoprazole or omeprazole. The withdrawal of cisapride in 2000 and limitations of other prokinetic drugs like metoclopramide are also reviewed.

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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
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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

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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

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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.

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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.
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