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PHARMACY UPDATE

UPDATE ON DRUGS FOR GASTRO-OESOPHAGEAL REFLUX DISEASE

Simon Keady

Arch Dis Child Educ Pract Ed 2007;92:ep114–ep118. doi: 10.1136/adc.2006.106328

__________________________

Correspondence to:Mr S Keady, University CollegeLondon Hospitals NHSFoundation Trust, 235 EustonRoad, London NW1 2BU, UK;simon.keady@uclh.nhs.uk__________________________

Gastro-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 manifesta-

tions,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 PEOPLEThe 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 GORDNormal 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 THICKENERSCarob-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 pre-

gelatinised 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)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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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 GORDDrug 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 1 Symptoms of gastro-oesophageal reflux disease(GORD)

Usual manifestations

Specific manifestationsNauseaVomitingRegurgitation

Symptoms related to GORD complicationsSymptoms related to iron deficiency anaemiaDysphagia (direct symptom of oesophagitis or from stricture formation)Weight loss and/or failure to thriveEpigastric or retrosternal painNon-cardiac angina-like chest painBelching, postprandial fullnessGeneral irritabilityIrritable oesophagus

Unusual presentationsGORD related to chronic respiratory disease (bronchitis, asthma,laryngitis, etc)Sandifer–Sutcliffe syndromeApnoeas, apparent life-threatening event and sudden infant deathsyndromeCongenital and/or central nervous system abnormalitiesIntracranial tumours, cerebral palsy, psychomotor retardation

Table 2 Summary of drugs used to treat GOR and GORD

DrugAvailableformulations Dose Frequency Licensed (Y/N)

Aluminium hydroxideMaalox Liquid 14–18 years: 10–20 ml After meals and at bedtime N (not ,14 years)Mucogel Liquid 12–18 years: 10–20 ml After meals and at bedtime N (not ,12 years)

Gaviscon Infant Sachets Neonate under 4.5 kg: 1 dose with feeds/water whenrequired

Max 6 times in 24 h Y

Neonate over 4.5 kg: 2 doses with feeds/water whenrequired

Max 6 times in 24 h Y

1 mo–12 years: 2 doses with feeds/water when required Max 6 times in 24 h YGaviscon Advance Suspension 2–12 years: 2.5–5 ml After meals and at bedtime N (not ,12 years)

12–18 years: 5–10 ml After meals and at bedtime YTablets 6–12 years: 1 tablet After meals and at bedtime N (not ,12 years)

12–18 years: 1–2 tablets After meals and at bedtime YDomperidone Liquid, tablets Neonate: 100–300 mg/kg 4–6 times daily before feeds N (not for GORD)

1 mo–12 years: 200–400 mg/kg (max 20 mg) 3–4 times daily before feeds N (not for GORD)12–18 years: 10–20 mg 3–4 times daily before food N (not for GORD)

Erythromycin Liquid, tablets Neonate – 18 years: 3 mg/kg Four times a day N (not for GORD)Metoclopramide Liquid, tablets Neonate: 100 mg/kg Every 6–8 h N (not for GORD)

1 mo–1 year and body-weight up to 10 kg: 100 mg/kg Twice daily N (not for GORD)1–3 year and body-weight 10–14 kg: 1 mg 2–3 times daily N (not for GORD)3–5 year and body-weight 15–19 kg: 2 mg 2–3 times daily N (not for GORD)5–9year and body-weight 20–29 kg: 2.5 mg Three times daily N (not for GORD)9–18 year and body-weight 30–60 kg: 5 mg Three times daily N (not for GORD)15–18 year and body-weight over 60 kg: 10 mg Three times daily N (not for GORD)

Ranitidine Liquid, tablets Neonate: 2 mg/kg (up to max 3 mg/kg) Three times daily N (not for GORD)1 mo–6 mo: 1 mg/kg (up to max 3 mg/kg) Three times daily N (not for GORD)6 mo–12 year: 2–4 mg/kg (max 150 mg) Twice daily N (not for GORD)12–18 year: 150 mg Twice daily N (not for GORD)

Lansoprazole Capsules, FastTabs(disp tabs),suspension

Child under 30 kg: 0.5–1 mg/kg (max 15 mg) Once daily in the morning NChild over 30 kg: 15 mg–30 mg Once daily in the morning N

Omeprazole Capsules, tablets Neonate: 700 mg/kg increasing to 1.4 mg/kg after7–14 days. Some neonates may require 2.8 mg/kg

Once daily Y (for children >1 yearwith severe ulceratingreflux oesophagitis)

1 mo–2 year: 700 mg/kg increased to 3 mg/kg ifnecessary (max 20 mg)

Once daily

Body weight 10–20 kg: 10 mg initially increasing to20 mg if necessary

Once daily

Body weight over 20 kg: 20 mg once dailyincreasing to 40 mg if necessary

Once daily

Doses based on recommendations from the British National Formulary for Children 2006.

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metoclopramide, the common prokinetic agents include dom-

peridone and erythromycin.

PROKINETIC DRUGSDomperidoneDomperidone 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 sub-

sequent 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.

ErythromycinErythromycin 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, arrhyth-

mias and infantile hypertrophic pyloric stenosis.

As with all antibiotics, especially for non-infectious condi-

tions, the potential for resistance should be considered prior to

initiating therapy.

MetoclopramideMetoclopramide 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 dyskne-

sia.33 34

Other prokinetic agents available now limit its use.

Withdrawal of cisaprideIn 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

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 SUPPRESSANTSHistamine-2-receptor antagonistsRantidine 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 oesopha-

gitis 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 inhibitorsLansoprazole 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 distur-

bances and minor reversible elevation of transaminase levels

have also been reported.

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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 pharmaco-

kinetic 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 administra-

tion 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 optionsIn 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 stimula-

tion 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 proki-

netic 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 in-

depth study.50

Surgical managementSurgery 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.

CONCLUSIONGORD 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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