The safety profile of ondansetron is favorable, as in the treatment of gastroenteritis, diarrhea is

the most common and only reported side effect according to the 7 randomized controlled trials
involving 854 participants. However, diarrhea associated with this treatment is usually mild and
self-limiting. Furthermore, the study by Bryson, evaluating the use of ondansetron in the
treatment of postoperative emesis in 1900 patients, found the incidence of adverse events was
similar to that of placebo.78 It did not cause extraparamidal reactions or sedation.56 However, in
other large clinical trials, including some pediatric patients, documented headache as the most
common adverse effect, followed by fatigue and constipation.79
Ondansetron has a good tolerability. It is completely and rapidly absorbed from the
gastrointestinal tract, and then metabolized by the cytochrome P450 enzyme system with
subsequent glucuronide or sulfate conjugation in the liver.80–82 It also has a low potential for
drug interactions. Peak plasma concentration occurs approximately 2 hours post oral and the
bioavailability is approximately 60%.80 Peak plasma concentration occurs 40 minutes post
intramuscular administration, and 10 minutes post intravenous administration. It has a half-life of
2 to 6 hours.81 Its antiemetic duration of action is variable from 2 to 8 hours with standard
dosing. The recommended intravenous dose of ondansetron is 0.1 to 0.15 mg/kg body weight, up
to a maximum of 4 mg.81 The recommended oral dose is 2 mg for children weighing 8 to 15 kg,
4 mg for children weighing 15 to 30 kg and 8 mg for children weighting >30 kg up to a
maximum of 3 times/day. However, a single dose of oral ondansetron is usually sufficient for the
treatment of gastroenteritis related vomiting.
The main drawback of ondansetron has been the cost; however, a generic form of ondansetron
has recently been available and so cost is no longer a barrier to its use. In addition, the use of the
medication can minimize the need for hospitalization (NNT = 14) and intravenous therapy (NNT
= 5).70 Even so there has been no formal study in terms of the cost saving, although judging
from the very high costs associated with hospitalization, the use of this medication may reduce
the overall health care costs of treating patients with gastroenteritis.

Other 5HT3 receptor antagonists

These include granisetron, tropisetron, dolasetron and ramosetron. These medications have been
evaluated in the management of post-operative and chemotherapy related nausea and vomiting.
One trial comparing granisetron and ondansetron and another comparing granisetron, tropisetron
and ondansetron in children undergoing chemotherapy found no significant differences in
efficacy outcomes.83,84 Three trials have compared dolasetron and ondansetron in children
undergoing surgical procedures and these also showed no significant difference in terms of
efficacy.85–87 There has been no controlled trial directly comparing ramosetron and
ondansetron. Moreover, none of these new 5HT3 receptor antagonists have evaluated in the
treatment of gastroenteritis related vomiting. Although one advantage of these medications is
that their longer half-life, the main disadvantage is they are usually more expensive.
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Other antiemetic medications

Antihistamine
Dimenhydrinate
Dimenhydrinate is a first generation H1 receptor antagonist. It not only blocks the H1 receptors
in the nucleus tractus solitarius, it also blocks the muscarinic-cholinergic receptors in both the
vestibular apparatus and the vomiting center.43,82 Dimenhydrinate is very convenient to use
because it can be given via oral, rectal, intramuscular or intravenous routes.88 The recommended
dose is 1.25 mg/kg body weight, with a maximum of 50 mg.43,82 It has also been used for the
treatment and prevention of motion sickness, radiation sickness, disturbances of labyrinthine
function, and post operative nausea and vomiting.89–92 The cost of dimenhydrinate is a lot less
expensive when compared to ondansetron. The main concern for the use of dimenhydrinate in
the treatment of acute gastroenteritis related vomiting is its sedative effect. It can jeopardize the
oral intake of rehydration fluids and further aggravate dehydration. There have been no efficacy
studies for dimenhydrinate in gastroenteritis until recently. In 2009, Uhlig and colleagues
published a prospective, randomized, placebo controlled, multicenter trial investigating
dimenhydrinate in children with infectious gastroenteritis.93 The investigators randomly
assigned 243 children (aged between 6 months and 6 years) with presumed gastroenteritis related
vomiting to treatment with rectal dimenhydrinate or placebo. The dose of dimenhydrinate
depended on body weight (40 mg <15 kg bodyweight; 80 mg for 15 to 25 kg bodyweight and
120 mg for bodyweights >25 kg). Additional doses could only be given in case of visible
excretion of the suppository immediately after administration or in case of persistent vomiting.
Children with none or mild dehydration were included. All children received oral rehydration
therapy. A short-term follow-up visit in the study center was scheduled at 18 to 24 hours after
treatment. The investigators called the families for a telephone interview 7 to 14 days after
enrollment. There was no change of bodyweight between children who received dimenhydrinate
or placebo. The mean number of vomiting episodes between treatment and the follow-up visit
was 0.64 in the dimenhydrinate group and 1.36 in the placebo group. In total, 69.6% of the
children in the dimenhydrinate group versus 47.4% in the placebo group were free of vomiting
between treatment and the follow-up visit. The numbers needed to treat were 2 (95% CI: 1–4) to
avoid 1 episode of vomiting and 5 (95% CI: 3–12) for complete cessation of vomiting. Hospital
admission rate, fluid intake, general well-being of the children, parental satisfaction and potential
adverse effects, including the number of diarrheal episodes, were similar for both groups.
Sedation occurred in 21.6% children who received dimenhydrinate and 18.6% children who
received placebo. The study showed that dimenhydrinate reduced the frequency of vomiting in
children with mild dehydration; however, the overall benefit was low, because it did not improve
oral rehydration or clinical outcome.

Promethazine
Promethazine is derived from phenothiazines with pronounced antihistamine activity.43 It also
has anti-cholinergic and anti-dopaminergic activities.88 Promethazine has also been used in the
management of post-operative nausea and vomiting and motion sickness.57,88 The medication is
not expensive and can also be given orally, rectally, intramuscularly or intravenously with a
doses of 0.25 mg to 1 mg/kg bodyweight (up to a maximum of 25 mg) every 4 to 6 hours as
required.43 It is well absorbed orally with clinical effects beginning 20 minutes after
administration. There has been only one study published, that being by Tibbs in 1968 involving
60 children that use promethazine and pyrilamine-pentobarbital for the treatment of children with
vomiting from gastroenteritis.94 However, this study did not include a placebo group and
included children with a variety of illnesses other than gastroenteritis. However, it showed that
promethazine was less effective than pyrilamine-pentobarbital for the relief of vomiting.
Since its approval in 1951, serious and often life-threatening adverse events; including
respiratory depression; over sedation; agitation; hallucinations; seizures; and dystonic reactions
have been reported with promethazine use in children.95,96 As of 2005, there were 38 cases of
respiratory depression, apnea, or cardiac arrest reported to the Food and Drug Administration
(FDA).97 Twenty two of them were in children aged 1.5 months to 2 years of age, 7 of which
died. Nine of these 22 patients received 1 mg or less of promethazine per kilogram of
bodyweight, plus another drug with respiratory depressant effects. A wide range of weight-based
doses (0.45 to 6.4 mg per kg) were associated with respiratory depression. Serious outcomes,
including death, disability, life-threatening events, and hospitalization, occurred with all routes
of administration (oral, rectal, and parenteral). Because of this, in late 2004, a “boxed warning”
was added to the labeling for promethazine hydrochloride (Phenergan), including a
contraindication for use in children less than two years of age and a strengthened warning with
regard to the use in children two years of age or older. It should also not be prescribed to children
who are already on other drugs with respiratory depressant effects as it may further aggravate the
effect on respiratory depression.

Dopamine receptor antagonists

Metoclopramide
Metoclopramide is a chlorinated procainamide derivative that has been marketed since the
1960s. It acts primarily as receptor antagonist and also has a D2 parasympathomimetic activity
with weak 5-HT3 receptor antagonist activity.88 It has both central and peripheral actions, and
alleviates nausea and vomiting by decreasing afferent impulses to the chemoreceptor trigger
zone, lowering gastric sphincter tone, stimulating gastric motility and accelerating gastric
emptying and small intestine transit time. It has been used for the prevention of chemotherapy
related vomiting, post-operative nausea and vomiting, and pregnancy associated nausea and
vomiting.98 Two studies evaluated metoclopramide as a treatment for vomiting associated with
gastroenteritis in 96 hospitalized children.55,99 The first double blind, randomized, controlled
study, in 1979, was published by Van Eygen and colleagues.99 The authors recruited 60 children
aged between 2 to 6 years in an in-patient setting. The children were randomized to receive a
suppository that contained placebo (n = 20), domperidone 30 mg (n = 20) or metoclopramide
10mg (n = 20) at study entry repeated up to 3 times throughout the 24 hour period as clinically
warranted. This study found that metoclopramide was more effective than placebo in reducing
symptoms of nausea and vomiting. No adverse events were reported. However, a second study
by Cubeddu and colleagues found that although metoclopramide reduced the number of vomiting
episodes the results did not reach any statistical significance.55 Significantly more episodes of
diarrhea were reported during the first 24 hours in the metoclopramide group than the placebo
group.
Metoclopramide can be given intravenously, intramuscularly or orally at a dose of 0.1 mg/kg (up
to a maximum of 10 mg), with the onset of action 1 to 3 minutes, 10 to 15 minutes, and 30 to 60
minutes, respectively.61 The half-life is 5 to 6 hours with a duration of action of 1 to 2
hours.61 Reported adverse effects in patients who received metoclopramide included:
drowsiness, cough, and tremor. Extrapyramidal reactions such as dystonia, a kathisia and
oculogyric crisis are more common in children and reported in up to 25% of
children.100,101 Extrapyramidal reactions occur regardless of the doses, (whether single or
multiple doses) or routes of administration. Other severe reactions such as: seizures; neuroleptic
malignant syndrome; methemoglobinemia; sulfhemoglobinemia; and gynecomastia have also
been reported.102–104

Droperidol
In June 1968 McNeil laboratories submitted a new drug application for droperidol to the FDA.
The drug was approved, on June 11 1970, for use preoperatively, during induction and
maintenance for sedation or tranquilization, for anti-anxiety activity, and for the reduction of the
incidence of nausea and vomiting. Droperidol is classified as a short acting butyrophenone and a
potent D2 antagonist that also has weak anti-cholinergic and antihistamine activity.43 It is
pharmacologically related to phenothiazines and thought to act both centrally and peripherally.
Droperidol has been well studied as a postoperative antiemetic agent, but there are no studies on
its efficacy in gastroenteritis related vomiting.105–107 It has a good anti-nausea effect although
a lesser antiemetic effect.108 The recommended dose of droperidol for vomiting is 0.05 to 0.06
mg/kg bodyweight/dose every 4 to 6 hours intramuscularly or intravenously and the onset of
action is within 3 to 10 minutes with a half-life of 2 hours. Droperidol is not recommended in
children younger than 2 years because its safety and efficacy have not yet been established. The
side effects of droperidol are mainly prolonged CNS depression and extrapyramidal symptoms.
Sedative effects can last up to 12 hours.109 However, in 2001, the FDA posted a black box
warning that droperidol could cause QT prolongation and torsades de pointes. The warning was
based on 273 cases reported over a 4-year period.110 Before administration of droperidol, a 12-
lead electrocardiogram should be performed. Furthermore, the patient must have
electrocardiographic monitoring for 2 to 3 hours after droperidol administration. Manufacturers
now only recommend droperidol in patients who fail to show a response to other treatments.
Janssen Pharmaceuticals has also stopped marketing droperidol outside of the United States since
2001. The fallout from the black box warning has the been near cessation of droperidol use in the
United States.111,112