V Vol.19, No.
2 February 1997
Continuing Education Article
FOCAL POINT
★Metoclopramide and
domperidone stimulate motility
of the proximal gastrointestinal
tract—the gastroesophageal
sphincter, stomach, and small
intestine.
KEY FACTS
■ Metoclopramide (0.2 to 0.5
mg/kg every 8 hours orally) is
more potent than domperidone
as a proximal gastrointestinal
prokinetic agent.
■ Metoclopramide and
domperidone stimulate
gastrointestinal motility via
mechanisms other than
dopaminergic receptor
antagonism—such as 5-HT3
receptor antagonism, 5-HT4
agonism, and indirect cholinergic
effects.
■ Delayed gastric emptying is best
managed by means of liquid
feedings, carbohydrate-enriched
diets, and metoclopramide.
■ Domperidone (0.05 to 0.10
mg/kg orally every 12 to 24
hours) is more potent than
metoclopramide as an
antiemetic agent.
N E W ! C O N T I N U I N G E D U C AT I O N S E R I E S
Successfully complete the quizzes at the end of each
CE article in this series, and receive a certificate suitable for framing.
This is the first of five articles.
Gastrointestinal
Prokinetic Therapy:
Dopaminergic
Antagonist Drugs
Oregon State University University of Pennsylvania
Jean A. Hall, DVM, PhD Robert J. Washabau, VMD, PhD
T
he dopaminergic antagonists are a group of drugs with gastrointestinal
prokinetic and antiemetic properties. These agents inhibit peripheral
and/or central dopamine receptors. Metoclopramide and domperi-
done, for example, reverse the gastric relaxation induced by dopamine infusion
in dogs,1 and they abolish the vomiting associated with apomorphine therapy.2
Although the role of dopamine receptors in chemoreceptor trigger zone–
induced vomiting is fairly well established,3,4 there is no definite evidence that
inhibitory dopaminergic neurons regulate gastrointestinal motility. The prokin-
etic effects of metoclopramide and domperidone thus may not be readily ex-
plained by dopamine receptor antagonism. Some dopaminergic antagonists
(e.g., metoclopramide) have been demonstrated to have other pharmacologic
properties (e.g., 5-HT3 [5-hydroxytryptamine3] receptor antagonism5 and 5-
HT4 receptor agonism6). Other dopaminergic antagonists (e.g., domperidone)
have been demonstrated to exhibit α2- and β2-adrenergic receptor antago-
nism7,8 (Figure 1). The characterization of these drugs as dopaminergic antago-
nists thus may not properly describe their in vivo effects.
This is Part I of a five-part presentation on gastrointestinal prokinetic thera-
py. The remaining parts will consider the following four topics, respectively:
motilin-like drugs; serotonergic drugs; acetylcholinesterase inhibitors or
parasympathetic potentiating drugs; and esophageal, gastric, and colonic motil-
ity disorders.
METOCLOPRAMIDE
Metoclopramide (2-methoxy-5-chloro-procainamide) has been available in
the United States since the 1970s and is used as a gastrointestinal prokinetic
and antiemetic agent. It is believed to exert its effects via antagonism of
dopaminergic D2 receptors and agonism of serotonergic 5-HT4 receptors.
The Compendium February 1997 Small Animal

Physicochemical flux of gastric con-

Properties tents from a positive-
Metoclopramide pressure cavity (the
hydrochloride is high- stomach) into a neg-
ly soluble in water.9–11 ative-pressure con-
The agent is available duit (the esophagus).
as 5- and 10-mg tab- The esophageal mu-
lets (Reglan®—A. H. cosa thus is protected
Robins), as an orange- from the injurious
colored syrup (1 effects of acid, pep-
mg/ml), and for in- sin, and bile salts.
jection at 5 mg/ml (2- Metoclopramide in-
and 10-ml single-dose creases pressure in
vials/ampules and 30- the lower esophageal
ml single-dose vials). sphincter. 12,13 The
A 1% aqueous solu- agent also stimulates
tion stored in a col- gastric emptying in
ored container is sta- human patients with
ble for as long as 5 Figure 1—Diagram of the pharmacologic effects of the gastrointestinal reflux esophagitis
prokinetic agents metoclopramide and domperidone. The release of
years.9 and delayed gastric
acetylcholine from postganglionic cholinergic neurons is enhanced by 14
blockade of presynaptic inhibitory dopamine or α-adrenergic receptors emptying. Delayed
Pharmacokinetics and postsynaptic inhibitory β-adrenergic receptors, antagonism of 5-HT3 gastric emptying pro-
Metoclopramide is receptors, or stimulation of 5-HT4 receptors (5-HT3 = ganglionic 5-HT3 motes gastroesoph-
well absorbed and serotonergic receptor; 5-HT4 = presynaptic 5-HT4 serotonergic receptor; ageal reflux by in-
rapidly excreted, with D2 = presynaptic D2 dopaminergic receptor; α2 = presynaptic α2-adrener- creasing the gastric
a half-life of 60 to 90 gic receptor; ACh = acetylcholine; M3 = postsynaptic M3 muscarinic volume and pressure
minutes in dogs. 9 cholinergic receptor; β2 = postsynaptic β2-adrenergic receptor; (–) = inhi- gradient. Diffusion
The agent undergoes bition; and (+) = stimulation). (Computer graphics created by Dr. Carl barriers (e.g., sucral-
significant first-pass Sammarco, School of Veterinary Medicine, University of Pennsylvania) fate), low-fat diets,
metabolism; bioavail- and avoidance of
ability is 50% to 70%. It is weakly bound to serum late-night meals are integral parts of the treatment of
proteins, rapidly distributed in most tissues, and highly gastroesophageal reflux and reflux esophagitis15; meto-
soluble in water and ethanol. In the brain, metoclo- clopramide is also beneficial in managing the condi-
pramide is concentrated in the area postrema, the site tion.
of chemoreceptor trigger zone–induced vomiting. The
major pathway for hepatic metabolism is N-demethyla- Gastric Emptying
tion. 9,10 The drug is excreted as the sulfate or glu- Delayed gastric emptying, which is a significant cause
curonide conjugate in bile or is unchanged in urine. of upper gastrointestinal tract disorders in dogs and
Impaired renal function prolongs the half-life.9 Re- cats, is characterized by chronic vomiting.4 Because
duced renal clearance makes side effects more likely; surgical procedures are often unsuccessful, dietary man-
the maintenance dosage thus should be decreased to agement and gastroprokinetic agents are used to treat
avoid drug accumulation. delayed gastric emptying disorders.4 Initially, dietary
The prokinetic dosage of metoclopramide for use in management is attempted. Small amounts of a semi-
dogs and cats is 0.2 to 0.5 mg/kg every 8 hours, admin- liquid, low-protein, low-fat diet should be fed at fre-
istered orally or parenterally. Continuous intravenous quent intervals. These recommendations are derived
infusions can be administered at dosages of 0.01 to from the observations that liquid emptying rates are
0.02 mg/kg/hr or 1 to 2 mg/kg/day. greater than those for solids and that carbohydrates are
emptied more rapidly than proteins, which are emptied
Clinical Applications more rapidly than fats. Drug therapy should be consid-
Lower Esophageal Sphincter ered in animals that fail to respond to dietary manage-
In normal physiologic conditions, the lower esoph- ment alone.
ageal sphincter relaxes to permit passage of food and Metoclopramide increases the amplitude and fre-
fluid into the stomach. This sphincter also prevents re- quency of antral contractions; inhibits fundic receptive

METOCLOPRAMIDE HYDROCHLORIDE ■ HEPATIC METABOLISM ■ CHRONIC VOMITING

Small Animal
relaxation; and coordinates gastric, pyloric, and duode-
nal motility. All of these actions accelerate gastric emp-
tying.16–20 Metoclopramide may be most effective in ac-
celerating the gastric emptying of liquids in dogs.18,19
One study in healthy dogs demonstrated that metoclo-
pramide increased emptying of the liquid phase 1 hour
after a meal but had no effect on emptying of the solid
phase.18 In another study of healthy dogs, the agent was
demonstrated to accelerate the emptying rate of liquids;
however, the emptying rate of digestible solids was sig-
nificantly impaired.19 Metoclopramide had no effect on
fed-state gastric motility in dogs after recovery from
gastric dilatation–volvulus.21
Small Bowel Motility
Studies in humans have demonstrated that meto-
clopramide increases the rate of gastric emptying and
reduces small bowel transit time compared with the
effects of a placebo.9 Metoclopramide also enhances
antropyloroduodenal coordination in dogs.20 The drug
thus may be most effective when delayed gastric empty-
ing results from poor antropyloroduodenal coordina-
tion.20 Metoclopramide is less effective in the distal
small intestine and colon.22–24
Emesis
Metoclopramide inhibits vomiting associated with
activation of dopaminergic D2 receptors in the che-
moreceptor trigger zone.3,4 The agent thus abolishes
vomiting associated with the administration of apo-
morphine, a dopamine agonist at the chemoreceptor
trigger zone. Metoclopramide is also indicated in treat-
ing patients with chemotherapy-induced emesis as well
as nausea and vomiting associated with delayed gastric
emptying, gastroesophageal reflux, and reflux gastritis.
Peripherally, metoclopramide may diminish the severity
of vomiting via its effects on motility, preventing gastric
stasis and the retrograde peristalsis that precedes vomit-
ing. The antiemetic dose of metoclopramide is 1.0 to
2.0 mg/kg/day given as a continuous intravenous infu-
sion. At subcutaneous doses of 1.0 to 3.0 mg/kg, the
drug inhibits vomiting associated with cis-platinum
chemotherapy; however, significant side effects (e.g.,
drowsiness, extreme weakness, and body tremors) are
occasionally observed.25
Contraindications
Metoclopramide should not be used if stimulation of
gastrointestinal motility could be harmful (e.g., in the
presence of gastrointestinal hemorrhage, mechanical
obstruction, or perforation). Because the frequency and
severity of seizures or extrapyramidal reactions may be
increased, metoclopramide should not be administered
EMPTYING RATE ■ NAUSEA ■ CHOLINERGIC PROPERTIES
The Compendium February 1997
to epileptics or patients receiving other drugs that are
likely to cause extrapyramidal reactions.
Pharmacologic Effects
Gastrointestinal Effects
Metoclopramide has mixed antidopaminergic and
cholinergic properties. It antagonizes presynaptic
dopaminergic D2 receptors and enhances the release of
acetylcholine from postganglionic cholinergic neu-
rons. 26 The exact mechanisms responsible for the
gastrointestinal stimulant effects of metoclopramide
are unclear. Although metoclopramide antagonizes
dopaminergic D2 receptors, the prokinetic effect of
metoclopramide probably does not involve dopamine
receptors.26 A prejunctional cholinergic mechanism is
more likely and may involve 5-HT (serotonin) recep-
tors.27 In the gastrointestinal tract, 5-HT may have di-
rect effects on smooth muscle cells and/or act indirectly
by stimulating intramural neurons to release acetyl-
choline or other neurotransmitters.26,28
The localization of 5-HT in enterochromaffin cells
and neurons of the myenteric plexus might account for
direct or modulatory effects. Several 5-HT receptor
subtypes have been identified throughout the gastroin-
testinal tract. Metoclopramide antagonizes the 5-HT3
receptor, but the mechanism of gastric prokinesis is
probably not related to activity at this receptor.5 Meto-
clopramide may instead exert its gastric prokinetic ef-
fect by stimulating enteric neuronal 5-HT4 receptors.6
Like the 5-HT3 receptor, the 5-HT4 receptor is located
presynaptically; when activated, it induces acetylcholine
release from the depolarized neuron.6,27–29 The choliner-
gic effect of metoclopramide thus might be mediated
through 5-HT4 receptor–mediated neuronal depolar-
ization. This mechanism may not operate in all animal
species or may operate at different sites within a single
species.27,30
Extragastrointestinal Effects
Metoclopramide is useful as an antiemetic agent be-
cause of its antidopaminergic effects at the chemorecep-
tor trigger zone.3,4 Metoclopramide exhibits all of the
effects of a central dopaminergic D2 receptor antago-
nist: it antagonizes apomorphine-induced abnormal be-
havior, depresses motor activity, induces catalepsy, and
inhibits conditioned behavior. The drug also has pro-
nounced antiemetic activity against the D2 receptor ag-
onist apomorphine.31,32
Adverse Reactions
Side effects (which have been reported in as many as
20% of treated humans) are usually mild, transient,
and reversible after withdrawal of the drug. These ef-
Small Animal
fects include nervousness, restlessness, listlessness, de-
pression, and dystonic reactions.10 Extrapyramidal side
effects are occasionally evident in small animals.
Gastrointestinal disorders may be observed. Constipa-
tion is commonly associated with long-term use. These
complications are probably manifestations of metoclo-
pramide’s antagonism of dopamine-mediated neuro-
transmission in the central nervous system.
Drug Interactions
Atropine and the opioid analgesics may antagonize
the action of metoclopramide. Additive sedative effects
can occur if metoclopramide is given with narcotics or
tranquilizers. Because chronic therapy with phenothi-
azines can produce side effects similar to those asso-
ciated with metoclopramide, concomitant use of me-
toclopramide and phenothiazine drugs should be
avoided. In human diabetic patients, metoclopramide
influences the delivery of food to the small intestine
and thus affects the rate of absorption. In small animals
that are receiving insulin, it may be necessary to modify
the dosage and timing of therapy.
DOMPERIDONE
Domperidone is a peripheral dopamine antagonist
that acts on dopaminergic D2 receptors in the gastro-
intestinal tract and chemoreceptor trigger zone.33 Dom-
peridone has prokinetic and antiemetic properties simi-
lar to those of metoclopramide, but domperidone does
not readily cross the blood–brain barrier.2,34,35
Physicochemical Properties
Domperidone is chemically related to the butyrophe-
nones.35 It has been available in most of Europe since
the 1980s but has not been marketed in the United
States. Domperidone is manufactured as 10-mg tablets,
1- or 10-mg/ml suspension, and 10-, 30-, or 60-mg
suppositories (Motilium®—Janssen Pharmaceutica).
Pharmacokinetics
The pharmacokinetics of domperidone have been
studied after intravenous (2.5 mg/kg) and oral (2.5, 10,
and 40 mg/kg) therapy in dogs. 35–37 Domperidone
pharmacokinetics are described by a two-compartment
model with a distribution half-life of 6 minutes and an
elimination half-life of 2.45 hours.35–37 The bioavailabil-
ity of domperidone is approximately 20%, and peak
plasma levels are reached 120 minutes after oral ad-
ministration. The drug is approximately 93% protein
bound in the circulation, and the plasma clearance is
14.6 ml/min/kg. Domperidone is extensively metabo-
lized and excreted as metabolites in the feces (66%) and
urine (31%). The main metabolic pathways are aro-
DOPAMINE–MEDIATED NEUROTRANSMISSION ■ TWO–COMPARTMENT MODEL
The Compendium February 1997
matic hydroxylation and oxidative N-dealkylation.
Domperidone has not been approved for use in the
United States, and there is scant clinical experience
with the drug in companion animals. Data from exper-
imental studies suggest that a clinically effective dose
would be 0.05 to 0.10 mg/kg administered orally once
or twice per day.
Clinical Applications
Lower Esophageal Sphincter
Early reports suggested that domperidone increases
lower esophageal sphincter pressure in healthy
humans. 35 Subsequent reports, however, failed to
demonstrate any effect of domperidone on lower
esophageal sphincter pressure or on the amplitude
or duration of esophageal contractions. 38 In dogs,
domperidone induces phasic contractions of the lower
esophageal sphincter but not the sustained increases in
pressure that would be beneficial in treating gastro-
esophageal reflux. Furthermore, the phasic contractions
are abolished by feeding.12 Domperidone thus may not
be beneficial in treating gastroesophageal reflux disease
in dogs or cats.
Gastric Emptying
As a prokinetic agent, domperidone is apparently
most effective in improving clinical signs (e.g., anorexia
and vomiting) associated with delayed gastric empty-
ing. Studies in human patients with gastric emptying
disorders have demonstrated efficacy of domperidone
in stimulating gastric emptying of solids and liquids.35
Similar studies in dogs have yielded equivocal results.
Preliminary reports suggested that domperidone im-
proves gastric motility39 or antroduodenal coordination
in dogs.40 A subsequent study demonstrated that dom-
peridone actually decreases the frequency of corporeal,
pyloric, and duodenal contractions and deteriorates
antropyloroduodenal coordination by decreasing the
frequency of contractions spreading from the antrum
or pylorus to the duodenum.20 The latter study suggest-
ed that domperidone may not be very useful as a
gastroprokinetic agent in dogs.20 The role of domperi-
done in gastroprokinetic treatment of dogs and cats
thus remains to be defined.
Small Intestine and Colon
Domperidone has no effect on small intestinal motil-
ity. Colonic motility is also not affected by the agent.41
Emesis
Domperidone is a potent antiemetic agent. It inhibits
dopaminergic D2 receptor–mediated vomiting at the
level of the chemoreceptor trigger zone.2,4,42 Vomiting
The Compendium February 1997
induced by the chemoreceptor trigger zone stimulants
(apomorphine and dopamine) thus is attenuated by
domperidone infusion.2,42 Domperidone is 12 to 25
times more potent than metoclopramide and 50 to 60
times more potent than prochlorperazine in attenuating
apomorphine-induced vomiting.2,43 Domperidone is
less effective in attenuating neurally mediated emesis in
dogs. Copper sulfate–induced vomiting, a centrally me-
diated phenomenon, is not affected by domperidone
doses as high as 2.5 mg/kg.42 Vomiting induced by ab-
dominal irradiation is also attenuated by domperidone
in dogs44; however, the mechanism of the antiemetic ef-
fect is unclear because gastrointestinal and chemorecep-
tor trigger zone dopamine receptors are apparently not
involved.44
Contraindications
Domperidone should not be administered to animals
treated with dopaminergic drugs. These drugs include
dopamine and dobutamine.
Pharmacologic Effects
Gastrointestinal Effects
Dopamine indirectly inhibits gastric smooth muscle
contraction by activating presynaptic D2 dopaminergic
and α2-adrenergic receptors on postganglionic choliner-
gic neurons7,8,45,46 (Figure 1). Dopamine also directly in-
hibits such contraction by activating postsynaptic β2-
adrenergic receptors on gastric smooth muscle cells.8
Domperidone antagonizes the indirect and direct in-
hibitory effects of dopamine, resulting in the stimu-
lation of gastric smooth muscle contraction. It is not
clear which pharmacologic effects (D2, α2, or β2) pre-
dominate in domperidone-induced contractions.
Extragastrointestinal Effects
The antiemetic effect of domperidone at the
chemoreceptor trigger zone is apparently explained en-
tirely by the inhibition of dopaminergic D 2 recep-
tors.2,4,34 Domperidone also antagonizes central nervous
system dopaminergic D3 and D4 receptors,47 but these
effects may not be clinically relevant because domperi-
done does not readily cross the blood–brain barrier.34
Adverse Reactions
Because domperidone has had limited use in veteri-
nary medicine, very few adverse reactions have been re-
ported in animals. Hyperprolactinemia, the most com-
monly reported adverse reaction in humans, is related
to dopamine receptor antagonism at the median emi-
nence of the adenohypophysis and in the tuberoin-
fundibular system.48
Somnolence and extrapyramidal reactions are rare
APOMORPHINE ■ DOBUTAMINE ■ ANTIEMETIC EFFECT
Small Animal
side effects associated with domperidone use in hu-
mans. Central nervous system side effects have been
attributed to a compromised or developmentally im-
mature blood–brain barrier.35 Several cases of cardiac
arrhythmia, cardiac arrest, and sudden death have been
associated with intravenous domperidone therapy. Be-
cause of documented cardiotoxicity, the parenteral form
of the drug has been withdrawn by the manufacturer.35
Drug Interactions
The oral absorption of domperidone is reduced by
concomitant antacid or H2-receptor antagonist ther-
apy.35 There is scant information concerning the effects
of domperidone on the pharmacokinetics of other
drugs.49
About the Authors
Dr. Hall is affiliated with the College of Veterinary
Medicine, Oregon State University, Corvallis, Oregon. Dr.
Washabau is affiliated with the Department of Clinical
Studies, School of Veterinary Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania. Drs. Hall and
Washabau are Diplomates of the American College of
Veterinary Internal Medicine.
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The Compendium February 1997
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