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Gastrointestinal Pro Kinetic Theraphy-Dopaminergic Antagonist Drugs

Gastrointestinal Pro Kinetic Theraphy-Dopaminergic Antagonist Drugs

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Vol.19, No. 2February 1997Continuing Education Article
FOCAL POINTKEY FACTS
5
Metoclopramide anddomperidone stimulate motilityof the proximal gastrointestinaltract—the gastroesophagealsphincter, stomach, and smallintestine.
GastrointestinalProkinetic Therapy:Dopaminergic Antagonist Drugs
Oregon State UniversityUniversity of Pennsylvania
 Jean A. Hall, DVM, PhDRobert J. Washabau, VMD, PhD
T
he dopaminergic antagonists are a group of drugs with gastrointestinalprokinetic and antiemetic properties. These agents inhibit peripheraland/or central dopamine receptors. Metoclopramide and domperi-done, for example, reverse the gastric relaxation induced by dopamine infusionin 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 thatinhibitory 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 pharmacologicproperties (e.g., 5-HT
3
[5-hydroxytryptamine
3
] receptor antagonism
5
and 5-HT
4
receptor agonism
6
). Other dopaminergic antagonists (e.g., domperidone)have been demonstrated to exhibit
α
2
- and
β
2
-adrenergic receptor antago-nism
7,8
(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 orparasympathetic potentiating drugs; and esophageal, gastric, and colonic motil-ity disorders.
METOCLOPRAMIDE
Metoclopramide (2-methoxy-5-chloro-procainamide) has been available inthe United States since the 1970s and is used as a gastrointestinal prokineticand antiemetic agent. It is believed to exert its effects via antagonism of dopaminergic D
2
receptors and agonism of serotonergic 5-HT
4
receptors.
V
s
Metoclopramide (0.2 to 0.5mg/kg every 8 hours orally) ismore potent than domperidoneas a proximal gastrointestinalprokinetic agent.
s
Metoclopramide anddomperidone stimulategastrointestinal motility viamechanisms other thandopaminergic receptorantagonism
such as 5-HT
3
receptor antagonism, 5-HT
4
agonism, and indirect cholinergiceffects.
s
Delayed gastric emptying is bestmanaged by means of liquidfeedings, carbohydrate-enricheddiets, and metoclopramide.
s
Domperidone (0.05 to 0.10mg/kg orally every 12 to 24hours) is more potent thanmetoclopramide as anantiemetic agent.
Successfully complete the quizzes at the end of eachCE article in this series, and receive a certificate suitable for framing.This is the first of five articles.
CONTINUING EDUCATION SERIESNEW!
 
PhysicochemicalProperties
Metoclopramidehydrochloride is high-ly soluble in water.
9
11
The agent is availableas 5- and 10-mg tab-lets (Reglan
®
 A. H.Robins), as an orange-colored syrup (1mg/ml), and for in- jection at 5 mg/ml (2-and 10-ml single-dosevials/ampules and 30-ml single-dose vials). A 1% aqueous solu-tion stored in a col-ored container is sta-ble for as long as 5years.
9
Pharmacokinetics
Metoclopramide is well absorbed andrapidly excreted, witha half-life of 60 to 90minutes in dogs.
9
The agent undergoessignificant first-passmetabolism; bioavail-ability is 50% to 70%. It is weakly bound to serumproteins, rapidly distributed in most tissues, and highly soluble in water and ethanol. In the brain, metoclo-pramide is concentrated in the area postrema, the siteof chemoreceptor trigger zone
induced vomiting. Themajor pathway for hepatic metabolism is N-demethyla-tion.
9,10
The drug is excreted as the sulfate or glu-curonide conjugate in bile or is unchanged in urine.Impaired renal function prolongs the half-life.
9
Re-duced renal clearance makes side effects more likely;the maintenance dosage thus should be decreased toavoid drug accumulation.The prokinetic dosage of metoclopramide for use indogs and cats is 0.2 to 0.5 mg/kg every 8 hours, admin-istered orally or parenterally. Continuous intravenousinfusions can be administered at dosages of 0.01 to0.02 mg/kg/hr or 1 to 2 mg/kg/day.
Clinical Applications
Lower Esophageal Sphincter 
In normal physiologic conditions, the lower esoph-ageal sphincter relaxes to permit passage of food andfluid into the stomach. This sphincter also prevents re-flux of gastric con-tents from a positive-pressure cavity (thestomach) into a neg-ative-pressure con-duit (the esophagus).The esophageal mu-cosa thus is protectedfrom the injuriouseffects of acid, pep-sin, and bile salts.Metoclopramide in-creases pressure inthe lower esophagealsphincter.
12,13
Theagent also stimulatesgastric emptying inhuman patients withreflux esophagitisand delayed gastricemptying.
14
Delayedgastric emptying pro-motes gastroesoph-ageal reflux by in-creasing the gastricvolume and pressuregradient. Diffusionbarriers (e.g., sucral-fate), low-fat diets,and avoidance of late-night meals are integral parts of the treatment of gastroesophageal reflux and reflux esophagitis
15
; meto-clopramide is also beneficial in managing the condi-tion.
Gastric Emptying 
Delayed gastric emptying, which is a significant causeof upper gastrointestinal tract disorders in dogs andcats, is characterized by chronic vomiting.
4
Becausesurgical procedures are often unsuccessful, dietary man-agement and gastroprokinetic agents are used to treatdelayed gastric emptying disorders.
4
Initially, dietary management is attempted. Small amounts of a semi-liquid, low-protein, low-fat diet should be fed at fre-quent intervals. These recommendations are derivedfrom the observations that liquid emptying rates aregreater than those for solids and that carbohydrates areemptied more rapidly than proteins, which are emptiedmore rapidly than fats. Drug therapy should be consid-ered in animals that fail to respond to dietary manage-ment alone.Metoclopramide increases the amplitude and fre-quency of antral contractions; inhibits fundic receptive
The Compendium 
February 1997Small Animal
METOCLOPRAMIDE HYDROCHLORIDE
s
HEPATIC METABOLISM
s
CHRONIC VOMITING
Figure 1—
Diagram of the pharmacologic effects of the gastrointestinalprokinetic agents metoclopramide and domperidone. The release of acetylcholine from postganglionic cholinergic neurons is enhanced by blockade of presynaptic inhibitory dopamine or
α
-adrenergic receptorsand postsynaptic inhibitory 
β
-adrenergic receptors, antagonism of 5-HT
3
receptors, or stimulation of 5-HT
4
receptors (
5-HT 
= ganglionic 5-HT
3
serotonergic receptor;
5-HT 
= presynaptic 5-HT
4
serotonergic receptor;
= presynaptic D
2
dopaminergic receptor;
α
= presynaptic
α
2
-adrener-gic receptor;
 ACh 
= acetylcholine;
= postsynaptic M
3
muscariniccholinergic receptor;
β
= postsynaptic
β
2
-adrenergic receptor;
(–) 
= inhi-bition; and
(+) 
= stimulation). (Computer graphics created by Dr. CarlSammarco, School of Veterinary Medicine, University of Pennsylvania)
 
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 hourafter a meal but had no effect on emptying of the solidphase.
18
In another study of healthy dogs, the agent wasdemonstrated to accelerate the emptying rate of liquids;however, the emptying rate of digestible solids was sig-nificantly impaired.
19
Metoclopramide had no effect onfed-state gastric motility in dogs after recovery fromgastric dilatation
volvulus.
21
Small Bowel Motility 
Studies in humans have demonstrated that meto-clopramide increases the rate of gastric emptying andreduces small bowel transit time compared with theeffects of a placebo.
9
Metoclopramide also enhancesantropyloroduodenal coordination in dogs.
20
The drugthus may be most effective when delayed gastric empty-ing results from poor antropyloroduodenal coordina-tion.
20
Metoclopramide is less effective in the distalsmall intestine and colon.
22
24
Emesis 
Metoclopramide inhibits vomiting associated withactivation of dopaminergic D
2
receptors in the che-moreceptor trigger zone.
3,4
The agent thus abolishesvomiting associated with the administration of apo-morphine, a dopamine agonist at the chemoreceptortrigger zone. Metoclopramide is also indicated in treat-ing patients with chemotherapy-induced emesis as wellas nausea and vomiting associated with delayed gastricemptying, gastroesophageal reflux, and reflux gastritis.Peripherally, metoclopramide may diminish the severity of vomiting via its effects on motility, preventing gastricstasis and the retrograde peristalsis that precedes vomit-ing. The antiemetic dose of metoclopramide is 1.0 to2.0 mg/kg/day given as a continuous intravenous infu-sion. At subcutaneous doses of 1.0 to 3.0 mg/kg, thedrug inhibits vomiting associated with cis-platinumchemotherapy; however, significant side effects (e.g.,drowsiness, extreme weakness, and body tremors) areoccasionally observed.
25
Contraindications
Metoclopramide should not be used if stimulation of gastrointestinal motility could be harmful (e.g., in thepresence of gastrointestinal hemorrhage, mechanicalobstruction, or perforation). Because the frequency andseverity of seizures or extrapyramidal reactions may beincreased, metoclopramide should not be administeredto epileptics or patients receiving other drugs that arelikely to cause extrapyramidal reactions.
Pharmacologic Effects
Gastrointestinal Effects 
Metoclopramide has mixed antidopaminergic andcholinergic properties. It antagonizes presynapticdopaminergic D
2
receptors and enhances the release of acetylcholine from postganglionic cholinergic neu-rons.
26
The exact mechanisms responsible for thegastrointestinal stimulant effects of metoclopramideare unclear. Although metoclopramide antagonizesdopaminergic D
2
receptors, the prokinetic effect of metoclopramide probably does not involve dopaminereceptors.
26
 A prejunctional cholinergic mechanism ismore 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 cellsand neurons of the myenteric plexus might account fordirect or modulatory effects. Several 5-HT receptorsubtypes have been identified throughout the gastroin-testinal tract. Metoclopramide antagonizes the 5-HT
3
receptor, but the mechanism of gastric prokinesis isprobably not related to activity at this receptor.
5
Meto-clopramide may instead exert its gastric prokinetic ef-fect by stimulating enteric neuronal 5-HT
4
receptors.
6
Like the 5-HT
3
receptor, the 5-HT
4
receptor is locatedpresynaptically; when activated, it induces acetylcholinerelease from the depolarized neuron.
6,27
29
The choliner-gic effect of metoclopramide thus might be mediatedthrough 5-HT
4
receptor
mediated neuronal depolar-ization. This mechanism may not operate in all animalspecies or may operate at different sites within a singlespecies.
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 theeffects of a central dopaminergic D
2
receptor antago-nist: it antagonizes apomorphine-induced abnormal be-havior, depresses motor activity, induces catalepsy, andinhibits conditioned behavior. The drug also has pro-nounced antiemetic activity against the D
2
receptor ag-onist apomorphine.
31,32
Adverse Reactions
Side effects (which have been reported in as many as20% of treated humans) are usually mild, transient,and reversible after withdrawal of the drug. These ef-
Small Animal
The Compendium 
February 1997
EMPTYING RATE
s
NAUSEA
s
CHOLINERGIC PROPERTIES

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