relaxation; and coordinates gastric, pyloric, and duode-nal motility. All of these actions accelerate gastric emp-tying.
Metoclopramide may be most effective in ac-celerating the gastric emptying of liquids in dogs.
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.
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.
Metoclopramide had no effect onfed-state gastric motility in dogs after recovery fromgastric dilatation
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.
Metoclopramide also enhancesantropyloroduodenal coordination in dogs.
The drugthus may be most effective when delayed gastric empty-ing results from poor antropyloroduodenal coordina-tion.
Metoclopramide is less effective in the distalsmall intestine and colon.
Metoclopramide inhibits vomiting associated withactivation of dopaminergic D
receptors in the che-moreceptor trigger zone.
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.
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.
Metoclopramide has mixed antidopaminergic andcholinergic properties. It antagonizes presynapticdopaminergic D
receptors and enhances the release of acetylcholine from postganglionic cholinergic neu-rons.
The exact mechanisms responsible for thegastrointestinal stimulant effects of metoclopramideare unclear. Although metoclopramide antagonizesdopaminergic D
receptors, the prokinetic effect of metoclopramide probably does not involve dopaminereceptors.
A prejunctional cholinergic mechanism ismore likely and may involve 5-HT (serotonin) recep-tors.
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.
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
receptor, but the mechanism of gastric prokinesis isprobably not related to activity at this receptor.
Meto-clopramide may instead exert its gastric prokinetic ef-fect by stimulating enteric neuronal 5-HT
Like the 5-HT
receptor, the 5-HT
receptor is locatedpresynaptically; when activated, it induces acetylcholinerelease from the depolarized neuron.
The choliner-gic effect of metoclopramide thus might be mediatedthrough 5-HT
mediated neuronal depolar-ization. This mechanism may not operate in all animalspecies or may operate at different sites within a singlespecies.
Metoclopramide is useful as an antiemetic agent be-cause of its antidopaminergic effects at the chemorecep-tor trigger zone.
Metoclopramide exhibits all of theeffects of a central dopaminergic D
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
receptor ag-onist apomorphine.
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-