Mechanism of Action
Metoclopramide is principally a dopamine D2 antagonist but also acts as an agonist on serotonin 5-HT4 receptors and causes weak inhibition of 5-HT3 receptors.
Actions on Gut Motility
Metoclopramide stimulates gut motility by affecting different receptors in the GI tract (Box 1). Most importantly, it acts as an antagonist of the dopamine D2 receptor subtype. Dopamine has a direct relaxant effect on the gut by activating muscular D2 receptors in the lower esophageal sphincter and stomach (fundus and antrum). It also inhibits the release of acetylcholine from intrinsic myenteric cholinergic neurons by activating prejunctional D2 receptors, which leads to an indirect inhibition of the musculature. Metoclopramide promotes gut motility by the following three mechanisms: inhibition of presynaptic and postsynaptic D2 receptors, stimulation of presynaptic excitatory 5-HT4 receptors and antagonism of presynaptic inhibition of muscarinic receptors (Figure 2A). This promotes release of acetylcholine, which in turn leads to increased lower esophageal sphincter (LES) and gastric tone, increased intragastric pressure, improved antroduodenal coordination and accelerated gastric emptying.[30–33] Overall, metoclopramide leads to increased gastric emptying by enhancing antral contractions as well as decreasing postprandial fundus relaxation. However, the prokinetic properties of metoclopramide are limited to the proximal gut.
Mechanism of action of metoclopramide. (A) Metoclopramide promotes gut motility by inhibiting presynaptic and postsynaptic D2 receptors as well as presynaptic 5-HT4 receptors. (B) Metoclopramide also produces antiemetic effects by inhibition of D2 and 5-HT3 receptors in the CTZ.
CTZ: Chemoreceptor trigger zone; GI: Gastrointestinal.
Adapted from .
Actions on Emesis
Emesis is a highly organized process that is coordinated by the vomiting center in the CNS and receives input from visceral afferent neurons in the GI tract. In animal models, stimulation of dopamine D2 receptors at the level of the chemoreceptor trigger zone (CTZ), located in the area postrema in the medulla oblongata, has been used to characterize vomiting as well as gastrointestinal motor correlates, including gastric relaxation and commencement of the retrograde giant contraction in the small bowel. Metoclopramide produces its antiemetic effects by inhibition of D2 and 5-HT3 receptors in the chemoreceptor trigger zone (Figure 2B).[36,37]
Expert Rev Endocrinol Metab. 2010;5(5):653-662. © 2010 Expert Reviews Ltd.
Cite this: Metoclopramide in the Treatment of Diabetic Gastroparesis - Medscape - Sep 01, 2010.