Metoclopramide in the Treatment of Diabetic Gastroparesis

Allen Lee; Braden Kuo

Expert Rev Endocrinol Metab. 2010;5(5):653-662.

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.^[29] 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.^[34] However, the prokinetic properties of metoclopramide are limited to the proximal gut.^[35]

(Enlarge Image)

Figure 2.

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 ^[30].

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]

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Table 1. Risk of tardive dyskinesia with metoclopramide.
Study (year)	Study design	Number studied	Result	Estimated prevalence	Ref.
Wilholm et al. (1984)	Scandinavian prescription database, 1977–1981	11 million Rx of metoclopramide	37 reports of EPS with 11 TD casesAll females, mean age of 76 years	One in 2000–28,000 patient-years, one in 17,800 perscriptions	^[71]
Bateman et al. (1985)	UK prescription database, 1967–1982	15.9 million Rx of metoclopramide	479 reports of EPS, four with TD	One in ~35,000 prescriptions, significantly higher risk in females, especially those 12–19 years old	^[64]
Sewell et al.(1992)	Analysis of 67 case reports of metaclopramide-induced TD	52 patients on at least 30 days of metoclopramide	Mean age of 70 ± 19 years, 3:1 female predominance and Rx duration of 20 ± 15 months; 47% TD cases persisted at 6 months despite discontinuation of metoclopramide	Not estimable	^[74]
Ganzini et al. (1993)	VA study using exposed/unexposed design, matched for age, gender, diabetes and comorbidities	51 chronic Rx of metoclopramide; 51 unexposed	Mean age of 63.9 ± 10.8 years, male predominant, duration of treatment 2.6 ± 2.0 years	29% TD in metoclopramide Rx vs 17.6% in nonusers (p = 0.08)	^[65]
Sewell et al. (1994)	VA cross-sectional study	51 patients with metoclopramide-associated TD; 35 controls matched for age, race, gender and diabetes	Duration of metoclopramide treatment of at least 30 days	27% TD in metoclopramide Rx vs 12% nonusers (p = 0.08) Patients on metoclopramide and diabetic more likely to develop TD (p = 0.05)	^[73]
Shafter et al. (2004)	International metoclopramide adverse event reports and US drug-use data	87 case reports	Mean duration of Rx of 753 ± 951 days; 37% used concomitant drugs, 18% had comorbid diseases with TD risk	Not estimableIncreased use of metoclopramide afer cisapride withdrawal	^[16]
Kenney et al. (2008)	Observational study in a tertiary-care movement-disorder clinic	434 patients referred for TD	Metoclopramide accounted for 39.4% of TD, the second-leading cause of TD after haloperidol	Not estimable	^[72]

EPS: Extrapyramidal side effects; TD: Tardive dyskinesia; VA: Veterans administration.
Adapted from ^{[14,16,64,65,71–74]}.

Box 1. Effects of metoclopramide.
Gastric motility D₂receptor antagonist Stimulation 5-HT₄receptors Muscarinic receptor antagonist Symptoms of gastroparesis Promotes gastric emptying Anti-emetic effects via central pathways Normalization of gastric slow wave dysrhythmias Modulates visceral hypersensitivity

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