Metoclopramide and domperidone are dopamine D2-receptor antagonists. Within the gastrointestinal tract, activation of dopamine receptors inhibits cholinergic smooth muscle stimulation; blockade of this effect is believed to be the primary prokinetic mechanism of action of these agents. These agents increase esophageal peristaltic amplitude, increase lower esophageal sphincter pressure, and enhance gastric emptying but have no effect on small intestine or colonic motility. Metoclopramide and domperidone also block dopamine D2 receptors in the chemoreceptor trigger zone of the medulla (area postrema), resulting in potent antinausea and antiemetic action.
1.
Gastroesophageal reflux disease—Metoclopramide is available for clinical use in the USA; domperidone is available in many other countries. These agents are sometimes used in the treatment of symptomatic GERD but are not effective in patients with erosive esophagitis. Because of the superior efficacy and safety of antisecretory agents in the treatment of heartburn, prokinetic agents are used mainly in combination with antisecretory agents in patients with regurgitation or refractory heartburn.
2.
Impaired gastric emptying—These agents are widely used in the treatment of patients with delayed gastric emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis. Metoclopramide is sometimes administered in hospitalized patients to promote advancement of nasoenteric feeding tubes from the stomach into the duodenum.
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Nonulcer dyspepsia—These agents lead to symptomatic improvement in a small number of patients with chronic dyspepsia.
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Prevention of vomiting—Because of their potent antiemetic action, metoclopramide and domperidone are used for the prevention and treatment of emesis.
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Postpartum lactation stimulation—Domperidone is sometimes recommended to promote postpartum lactation (see also Adverse Effects).
The most common adverse effects of metoclopramide involve the central nervous system. Restlessness, drowsiness, insomnia, anxiety, and agitation occur in 10–20% of patients, especially the elderly. Extrapyramidal effects (dystonias, akathisia, parkinsonian features) due to central dopamine receptor blockade occur acutely in 25% of patients given high doses and in 5% of patients receiving long-term therapy. Tardive dyskinesia, sometimes irreversible, has developed in patients treated for a prolonged period with metoclopramide. For this reason, long-term use should be avoided unless absolutely necessary, especially in the elderly. Elevated prolactin levels (caused by both metoclopramide and domperidone) can cause galactorrhea, gynecomastia, impotence, and menstrual disorders.
Domperidone is extremely well tolerated. Because it does not cross the blood-brain barrier to a significant degree, neuropsychiatric and extrapyramidal effects are rare.
Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle and promote the onset of a migrating motor complex. Intravenous erythromycin (3 mg/kg) is beneficial in some patients with gastroparesis; however, tolerance rapidly develops. It may be used in patients with acute upper gastrointestinal hemorrhage to promote gastric emptying of blood before endoscopy.
The overwhelming majority of people do not need laxatives; yet they are self-prescribed by a large portion of the population. For most people, intermittent constipation is best prevented with a high-fiber diet, adequate fluid intake, regular exercise, and the heeding of nature’s call. Patients not responding to dietary changes or fiber supplements should undergo medical evaluation before initiating long-term laxative treatment. Laxatives may be classified by their major mechanism of action, but many work through more than one mechanism.