CASE 32
A 58-year-old woman with a 20-year history of poorly controlled type II diabetes mellitus comes in for routine follow-up. She has had multiple complications from her diabetes, including retinopathy and peripheral neuropathy. She complains of having several months of feeling as if her stomach is full after eating very little. She is frequently nauseous and bloated. She is on a combination of regular and neutral protamine Hagedorn (NPH) insulin for her diabetes, an angiotensin-converting enzyme (ACE) inhibitor for her blood pressure, and a statin for her lipids. Her examination today is unremarkable. A radiographic gastric emptying study shows a prolonged gastric emptying time. You diagnose her with diabetic gastroparesis and prescribe metoclopramide.
What is the mechanism of action of metoclopramide for gastroparesis?
What are some common side effects of metoclopramide?
ANSWERS TO CASE 32:
Prokinetic Agents
Summary: A 58-year-old woman presents with diabetic gastroparesis and is prescribed metoclopramide.
Mechanism of action of metoclopramide: Dopamine D2-receptor antagonist in the GI tract.
Common side effects: Sedation, extrapyramidal side effects, increased prolactin secretion.
CLINICAL CORRELATION
Metoclopramide, administered orally or parenterally, works as a prokinetic agent in the GI tract. In the GI tract, dopamine acts to inhibit ACh stimulation of smooth muscle. As a dopamine D2-receptor antagonist, metoclopramide allows for a greater stimulatory effect of ACh. It may also promote the release of ACh. The increased ACh effect at muscarinic receptors results in increased lower esophageal sphincter pressure and increased gastric emptying. Serotonin 5-HT4 receptors also increase upper GI motility by direct effects as well as by increasing ACh release. Many 5-HT4 agonists are available in other countries. Ghrelin, produced by the stomach, has important effects on gastrointestinal motility. Like motilin, a hormone released by endocrine cells in the duodenum, it induces hunger contractions in the fasting state and acts postprandially to accelerate gastric emptying. Gherlin agonists are in last phase clinical trials for treatment of gastroparesis. Diabetic gastroparesis is a common (~10%) complication of poorly controlled diabetes, particularly in diabetics with peripheral neuropathy. It is associated with damage to the vagus nerve. In this setting, metoclopramide can promote emptying of the stomach and help to alleviate the symptoms. Metoclopramide can be administered orally or parenterally and its half-life is 5 to 6 hours. It is also used clinically in combination with antacids to treat gastroesophageal reflux disease (GERD). Metoclopramide also has central actions. Dopamine D2-receptor blockade in the CTZ in the CNS is the basis for clinical use of metoclopramide for treatment of nausea and vomiting. Restlessness, anxiety, and insomnia are common adverse effects of metoclopramide and, like other dopamine D2-receptor antagonists such as haloperidol, metoclopramide at high doses can cause extrapyramidal side effects and tardive dyskinesia. It can also cause increased prolactin secretion that can result in galactorrhea, menstrual dysfunction, gynecomastia, and sexual dysfunction. Other prokinetic agents include erythromycin, which stimulates motilin receptors, and can be administered orally or IV for refractory gastroparesis; cisapride, a 5-HT4-receptor agonist that is only available for compassionate use due to its cardiotoxicity; and domperidone (not available in the United States), which is also a dopamine D2-receptor antagonist, but one that acts only peripherally and, therefore, has few neural adverse effects.
DEFINITIONS
Gastroparesis: Slight paralysis of the muscular coat of the stomach.
COMPREHENSION QUESTIONS
32.1 Metoclopramide is which of the following?
A. α1-Adrenoceptor antagonist
B. Dopamine D2-receptor antagonist
C. Muscarinic cholinoreceptor antagonist
D. Serotonin 5-HT4-receptor agonist
32.2 Which of the following is the most likely adverse effect of metoclopramide?
A. Hallucinations
B. Hyperactivity
C. Hyperthyroidism
D. Tardive dyskinesia
32.3 Metoclopramide acts to achieve which of the following?
A. Increase gastric emptying
B. Decrease transit through the small intestine
C. Decrease lower esophageal sphincter pressure
D. Stimulate vomiting
ANSWERS
32.1 B. Metoclopramide is a dopamine D2-receptor antagonist.
32.2 D. Adverse effects of metoclopramide include insomnia, tardive dyskinesia, and sexual dysfunction, as well as extrapyramidal side effects similar to haloperidol and endocrine effects related to increased prolactin secretion (galactorrhea, menstrual dysfunction, gynecomastia).
32.3 A. Metoclopramide increases gastric emptying, increases lower esophageal sphincter pressure, and inhibits vomiting.
PHARMACOLOGY PEARLS
Metoclopramide works as a prokinetic agent in the GI tract, acting as a dopamine antagonist.
Common side effects of metoclopramide are restlessness and anxiety. Also, like other dopamine D2-receptor antagonists such as haloperidol, metoclopramide can cause extrapyramidal side effects and tardive dyskinesia.
Metoclopramide increases prolactin secretion that can result in galactorrhea and menstrual irregularities.
REFERENCES
Farmer AD, Kadirkamanathan SS, Aziz Q. Diabetic gastroparesis: pathophysiology, evaluation and management. Br J Hosp Med (Lond). 2012;73:451–6.
Hejazi RA, McCallum RW, Sarosiek I. Prokinetics in diabetic gastroparesis. Curr Gastroenterol Rep. 2012;14:297–305.
Tonini M, Cipollina L, Poluzzi E, et al. Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment Pharmacol Ther. 2004;19(4):379–90.