What drugs increase intestinal motility? A Guide to Prokinetic Agents

October 12, 2025 •

4 min read

Functional gastrointestinal disorders (FGIDs), which often involve issues with intestinal motility, affect more than 40% of people worldwide [1.2.4]. Understanding what drugs increase intestinal motility is key to managing these common and often debilitating conditions.

Quick Summary

Drugs that increase intestinal motility, known as prokinetic agents, enhance gastrointestinal contractions to improve the transit of food. They are used for conditions like gastroparesis, GERD, and chronic constipation by acting on various receptors.

Key Points

Prokinetics Increase Contractions: Drugs that increase intestinal motility are called prokinetic agents; they enhance the frequency and strength of GI muscle contractions [1.5.7].
Multiple Drug Classes: Major classes include dopamine antagonists (metoclopramide), serotonin 5-HT4 agonists (prucalopride), and motilin agonists (erythromycin) [1.3.8].
Treat Specific Conditions: These drugs are used for conditions like gastroparesis, chronic constipation, and severe GERD [1.4.1, 1.3.2].
Metoclopramide is FDA Approved: Metoclopramide is the only FDA-approved drug for gastroparesis but has risks of significant side effects [1.3.5, 1.6.6].
Side Effects are a Concern: All prokinetics have potential side effects, ranging from diarrhea and headache to serious cardiac or neurological issues, requiring careful medical supervision [1.6.1, 1.6.7].
New Drugs are in Development: Research is active, with new agents like ghrelin agonists and novel serotonin agonists being investigated for better safety and efficacy [1.7.3].
Mechanism Varies: Prokinetics work by targeting different neurotransmitters and receptors, such as blocking inhibitory dopamine or stimulating excitatory serotonin and motilin receptors [1.5.2, 1.5.6].

Understanding Intestinal Motility and Its Disorders

Intestinal motility refers to the coordinated, involuntary muscle contractions, called peristalsis, that move food through the gastrointestinal (GI) tract [1.5.2]. When this process is impaired, it can lead to a variety of symptoms and conditions, including abdominal discomfort, bloating, nausea, vomiting, constipation, and gastroparesis (paralysis of the stomach) [1.5.7, 1.5.2]. Gastrointestinal motility disorders are highly prevalent, impacting a significant portion of the global population and affecting quality of life [1.2.3, 1.2.7]. For instance, it's estimated that these disorders comprise about 40% of the problems for which patients visit a gastroenterologist in the United States [1.2.1].

What Are Prokinetic Agents?

Prokinetic agents are a class of drugs designed to enhance GI motility [1.4.1]. They work by increasing the frequency or strength of muscle contractions without disrupting their natural rhythm [1.5.7]. These medications can act in several ways [1.5.2, 1.5.6]:

Strengthening the lower esophageal sphincter (LES) to prevent acid reflux.
Promoting the emptying of stomach contents into the intestines.
Increasing wave-like contractions in the esophagus and stomach.

These actions are achieved by stimulating excitatory neurotransmitters like acetylcholine or suppressing inhibitory ones like dopamine [1.5.6].

Major Classes of Prokinetic Drugs

Prokinetics are categorized based on their mechanism of action. The main classes include Dopamine Antagonists, Serotonin (5-HT4) Agonists, and Motilin Agonists [1.3.8, 1.5.2].

Dopamine D2 Receptor Antagonists

Dopamine is a neurotransmitter that normally inhibits GI motility [1.4.2]. By blocking D2 receptors in the gut, these drugs neutralize dopamine's inhibitory effect, leading to increased pressure in the lower esophageal sphincter and more coordinated GI contractions [1.4.2].

Metoclopramide (Reglan): This is the only drug currently approved by the FDA for treating gastroparesis [1.3.5, 1.5.1]. It blocks dopamine receptors and also acts on serotonin receptors to promote motility [1.4.7]. However, due to the risk of serious side effects like tardive dyskinesia (involuntary movements), its use is typically recommended for less than 12 weeks [1.6.6, 1.5.1].
Domperidone (Motilium): Domperidone acts similarly to metoclopramide but does not cross the blood-brain barrier as easily, resulting in fewer central nervous system side effects [1.6.6, 1.4.2]. It is not approved for sale in the U.S. but can be accessed through a special FDA program [1.5.1, 1.4.5]. It carries a risk of cardiac side effects, including arrhythmias [1.3.7, 1.6.1].

Serotonin 5-HT4 Receptor Agonists

Serotonin plays a crucial role in controlling gut motility [1.5.3]. Agonists that target the 5-HT4 receptor stimulate the release of acetylcholine, a neurotransmitter that promotes peristalsis [1.5.4].

Prucalopride (Motegrity): This is a high-affinity 5-HT4 agonist approved for treating chronic constipation [1.4.1, 1.4.4]. It stimulates mass movements in the colon, which are the main propulsive force for defecation [1.4.1]. Unlike older drugs in this class (like cisapride), prucalopride has a better safety profile and does not appear to carry the same cardiac risks [1.4.1, 1.5.3].
Cisapride (Propulsid): This drug was widely used but has been withdrawn or restricted in most countries due to the risk of serious cardiac arrhythmias [1.4.5, 1.6.7].

Motilin Receptor Agonists (Macrolides)

Motilin is a hormone that stimulates contractions in the stomach and small intestine, often called the "housekeeper of the gut" [1.5.3]. Certain macrolide antibiotics act as motilin agonists.

Erythromycin: This antibiotic can induce powerful gastric contractions and accelerate gastric emptying [1.3.3]. It is used off-label for gastroparesis, often in a hospital setting for short-term relief [1.4.5]. Its effectiveness can decrease over time (tachyphylaxis), and long-term use raises concerns about antibiotic resistance and side effects like abdominal cramps and diarrhea [1.4.5, 1.6.5].

Comparison of Prokinetic Drug Classes


Drug Class	Mechanism of Action	Common Examples	Primary Uses	Common Side Effects
Dopamine Antagonists	Blocks inhibitory dopamine D2 receptors, increasing acetylcholine release [1.4.2].	Metoclopramide, Domperidone [1.3.2]	Gastroparesis, GERD, nausea/vomiting [1.4.2, 1.5.2]	Drowsiness, restlessness, tardive dyskinesia (Metoclopramide), cardiac arrhythmias (Domperidone) [1.6.6, 1.6.7].
Serotonin Agonists	Stimulates 5-HT4 receptors to promote acetylcholine release and peristalsis [1.4.1, 1.5.2].	Prucalopride, Tegaserod [1.4.1]	Chronic constipation [1.4.4]	Headache, abdominal pain, nausea, diarrhea [1.6.1, 1.6.2].
Motilin Agonists	Mimics the hormone motilin to stimulate strong gastric contractions [1.5.2, 1.5.3].	Erythromycin, Azithromycin [1.5.2]	Gastroparesis (off-label) [1.3.3]	Abdominal cramps, nausea, diarrhea, risk of antibiotic resistance, cardiac issues [1.6.5, 1.4.5].
Cholinergic Agonists	Mimic the neurotransmitter acetylcholine to stimulate intestinal muscles [1.5.2].	Bethanechol, Pyridostigmine [1.5.2]	Gastroparesis, pseudo-obstruction [1.3.7, 1.6.1]	Blurred vision, abdominal cramps, flushing, diarrhea [1.6.1, 1.6.7].

Newer and Investigational Agents

Research continues into new prokinetic therapies with better efficacy and safety profiles. These include novel 5-HT4 agonists (like velusetrag and felcisetrag), ghrelin receptor agonists (like relamorelin), and agents targeting other pathways like neurokinin (NK1) antagonists (aprepitant) [1.7.3, 1.4.5]. Cinitapride, which acts on both serotonin and dopamine receptors, has also shown promise in treating functional dyspepsia [1.7.6].

Conclusion

Drugs that increase intestinal motility play a vital role in managing various gastrointestinal disorders characterized by delayed transit. Prokinetic agents, from dopamine antagonists like metoclopramide to serotonin agonists like prucalopride, offer targeted ways to enhance gut function. However, their use must be carefully balanced against their potential side effects, with treatment decisions tailored to the individual patient's condition and risk profile. The development of newer agents brings hope for more effective and safer options in the future. For more information, an authoritative source is the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): https://www.niddk.nih.gov/health-information/digestive-diseases/gastroparesis.

Frequently Asked Questions

The main purpose of a prokinetic agent is to enhance gastrointestinal motility, which means it helps increase the strength and frequency of muscle contractions to move food through the digestive tract [1.5.7].

Metoclopramide is the only medication currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of gastroparesis [1.3.5, 1.5.1].

Yes, certain macrolide antibiotics, most notably erythromycin, can act as motilin receptor agonists to stimulate strong contractions in the stomach and are used off-label to treat gastroparesis [1.5.2, 1.4.5].

Common side effects can include abdominal pain, diarrhea, nausea, and headache [1.6.1, 1.6.2]. More serious side effects depend on the drug and can include involuntary movements (tardive dyskinesia) with metoclopramide or cardiac arrhythmias with domperidone [1.6.7, 1.6.1].

While this article focuses on pharmacological options, lifestyle and dietary changes are often recommended first. These can include eating smaller, more frequent meals, consuming low-fat and low-fiber foods, staying hydrated, and regular physical activity.

Cisapride was largely withdrawn from the market or had its use severely restricted because it was linked to a risk of serious, life-threatening cardiac arrhythmias, specifically QT prolongation [1.4.5, 1.5.3].

Both are dopamine antagonists, but domperidone does not cross the blood-brain barrier to the same extent as metoclopramide. This means domperidone has a lower risk of causing central nervous system side effects like drowsiness or movement disorders, though it has a higher risk of cardiac side effects [1.4.2, 1.6.6].