What medications are used to increase motility? An overview of prokinetic agents

October 12, 2025 •

5 min read

According to research published in Frontiers in Pharmacology, the development of new prokinetic agents is a significant area of focus due to the unmet clinical need in treating motility disorders like gastroparesis. So, what medications are used to increase motility? These agents enhance the coordinated muscle contractions of the gastrointestinal tract to accelerate the transit of contents and relieve uncomfortable symptoms.

Quick Summary

Prokinetic agents are medications that amplify and coordinate gastrointestinal muscle contractions to speed up transit time. This class of drugs is used to treat conditions characterized by slow gut movement, such as gastroparesis and chronic constipation.

Key Points

Prokinetic agents boost gut motility: These medications stimulate and coordinate the muscle contractions of the gastrointestinal tract to improve digestion and transit.
Diverse mechanisms of action: Different classes of prokinetics, such as dopamine antagonists, serotonin agonists, and motilin agonists, act on various receptors and neurotransmitters to achieve their effects.
Treats multiple conditions: Prokinetic agents are used to manage disorders like gastroparesis (delayed gastric emptying) and various forms of chronic constipation, including opioid-induced.
Significant side effect profiles: Many prokinetics have notable side effects, with some older agents carrying risks of serious neurological or cardiac complications.
Availability varies by region: Some medications, like domperidone, have restricted availability in certain countries due to safety concerns.
Secretagogues offer an alternative approach: Drugs like lubiprostone and linaclotide increase intestinal fluid secretion to soften stool and accelerate transit, providing a different way to increase motility.
Medical supervision is critical: Choosing and managing motility-increasing medication requires a healthcare provider's guidance to balance efficacy with safety, given the complex side effects.

The gastrointestinal tract's ability to move food and waste through the digestive system is a complex process known as motility. When this process is impaired, it can lead to a range of digestive disorders, including gastroparesis (delayed stomach emptying) and chronic constipation. Medications used to increase motility, known as prokinetic agents, are prescribed to stimulate and coordinate the contractions of the digestive muscles to alleviate symptoms. These agents work through various mechanisms by interacting with specific receptors and neurotransmitters within the digestive system.

Types of Prokinetic Agents

Dopamine Antagonists

This class of drugs works by blocking dopamine-2 (D2) receptors, which normally have an inhibitory effect on gastrointestinal motility. By blocking these receptors, they increase the release of acetylcholine, a neurotransmitter that stimulates muscle contractions in the GI tract.

Metoclopramide (Reglan): The only FDA-approved prokinetic for gastroparesis in the United States, it is a first-line therapy. However, its use is typically limited to less than 12 weeks due to the risk of neurological side effects, including tardive dyskinesia. It is also used for severe GERD that does not respond to other treatments.
Domperidone (Motilium): This agent works similarly to metoclopramide but does not readily cross the blood-brain barrier, resulting in fewer central nervous system side effects. It is available by prescription in many countries but only through a special access program in the U.S., primarily due to concerns about potential cardiac side effects like QT-interval prolongation. It has proven effective for gastroparesis, functional dyspepsia, and refractory nausea.

Macrolide Antibiotics

Certain macrolide antibiotics, notably erythromycin, have a potent prokinetic effect that is independent of their antibacterial properties. They act as agonists at motilin receptors in the stomach and duodenum, which stimulates strong, coordinated muscle contractions known as the migrating motor complex.

Erythromycin: This antibiotic is used off-label as a short-term prokinetic, particularly in hospitalized patients with severe gastroparesis, to accelerate gastric emptying. Its long-term use is limited by tachyphylaxis (decreasing effectiveness over time) and the risk of developing antibiotic resistance.

Serotonin (5-HT4) Receptor Agonists

This class of drugs activates serotonin 5-HT4 receptors, which play a crucial role in stimulating intestinal motility and secretion.

Prucalopride (Motegrity): A highly selective 5-HT4 agonist, prucalopride is effective for treating chronic idiopathic constipation (CIC) in adults. It works by increasing colonic motility and transit, and some studies suggest it may also benefit gastroparesis patients. Common side effects include headache, nausea, and abdominal pain.
Tegaserod (Zelnorm): This drug was used to treat constipation-predominant IBS but was withdrawn from the market due to cardiovascular risks. Its use is now restricted and available only under specific conditions.

Secretagogues

These agents increase fluid secretion into the intestines, softening stool and promoting motility. They work differently than traditional laxatives and are used for chronic constipation and certain types of irritable bowel syndrome.

Lubiprostone (Amitiza): This drug activates chloride channel-2 (ClC-2) in the small intestine, which increases fluid secretion and accelerates colonic transit. It is used for chronic idiopathic constipation and opioid-induced constipation in adults. Nausea and diarrhea are common side effects.
Linaclotide (Linzess): A guanylate cyclase-C agonist, linaclotide increases intestinal fluid and accelerates transit. It is approved for chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults. Diarrhea is the most frequent side effect.

Other Agents and Future Directions

Other agents exist, such as acetylcholinesterase inhibitors like neostigmine, used for colonic pseudo-obstruction, but carry significant side effects. Additionally, research is ongoing for new prokinetics, including ghrelin receptor agonists, to develop more effective and safer therapies for gastric motility disorders.

Comparison of Medications to Increase Motility


Feature	Metoclopramide	Domperidone	Erythromycin	Prucalopride	Lubiprostone	Linaclotide
Drug Class	Dopamine Antagonist	Dopamine Antagonist	Macrolide Antibiotic	5-HT4 Agonist	Chloride Channel Activator	Guanylate Cyclase-C Agonist
Primary Use	Gastroparesis (FDA-approved), GERD	Gastroparesis, functional dyspepsia (restricted access in U.S.)	Acute gastroparesis (off-label)	Chronic idiopathic constipation	CIC, OIC, IBS-C (women)	CIC, IBS-C
Mechanism	Blocks D2 receptors, increases acetylcholine	Blocks D2 receptors peripherally, increases acetylcholine	Binds to motilin receptors	Activates 5-HT4 receptors in colon	Activates ClC-2 channels, increases intestinal fluid	Activates guanylate cyclase-C, increases intestinal fluid
Key Side Effects	Tardive dyskinesia, neurological issues	QT-prolongation risk, hyperprolactinemia	Tachyphylaxis, cardiac risk with interactions	Headache, abdominal pain, nausea	Nausea, diarrhea, headache	Diarrhea
U.S. Availability	Yes (restricted duration)	Limited Access Program only	Off-label use	Yes	Yes	Yes

Potential Side Effects and Safety Considerations

When considering medications to increase motility, it is crucial to understand their side effect profiles. The choice of medication is often a balance of efficacy and managing potential risks. Many prokinetic agents, especially older ones, have been associated with significant side effects.

Neurological Side Effects: Metoclopramide's ability to cross the blood-brain barrier can lead to central nervous system effects like fatigue, restlessness, and serious, potentially irreversible involuntary movements such as tardive dyskinesia. Domperidone, while having a better neurological safety profile, is still associated with some adverse events.
Cardiac Risks: Concerns over cardiac arrhythmias and QT-interval prolongation have led to the withdrawal of some prokinetics like cisapride from the U.S. market. Domperidone and macrolides also carry specific cardiac risks, requiring careful patient monitoring and consideration of drug interactions.
Gastrointestinal Distress: Nausea, vomiting, abdominal pain, and diarrhea are common side effects across many prokinetic and secretagogue medications. These effects are often dose-dependent and can sometimes be managed by adjusting the dosage or taking the medication with food.
Hormonal Effects: Domperidone can cause elevated prolactin levels due to its dopamine-blocking effects, potentially leading to galactorrhea or gynecomastia.

Conclusion

Medications designed to increase motility are a vital part of managing various gastrointestinal disorders, particularly gastroparesis and chronic constipation. These agents, including dopamine antagonists, macrolide antibiotics, serotonin agonists, and secretagogues, offer different mechanisms of action to address underlying issues of slow transit. However, the use of these medications requires careful consideration of their potential side effects, including neurological complications, cardiac risks, and gastrointestinal distress. The ideal treatment is determined by the patient's specific condition, symptom profile, and tolerance for potential adverse effects, underscoring the importance of close medical supervision. The continuous research and development of newer agents offer promise for more selective and safer options in the future. Patients should consult a healthcare provider to determine the most appropriate and safest medication to meet their needs.

Learn more about gastrointestinal motility disorders on Medscape.

Frequently Asked Questions

Prokinetics are medications that act on the nervous system of the gut to enhance the coordinated muscular contractions (peristalsis) that move contents along the digestive tract. Laxatives primarily work by either bulking up stool, softening it, or stimulating intestinal fluid secretion, but don't necessarily coordinate contractions.

Metoclopramide's use is often limited to less than 12 weeks because it can cause serious neurological side effects, including tardive dyskinesia, which can be irreversible. Your doctor will determine the safest duration of use for your condition.

In the United States, domperidone is not commercially available. It can only be accessed by healthcare providers through a restricted FDA-approved Expanded Access to Investigational Drugs program for specific, refractory cases due to concerns about cardiac side effects.

Medications to increase motility are primarily used for conditions involving impaired gut movement. This includes gastroparesis, chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), and constipation-predominant irritable bowel syndrome (IBS-C).

No, erythromycin is generally not recommended for long-term use as a prokinetic. Its efficacy can wane over time (tachyphylaxis) as motilin receptors are downregulated. Additionally, long-term use poses risks associated with developing antibiotic resistance.

Lubiprostone works by activating chloride channels to increase intestinal fluid, while linaclotide activates guanylate cyclase-C, which also increases fluid and accelerates transit. Both increase fluid secretion to soften stool and promote bowel movements, but through different cellular pathways.

Common side effects vary by medication but can include headache, nausea, diarrhea, and abdominal pain. More serious side effects, such as tardive dyskinesia with metoclopramide or cardiac issues with domperidone, can also occur, emphasizing the need for careful medical monitoring.