Serotoninergic neuroenteric modulators

Definition and Overview
Serotoninergic neuroenteric modulators are pharmacological agents that influence serotonin (5-hydroxytryptamine, 5-HT) receptors in the enteric nervous system (ENS) to regulate gastrointestinal (GI) motility, secretion, and visceral sensation. These agents modulate serotonergic signaling at various receptor subtypes (notably 5-HT3, 5-HT4, and 5-HT1), which are involved in the regulation of intestinal peristalsis, secretion, pain perception, and nausea.

They are used in the treatment of functional GI disorders, especially irritable bowel syndrome (IBS), chronic constipation, gastroparesis, and chemotherapy-induced nausea and vomiting (CINV).

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Pharmacological Basis and Receptor Targets

Receptor Subtype	Function in GI Tract	Agonists/Antagonists Role
5-HT3	Mediate nausea, vomiting, visceral pain	Antagonists block afferent pain & nausea
5-HT4	Enhance acetylcholine release, motility	Agonists enhance GI motility
5-HT1	Modulate smooth muscle tone and nociception	Less commonly targeted

Main Categories of Serotoninergic Neuroenteric Modulators

1. 5-HT3 Receptor Antagonists

Used mainly for nausea, vomiting, and diarrhea-predominant IBS.

Mechanism: Block 5-HT3 receptors on enteric neurons and vagal afferents to reduce visceral pain and hypermotility.

Examples:

• Alosetron – for severe IBS-D in women (restricted use)

• Ondansetron – antiemetic, off-label for IBS-D

• Granisetron, Palonosetron, Tropisetron – primarily antiemetics in CINV and postoperative nausea

Adverse Effects:

• Constipation (notable with Alosetron)

• Ischemic colitis (rare, black box warning for Alosetron)

• QT prolongation (Ondansetron)

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2. 5-HT4 Receptor Agonists

Used to enhance GI motility, especially in chronic constipation and IBS-C (constipation-predominant).

Mechanism: Stimulate 5-HT4 receptors to release acetylcholine and calcitonin gene-related peptide (CGRP), enhancing peristalsis and promoting bowel movement.

Examples:

• Prucalopride – selective, for chronic idiopathic constipation

• Tegaserod – partial agonist; approved for IBS-C in women

• Cisapride (withdrawn in many countries due to cardiac toxicity)

Adverse Effects:

• Headache, diarrhea

• Cardiovascular risk with non-selective agonists (e.g., Cisapride)

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3. Mixed Serotoninergic Modulators

Act as agonists at one receptor subtype and antagonists at another.

Examples:

• Tegaserod – 5-HT4 partial agonist, 5-HT2B antagonist

• Mosapride – 5-HT4 agonist and weak 5-HT3 antagonist (used in Asia)

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Clinical Indications

Condition	Drug Class Targeted	Preferred Drugs
IBS with Diarrhea (IBS-D)	5-HT3 Antagonists	Alosetron (severe cases), Ondansetron (off-label)
IBS with Constipation (IBS-C)	5-HT4 Agonists	Tegaserod, Prucalopride
Chronic Idiopathic Constipation	5-HT4 Agonists	Prucalopride
Gastroparesis	5-HT4 Agonists (off-label)	Prucalopride, Cisapride (where available)
Chemotherapy/Postoperative Nausea	5-HT3 Antagonists	Ondansetron, Palonosetron

Examples of Drugs and Brand Names

Generic Name	Brand Name(s)	Receptor Action	Indication
Alosetron	Lotronex	5-HT3 antagonist	IBS-D (women only)
Ondansetron	Zofran	5-HT3 antagonist	CINV, off-label IBS-D
Prucalopride	Resolor	5-HT4 agonist	Chronic constipation
Tegaserod	Zelnorm	5-HT4 partial agonist	IBS-C (women <65 yrs)
Cisapride	Propulsid (withdrawn)	5-HT4 agonist	Prokinetic (cardiac concerns)
Mosapride	Gasmotin (Asia)	5-HT4 agonist	Functional dyspepsia, constipation
Granisetron	Kytril	5-HT3 antagonist	CINV, radiation-induced nausea
Palonosetron	Aloxi	5-HT3 antagonist	Long-acting antiemetic

Mechanism of Action Summary

• 5-HT3 Antagonists:

  • ↓ Nausea and visceral pain

  • ↓ Diarrhea in IBS

  • ↓ Vomiting signals in brainstem

• 5-HT4 Agonists:

  • ↑ ACh release → ↑ peristalsis

  • ↑ Lower esophageal sphincter tone

  • ↓ colonic transit time

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Adverse Effects

Drug Class	Common Side Effects	Serious Risks
5-HT3 Antagonists	Constipation, headache	QT prolongation, ischemic colitis (Alosetron)
5-HT4 Agonists	Headache, abdominal cramps	Cardiovascular events (esp. Cisapride)

Contraindications

• Alosetron: History of constipation or ischemic colitis, IBD

• Tegaserod: History of cardiovascular disease, ischemia

• Prucalopride: Severe renal impairment (with caution), IBD (relative)

• All 5-HT Modulators: Pregnancy (varies by agent), severe hepatic dysfunction

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Drug Interactions

Interacting Agent	Effect	Relevant Drugs
CYP3A4 inhibitors	↑ levels of 5-HT4 agents (e.g., cisapride)	Cisapride, Mosapride
QT-prolonging drugs	Additive QT risk	Alosetron, Ondansetron
MAO inhibitors	Serotonin syndrome risk (with serotonin modulators)	Caution with all
Erythromycin	↑ QT risk with 5-HT3 antagonists	All 5-HT3 agents

Monitoring Requirements

• Alosetron: Constipation, ischemic symptoms, CBC if bleeding suspected

• Prucalopride: ECG in high-risk patients, renal function

• Ondansetron: QT interval, especially in IV use

• Tegaserod: Cardiovascular history screening

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Clinical Considerations

• Gender-Specific Approval: Alosetron and Tegaserod are often restricted to women due to trial data

• Access Programs: Alosetron is under strict risk evaluation and mitigation strategy (REMS) in the U.S.

• Off-label Use: Ondansetron is widely used for IBS-D despite being indicated for emesis

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Alternative and Adjunctive Therapies

• Lubiprostone, Linaclotide, and Plecanatide – for IBS-C, act via chloride channels and GC-C receptors

• Loperamide, Eluxadoline – for IBS-D with different mechanisms

• Tricyclic antidepressants – modulate visceral pain in IBS