5HT3 receptor antagonists

Overview

5-HT₃ receptor antagonists are a class of antiemetic medications that block serotonin (5-hydroxytryptamine, 5-HT) at 5-HT₃ receptors, which are ligand-gated ion channels found in both the central nervous system (CNS) and gastrointestinal (GI) tract. They are primarily used for the prevention and treatment of nausea and vomiting, especially those caused by chemotherapy, radiotherapy, postoperative recovery, and, in some cases, acute gastroenteritis or IBS-D (diarrhea-predominant irritable bowel syndrome).

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Approved Generic Names

1. Ondansetron

2. Granisetron

3. Dolasetron

4. Palonosetron

5. Alosetron

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1. Ondansetron

Formulations

• Oral tablet: 4 mg, 8 mg

• Oral disintegrating tablet (ODT): 4 mg, 8 mg

• Oral solution: 4 mg/5 mL

• Injectable solution: 2 mg/mL

Indications

• Prevention and treatment of nausea and vomiting associated with:

  • Chemotherapy (CINV)

  • Radiation therapy (RINV)

  • Postoperative nausea and vomiting (PONV)

Mechanism of Action

Blocks serotonin binding to 5-HT₃ receptors in the vagal nerve terminals and in the chemoreceptor trigger zone of the CNS.

Pharmacokinetics

• Onset: ~30 min (oral), rapid (IV)

• Peak plasma concentration: 1.5–2 hours (oral)

• Metabolism: Hepatic (CYP3A4, CYP2D6, CYP1A2)

• Half-life: 3–6 hours

• Excretion: Renal and hepatic

Common Doses

• CINV prophylaxis: 8 mg orally twice daily

• PONV: 4 mg IV before induction

• Pediatric dosing adjusted by body weight

Adverse Effects

• Headache

• Constipation

• QT interval prolongation

• Fatigue

• Dizziness

Contraindications

• Known hypersensitivity

• Congenital long QT syndrome

Monitoring

• ECG in high-risk patients

• Serum electrolytes (K⁺, Mg²⁺)

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2. Granisetron

Formulations

• Oral tablet: 1 mg

• Oral solution: 1 mg/mL

• Injectable solution: 1 mg/mL

• Transdermal patch (Sancuso)

Indications

• Prevention and treatment of:

  • CINV

  • RINV

  • PONV (off-label)

• Transdermal formulation indicated for delayed CINV

Mechanism of Action

Selective 5-HT₃ receptor blockade in both central and peripheral sites.

Pharmacokinetics

• Onset: ~1–2 hours (oral)

• Half-life: ~9 hours (longer in elderly)

• Metabolism: Hepatic (CYP3A4)

• Excretion: Urinary and fecal

Common Doses

• Oral: 1 mg twice daily or 2 mg once

• IV: 10 mcg/kg before chemotherapy

• Patch: Apply 24–48 hours prior to chemotherapy

Adverse Effects

• Headache

• Constipation

• Injection site reactions

• Sleep disturbances

• QT prolongation (less than ondansetron)

Contraindications

• Known hypersensitivity

• Use caution in patients with cardiac history

Monitoring

• ECG for QT risk

• Bowel function (risk of constipation)

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3. Dolasetron

Formulations

• Oral tablet: 100 mg

• Injectable solution: 12.5 mg/mL (withdrawn in some countries for IV use due to cardiac risk)

Indications

• Prevention of nausea and vomiting associated with:

  • Chemotherapy (oral)

  • Postoperative recovery (oral)

Mechanism of Action

Antagonizes 5-HT₃ receptors in the GI tract and chemoreceptor trigger zone.

Pharmacokinetics

• Prodrug: Rapidly converted to active metabolite (hydrodolasetron)

• Half-life: 8 hours

• Metabolism: Hepatic and non-CYP pathways

• Excretion: Urinary and fecal

Common Doses

• CINV: 100 mg orally 1 hour before chemotherapy

• PONV: 100 mg orally within 2 hours before surgery

Adverse Effects

• QT interval prolongation (higher risk than other 5-HT₃ antagonists)

• Headache

• Dizziness

• Bradycardia

Contraindications

• Known hypersensitivity

• Congenital long QT syndrome

• Caution in patients with cardiac arrhythmias

Monitoring

• ECG before and after dose

• Serum potassium and magnesium

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4. Palonosetron

Formulations

• Injectable solution: 0.25 mg/5 mL

• Oral capsule (in fixed-dose combination): Netupitant + Palonosetron

Indications

• Prevention of acute and delayed CINV (moderate and highly emetogenic regimens)

• Prevention of PONV

Mechanism of Action

High-affinity, long-acting 5-HT₃ receptor antagonist. Blocks serotonin centrally and peripherally with higher receptor binding than first-generation agents.

Pharmacokinetics

• Half-life: ~40 hours

• Peak concentration: ~5 hours (IV)

• Metabolism: Minimal hepatic metabolism (CYP2D6, 3A4, 1A2)

• Excretion: Renal (50%), fecal (40%)

Common Doses

• 0.25 mg IV once, 30 minutes prior to chemotherapy

• 0.075 mg IV for PONV

Adverse Effects

• Headache

• Constipation

• QT prolongation (lower risk than others)

• Injection site pain (rare)

Contraindications

• Hypersensitivity

• Caution in patients with bradyarrhythmias

Monitoring

• ECG for patients with cardiac risk

• Bowel movement regularity

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5. Alosetron

Formulations

• Oral tablet: 0.5 mg, 1 mg

Indications

• Treatment of severe diarrhea-predominant irritable bowel syndrome (IBS-D) in women who have not responded to conventional therapy

Mechanism of Action

Selective blockade of 5-HT₃ receptors in the GI tract reduces GI motility, secretion, and visceral sensation.

Pharmacokinetics

• Onset: Days to weeks

• Peak concentration: 1 hour

• Half-life: ~1.5 hours

• Metabolism: CYP2C9, CYP3A4, CYP1A2

• Excretion: Hepatic metabolism; excreted in urine

Common Doses

• Initial: 0.5 mg twice daily

• Maintenance: May be increased to 1 mg twice daily after 4 weeks

Adverse Effects

• Constipation (up to 30%)

• Ischemic colitis (boxed warning)

• Abdominal pain

• Nausea

Contraindications

• History of:

  • Constipation-related complications

  • Ischemic colitis

  • Crohn’s disease or ulcerative colitis

  • Diverticulitis

• Not approved for use in men

Monitoring

• Monitor for signs of constipation and ischemic colitis

• Discontinue immediately if bloody diarrhea or abdominal pain develops

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Comparison Table

Generic Name	Primary Use	Formulation	Half-life	QT Prolongation Risk	Unique Feature
Ondansetron	CINV, RINV, PONV	Oral, ODT, IV	3–6 h	Moderate	Widely used; cost-effective
Granisetron	CINV, RINV	Oral, IV, Patch	9 h	Moderate	Transdermal patch for multi-day coverage
Dolasetron	CINV, PONV	Oral only	8 h	High	Prodrug; IV withdrawn in many regions
Palonosetron	CINV (acute/delayed)	IV	~40 h	Low	Longest half-life; best for delayed CINV
Alosetron	IBS-D in women	Oral	1.5 h	Minimal	Only 5-HT₃RA used for chronic GI disorder

Global Regulatory Approvals

All five drugs are approved by major regulatory agencies:

• FDA (U.S. Food and Drug Administration)

• EMA (European Medicines Agency)

• MHRA (UK)

• Health Canada

• TGA (Australia)

• PMDA (Japan)

Alosetron is under restricted distribution programs in some countries due to ischemic colitis risk.

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Clinical Guidelines and Usage

• CINV and RINV: First-line agents, especially in combination with corticosteroids and NK1 receptor antagonists

• PONV: Given as pre-anesthetic prophylaxis

• IBS-D: Only alosetron is indicated, with strict safety regulations