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Tuesday, August 19, 2025

Antiemetic / antivertigo agents


Introduction

Nausea, vomiting, and vertigo are complex symptoms mediated by multiple neurotransmitters and pathways involving the chemoreceptor trigger zone (CTZ), vestibular system, gastrointestinal tract, and higher cortical centers.

Antiemetic and antivertigo agents act on specific receptor targets such as dopamine (D2), serotonin (5-HT3), histamine (H1), muscarinic (M1), neurokinin (NK1), and cannabinoid (CB1) receptors. Their clinical applications include the prevention and treatment of motion sickness, vertigo, chemotherapy-induced nausea and vomiting (CINV), postoperative nausea and vomiting (PONV), pregnancy-related nausea, and vestibular disorders.

Classification of Antiemetic and Antivertigo Agents

1. Serotonin (5-HT3) Receptor Antagonists

  • Mechanism: Block 5-HT3 receptors in the CTZ and GI tract, preventing serotonin-mediated emesis.

  • Generic Names: ondansetron, granisetron, dolasetron, palonosetron.

  • Uses:

    • CINV (acute phase)

    • PONV

    • Radiation-induced nausea

  • Adverse Effects: Headache, constipation, QT prolongation (except palonosetron, which has minimal effect).

  • Contraindications: Congenital long QT syndrome, caution with other QT-prolonging drugs.

2. Dopamine (D2) Receptor Antagonists

  • Mechanism: Block D2 receptors in CTZ.

  • Generic Names:

    • Phenothiazines: prochlorperazine, chlorpromazine.

    • Butyrophenones: droperidol, haloperidol.

    • Benzamides: metoclopramide, domperidone (not widely available in all countries).

  • Uses:

    • CINV and PONV

    • Gastrointestinal motility disorders (metoclopramide as prokinetic)

    • Vertigo (prochlorperazine)

  • Adverse Effects: Extrapyramidal symptoms (dystonia, akathisia, Parkinsonism), sedation, hypotension, QT prolongation.

  • Contraindications: Parkinson’s disease, seizure disorders, prolonged QT.

3. Antihistamines (H1 Receptor Antagonists)

  • Mechanism: Block H1 receptors in the vestibular system and vomiting center.

  • Generic Names: diphenhydramine, dimenhydrinate, meclizine, cyclizine, promethazine.

  • Uses:

    • Motion sickness

    • Vertigo (Ménière’s disease, vestibular neuritis)

    • Mild PONV

  • Adverse Effects: Sedation, anticholinergic effects (dry mouth, urinary retention, blurred vision).

  • Contraindications: Narrow-angle glaucoma, severe asthma, urinary retention, elderly (fall risk).

4. Anticholinergics (Muscarinic Receptor Antagonists)

  • Mechanism: Block M1 receptors in vestibular pathways and vomiting center.

  • Generic Names: scopolamine (hyoscine).

  • Uses:

    • Motion sickness (most effective prophylactic agent)

    • PONV (patch form)

  • Adverse Effects: Dry mouth, blurred vision, drowsiness, confusion, urinary retention.

  • Contraindications: Glaucoma, prostatic hypertrophy, elderly patients (cognitive impairment risk).

5. Neurokinin-1 (NK1) Receptor Antagonists

  • Mechanism: Block NK1 receptors in the brainstem, preventing substance P–mediated emesis.

  • Generic Names: aprepitant, fosaprepitant, netupitant, rolapitant.

  • Uses:

    • CINV (especially delayed phase, used with 5-HT3 antagonists + corticosteroids)

  • Adverse Effects: Fatigue, hiccups, constipation, drug interactions via CYP3A4.

  • Contraindications: Concomitant use with certain CYP3A4 substrates (e.g., pimozide).

6. Corticosteroids

  • Mechanism: Exact mechanism unknown; thought to enhance efficacy of 5-HT3 antagonists and reduce inflammation.

  • Generic Names: dexamethasone, methylprednisolone.

  • Uses:

    • CINV (in combination regimens)

    • PONV prophylaxis

  • Adverse Effects: Hyperglycemia, insomnia, mood changes, immunosuppression (with prolonged use).

7. Benzodiazepines

  • Mechanism: Enhance GABA-A receptor activity → anxiolysis, sedation, and indirect antiemetic effect via reduced anticipatory nausea.

  • Generic Names: lorazepam, diazepam, alprazolam.

  • Uses:

    • Anticipatory nausea in chemotherapy

    • Adjunct for vertigo (vestibular suppression)

  • Adverse Effects: Sedation, dependence, cognitive impairment.

  • Contraindications: Respiratory depression, severe hepatic impairment.

8. Cannabinoids

  • Mechanism: Activate CB1 receptors in the brain, inhibiting emetic pathways.

  • Generic Names: dronabinol, nabilone.

  • Uses:

    • Refractory CINV

    • Appetite stimulation in AIDS/cancer cachexia

  • Adverse Effects: Euphoria, hallucinations, dysphoria, tachycardia, hypotension.

  • Contraindications: Psychiatric disorders, cardiovascular disease.

9. Other Antivertigo Agents

  • Betahistine: Histamine H1 agonist and H3 antagonist → increases inner ear blood flow, improves vestibular compensation. Used in Ménière’s disease.

  • Cinnarizine: Antihistamine with calcium channel-blocking properties; used in vertigo and motion sickness.

Therapeutic Uses

  • Chemotherapy-Induced Nausea and Vomiting (CINV):

    • Combination therapy: 5-HT3 antagonist + dexamethasone + NK1 antagonist ± olanzapine.

  • Postoperative Nausea and Vomiting (PONV):

    • Ondansetron, dexamethasone, scopolamine patch, promethazine.

  • Radiation-Induced Nausea:

    • 5-HT3 antagonists ± corticosteroids.

  • Motion Sickness:

    • Scopolamine, meclizine, dimenhydrinate.

  • Vertigo (vestibular disorders):

    • Meclizine, betahistine, cinnarizine, benzodiazepines (acute severe vertigo).

  • Pregnancy-Related Nausea (Hyperemesis Gravidarum):

    • Pyridoxine (vitamin B6), doxylamine, metoclopramide, ondansetron (caution, later line).

Contraindications (Class-Specific)

  • 5-HT3 antagonists: QT prolongation, hypersensitivity.

  • D2 antagonists: Parkinson’s disease, seizure disorders.

  • H1 blockers & anticholinergics: Glaucoma, urinary retention, elderly cognitive decline.

  • Cannabinoids: Severe psychiatric illness, unstable cardiac disease.

  • Corticosteroids: Systemic fungal infections, uncontrolled diabetes (relative contraindication).

Adverse Effects Summary

  • 5-HT3 antagonists: Constipation, headache, QT prolongation.

  • D2 antagonists: Extrapyramidal effects, hyperprolactinemia, sedation.

  • H1 blockers: Sedation, anticholinergic effects.

  • Anticholinergics: Confusion, dry mouth, blurred vision, urinary retention.

  • NK1 antagonists: Fatigue, drug interactions.

  • Corticosteroids: Hyperglycemia, mood changes.

  • Benzodiazepines: Dependence, sedation.

  • Cannabinoids: Psychotropic effects, dizziness, hypotension.

  • Betahistine: Headache, GI upset.

Clinical Considerations

  • Combination therapy is often required in chemotherapy and postoperative settings.

  • Choice of agent depends on etiology (motion sickness vs. CINV vs. vestibular disorder).

  • Elderly patients are highly sensitive to anticholinergic and sedative side effects; safer alternatives should be chosen.

  • Pregnancy: Pyridoxine/doxylamine preferred; ondansetron and metoclopramide considered if refractory.

  • Vertigo: Vestibular suppressants (H1 blockers, benzodiazepines) should be limited to acute episodes; long-term use may impair compensation.




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