What is the classification of antiemetic drugs?

Classification of Antiemetic Drugs

Antiemetic drugs are primarily classified into seven major categories based on their mechanism of action: serotonin (5-HT3) receptor antagonists, neurokinin-1 (NK1) receptor antagonists, dopamine antagonists, corticosteroids, antihistamines, benzodiazepines, and cannabinoids. This classification provides a framework for defining antiemetic treatment guidelines and helps clinical investigators attain more precise definitions of emetogenic challenges in antiemetic trials 1.

Major Classes of Antiemetic Drugs

1. Serotonin (5-HT3) Receptor Antagonists

• Examples: Ondansetron, granisetron, dolasetron, palonosetron
• Mechanism: Selectively block serotonin receptors in the chemoreceptor trigger zone and GI tract
• Primary Use: Highly effective for acute chemotherapy-induced nausea and vomiting (CINV)
• Notable Feature: Palonosetron has approximately 100-fold higher binding affinity for 5-HT3 receptors and a longer half-life (40 hours) compared to other agents in this class 1

2. Neurokinin-1 (NK1) Receptor Antagonists

• Examples: Aprepitant, fosaprepitant
• Mechanism: Selective high-affinity antagonists of substance P/neurokinin-1 receptors
• Primary Use: Particularly effective for delayed CINV when combined with 5-HT3 antagonists and dexamethasone
• Notable Feature: Crosses the blood-brain barrier and occupies brain NK1 receptors, inhibiting both acute and delayed phases of cisplatin-induced emesis 2

3. Dopamine Antagonists

• Phenothiazines: Promethazine, prochlorperazine
• Non-phenothiazines: Metoclopramide, droperidol
• Mechanism: Block dopamine receptors in the chemoreceptor trigger zone
• Primary Use: Broad-spectrum antiemetics for various causes of nausea and vomiting
• Notable Feature: Risk of extrapyramidal adverse effects, particularly in children 3

4. Corticosteroids

• Examples: Dexamethasone
• Mechanism: Multiple proposed mechanisms including anti-inflammatory effects
• Primary Use: Often used in combination therapy for CINV
• Notable Feature: Enhances efficacy of other antiemetics when used in combination regimens 1

5. Antihistamines

• Examples: Diphenhydramine, meclizine
• Mechanism: Block histamine H1 receptors in the vestibular apparatus and vomiting center
• Primary Use: Motion sickness, vertigo, and as first-line options for nausea in pregnancy
• Notable Feature: Often cause sedation as a side effect 3

6. Benzodiazepines

• Examples: Lorazepam
• Mechanism: Enhance GABA inhibitory effects in the central nervous system
• Primary Use: Anticipatory nausea and vomiting, anxiety-related nausea
• Notable Feature: Often used as adjunctive therapy rather than primary antiemetics 1

7. Cannabinoids

• Examples: Dronabinol, nabilone
• Mechanism: Act on cannabinoid receptors in the brain
• Primary Use: Refractory CINV
• Notable Feature: May cause psychotropic side effects 4

Clinical Application Based on Emetogenic Potential

Antiemetic selection is often guided by the emetogenic potential of chemotherapy agents, which are classified into four levels 1:

1. High emetic risk (>90% frequency of emesis):

   • Recommended regimen: 5-HT3 antagonist + NK1 antagonist + dexamethasone

2. Moderate emetic risk (30-90% frequency):

   • Recommended regimen: 5-HT3 antagonist + dexamethasone ± NK1 antagonist

3. Low emetic risk (10-30% frequency):

   • Recommended regimen: Single agent (usually dexamethasone)

4. Minimal emetic risk (<10% frequency):

   • No routine prophylaxis recommended

Special Considerations

Drug Interactions

• NK1 antagonists like aprepitant inhibit CYP3A4, potentially increasing levels of drugs metabolized by this pathway
• Caution is needed when using aprepitant with chemotherapeutic agents metabolized by CYP3A4 (docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine) 1
• Aprepitant may reduce the efficacy of oral contraceptives and warfarin 1

Specific Patient Populations

• Pregnancy: Metoclopramide and antihistamines are first-line options 3
• Elderly: Use caution due to increased risk of side effects, particularly with dopamine antagonists 2
• Hepatic impairment: No dosage adjustment needed for mild to moderate impairment with aprepitant, but additional monitoring for adverse reactions may be warranted in severe impairment 2

Pitfalls to Avoid

1. QT prolongation: Serotonin antagonists and some dopamine antagonists can prolong the QT interval 3
2. Extrapyramidal symptoms: Common with dopamine antagonists, particularly in children and young adults 3
3. Sedation: Significant with antihistamines and benzodiazepines, which may be undesirable in certain clinical scenarios 5
4. Inadequate prophylaxis for delayed emesis: Often overlooked but requires specific antiemetic coverage, particularly with NK1 antagonists 1
5. Drug interactions: Particularly important with aprepitant and drugs metabolized by CYP3A4 1

Understanding these classifications helps guide appropriate antiemetic selection based on the specific cause of nausea and vomiting, patient factors, and potential drug interactions, ultimately improving patient outcomes and quality of life.