Antiemetics: Mechanisms and Clinical Use

Antiemetics are the drugs used to suppress nausea and vomiting. They act on various receptors and pathways, depending on the cause of the symptoms. A deep understanding of antiemetics is essential in clinical practice, particularly in oncology, gastroenterology, anesthesia, and primary care.

Nausea and vomiting are complex reflexes coordinated by brainstem centers (the vomiting center and the chemoreceptor trigger zone, CTZ) that integrate inputs from the gut, vestibular system, higher centers, and blood-borne agents[1][2]. The CTZ (area postrema) lies outside the blood–brain barrier and contains multiple receptors (dopamine D2, serotonin 5-HT3, histamine H1, acetylcholine M1, neurokinin NK1, and opioid receptors)[2][3]. Afferent signals from the gastrointestinal tract (via vagal 5-HT3 receptors), the vestibular apparatus (via H1/M1 receptors), and cortical or limbic centers (anxiety, fear) converge on the vomiting center, triggering the motor act of emesis[1][2]. Because persistent vomiting can lead to dehydration, electrolyte imbalance, malnutrition and poor quality of life[4], effective antiemetic therapy is essential in many clinical settings.

Mechanisms of Action by Receptor

• Serotonin (5-HT₃): Serotonin release from enterochromaffin cells in the gut (e.g. after chemotherapy or radiation) activates 5-HT₃ receptors on vagal afferents and in the CTZ[5]. 5-HT₃ antagonists (ondansetron, granisetron, palonosetron, etc.) block these receptors, preventing signaling of nausea/vomiting[5]. These drugs are especially effective for acute chemotherapy-induced nausea and vomiting (CINV) and for PONV.
• Dopamine (D₂): Dopamine receptors in the CTZ mediate chemoreceptor-induced emesis[2]. D₂ antagonists (phenothiazines like prochlorperazine, butyrophenones like droperidol/haloperidol, metoclopramide) block D₂ in the CTZ and also enhance gut motility (metoclopramide has mixed D₂ antagonism and 5-HT₃/4 modulation)[6]. These agents are useful for many causes of nausea (CINV, PONV, gastroenteritis, migraine). (Metoclopramide’s mechanism: antagonizes D₂ and 5-HT₃ receptors in the CTZ and agonizes 5-HT₄ to increase gastric emptying[6].)
• Histamine (H₁): The vestibular system (motion sickness) and nucleus tractus solitarius have abundant H₁ receptors[7]. H₁ antihistamines (diphenhydramine, dimenhydrinate, meclizine) block central vestibular H₁ receptors, preventing motion-induced vomiting[7]. Some (like promethazine) also have anticholinergic and D₂-blocking effects.
• Muscarinic (M₁): Vestibular inputs and central pathways use acetylcholine. Antimuscarinics (scopolamine) block M₁ receptors in the vestibular nuclei and brainstem, reducing motion sickness and postoperative nausea[3][7]. (The CTZ also has cholinergic receptors[3].)
• Neurokinin-1 (NK₁): Substance P is the natural ligand for NK₁ receptors in the brainstem (area postrema and nucleus tractus solitarius) and gut. NK₁ antagonists (aprepitant, fosaprepitant, rolapitant, netupitant) competitively inhibit NK₁ receptors, blocking substance P–mediated emetic signals[8]. This class is particularly important for preventing delayed CINV and enhancing efficacy of 5-HT₃ regimens[8].
• Corticosteroids: Dexamethasone has an unclear antiemetic mechanism but likely reduces inflammation and prostaglandin-mediated signals. It synergizes with other antiemetics and is FDA-approved for CINV and PONV prophylaxis[9].
• Cannabinoids: THC analogs (dronabinol, nabilone) act on CB₁ receptors (and indirectly on 5-HT₃ receptors) in the dorsal vagal complex[10]. Activation of CB₁ reduces neuronal excitability and serotonin release, which suppresses nausea/vomiting[10]. These are used for refractory CINV.
• Benzodiazepines: Lorazepam, midazolam, etc., are not primary antiemetics but provide anxiolysis and sedation (via GABA_A) that can relieve anticipatory nausea and reduce perioperative nausea[11]. (Midazolam given at induction lowers PONV rates comparable to ondansetron[11].)

Major Antiemetic Drug Classes

5-HT₃ Receptor Antagonists

Examples: Ondansetron, granisetron, dolasetron, palonosetron.
Mechanism: Block serotonin 5-HT₃ receptors on vagal afferents and in the CTZ[5].
Indications: First-line for acute CINV and radiation-induced emesis; also used for PONV, hyperemesis gravidarum, gastroparesis, and viral gastroenteritis. (Palonosetron, a second-generation agent, has prolonged action useful for delayed CINV.)[5]
Side Effects/Precautions: Headache, constipation, QT prolongation (especially ondansetron, droperidol can also prolong QT). Palonosetron has fewer cardiac effects. Avoid combining multiple QT-prolonging drugs. Use caution in patients with congenital long QT or electrolyte abnormalities.

Dopamine (D₂) Antagonists

Examples: Prochlorperazine, promethazine, metoclopramide, chlorpromazine, haloperidol, droperidol.
Mechanism: Block D₂ receptors in the CTZ (and some also block 5-HT₃ or muscarinic receptors). Metoclopramide also agonizes 5-HT₄ to promote gut motility[6].
Indications: Versatile: used for CINV (especially low/moderate emetogenic), PONV (droperidol, metoclopramide), migraine, gastroenteritis, gastroparesis (metoclopramide). Also effective for opiate-induced nausea and dystonic reactions (antidopaminergic).
Side Effects/Precautions: Extrapyramidal symptoms (dystonia, akathisia; risk high with prochlorperazine, droperidol) and tardive dyskinesia (black-box warning for metoclopramide with long use[12]). Sedation, orthostatic hypotension. Haloperidol and droperidol can prolong QT, so monitor ECG. Avoid in Parkinson’s disease (worsens motor symptoms).

Histamine-1 (H₁) Antagonists

Examples: Diphenhydramine, dimenhydrinate, meclizine, promethazine, doxylamine.
Mechanism: Block central H₁ receptors in vestibular and emetic centers, reducing motion-induced emesis[7]. Promethazine also blocks D₂ and M₁.
Indications: First-line for motion sickness and vertigo; adjunct for PONV. Doxylamine (often with vitamin B₆) is first-line for pregnancy nausea[13]. Also used for allergic nausea and vestibular migraine.
Side Effects/Precautions: Sedation and anticholinergic effects (dry mouth, blurred vision, urinary retention). Paradoxical excitation in children. Use caution in glaucoma and BPH.

Muscarinic (M₁) Antagonists

Example: Scopolamine (transdermal or oral).
Mechanism: Blocks central muscarinic (M₁) receptors in vestibular nuclei and brainstem, interrupting motion- and anesthesia-related emetic signaling.
Indications: Motion sickness prophylaxis (patch behind ear is standard), PONV prevention (especially in high-risk patients).
Side Effects/Precautions: Marked anticholinergic side effects: dry mouth, sedation, blurred vision, tachycardia, urinary retention. Should not be used in angle-closure glaucoma. Advise patients not to drive if drowsy.

Neurokinin-1 (NK₁) Antagonists

Examples: Aprepitant (PO/IV), fosaprepitant (IV), netupitant (with palonosetron as NEPA), rolapitant.
Mechanism: Selectively block NK₁ receptors for substance P in the area postrema and NTS[8], preventing both central and peripheral emetic signaling.
Indications: Added to 5-HT₃ antagonists and dexamethasone for highly emetogenic chemotherapy (HEC) to prevent delayed CINV[8]. Also approved for PONV prophylaxis. (Use with palonosetron or ondansetron + steroid improves control of CINV.)[8]
Side Effects/Precautions: Generally well-tolerated. Can cause fatigue, hiccups, constipation. Significant CYP3A4 interactions: aprepitant induces/inhibits various enzymes, requiring dose adjustments of dexamethasone and other drugs. Monitor for interactions.

Corticosteroids

Example: Dexamethasone.
Mechanism: Exact antiemetic mechanism unknown (likely prostaglandin inhibition/anti-inflammatory effects). Enhances efficacy of 5-HT₃ and NK₁ antagonists.
Indications: Part of standard antiemetic regimens for CINV and PONV. Widely used in cancer chemotherapy protocols and perioperative settings[9]. Also used in intracranial hypertension and malignant bowel obstruction vomiting[14].
Side Effects/Precautions: Hyperglycemia, insomnia, mood changes, immunosuppression. Use lowest effective dose for shortest time. Avoid long-term use unless necessary.

Cannabinoids (CB₁ Agonists)

Examples: Dronabinol, nabilone (synthetic THC).
Mechanism: Activate central CB₁ receptors and modulate 5-HT₃ signaling in the dorsal vagal complex[10], leading to antiemetic and appetite-stimulating effects.
Indications: Second-line for refractory CINV (after standard therapy), appetite stimulant in AIDS-related cachexia. ASCO endorses use if first-line prophylaxis fails[15].
Side Effects/Precautions: CNS effects (euphoria, dysphoria, sedation, dizziness, paranoia[16]), tachycardia, orthostatic hypotension. Potential for abuse. Contraindicated in pregnancy. Monitor mental status.

Benzodiazepines

Examples: Lorazepam, midazolam, alprazolam.
Mechanism: Enhance GABA_A receptor–mediated inhibition in the CNS; reduce anxiety and cortical inputs to vomiting center.
Indications: Adjunctive therapy for CINV (anticipatory nausea), PONV prophylaxis in anxious patients, and short-term relief of nausea. Midazolam given at anesthesia induction reduces PONV nearly as effectively as ondansetron[11]. Benzos are not used as monotherapy for emesis due to sedative drawbacks.
Side Effects/Precautions: Sedation, amnesia, respiratory depression (especially with opioids), dependence with long-term use. Use lowest effective dose and avoid in patients with respiratory insufficiency.

Clinical Applications of Antiemetics

• Chemotherapy-Induced Nausea and Vomiting (CINV): Prophylaxis is stratified by emetogenic risk. Highly emetogenic chemo regimens (e.g. cisplatin) require multi-drug prophylaxis: a 5-HT₃ antagonist + NK₁ antagonist + dexamethasone (often with olanzapine)[8]. Moderately emetogenic regimens typically use 5-HT₃ antagonist + dexamethasone (± NK₁ antagonist). Minimal emetogenic chemo may use dexamethasone or 5-HT₃ antagonist alone. Breakthrough or delayed CINV can be treated with additional agents (e.g. add olanzapine or prochlorperazine) or PRN antiemetics (metoclopramide, prochlorperazine, lorazepam)[17][8].
• Postoperative Nausea and Vomiting (PONV): Identify risk factors (female, non-smoker, history of PONV/motion sickness, use of volatile anesthetics or opioids). Prophylaxis is multimodal: commonly dexamethasone at induction plus a 5-HT₃ antagonist (ondansetron) and/or other agent (scopolamine patch, droperidol, or NK₁ antagonist)[18][11]. Ondansetron + dexamethasone is a well-studied combo[18]. Lorazepam or midazolam may be given for anxiety (midazolam at induction reduces PONV[11]). Rescue treatment can include antiemetics from other classes than those used prophylactically.
• Motion Sickness: Best prevented by H₁ and M₁ blockade. First-line agents are scopolamine (transdermal patch) and antihistamines (meclizine, dimenhydrinate). These should be started 1–2 hours before travel. D2 antagonists and 5-HT₃ antagonists are generally not effective for motion-induced nausea.
• Pregnancy (Morning Sickness): Initial therapy is lifestyle/dietary measures. First-line medication is doxylamine plus pyridoxine (vitamin B₆)[13]. Other options include metoclopramide or ondansetron (though caution with ondansetron in pregnancy) and antihistamines (diphenhydramine, dimenhydrinate) if needed. Steroids are avoided unless hyperemesis gravidarum. Importantly, avoid teratogens.
• GI-related Nausea (Gastritis, Gastroparesis, Bowel Obstruction): Prokinetic antiemetics like metoclopramide are useful for gastroparesis. Anticholinergics (hyoscyamine) and anti-secretory agents can help in bowel obstruction. Ondansetron or other 5-HT₃ antagonists can treat severe gastritis or chemotherapy-like symptoms from GI causes. Phenothiazines (prochlorperazine/promethazine) are often used for symptomatic relief in gastroenteritis.

Adverse Effects & Precautions by Class

• 5-HT₃ Antagonists: Headache, constipation. Risk of QT prolongation (especially ondansetron/dolasetron) and serotonin syndrome if combined with SSRIs.
• D₂ Antagonists: Extrapyramidal reactions (acute dystonia, akathisia, Parkinsonism), tardive dyskinesia (especially with metoclopramide[12]), sedation, hypotension. Check for contraindications (e.g. Parkinson’s, seizure risk).
• H₁ Antihistamines: Sedation, dry mouth, blurred vision, urinary retention. Caution in elderly (confusion) and conditions exacerbated by anticholinergics.
• M₁ Antagonists (Scopolamine): Dry mouth, blurred vision, drowsiness, dizziness, confusion. Use with caution in elderly or closed-angle glaucoma.
• NK₁ Antagonists: Fatigue, hiccups, constipation. Many drug interactions (e.g. aprepitant induces CYP3A4 and 2C9; adjust steroid dosing)[8]. Monitor liver enzymes.
• Corticosteroids: Hyperglycemia, insomnia, mood changes, increased infection risk. Taper if used longer than a few days.
• Cannabinoids: Dizziness, sedation, euphoria/paranoia, tachycardia, orthostatic hypotension[16]. Avoid in psychiatric illness or pregnancy.
• Benzodiazepines: Sedation, respiratory depression (especially with opioids), dependence/tolerance. Use short-term; avoid use in sleep apnea or acute intoxication.