Anti emetic drugs pharmacology according to kdt
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I now have comprehensive content to write a detailed, KDT-style answer on antiemetic drug pharmacology. Let me compile it all.
Antiemetic Drugs - Pharmacology (KDT Style)
Note: KDT (Tripathi's Essentials of Medical Pharmacology) is not in the textbook library, but the content below is drawn from Katzung's Basic & Clinical Pharmacology (16th ed.) and Lippincott Illustrated Reviews: Pharmacology, which follow the same pharmacological framework as KDT.
Physiology of Vomiting - The Basis of Drug Action
Understanding antiemetics requires knowing the vomiting reflex pathways:
The vomiting center (VC) in the medulla receives input from four major sources:
-
Chemoreceptor Trigger Zone (CTZ) - located at the caudal end of the 4th ventricle (area postrema), outside the blood-brain barrier. It is accessible to emetogenic stimuli in blood/CSF. Rich in D2, opioid, 5-HT3, and NK1 receptors.
-
Vestibular system - via CN VIII; important in motion sickness. Rich in muscarinic M2 and H1 receptors.
-
Vagal/spinal GI afferents - rich in 5-HT3 receptors. GI mucosal irritation (chemotherapy, radiation, acute gastroenteritis) releases serotonin from enterochromaffin cells → activates 5-HT3 receptors → stimulates vagal afferents to VC and CTZ.
-
Higher CNS centers - involved in anticipatory vomiting, psychiatric disorders, stress.
Classification of Antiemetic Drugs
| Class | Drugs | Receptor Targeted |
|---|---|---|
| 5-HT3 antagonists | Ondansetron, Granisetron, Dolasetron, Palonosetron | 5-HT3 (central + peripheral) |
| NK1 antagonists | Aprepitant, Fosaprepitant, Rolapitant, Netupitant | NK1 (Substance P receptor) |
| Dopamine D2 antagonists | Metoclopramide, Domperidone, Prochlorperazine, Droperidol | D2 in CTZ |
| Phenothiazines | Prochlorperazine, Promethazine, Thiethylperazine | D2 + muscarinic + H1 |
| H1 antihistamines | Dimenhydrinate, Meclizine, Cyclizine, Diphenhydramine, Promethazine | H1 |
| Anticholinergics | Scopolamine | Muscarinic M1 |
| Corticosteroids | Dexamethasone, Methylprednisolone | Unknown |
| Cannabinoids | Dronabinol (THC), Nabilone | CB1 |
| Benzodiazepines | Lorazepam | GABAergic (for anticipatory vomiting) |
1. Serotonin 5-HT3 Receptor Antagonists ("Setrons")
Drugs: Ondansetron, Granisetron, Dolasetron, Palonosetron (tropisetron, ramosetron outside USA)
Mechanism
Block 5-HT3 receptors both centrally (in the VC and CTZ) and peripherally (on vagal afferent nerve terminals in the gut). Their antiemetic action is mainly through peripheral 5-HT3 blockade, reducing the GI serotonin signal that triggers the vomiting reflex. - Katzung's Basic and Clinical Pharmacology, 16th Ed.
Pharmacokinetics
- First-generation (ondansetron, granisetron, dolasetron): serum half-life 4-9 hours
- Second-generation (palonosetron): greater receptor affinity, half-life ~40 hours - more effective for delayed CINV
- All undergo extensive hepatic metabolism; dose reduction may be needed with ondansetron in hepatic insufficiency
- Available IV and oral; granisetron also available as transdermal patch
Clinical Uses
- First-line for chemotherapy-induced nausea and vomiting (CINV) - both prophylaxis and treatment
- Postoperative nausea and vomiting (PONV)
- Radiation-induced nausea (whole-body or abdominal radiation)
- Efficacy is enhanced by combining with dexamethasone + NK1 antagonist (triple therapy for CINV)
Doses (IV, 30 min before chemotherapy)
- Ondansetron: 8 mg IV or oral
- Granisetron: 1 mg IV, 2 mg oral
- Dolasetron: 100 mg
- Palonosetron: 0.25 mg IV, 0.5 mg oral
Adverse Effects
- Headache, dizziness, constipation (most common)
- QT prolongation - especially dolasetron; avoid in patients with long QT or on other QT-prolonging drugs. Palonosetron does NOT prolong QT.
- Serotonin syndrome risk when combined with SSRIs/SNRIs
2. NK1 (Neurokinin-1) Receptor Antagonists
Drugs: Aprepitant (oral), Fosaprepitant (IV prodrug), Rolapitant, Netupitant (in combo as AKYNZEO)
Mechanism
Block NK1 receptors (Substance P receptors) centrally in the CNS, specifically in the VC. Substance P is a key mediator of the delayed vomiting response. No effect on 5-HT, dopamine, or steroid receptors.
Clinical Uses
- Effective for both early AND delayed emesis in cancer chemotherapy - especially useful for delayed CINV (24-120 hours)
- Always used as add-on to a 5-HT3 antagonist + dexamethasone (triple antiemetic regimen)
Pharmacokinetics
- Aprepitant is given orally (125 mg day 1, 80 mg days 2-3)
- Fosaprepitant is an IV prodrug converted to aprepitant
- Metabolized by CYP3A4 - significant drug interactions
Adverse Effects & Drug Interactions
- Generally well tolerated: fatigue, dizziness, diarrhea
- CYP3A4 inhibitor/substrate: may increase levels of docetaxel, paclitaxel, etoposide, imatinib, vincristine, dexamethasone
- Reduces INR in patients on warfarin
- Drugs that inhibit CYP3A4 (ketoconazole, clarithromycin, ritonavir) significantly increase aprepitant levels
- Katzung's Basic and Clinical Pharmacology, 16th Ed.
3. Dopamine D2 Receptor Antagonists
A. Metoclopramide & Domperidone (Substituted Benzamides / Prokinetics)
Mechanism:
- Block D2 receptors in the CTZ (area postrema) → antiemetic
- Block peripheral D2 receptors in the GI tract → prokinetic (accelerates gastric emptying, increases LES tone)
- Metoclopramide also has mild 5-HT4 agonist activity (prokinetic) and at high doses blocks 5-HT3 receptors
Key Difference - Domperidone vs. Metoclopramide:
| Feature | Metoclopramide | Domperidone |
|---|---|---|
| BBB penetration | Yes | Minimal |
| CNS/extrapyramidal side effects | Common (5-25%) | Rare |
| Tardive dyskinesia risk | Yes (with long-term use) | Very rare |
| Galactorrhea/prolactin elevation | Yes | Yes (via pituitary, outside BBB) |
| Cardiac QT prolongation | No | Yes (avoid in cardiac disease) |
Clinical Uses:
- CINV, PONV
- Gastroparesis (diabetic, postsurgical)
- GERD
- Metoclopramide: facilitating nasoenteric tube placement
Doses: Metoclopramide 10-20 mg oral/IV every 6 hours
Adverse Effects of Metoclopramide:
- Extrapyramidal effects (dystonias, akathisia, parkinsonism) - acute in 25% at high doses, 5% long-term
- Tardive dyskinesia (irreversible) - avoid long-term use especially in elderly
- Restlessness, drowsiness, anxiety, insomnia (10-20%)
- Galactorrhea, gynecomastia, impotence, menstrual disorders (hyperprolactinemia)
- Black box warning for tardive dyskinesia
B. Phenothiazines
Drugs: Prochlorperazine, Promethazine, Thiethylperazine
Mechanism: Block D2 and muscarinic receptors (antiemetic action); also block H1 receptors (sedation). Act on the CTZ and VC.
Clinical Uses:
- Moderate efficacy for CINV, PONV, opioid-induced vomiting
- Prochlorperazine widely used in emergency settings
Adverse Effects: Sedation, extrapyramidal effects, anticholinergic effects, hypotension, QT prolongation
C. Butyrophenones
Drugs: Droperidol, Haloperidol
Mechanism: Central D2 blockade → potent antiemetic
Clinical Uses: PONV (droperidol); droperidol used IM/IV but causes extreme sedation
Adverse Effects:
- Extrapyramidal effects, hypotension
- QT prolongation → risk of torsades de pointes (fatal) - use only when other agents fail; screen for QT prolongation before use
4. H1 Antihistamines
Drugs: Dimenhydrinate, Meclizine, Cyclizine, Diphenhydramine, Promethazine
Mechanism: Block H1 receptors in the vestibular nuclei and VC
Clinical Uses:
- Most effective for motion sickness
- Effective for morning sickness (pregnancy-associated vomiting) - promethazine used
- Ineffective against CTZ-mediated emesis (chemo, drugs, toxins)
Adverse Effects: Sedation, anticholinergic effects (dry mouth, urinary retention, blurred vision, constipation)
5. Anticholinergic (Muscarinic Antagonists)
Drug: Scopolamine (hyoscine)
Mechanism: Block muscarinic M1 receptors in the vestibular apparatus and CNS
Clinical Uses:
- Best drug for motion sickness - transdermal patch applied behind ear
- Effective for postoperative nausea
- NOT effective for CINV or CTZ-mediated vomiting
Adverse Effects: Dry mouth, blurred vision, urinary retention, sedation, confusion (especially elderly)
6. Corticosteroids
Drugs: Dexamethasone, Methylprednisolone
Mechanism: Unknown - but they have clear antiemetic activity, especially potentiating the effect of 5-HT3 antagonists
Clinical Uses:
- Used as adjuncts in CINV regimens
- Standard regimen: dexamethasone 8-20 mg IV before chemotherapy, then 8 mg/day orally for 2-4 days
- Enhance efficacy of 5-HT3 antagonists for both acute and delayed CINV
7. Cannabinoids
Drugs: Dronabinol (delta-9-THC), Nabilone
Mechanism: Activate CB1 (cannabinoid) receptors in the CNS - suppress the vomiting center
Clinical Uses:
- Reserved for CINV refractory to other antiemetics
- FDA-approved for cancer chemotherapy-induced nausea
Adverse Effects:
- CNS effects (euphoria, dysphoria, sedation, "high"), dizziness
- Tachycardia, hypotension
- Potential for abuse; psychosis in susceptible individuals
- Not used first-line due to CNS side effects
Standard Antiemetic Regimens (KDT-style summary)
| Clinical Situation | Preferred Drugs |
|---|---|
| Highly emetogenic chemotherapy | 5-HT3 antagonist + NK1 antagonist + Dexamethasone (triple therapy) |
| Moderately emetogenic chemotherapy | 5-HT3 antagonist + Dexamethasone ± NK1 antagonist |
| Delayed CINV (>24 hrs) | Aprepitant + Dexamethasone |
| Motion sickness | Scopolamine (best) / H1 antihistamines |
| Postoperative vomiting | Ondansetron, Droperidol, Dexamethasone |
| Pregnancy (morning sickness) | Promethazine, Meclizine, Metoclopramide |
| Gastroparesis / GI motility disorder | Metoclopramide, Domperidone |
| Opioid-induced nausea | Metoclopramide, Prochlorperazine, Ondansetron |
| Refractory CINV | Dronabinol / Cannabinoids |
| Anticipatory vomiting | Lorazepam (benzodiazepine) |
Quick Comparison Table
| Drug | Receptor | Motion Sickness | CINV | PONV | ADRs |
|---|---|---|---|---|---|
| Ondansetron | 5-HT3 | No | +++ | +++ | Headache, QT ↑, constipation |
| Palonosetron | 5-HT3 (high affinity) | No | +++ (acute+delayed) | ++ | Headache, constipation; no QT |
| Aprepitant | NK1 | No | +++ (esp. delayed) | + | CYP3A4 interactions |
| Metoclopramide | D2 + 5-HT4 | No | ++ | ++ | Tardive dyskinesia, EPS |
| Domperidone | D2 (peripheral) | No | ++ | + | Cardiac QT ↑ |
| Prochlorperazine | D2, M, H1 | + | + | ++ | Sedation, EPS |
| Droperidol | D2 | No | + | ++ | QT ↑, sedation, EPS |
| Scopolamine | Muscarinic M1 | +++ | No | ++ | Anticholinergic |
| Dimenhydrinate | H1 | ++ | + | + | Sedation |
| Dexamethasone | Unknown | No | ++ (adjunct) | + | Hyperglycemia |
| Dronabinol | CB1 | No | + (refractory) | No | CNS "high", dysphoria |
Key KDT Points to Remember:
- The CTZ (outside BBB) responds to drugs/toxins in blood → targeted by D2 antagonists and 5-HT3 antagonists
- Vestibular emesis (motion sickness) → best treated with scopolamine or H1 antihistamines
- CINV → setrons are first-line; triple therapy with NK1 + steroid for highly emetogenic agents
- Metoclopramide crosses BBB → EPS and tardive dyskinesia risk; domperidone does NOT → safer CNS profile
- Palonosetron (2nd gen setron) is superior for delayed CINV due to its 40-hour half-life
- NK1 antagonists (aprepitant) uniquely cover delayed emesis (>24 hours) which setrons alone miss
Sources: Katzung's Basic and Clinical Pharmacology, 16th Ed.; Lippincott Illustrated Reviews: Pharmacology
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