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ANTI-EMETIC DRUGS

ANTI-EMETIC DRUGS

Introduction:

Physiology of vomiting (emesis):

Step 1:

Due to vomiting center (VC) stimulation in lateral medullary reticular formation.

Step 2:

Input received from GI mucosa, chemoreceptor trigger zone (CTZ) & vestibular apparatus.

Step 3:

GI mucosa irritation (by drugs/irritants) –> Releases serotonin –> Stimulating VC via 5HT₃ receptors.
CTZ – Rich in dopamine (D₂), serotonin (5HT₃) & neurokinin (NK₁) receptor.

Step 4:

Motion sickness – Due to stimulation of vestibular apparatus & cerebellum.

Step 5:

Results in VC stimulation by activating M₁ & H₁ receptors.
H₁ receptor stimulation & histamine – Permissive role in all vomiting types.

I) Drugs for motion sickness:

Hyoscin:
- For prophylaxis of motion sickness.
- As i.m. injection or transdermal patch (applied behind pinna).
- No role in treatment.
Antihistaminics:
- Drugs: Promethazine, diphenhydramine, cinnarizine, cyclizine & meclizine.
- Used for prophylaxis.
Cinnarizine:
- Antihistaminic with anticholinergic & antiserotonergic properties.
- For vertigo treatment.

II) Drugs for morning sickness:

Combination of antihistaminic with Vit B:
- Doxylamine (antihistaminic) + pyridoxine (Vit B) in high dose.
- Safest anti-emetic drug in pregnancy
D₂ blockers:
- Effective.
- Not used due to teratogenic potential

III) Drugs for chemotherapy & radiation therapy-induced vomiting:

5 HT₃ blockers:
- Drugs: Ondansetron, granisetron, dolasetron, palonosetron & ramosetron.
- DOC for this condition.
Palonosetron:
- Most potent 5 HT₃ blocker.
- Has longest t_1/2.
- Effective in delayed emesis.
Dolasetron:
- Prolongs QT interval.
Ondansetron:
- Shortest t_1/2
- Increased efficacy in combination with antihistaminics, D₂blockers or dexamethasone.
- Effective in pregnancy hyperemesis & postoperative nausea.
D₂blockers:

Drugs: Metoclopramide & domperidone.

NK₁ receptor antagonists:

Drugs: Aprepitant, Fosaprepitant & Netupitant.

Aprepitant:
- Highly selective NK₁receptor antagonist.
- Orally active.
- Enters brain.
- Metabolized by CYP3A4 enzymes – Hence, inhibit drugs metabolized by this enzyme (warfarin).
Fosaprepitant:

Intravenous prodrug of aprepitant.

Netupitant:
- Newer NK₁ antagonist.
- Indicated for chemotherapy-induced vomiting (both acute & delayed)
- Used in combination with palonosetron.

V) Drugs for postoperative vomiting:

5 HT₃ antagonists – Preferred over other drugs.

VI) Other drugs for vomiting:

Steroids:
- Dexamethasone – In chemotherapy-induced vomiting.
Benzodiazepines:
- Lorazepam & alprazolam – As anticipatory component of nausea & vomiting before surgery.
Cannabinoid:
- Dronabinol
MOA:
- Anti-emetic properties due to CB receptor stimulation.
- Also by appetite stimulation.
- Used for AIDS with anorexia.
Adverse effects:

Central sympathomimetic effects (tachycardia, palpitations)
Paranoid reaction.
Thinking abnormalities.

Propofol:
- Anesthetic agent with anti-emetic property.

Exam Important

GI mucosa irritation (by drugs/irritants) in turn releasing serotonin by stimulating VC via 5HT₃ receptors.
Motion sickness is caused due to stimulation of vestibular apparatus & cerebellum.
H₁ receptor stimulation & histamine plays a permissive role in all vomiting types.
Stimulation of vestibular apparatus & cerebellum results in VC stimulation by activating M₁ & H₁ receptors.
Hyoscin is used for prophylaxis of motion sickness.
Hyoscin is used as i.m. injection or transdermal patch (applied behind pinna).
Antihistaminics used for motion sickness prophylaxis are promethazine, diphenhydramine, cinnarizine, cyclizine & meclizine.
Cinnarizine is an antihistaminic with anticholinergic & antiserotonergic properties useful for vertigo treatment.
Combination of doxylamine (antihistaminic) + pyridoxine (Vit B) in high dose is the safest anti-emetic drug in pregnancy.
Ondansetron, granisetron, dolasetron, palonosetron & ramosetron are all 5 HT₃ blockers which are DOC for chemotherapy & radiation therapy-induced vomiting.
Most potent 5 HT₃ blocker is Palonosetron, with longest t_1/2,effective in delayed emesis.
Dolasetron prolongs QT interval.
Ondansetron has shortest t_1/2is effective in pregnancy hyperemesis & postoperative nausea, when used in combination with antihistaminics, D₂blockers or dexamethasone.
Aprepitant, Fosaprepitant & Netupitant are all NK₁ receptor antagonists.
Aprepitant is a highly selective NK₁receptor antagonist, used as antiemetic drug.
Fosaprepitant is an intravenous prodrug of aprepitant.
Netupitant is a newer NK₁ antagonist indicated for chemotherapy-induced vomiting (both acute & delayed), in combination with palonosetron.
Dexamethasone is used in chemotherapy-induced vomiting.
Dronabinol is a Cannabinoid with anti-emetic properties due to CB receptor stimulation, used for AIDS with anorexia.
Dronabinol can cause central sympathomimetic effects (tachycardia, palpitations) & paranoid reaction.
Propofol, an anesthetic agent with anti-emetic property.

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ANTI-EMETIC DRUGS