Anti-Emetic Drugs

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 t1/2.
    • Effective in delayed emesis.
  • Dolasetron:
    • Prolongs QT interval.
  • Ondansetron:
    • Shortest t1/2
    • Increased efficacy in combination with antihistaminics, Dblockers or dexamethasone.
    • Effective in pregnancy hyperemesis & postoperative nausea.
  • Dblockers:
    • 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:
    • DexamethasoneIn 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 t1/2, effective in delayed emesis.
  • Dolasetron prolongs QT interval.
  • Ondansetron has shortest t1/2 is effective in pregnancy hyperemesis & postoperative nausea, when used in combination with antihistaminics, Dblockers 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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