Department of Pharmacology Antiemetics Dr.S.Manikandan Department of Pharmacology Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry. INDIA.

Pathophysiology of Emesis Cerebral cortex Cancer chemotherapy Opioids Smell Sight Thought Anticipatory emesis Chemoreceptor Trigger Zone (CTZ) Vestibular nuclei Vomiting Centre (medulla) Motion sickness Muscarinic Histaminic H1 Muscarinic, 5 HT3 & Histaminic H1 (Outside BBB) Dopamine D2 5 HT3,,Opioid Receptors Chemo & radio therapy Gastroenteritis Pharynx & GIT 5 HT3 receptors Manikandan 2

Now answer this question Which group of drugs can be used as antiemetics ? Serotonin 5 HT3 Antagonists Dopamine D2 Antagonist Anticholinergics H1 Antihistaminics Cannabinoids Manikandan 3

Serotonin 5 HT3 Antagonist Potent antiemetics Even though 5 HT3 receptors are present in vomiting centre & CTZ, the antiemetic action is restricted to emesis caused by vagal stimulation. High first pass metabolism Excreted by liver & kidney No dose reduction in renal insufficiency but needed in hepatic insufficiency Given once or twice daily – orally or intravenously. Manikandan 4

Drugs Available Indications Ondansetron 32 mg / day Granisetron 10 mg / kg / day Dolasetron 1.8 mg / kg / day Indications Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy. Postoperative & postradiation nausea & vomiting Manikandan 5

Adverse Effects Excellent safety profile Headache & constipation All three drugs cause prolongation of QT interval, but more pronounced with dolasetron. Manikandan 6

Dopamine D2 Antagonist Antagonise D2 receptors in CTZ. Drugs available Metoclopramide 2.5 mg b.d Domperidone 10 mg b.d Both drugs are also prokinetic agents due to their 5 HT4 agonist activity. Domperidone – oral ; Metoclopramide – oral & i.v Metoclopramide crosses BBB but domperidone cannot. Manikandan 7

Now answer this question Which is a better antiemetic – Metoclopramide or Domperidone ? As CTZ is outside BBB both have antiemetic effects. But as metoclopramide crosses BBB it has adverse effects like extrapyramidal side effects.. Domperidone is well tolerated. Manikandan 8

Phenothiazines & Butyrophenones Prochlorperazine Promethazine Phenothiazines are antipsychotics with potent antiemetic property due to D2 antagonism. Butyrophenone Droperidol Droperidol used for postop. nausea & vomiting, but cause QT prolongation. Manikandan 9

H1 Antihistaminics Most effective drugs for motion sickness Drugs available Meclizine Cyclizine Dimenhydrinate Diphenydramine Promethazine – Used in pregnancy, used by NASA for space motion sickness Manikandan 10

Anticholinergics Cannabinoids Scopolamine (hyoscine) – used as transdermal patch for motion sickness Cannabinoids Dronabinol – used as adjuvant in chemotherapy induced vomiting.It is a psychoactive substance Nabilone Manikandan 11

Now answer this question A physician prescribed Tab.Ondansetron for prophylaxis of motion sickness. Even though ondansetron is a potent antiemetic it didn’t produce any effect in this patient. Can you explain why ? Manikandan 12

Vestibular nuclei has only muscarinic and H1 histaminic receptors. Explanation : Vestibular nuclei has only muscarinic and H1 histaminic receptors. Manikandan 13

Points to Ponder Manikandan 14

Even though both atropine and scopolamine are antimuscarinic, only scopolamine is used in the treatment of motion sickness. Why ? Generally transdermal patches are applied over the arm or chest. But scopolamine transdermal patch is applied behind the ear. Why? Manikandan 15

Thank you Manikandan 16