ANTIEMETICS AND PROKINETIC AGENTS

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ANTIEMETICS AND PROKINETIC AGENTS

  1. 1. 1Dr Anuj
  2. 2.  Vomiting:- Expulsion of gastric contents through mouth due to mass antiperistalsis  Nausea:- An uneasy feeling in anticipation of vomiting  Retching:- Series of weaker and unproductive vomiting movement 2 Dr Anuj
  3. 3.  Vomiting results due to stimulation of vomiting centre (VC) which is located in lateral medullary reticular formation 3Dr Anuj
  4. 4. Cerebral Centers Affecting Vomiting 4Dr Anuj
  5. 5.  VC recieves input from GI mucosa, Chemoreceptor trigger zone(CTZ), and vestibular apparatus.  Efferents fibre from this centre when stimulated , cause stimulation of phrenic nerve supplying to diaphragm and of somatic nerve supplying the abdominal muscles to promote emesis 5Dr Anuj
  6. 6.  Irritation of GI mucosa by drugs or irritants leads to release of serotonin that stimulates VC via 5HT3 receptors  CTZ is rich in dopamine D2 and serotonin 5HT3 and neurokinin NK1 receptor  Motion sickness occurs due to stimulation of vestibular apparatus and cerebellum, these structures result in stimulation of VC by activating M1& H1 receptors  By stimulation of H1 receptors histamine play a permissive role in all types of vomiting 6Dr Anuj
  7. 7. Vomiting centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Vestibular nucleiMotion sickness Pharynx & GIT Chemo & radio therapy Gastroenteritis Chemoreceptor Trigger Zone (CTZ) (Outside BBB) Cancer chemotherapy Opioids Muscarinic, 5 HT3 & Histaminic H1 5 HT3 receptors Dopamine D2 5 HT3,,Opioid Receptors Muscarinic Histaminic H1 Pathophysiology of Emesis 7Dr Anuj
  8. 8. Now answer this question Which group of drugs can be used as antiemetics ? Serotonin 5 HT3 Antagonists Dopamine D2 Antagonist Anticholinergics H1 Antihistaminics Cannabinoids 8Dr Anuj
  9. 9. CLASSIFICATION 1. Anticholinergics :- Hyoscine, Dicyclomine 2. H1 antihistaminics :- Promethazine, Diphenhydramine, Dimenhydrinade, Doxylamine, Meclozine, Cinnarzine 3. Neuroleptics:- Chlorpromazine, Triflupromazine, Prochlorperazine, Haloperidol 4. Prokinetic drugs:- Metoclopramide, Domperidone, Cisapride, Mosapride, Itopride 5. 5-HT3 antagonist:- Ondansetron, Granisetron, Palonosetron 6. NK1 receptor antagonist:-Aprepitant, Fosaprepitant 7. Adjuvent antiemetics :- Dexamethasone, Benzodiazepines 8. Cannabinoids :- Dronabinol, Nabilone Dr Anuj 9
  10. 10. 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. 10Dr Anuj
  11. 11. Drugs Available Ondansetron (ONDEM) 32 mg / day Granisetron (GRANISET) 10 mg / kg / day Dolasetron 1.8 mg / kg / day Palonosetron 250µg by slow iv inj 30 min before chemo Indications Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy. Postoperative & postradiation nausea & vomiting 11Dr Anuj
  12. 12. Adverse Effects Excellent safety profile Headache & constipation All three drugs cause prolongation of QT interval, but more pronounced with dolasetron. Palonosetron :- longest acting 5HT3 receptor blocker with highest affinity for 5HT3 receptor (t1/2=40 hrs) Rapid i.v. injection causes blurring of vision 12Dr Anuj
  13. 13. Dopamine D2 Antagonist Antagonise D2 receptors in CTZ. Drugs available Metoclopramide(PERINORM, REGLAN) 2.5 mg b.d Domperidone(DOMSTAL) 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. 13Dr Anuj
  14. 14. 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. 14Dr Anuj
  15. 15. Neuroleptics : Phenothiazines & Butyrophenones Phenothiazines Prochlorperazine( STEMETIL) Promethazine ( AVOMINE) Phenothiazines are antipsychotics with potent antiemetic property due to D2 antagonism. Butyrophenone Droperidol(DROPEROL) Droperidol used for postop. nausea & vomiting, but cause QT prolongation. 15Dr Anuj
  16. 16. 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 16Dr Anuj
  17. 17. Anticholinergics Scopolamine (hyoscine) – used as transdermal patch for motion sickness Cannabinoids Dronabinol & Nabilone are analogues of delta-9-THC, an active principle of cannabis sativa. Probably act by stimulating CB1 subtype of cannabinoid receptor present in neurons around vomiting centre Dronabinol – used as adjuvant in chemotherapy induced vomiting. It is a psychoactive substance Nabilone 17Dr Anuj
  18. 18. NK1 receptor antagonist  Aprepitant :- selective high affinity NK1 receptor antagonist that blocks the emetic action of substance P For pt undergoing multiple cycles of chemotherapy Well absorbed orally and penetrates BBB Metabolised in liver by CYP3A4 S/E weakness fatigue flatulence rise in liver enzymes Dr Anuj 18
  19. 19. 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 ? 19Dr Anuj
  20. 20. Explanation : Vestibular nuclei has only muscarinic and H1 histaminic receptors. 20Dr Anuj
  21. 21. Points to remember 21Dr Anuj
  22. 22. Clinical use of anti-emetic drugs: H1-receptor antagonists:  cylizine - motion sickness cinnarizine - motion sickness, vestibular disorders (e.g.Meniére´s disease) promethazine - severe morning sickness of pregnancy (only if absolutely essential) 22Dr Anuj
  23. 23. D2-receptor antagonists: phenothiazines (e.g. thiethylperazine) - vomiting caused by uraemia, radiation, viral gastroenteritis (drugs of choice); severe morning sickness of pregnancy (if absolutely essential) metoclopramide - vomiting caused by uraemia, radiation, gastrointestinal disorders, cytotoxic drugs Dr Anuj 23
  24. 24. Muscarinic-receptor antagonists: hyoscine - motion sickness (drug of choice) 5-HT3receptor antagonists: ondansetron - vomiting caused by cytotoxic anticancer drugs (drug of choice), postoperative vomiting; radiation- induced vomiting Cannabinoids: nabilone - for vomiting caused by cytotoxic anticancer drugs 24Dr Anuj
  25. 25. Commonest Antiemetics used in Hospital  Prochlorperazine (stemetil)  12.5mg IM  3mg Buccal (Buccastem)  Cyclizine  50mg PO/IM/IV  Metoclopramide  10mg PO/IM/IV  Ondansetron  4-8mg PO/IM/IV 25Dr Anuj
  26. 26. Some more questions  Vitamin used for tt of Morning sickness Pyridoxine (Vitamin B6)  Antivertigo drug having antimotion sickness property Cinnarizine  Labyrinthine suppressant having selective antivertigo and antiemetic action Prochlorperazine  Blurring of vision caused by Rapid iv inj of palonosetron Dr Anuj 26

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