1. Emetics and antiemetics

2. Emesis (vomiting) Act of forceful expulsion of gastric contents through the mouth Often preceded by nausea

3. Emesis Rational (valuable) reflex prevention of ingestion of noxious substances (sight, smell, taste, texture) local gut reflexes stimulate vomiting e.g. toxins Irrational reflexes labyrinth pregnancy

5. Neurotransmitters Involved Histamine via H 1 receptors Serotonin via 5HT 3 receptors Acetylcholine via M receptors Dopamine via D 2 receptors

6. Manikandan 6 Emetic Centre CTZ Hormones Azotaemia Diabetes Vestibular Sights Smell Taste Vomiting Gut Opioids Chemotherapy Anaesthetics BBB Hypotension Hypoxaemia

7. Vomiting Centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Vestibular nuclei Motion sickness Pharynx & GIT Chemo & radio therapy Gastroenteritis Chemoreceptor Trigger Zone (CTZ) (Outside BBB) Cancer chemotherapy Opioids Muscarinic, 5 HT 3 & Histaminic H 1 5 HT 3 receptors Dopamine D 2 5 HT 3,, Opioid Receptors Muscarinic Histaminic H 1 Pathophysiology of Emesis

8. Emetics They are required when an undesirable substance has been ingested

9. Emetic Drugs - Uses Acute cases of poisoning (except in corrosive substances poisoning or if patient is not fully conscious) Alcoholic intoxication Removal of foreign bodies from the oesophagus Certain cases of paroxysmal tachycardia

10. Emetic Drugs - Contraindications Hernias Aneurysm Severe heart diseases Peptic ulcer Pulmonary TB Prolapse of rectum or uterus Threatened abortion Weak / debilitated persons

11. Emetic Drugs Apomorphine Centrally acting: Apomorphine directly stimulate the CTZ or VC Ipecacuanha Reflexly acting : Ipecacuanha stimulate the VC by irritating gastric & duodenal mucosa which stimulate afferent fibres of vagus nerve Aluminum, Sodium Chloride Locally acting: Aluminum, Sodium Chloride (Concentrated Solution) Morphine, Digitalis, Emetine, Aspirin, Quinine & Anticancer drugs Other Drugs as Adverse Effect: Morphine, Digitalis, Emetine, Aspirin, Quinine & Anticancer drugs

13. Emetic drugs Apomorphine Ipecacuanha

14. Manikandan 14 Apomorphine Semi synthetic derivative of morphine Given IM or SC, act centrally; local effect on GIT not required. Dose is 6 mg (2-8mg) Induces vomiting in 5 -10 min CNS depressant contraindicated in respiratory depression

15. Manikandan 15 Ipecacuanha Contains two alkaloids- emetine & cephaeline Used as syrup ipecac. Produces effect in 15 min. Acts by irritating gastric mucosa & through CTZ centre. Dose = 5ml in infants = 10-15ml in children = 15-20ml in adults

16. Manikandan 16 Contraindications Corrosive poisoning Kerosene poisoning Unconscious patients Morphine poisoning

17. Manikandan 17 Anti-emetics

18. Manikandan 18 Introduction - Anti-emetics Two centres: vomiting centre (VC) and chemoreceptor trigger zone (CTZ) Both near the floor of the fourth ventricle, close to the vital centres VC is within the blood brain barrier (BBB) CTZ outside in the area postrema They are connected together

19. ANTIEMETIC DRUGS A group of drugs which are used to control nausea and vomiting Provide symptomatic relief Removal of causative factor to have ultimate relief

20. Manikandan 20 Vomiting Centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Vestibular nuclei Motion 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

21. Manikandan 21

22. Classification - Antiemetic drugs 1. H 1 antihistamines Meclizine, Cinnarizine, Cyclizine, Dimenhydrinate & Diphenhydramine. 2. Muscarinic Antagonist Hyoscine (Scopolamine). 3. Selective 5-HT3 Antagonists Ondansetron, Granisetron, Palonosetron & Dolasetron.

23. 4. D2 Antagonists Substituted Benzamides a. Substituted Benzamides Metoclopramide, Trimethobenzamide Butyrophenones b. Butyrophenones Domperidone, Droperidol c. Phenothiazines Prochlorperazine, Promethazine & Thiethylperazine. 5. Cannabinoids Dronabinol, Nabilone 6. Glucocorticoids Dexamethasone, Methylprednisolone 7. Benzodiazepines Diazepam, Lorazepam 8. Neurokinin-I Antagonist Aprepitant (oral formulation), Fosaprepitant (IV formulation)

24. D 2 Antagonists a. Substituted Benzamides Metoclopramide, Trimethobenzamide b. Butyrophenones Domperidone, Droperidol c. Phenothiazines Prochlorperazine, Promethazine & Thiethylperazine.

25. Metoclopramide Chemistry: Chemistry: Substituted Benzamide MOA: MOA: Dopamine D 2 receptors antagonist It is potent Antiemetic & Prokinetic agent As Antiemetic It has potent Antiemetic & antinausea effect. Blocks D 2 receptors in CTZ of the medulla (area postrema ) As Prokinetic agent It can selectively stimulate gut motor function. Blocks D 2 receptor in GIT & blocks the normal inhibitory effect of Dopamine on cholinergic smooth muscle stimulation--- ↑ motility.

26. Manikandan 26 The Uses - Metroclopramide Potent antiemetic controls / reduces vomiting due to Uremia Radiation Viral gastro enteritis, hepatic-biliary disease Anticancer drugs Migraine Post operatively & pre-operatively

27. Manikandan 27 Metroclopramide…Pharmacokinetics Rapidly absorbed from GIT after oral administration. Undergoes a high degree first pass metabolism. It is excreted in the urine as free and as metabolites. It is also excreted in the breast milk. DOSE: 10-20mg orally or IV every 6 hrs

28. Adverse Effects - Metroclopramide Extrapyramidal reactions with facial and skeletal muscle spasms- Restlessness, Dystonias, Parkinsonian symptoms. -----More common in young and very old. Usually occur shortly after staring treatment and subside with in 24 hours of stopping the drug. Bowel upsets, Diarrhea Drowsiness and fatigue, dizziness, restlessness and anxiety. Galactorrhoea, Gynecomastia, impotence and menstrual disorders – due to increased prolactin levels

29. Manikandan 29 Trimethobenzamide Substituted Benzamide Antiemetic like Metoclopramide Antiemetic like Metoclopramide. D 2 Antagonist & mild anti- histaminic activity DOSE: 250mg orally, 200mg rectally, 200mg IM

30. Manikandan 30 Phenothiazines Prochlorperazine, Promethazine & Thiethylperazine properties Phenothiazines are antipsychotics with potent antiemetic property due to D 2 antagonism and anti-maucarinic properties Sedative property due to anti-histaminic property Mainly used as anti-emetic in severe N& V Main A/E: EPS, sedation, postural hypotension

31. Manikandan 31 Butyrophenones Antipsychotic drugs, D 2 antagonistsDroperidol Central D 2 antagonist Main A/E: EPS, postural hypotension QT prolongation may occurDomperidone Does not cross BBB. Only blocks D 2 in CTZ where BBB is leaky. May be used in N&V due to Levodopa, without affecting its efficacy. No EPS. Used as antiemetic, prokinetic agent & for post partum lactation stimulation.

32. Selective 5-HT 3 Antagonists Ondansetron, Granisetron, Dolasetron & Palonosetron MOA Act as anti-emetic by Selectively blocking central 5HT 3 receptors in Vomiting center & CTZ & Mainly by blocking Periphery 5HT 3 receptors on intestinal vagal and spinal afferent fibers Act as anti-emetic by Selectively blocking central 5HT 3 receptors in Vomiting center & CTZ & Mainly by blocking Periphery 5HT 3 receptors on intestinal vagal and spinal afferent fibers Antiemetic action is restricted to emesis caused by vagal stimulation (e..g post operative) & chemotherapy Palonosetron: newer with greater affinity for 5-HT3 receptor & comparatively longer half life No effect on Dopamine / muscarinic receptors

33. Manikandan 33 Ph. K - Selective 5-HT 3 Antagonists High first pass metabolism t 1/2 : 4-9 hrs (Ondansetron, Granisetron & Dolasetron) 40 hrs (Palonosetron) Given once or twice daily – orally or intravenously Excreted by liver & kidney No dose reduction in renal insufficiency but needed in hepatic insufficiency (Ondansetron)

34. Manikandan 34 The Uses - Selective 5-HT 3 Antagonists Chemotherapy- Induced Nausea & vomiting Chemotherapy- Induced Nausea & vomiting Primary Agents - prevention of acute chemotherapy induced Nausea & vomiting Effective alone in most of the cases. Efficacy is enhanced in combination. Can be given I/V 1/2 hr before chemotherapy To prevent Delayed Nausea & vomiting occurring after 24 hrs of Cancer chemotherapy in combination with Dexamethasone & NK1 receptor antagonist. To prevent & treat post operative & post radiation Nausea & vomiting To prevent & treat post operative & post radiation Nausea & vomiting

35. Manikandan 35 A/Es - Selective 5-HT 3 Antagonists Excellent safety profile Headache, Dizziness & constipation All three drugs cause prolongation of QT interval, but more pronounced with dolasetron.DIs Hepatic clearance may decrease by enzyme inhibitors

36. Manikandan 36 H 1 antihistamines & Muscarinic Antagonists H 1 antihistamines Meclizine, Cinnarizine, Cyclizine & Diphenhydramine & its salt Dimenhydrinate. They have anticholinergic & H1 antagonist sedating properties (1 st generation). They produce specific depression of conduction in vestibulocerebellar pathway. MuscarinicAntagonist Hyoscine (Scopolamine).

37. Manikandan 37 H 1 antihistamines & Muscarinic Antagonists… Theraputic Uses Vestibular system is important in motion sickness via cranial nerve VIII - rich in Cholinergic M 1 & Histamine H 1 receptors Most effective drugs for motion sickness Effective for nausea & vomiting associated with motion sickness. Vestibular disorders ( Meniere’s disease) (hyoscine) – used as transdermal patch for motion sickness Meclozine is long acting so useful in sea sickness Cinnarizine also has antivertigo effect. Act by inhibiting influx of calcium to vestibular sensory cells from endolymph

38. Cannabinoids (Dronabinol, Nabilone) Dronabinol Tetrahydrocannabinol (THC) main psychoactive chemical in marijuana complete absorption on oral administration, significant 1 st pass effect, metabolites excreted slowly over days to weeks in faeces & urine Pharmacokinetics: complete absorption on oral administration, significant 1 st pass effect, metabolites excreted slowly over days to weeks in faeces & urine

39. MOA: Act as antiemetic & appetite stimulant in addition to psychoactive action. MOA not clear. Cancer chemotherapy induced Nausea & vomiting with Phenothiazines – synergistic effect but AEs are added – not used as better drugs are available Nabilone closely related THC analog

40. Glucocorticoids Dexamethasone, Methylprednisolone Antiemetic MOA not clear Enhance action of 5HT 3 antagonists in Cancer chemotherapy induced Nausea & vomiting

41. Manikandan 41 Benzodiazepines Diazepam, Lorazepam Used prior to Cancer chemotherapy to reduce anticipatory vomiting Vomiting caused by anxiety

42. Neurokinin-1 (NK 1 )Antagonists Aprepitant, Fosaprepitant Given orally BA = 65%, Crosses BBB. t ½ : 11 hrs, Metabolized by hepatic CYP3A4. MOA Act as Antiemetic: Selectively block NK 1 receptor in area postrema. No effect on Serotonin, Dopamine or Corticoid receptors.

43. Manikandan 43 Aprepitant Non peptide, selective, Neurokinin type 1 (NK 1) receptors antagonist Block substance P from binding to NK1 receptor Broader spectrum and activity in delayed emesis (In Preclinical studies) Augment the antiemetic activity of 5HT3 receptor antagonists and dexamethasone Inhibit both acute and delayed CINV

44. Manikandan 44 Neurokinin-1 (NK 1 )Antagonists Uses Used in combination with 5HT 3 antagonists & Corticosteroids for prevention of acute & chronic nausea and vomiting from Cancer chemotherapy

45. Manikandan 45 Neurokinin-1 (NK 1 )Antagonists A/Es Fatigue, dizziness & diarrhoea. Enzyme inhibition Metabolized by CYP3A4 & may inhibit metabolism of many anticancer drugs (Docetaxel, Paclitaxel, Etoposide, Vinblastine, Imatinib) ---- ↑ levels --- toxicity. Metabolism of Aprepitant may be inhibited by Ketoconazole, Ciprofloxacin, Clarithromycin, Nafazodone, Ritonavir, Nelfinavir, Verapamil & Quinidine) Aprepitant ↓ INR in patients taking warfarin.

46. Manikandan 46 Therapeutic Uses of Anti-emetics Hyoscine Motion sickness: Hyoscine Cinnerazine Vestibular disorders( Menieres, disease): Cinnerazine Prochlorperazine, Metroclopramide Vomiting due to Uremia, Radiation, Viral gastro enteritis, Liver disease, Migraine, Prochlorperazine, Metroclopramide Meclizine with vit. B 6 (Navidoxine) Vomiting due to pregnancy ( hyperemesis gravidarum), Meclizine with vit. B 6 (Navidoxine)

47. Manikandan 47 5HT 3 Antagonists Metroclopramide, Cannabinoids, corticosteroids, Aprepitant Vomiting due to Cytotoxic Anticancer drugs: 5HT 3 Antagonists Metroclopramide, Cannabinoids, corticosteroids, Aprepitant Benzodiazepines (Diazepam) Anticipatory Vomiting due to Cytotoxic Anticancer drugs. Benzodiazepines (Diazepam) Metoclopramide, Prochlorperazine, Dimenhydrinate, 5HT 3 Antagonists (Ondensetron) Post Operative Vomiting: Metoclopramide, Prochlorperazine, Dimenhydrinate, 5HT 3 Antagonists (Ondensetron)

48. Manikandan 48 Thank You

49. Manikandan 49

50. Manikandan 50

51. Manikandan 51 Aprepitant: A new Drug for Chemotherapy Induced Nausea and Vomiting Girish C Dept. of Pharmacology, JIPMER, Pondicherry, INDIA