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Antiemetics
This document discusses emetics, which induce vomiting, and antiemetics, which prevent vomiting. It describes the physiology of vomiting including the vomiting center and chemoreceptor trigger zone in the brain. It explains the mechanisms and sites of action of various classes of antiemetic drugs including antihistamines, 5-HT3 receptor antagonists, dopamine antagonists, cannabinoids, glucocorticoids, and others. It provides details on specific antiemetic drugs like metoclopramide, ondansetron, dexamethasone, and their indications, mechanisms, pharmacokinetics and adverse effects.
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Antiemetics
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- 2. Emesis (vomiting) • Actof 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 • Histaminevia H1 receptors • Serotonin via 5HT3 receptors • Acetylcholine via M receptors • Dopamine via D2 receptors
- 6. Manikandan 6 Emetic Centre CTZ Hormones Azotaemia Diabetes Vestibular Sights Smell Taste VomitingGut Opioids Chemotherapy Anaesthetics BBB Hypotension Hypoxaemia
- 7. Vomiting Centre (medulla) Cerebral cortex Anticipatoryemesis 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
- 8. Emetics They are requiredwhen 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 • Centrallyacting: Apomorphine • directly stimulate the CTZ or VC • Reflexly acting: Ipecacuanha • stimulate the VC by irritating gastric & duodenal mucosa which stimulate afferent fibres of vagus nerve • Locally acting: Aluminum, Sodium Chloride (Concentrated Solution) • Other Drugs as Adverse Effect: Morphine, Digitalis, Emetine, Aspirin, Quinine & Anticancer drugs
- 12. Emetic drugs • Apomorphine •Ipecacuanha
- 13. Manikandan 13 Apomorphine • Semisynthetic 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 •
- 14. Manikandan 14 Ipecacuanha • Containstwo 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
- 15. Manikandan 15 Contraindications • Corrosivepoisoning • Kerosene poisoning • Unconscious patients • Morphine poisoning
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- 17. Manikandan 17 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
- 18. ANTIEMETIC DRUGS A group ofdrugs which are used to control nausea and vomiting Provide symptomatic relief Removal of causative factor to have ultimate relief
- 19. Manikandan 19 Vomiting Centre (medulla) Cerebralcortex 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
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- 21. Classification - Antiemeticdrugs 1. H1antihistamines Meclizine, Cinnarizine, Cyclizine, Dimenhydrinate & Diphenhydramine. 2. Muscarinic Antagonist Hyoscine (Scopolamine). 3. Selective 5-HT3 Antagonists Ondansetron, Granisetron, Palonosetron & Dolasetron.
- 22. 4. D2 Antagonists a.Substituted Benzamides Metoclopramide, Trimethobenzamide 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)
- 23. D2 Antagonists a. SubstitutedBenzamides Metoclopramide, Trimethobenzamide b. Butyrophenones Domperidone , Droperidol c. Phenothiazines Prochlorperazine, Promethazine & Thiethylperazine.
- 24. Metoclopramide Chemistry: Substituted Benzamide MOA:Dopamine D2 receptors antagonist It is potent Antiemetic & Prokinetic agent As Antiemetic • It has potent Antiemetic & antinausea effect. • Blocks D2 receptors in CTZ of the medulla (area postrema) As Prokinetic agent • It can selectively stimulate gut motor function. • Blocks D2 receptor in GIT & blocks the normal inhibitory effect of Dopamine on cholinergic smooth muscle stimulation--- ↑ motility.
- 25. Manikandan 25 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
- 26. Manikandan 26 Metroclopramide… Pharmacokinetics • Rapidlyabsorbed 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
- 27. 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
- 28. Manikandan 28 Trimethobenzamide Substituted Benzamide Antiemeticlike Metoclopramide. D2 Antagonist & mild anti- histaminic activity DOSE: 250mg orally, 200mg rectally, 200mg IM
- 29. Manikandan 29 Phenothiazines Phenothiazines Prochlorperazine, Promethazine& Thiethylperazine Phenothiazines are antipsychotics with potent antiemetic property due to D2 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
- 30. Manikandan 30 Butyrophenones Antipsychotic drugs, D2 antagonists Droperidol Central D2 antagonist Main A/E: EPS , postural hypotension QT prolongation may occur Domperidone • Does not cross BBB. Only blocks D2 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.
- 31. Selective 5-HT3 Antagonists Ondansetron,Granisetron , Dolasetron & Palonosetron MOA Act as anti-emetic by Selectively blocking central 5HT3 receptors in Vomiting center & CTZ & Mainly by blocking Periphery 5HT3 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
- 32. Manikandan 32 Ph. K- Selective 5-HT3 Antagonists • High first pass metabolism • t1/2 : 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)
- 33. Manikandan 33 The Uses- Selective 5-HT3 Antagonists • 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
- 34. Manikandan 34 A/Es -Selective 5-HT3 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
- 35. Manikandan 35 H1antihistamines &Muscarinic Antagonists H1antihistamines Meclizine, Cinnarizine, Cyclizine & Diphenhydramine & its salt Dimenhydrinate. • They have anticholinergic & H1 antagonist sedating properties (1st generation). • They produce specific depression of conduction in vestibulocerebellar pathway. MuscarinicAntagonist Hyoscine (Scopolamine).
- 36. Manikandan 36 H1antihistamines &Muscarinic Antagonists… Theraputic Uses • Vestibular system is important in motion sickness via cranial nerve VIII - rich in Cholinergic M1 & Histamine H1receptors • 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
- 37. Cannabinoids (Dronabinol , Nabilone) Dronabinol Tetrahydrocannabinol(THC) main psychoactive chemical in marijuana Pharmacokinetics: complete absorption on oral administration, significant 1st pass effect, metabolites excreted slowly over days to weeks in faeces & urine
- 38. • MOA: Actas 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
- 39. Glucocorticoids Dexamethasone , Methylprednisolone AntiemeticMOA not clear Enhance action of 5HT3 antagonists in Cancer chemotherapy induced Nausea & vomiting
- 40. Manikandan 40 Benzodiazepines Diazepam, Lorazepam •Used prior to Cancer chemotherapy to reduce anticipatory vomiting • Vomiting caused by anxiety
- 41. Neurokinin-1 (NK1 )Antagonists Aprepitant,Fosaprepitant Given orally BA = 65% , Crosses BBB. t ½ : 11 hrs, Metabolized by hepatic CYP3A4. MOA Act as Antiemetic: Selectively block NK1 receptor in area postrema. No effect on Serotonin , Dopamine or Corticoid receptors
- 42. Manikandan 42 Aprepitant • Nonpeptide, 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
- 43. Manikandan 43 Neurokinin-1 (NK1)Antagonists Uses Used in combination with 5HT3 antagonists & Corticosteroids for prevention of acute & chronic nausea and vomiting from Cancer chemotherapy
- 44. Manikandan 44 Neurokinin-1 (NK1)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.
- 45. Manikandan 45 Therapeutic Usesof Anti-emetics • Motion sickness: Hyoscine • Vestibular disorders( Menieres, disease): Cinnerazine • Vomiting due to Uremia, Radiation, Viral gastro enteritis, Liver disease, Migraine, Prochlorperazine , Metroclopramide • Vomiting due to pregnancy ( hyperemesis gravidarum), Meclizine with vit. B6 (Navidoxine)
- 46. Manikandan 46 • Vomitingdue to Cytotoxic Anticancer drugs: 5HT3 Antagonists Metroclopramide, Cannabinoids, corticosteroids , Aprepitant • Anticipatory Vomiting due to Cytotoxic Anticancer drugs. Benzodiazepines (Diazepam) • Post Operative Vomiting: Metoclopramide , Prochlorperazine , Dimenhydrinate, 5HT3 Antagonists (Ondensetron)
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