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Emetics & antiemetics

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emetics and antiemetics medicine

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Emetics & antiemetics

  1. 1. EMETICS & ANTIEMETICS Dr Chinmaya Debasis Panda MBBS,MD
  2. 2. Emesis: • A protective reflex that serves to rid the stomach and intestine of toxic substances and prevent their further ingestion. • Vomiting consists of: Pre-ejection phase: gastric relaxation & retroperistalsis Retching: rhythmic action of respiratory muscles preceding vomiting and consisting of contraction of abdominal and intercostal muscles and diaphragm against a closed glottis Ejection: intense contraction of the abdominal muscles and relaxation of the upper esophageal sphincter
  3. 3. Neuronal path: • Centre: lateral reticular formation of Medulla Oblongata • Relay Centres: chemoreceptor trigger zone (CTZ) and nucleus tractus solitarius (NTS) • Afferent impulses: GIT, throat (vagus via NTS), other viscera (spinal cord), cerebral cortex (anticipatory) & vestibular apparatus(motion sickness)
  4. 4. Receptors: CTZ: • serotonin(5-HT3), • dopamine (D2), • and opioids(µ) NTS: • enkephalin, • Histamine(H1), • Ach(M), • and also contains 5-HT3 Also neurokinin(NK1 activated by substance-p), cannabinoid(CB1)
  5. 5. Path: Exposure to Cytotoxic drugs, radiation and other g.i. irritants release 5-HT from enterochromaffin cells Acts on 5-HT3 receptors present on extrinsic primary afferent neurones (PAN) of the enteric nervous system (ENS) with vagal and spinal visceral afferents impulses reach NTS and CTZ Vomiting 5-HT may also spill into circulation and reach CTZ via the vascular route
  6. 6. Emetics: • Drugs which induce vomiting • Acts on CTZ: Apomorphine • Acts reflexly and on CTZ: Ipecacuanha Apomorphine: Morphine derivative – semisynthetic – Dopaminergic agonist in CTZ • 6 mg IM/SC – acts within 5 minutes • Respiratory depression • Orally – not recommended (large dose – slow inconsistent) • Parkinsonism Ipecacuanha: Cephaelais ipecacuanha • Syrup ipecac – 15 to 30 ml (10 to 15 in child) • Action takes 15 minutes • MOA: Irritation of Gastric mucosa and directly on CTZ Also salt water, mustard seed
  7. 7. Contraindications: Corrosive poisoning CNS stimulant drug poisoning Kerosine(petroleum product) poisoning Unconsious patients Morphine or phenothiazine poisoning
  8. 8. ANTIEMETICS: 1. Anticholinergics : Hyoscine, Dicyclomine 2. H1 antihistaminics: Promethazine, Diphenhydramine, Dimenhydrinate, Doxylamine, Meclozine (Meclizine), Cinnarizine. 3. Neuroleptics (D2 blockers): Chlorpromazine, Triflupromazine, Prochlorperazine, Haloperidol, etc. 4. Prokinetic drugs: Metoclopramide, Domperidone, Cisapride, Mosapride, Itopride 5. 5-HT3 antagonists: Ondansetron, Granisetron, Palonosetron, Ramosetron 6. NK1 receptor antagonists: Aprepitant, Fosaprepitant 7. Adjuvant antiemetics: Dexamethasone, Benzodiazepines, Dronabinol, Nabilone
  9. 9. Anticholinergics: Hyoscine: Motion Sickness (0.2 to 0.4 mg IM) • Used IM/SC, but short duration of action • MOA: Blocking of cholinergic link of vestibular apparatus to the vomiting centre – does not work in vomiting due to other aetiology • ADRs: Sedation, dry mouth and other anticholinergic effects • Transdermal delivery system (1.5 mg) Dicyclomine: Prophylaxis of motion sickness and morning sickness
  10. 10. H1 ANTIHISTAMINICS: • Primarily used in motion sickness, morning sickness and some other vomiting to lesser extent – • Also anticholinergic, antihistaminic and antidopaminergic actions • Promethazine (Phenothiazine), diphenhydramine: 4 – 6 Hours protection • Combined with metoclopramide in CINV: additive effect plus counters extra pyramidal effects • Promethazine theoclate (Avomine) – motion sickness • Doxylamine: Sedative H1 antihistaminic – marketed in combination with Pyridoxine – specifically for morning sickness – duration of action 10 Hours (at bed time) – drowsiness, dry mouth, vertigo • Meclizine: Long duration of action – sea sickness • Cinnarizine: anti vertigo action – inhibits Ca++ influx in endolymph
  11. 11. Motion Sickness: Anticholinergics & H1 Antihistaminics are preferred antidopaminergics do not work Morning Sickness: Preferably drugs should be avoided Reassurance and dietary modification tried first Dicyclomine, promethazine or metoclopramide are preferred at low doses
  12. 12. Neuroleptics: (phenothiazines, haloperidol) Uses: • Drug induced and postoperative nausea and vomiting (PONV). • Disease induced vomiting: gastroenteritis, uraemia, liver disease, migraine, etc. • Malignancy associated and cancer chemotherapy (mildly emetogenic) induced vomiting. • Radiation sickness vomiting (less effective). • Morning sickness: should not be used except in hyperemesis gravidarum. ADRs: Sedation, acute muscle dystonia (diagnose the cause first before administering) • Prochlorperazine (Stemetil) – D2 blocking agent - labyrinthine suppressant – antivertigo and antiemetic action. Effective in CINV with vertigo • EPS and muscle dystonia
  13. 13. PROKINETIC DRUGS: Metoclopramide Actions on GIT: On upper GIT – Increases gastric peristalsis • Relaxes pylorus and 1st part of duodenum – better gastric emptying • LES tone increased – also increases Intestinal peristalsis Actions on CNS: Acts on CNS – can counter Apomorphine induced vomiting • Gastrokinetic action contributes • No antipsychotic property, but has extra pyramidal and prolactin secreting effects (Promethazine context)
  14. 14. MOA: 1. D2 antagonism: Dopamine is inhibitory transmitter via D2 receptor – delays gastric emptying – also relaxation of LES – nausea and vomiting – Metoclopramide causes opposite effect • Also central antidopaminergic action 2. 5-HT4 agonism: enhanced Acetylcholine release in myenteric plexus – gastric hurrying and increased LES tone 3. 5-HT3 antagonism: at high concentration • Blocks at inhibitory myenteric interneurons and CTZ/NTS Pharmacokinetics: Absorbed orally, crosses BBB and placenta and secreted in milk. Conjugated in liver, t1/2 = 4 – 6 Hrs.
  15. 15. Conntd. ADRs: Sedation, dizziness, loose stool and muscle dystonia • Long use: Parkinsonism, galactorrhoea, gynaecomastia • Safe in pregnancy but in lactating mother children may have loose stool, dystonia etc. DI – abolishes levodopa action Uses: • Antiemetic: Postoperative, drug induced, disease associated, radiation induced etc. but not effective in motion sickness. Still preferred in vomiting due to anticancer drug – in combination with Promethazine • Gastrokinetic: To accelerate gastric emptying – Emergency GA, gastroparesis (post vagotomy), duodenal intubation etc. • Dyspepsia: stops hiccup • GERD: Does not aid in healing, PPIs are preferred – used as adjuvant
  16. 16. Domperidone: • Chemically related to haloperidol but action like Metoclopramide • D2 antagonist – in upper GIT (not attenuated by atropine) • Rarely EP side effect – does not cross BBB, but hyperprolactinemia occurs • Acts mainly through CTZ – outside BBB • Does not abolish action of levodopa • Kinetics: absorbed orally but 15% bioavailability – high 1st pass metabolism, completely metabolized and excreted in urine.T1/2 – 7 – 8 Hrs • ADRs: Less than Metoclopramide – dry mouth, loose stool, headache, galactorrhoea etc. Arrhythmia on injection • Uses: Similar as Metoclopramide but milder spectrum of action –not effective in chemotherapy
  17. 17. Cisapride: • Lacks D2 receptor action(no antiemetic action) • Fascilitate motility throughout the GI tract(also colon) • Also 5-HT4 mediated Cl– secretion in the colon- loose stool • Prolongs QTc- not marketed now Mosapride: • Relatively safer Itopride: • D2 and Ach receptor blocking action, less 5HT4 affinity. • Lack QTc prolongation and metabolized by flavin monooxigenases • safer
  18. 18. 5-HT3 ANTAGONISTS: Ondansetron • Developed for Chemotherapy/radiotherapy induced vomiting – also effective in others (PONV) • MOA: Acts peripherally as well as centrally – Blocks depolarizing action of 5-HT3 receptors in vagus at GIT and CTZ/NTS • No action on Dopamine receptor – does not block Apomorphine induced vomiting and mild gastrokinetic effect • Kinetics: 60 – 70% bioavailability – first pass metabolism. • Metabolized as glucoronide and sulfate. Eliminated in urine and faeces. T1/2 life 5-7 Hrs
  19. 19. • Dose: 8 mg slow IV for 15 minutes ½ hr before chemotherapy. Followed by 2 such doses 4 hours apart. Then 8 mg orally twice daily for 1 week. For others 4 – 8 mg IV followed by every 8 hourly. • 80% success – better/equal to Metoclopramide – no dystonia or sedation. Adjuvant improve response. • ADRs: Headache and dizziness. Mild constipation and abdominal discomfort. Hypotension, allergic reactions, chest pain and bradycardia etc. Granisetron: 10 times more potent, Palonosetron: longest acting and highest affinity for 5-HT3 receptor(t1/2-40hrs)
  20. 20. NK 1 receptor antagonists: Aprepitant: Newer antiemetic MOA: Emetogenic chemotherapy releases Substance P – stimulates CTZ and NTS by acting on NK1 - blocking of NK1 receptors causes emesis blocking • Little effect on 5-HT3 or D2 receptor • GIT motility not affected Uses: 125 mg + 80 mg + 80 mg for 3 days with IV Ondansetron and Dexamethasone – for cisplatin induced vomiting – useful in multiple cycle patients – Orally 40 mg can be used for PONV • Kinetics: well absorbed orally, metabolized in liver, excreted in faeces and urine. T1/2 10 – 13 Hrs • ADRs: Weakness, fatigue, flatulence etc.
  21. 21. ADJUVANT ANTIEMETICS: Corticosteroids: through anti-inflammatory action, also reduce side effects of other antiemetics Benzodiazepines: Through sedative action, reduce psychogenic component and suppress dystonic side effects of others Cannabinoids: CB1 receptors on CTZ and vomiting center e.g: dronabinol, nabilone
  22. 22. T H A N K Y O U