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Antiemetics
This document provides an overview of different classes of antiemetic drugs, including their mechanisms of action, pharmacokinetics, and clinical uses. It discusses 5HT3 antagonists like ondansetron, prokinetic drugs like metoclopramide, neuroleptics, H1 antihistamines, anticholinergics, and corticosteroids like dexamethasone. The document also reviews the pathophysiology of nausea and vomiting, focusing on the role of the chemoreceptor trigger zone and receptors like 5HT3, dopamine D2, muscarinic, and histaminic H1. It provides dosing guidelines for representative drugs in each class.
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Antiemetics
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- 2. INTRODUCTION • Short descriptionpathophysiology of nausea and vomiting • Classification of antiemetics based on mechanism of action and specific receptor activity. • Pharmacodynamics and pharmacokinetics of antiemetic drugs.
- 3. Classification • 5HT3 Antagonists– Ondansetron Granisetron Dolasetron Palonosetron Ramosetron • Prokinetic Drugs – Metoclopramide Domperidone Cisapride Mosapride
- 4. • Neuroleptics – Chlorpromazine Prochlorperazine Haloperidoletc… • H1 Antihistaminics - Promethazine Diphenhydramine Dimenhydrinate Cylizine Meclizine Cinnarizine
- 5. • Anticholinergics- Hyoscine (Scopolamine) Dicylomine •Adjuvant Antiemetics- Dexamethasone Benzodiazepines Cannabinoids
- 6. Pathophysiology - Vomitingcentre lies in the medulla oblongata. The chemoreceptor trigger zone (CTZ) and the nucleus tractus solitarius (NTS) the most important relay areas for afferent impulses arising in the G.I.T., throat ,and other viscera. The CTZ is accessible to blood born drugs, toxins etc because of it lack blood brain barrier. The CTZ and NTS expresses different receptors eg Histaminic H1,Dopamine D2, Serotonin 5HT3,Cholinergic M And opoid
- 7. Emetic signalsare relayed through these receptors, which could be target of antiemetic drug action. Impulses from vestibular apparatus reaches vomiting centre mainly relayed from the cerebellum and utilises muscarinic and H1 receptors. Cytotoxic drugs, radiation , and other G.I. irritant release serotonin (5HT) from enterochromaffin cells acts on 5 HT receptors present on vagal afferent and send impulse to NTS and CTZ . Released in large quantities 5HT may also spill into circulation and reach CTZ.
- 8.
- 9. 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
- 10. Drug Dopamine AcetylcholineHistamine Serotonin Anticholinergic scopolamine + ++++ + _ Antihistamines + ++/+++ ++++ _ Antiserotonins _ _ _ ++++ Benzamides - Domperidone Metoclopramide ++++ +++ _ _ _ _ + ++ Neuroleptics ++++ +/- +/++ -/+ Steroids _ _ _ _ RECEPTOR Specificity-
- 11. 5HT3 Antagonists- ONDANSETRON- -Developed tocontrol cancer chemotherapy /radiotherapy induced vomiting but is also highly effective in post operative nausea and vomiting. Mechanism of action – Cytotoxic drugs / radiation produces nausea and vomiting by causing cellular damage Release of mediators of inflammation including 5HT from intestinal mucosa Activation of vagal affarent in gut Emetogenic impulse to NTS and CTZ.
- 12. Ondansetron blocksemetogenic impulse both at their peripheral origin and central relay. Does not block D2 receptors. Do not affect GI motility or lower esophageal sphincter tone Pharmacokinetics- Oral bioavailability -60-70% Hydroxylated by CYP1A2 , 2D6 and 3A. Excreted by liver and kidney. No dose reduction in renal insufficiency but needed in hepatic insufficiency. t1/2 -3-5 hours. Duration of action - 4-12 hours.
- 13. Side effects – Welltolerated Headache (most common) Mild constipation or diarrhoea and abdominal discomfort Prolongation of QT interval. Granisetron- More potent (10 -15)times and plasma half life is longer (6-8) hours. Needs to be given twice daily. More pronounced prolongation of QT interval..
- 14. 5HT3 antagonists I.V.dose Oral dose Ondansetron 4 mg (0.15mg/kg) 4mg (0.15mg/kg) Dolasetron 12.5 mg(0.6- 3mg/kg) 100 mg Granisetron 1 mg(10 mg/kg) 1 mg (10mg/kg) Dose- Drug interaction- No significant interaction
- 15. Prokinetic drugs- Metoclopramide- Chemicallyrelated to procainamide but no pharmacological similarity with it. GASTRIC HURRYING AGENT. ’ Mechanism of action – Acts through both dopaminergic and serotonergic receptors.
- 16. D2 Antagonism – Dopamineacting through D2 receptors is an inhibitory transmitter in g.i.t. Delays gastric emptying when food is present in stomach. Metoclopramide blocks D2 receptor Increases gastric peristalsis while relaxing the pylorus and first part of duodenum hastening gastric emptying and enhancing LES tone. Metoclopramide antagonizes D2 receptors in NTS Antiemetic Property.
- 17. 5HT4 Agonism- Metoclopramide enhancesAcetylcholine (Ach) release from myenteric neurons. Gastric hurrying and LES tonic action. 5HT3 Antagonism- At high concentration Metoclopramide block 5HT3 receptors on inhibitory myenteric interneurones and in NTS/CTZ.
- 18. Pharmacokinetics- Rapidly absorbed orally. Crossesblood brain barrier. Conjugated in liver and excreted in urine Dose should be reduced in renal dysfunction. t1/2- 3-6 hours. Side effects- Sedation,Dizziness,Diarrhoea. Extra pyramidal side effects. Parkinsonism Galactorrhoea and Gynaecomastia on long term use.
- 19. Dose- 0.25 mg/kg (10-20mg adult dose) is effective orally ,i.m. or i.v. Higher dose (1-2 mg) is used for emesis during chemotherapy. Drug interactions- Antimuscarinic drugs block GI effects of metoclopramide. Decreases absorption of orally administered Cimetidine. Concurrent use of neuroleptics increases likelihood of extra pyramidal side effects.
- 20. Domperidone- • D2 Antagonists. •Chemically related to haloperidol but pharmacologically related to metoclopramide. • Lower ceiling antiemetic and prokinetic action . • Crosses blood brain barrier poorly . • Extra pyramidal side effects are rare but hyperprolactenemia can occur.
- 21. Cisapride- • Prokinetic drugwith little anti emetic property. • Action is mainly due to 5HT4 agonism and 5HT3 antagonism. • Lacks D2 receptor antagonism. • Oral bioavailability is 33% • Hepatic metabolism by CYP3A4. • Severe ventricular arrhythmias ,prolongation of QTc interval and torsades de pointes,when taken with CYP3A4 inhibitors
- 22. Neuroleptics-( CHLORPROMAZINE) • D2Antagonists. • Potent antiemetics. • Broad spectrum antiemetic action but not effective in motion sickness. • Antiemetic dose is lower generally than antipsychotic doses. • Side effects – Sedation Acute muscle dystonia Extra pyramidal signs.
- 23. H1 Antihistaminics- Mechanism ofaction - Based on anticholinergic, antihistaminic and sedative properties. • Mainly used in motion sickness and to a lesser extent in morning sickness and PONV. • When combined with Metoclopramide , blocks extra pyramidal side effect while supplementing its antiemetic action.
- 24. Anticholinergics • Most effectivefor motion sickness. • Shown to have some activity in PONV. • Side effects are urinary retention ,difficulty in visual accommodation , exacerbation of glaucoma. • eg. Hyosine , dicyclomine.
- 25. Corticosteroids- DEXAMETHASONE- o Synthetic glucocorticoid oEffective antiemetics for PONV , chemotherapy and radiation induced nausea vomiting. o Effective for refractory nausea and vomiting particularly in children. o Effective up to 24 hrs ,useful for postdischarge nausea and vomiting.
- 26. Mechanism of Action oAnti-emetic mechasnism of Dexa. is still unclear o Some experimental studies results suggest that dexamethasone exerts its central anti-emetic action through an activatoin of the gluco-corticoid receptors in the B/L (Bilateral) NTS in the medulla, not AP (area of postrema)
- 27. Dose: - (anti-emetic) 150µg/kg in child & 8 mg i.v.in adult The anti-emetic effect are more when Dexa. is used with the combination of ondansetron.
Editor's Notes
- #4 5HT3 Antagonists – Ondansetron Granisetron Dolasetron Parovasetron Prokinetic Drugs – Metoclopramide Domperidone Cisapride Mosapride
- #5 Neuroleptics – Chlorpromazine Prochlorperazine Haloperidol etc… H1 Antihistaminics - Promethazine Diphenhydramine Dimenhydrinate cylizine meclizine cinnarizine
- #6 Anticholinergics- Hyoscine Dicylomine Adjuvent Antiemetics- Dexamethasone Benzodiazepines Cannabinoides
- #7 Pathophysiology - Vomiting centre lies in the medulla oblongata. The chemoreceptor trigger zone (CTZ) and the nucleus tractus solitarius (NTS) the most important relay areas for afferent impulses arising in the g.i.t , throat ,and other viscera. The CTZ is accessible to blood born drugs, toxins etc because of lack blood brain barrier. The CTZ and NTS expresses different receptors eg histaminics H1,dopa mine D2, serotonin 5HT3,cholinergic M And opoid
- #11 Receptor Specificity-
- #14 Granisetron- More potent (10 -15)times and plasma half life is longer (6-8) hours. Needs to be given twice daily. More pronounced prolongation of QT interval..
- #16 D2 Antagonism – Dopamine acting through D2 receptors is an inhibitory trasmittor in g.i.t.Delays gastric emptying when food is present in stomach. Metoclopramide blocks D2 receptor hastening gastric emptying and enhancing LES tone.
- #18 5HT4 Antagonism- Metoclopramide enhances Acetylcholine (Ach) release from myenteric neurons. Gastric hurrying and LES tonic action. 5HT3 Antagonism- At high concentration metoclopramide block 5HT3 receptors on inhibitory nuenteric interneurones and in NTS/CTZ.
- #19 Side effects- Sedation,dizziness,diarrhoea Extrapyramidal side effects parkinsonism galactorrhoea and gynaecomatia on long term use.
- #20 Dose- 0.25 mg/kg (10-20 mg adult dose) is effective orally ,i.m. or i.v. Higher dose (1-2 mg) is used for emesis during chemotherapy. Drug interactions- Antimuscarinic drugs block GI effects of metoclopramide. Decreases absorption of orally administered cimetidine. concurrent use of nuroleptics increases likelihood of extra pyramidal side effects.
- #21 Domperidone- -D2 Antagonists. -Chemically related to haloperidol but pharmacologically related to metoclopramide. -Lower ceiling antiemetic and prokinetic action . -crosses blood brain barrier poorly . -Extrapyramidal side effects are rare but hyperprolactenemia can occur.
- #22 Cisapride- prokinetic drug with little anti emetic property. Action is mainly due to 5HT4 agonism and 5HT3 antagonism. Lacks D2 receptor antagonism. Oral bioavailability is 33% Hepatic metabolism by CYP3A4. Severe ventricular arrythmia ,prolongation of QTc interval and torsades de pointes,when taken with CYP3A4 inhibitors.
- #23 Neuroleptics- -D2 Antagonists. -Potent antiemetics. -broad spectrum antiemetic action but not effective in motion sickness. -Antiemetic dose is lower generally than antipsychotic doses. side effects – sedation acute muscle dystonia extrapramidal signs.
- #24 HH1 Antihistaminics- Mechanism of action -] based on anticholinergic, antihistaminic and sedative properties. Mainly used in motion sickness and to a lesser extent in morning sickness and PONV. When combined with metoclopramide , blocks extrapyamidal side effect while supplementing its antiemetic acyion.
- #25 Anticholinergics- Most effective for motion sickness. Shown to have some activity in PONV. Side effects are urinary retention ,difficulty in visual accommodation , exacerbation of glaucoma.
- #26 Benzodiazepines- Not very effective antiemetic Sedative, amnestic and antianxity effects helpful in reducing the anticipatory component of nausea and vomiting. suppress dystonic side effects of metoclopramide.