Antiemetics

Antiemetics

• 1.
  ANTIEMETICS DR.ZIKRULLAH
• 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.
  pathophysiology
• 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.