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ANTIEMETICS AND PROKINETICS.pptx
- 2. EMESIS •Protective reflex - to get rid the stomach and intestine of toxic substances and prevent their further ingestion. 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
- 5. Serotonin(5-HT3), Dopamine(D2), Ach(M1/M3), Neurokinin(NK1 ) Opioids(µ) Cannabinoid(CB1) Histamine(H1),
- 6. EMETICS According to site of action: a.Centrally acting: Apomorphine & Morphine b.Peripherally acting: Mustard, Potassium tartrate (tartar emetic) and hypertonic sodium chloride c.Both: Ipecacuanha
- 7. APOMORPHINE D2 AGONIST • Given SC/IM -6mg Causes vomiting within 15 min Vomiting is often accompanied by sedation Should not be used if respiration is depressed Large doses often produce restlessness, tremors, occasionally convulsions Sometimes may cause hypotension, syncope and coma
- 8. Emetics –Peripherally acting Mustard: Volatile oil safe and easily available Dose -1 tsp inwater Sodium chloride: Given orally Withdraws fluid from the cells lining the stomach causes irritation which causes reflex emesis
- 9. Emetics –contraindication Corrosive (alkali, acid) poisoning C N S stimulant drugpoisoning Kerosine (petroleum) poisoning Unconscious patient
- 10. LIST OF DRUGS INDUCE VOMITING Anticancer drugs Amiodarone Apomorphine Chloroquine, quinine Diltiazem Emetine Ergot derivatives Erythromycin, tetracyclines Fluroquinolones Metronidazole
- 12. ANTICHOLINERGICS HYOSCINE Dosage: 0.2-0.4 mg oral, i.m. Most effective drug for motion sickness But action is brief; & sedation & other anticholinergic side-effects MOA – Block cholinergic NT in the vestibular-emetic centre pathway not useful for vomiting other than due to motion sickness TTDS – 1.5 mg over 3 days; applied behind pinna, good efficacy and minimal side effects DICYCLOMINE – 10-20 mg P/O For prophylaxis of motion sickness and morning sickness; no teratogenicity seen now; blocks M receptors 12
- 13. H1 ANTIHISTAMINES 13 PROMETHAZINE, DIPHENHYDRAMINE, DIMENHYDRINATE – • Motion sickness for 4-6 hrs • ADE – sedation & mouth dryness ++ Combined with metoclopramide, it abolishes its extra pyramidal side effects combination is useful in motion sickness (more efficacy, less side effects) DOXYLAMINE – • A sedative H1-antihistamine + anti cholinergic Combined with pyridoxine for early pregnancy morning sickness Pk - Oral absorption – slow ADE – dry mouth, drowsiness, vertigo & Abd. Upset Dose - 10-20 mg at bedtime is the dose frequency can be increased to thrice daily if needed CYCLIZINE & MECLIZINE – • Less sedative & less anticholinergic side-effects Meclizine = longer acting, protects against sea sickness for ~ 24 hrs. CINNARIZINE – • Anti-vertigo drug in motion sickness Inhibits Ca++ influx from endolymph into vestibular sensory cells regain labyrinthine reflexes no vertigo / emesis
- 14. GENERAL POINTS ABOUT H1 BLOCKERS IN EMESIS Rx - First choice in motion sickness Taken ½ - 1 hr before journey; like all anti-motion sickness drugs Once motion sickness starts, it is difficult to control higher/parenteral doses required Due to some teratogenic potential, avoid them if possible Other modalities – reassure & diet adjustment 17-05-2023 14
- 15. NEUROLEPTICS Potent anti-emetics Block D2 receptors in CTZ + antimuscarinic + antiH1 properties Broad spectrum anti-emetic action Drug-induced & post-GA nausea/vomiting Gastroenteritis-, uraemia-, liver disease- & migraine- induced vomiting Malignancy- & chemotherapy-induced vomiting Radiation sickness vomiting (less effective) Hyper emesis gravid arum Less effective in motion sickness as vestibular pathway does not involve DA 17-05-2023 15
- 16. PROCHLORPERAZINE D2 – blocker phenothiazine labyrinthine suppressant Antivertigo & antiemetic actions Useful in vertigo-associated & chemotherapy- induced nausea/vomiting ADE: Extra pyramidal side-effects & muscle dystonia Antiemetic dose << anti-psychotic dose Not given till cause of emesis is diagnosed 17-05-2023 16
- 17. PROKINETIC AGENTS - Promote gastrointestinal transit and speed gastric emptying by enhancing coordinated propulsive motility. Metoclopramide Domperidone/Tegaserod Cisapride/Mosapride METOCLOPRAMIDE GIT ACTIONS: Speeds gastric emptying decreases transit time in stomach + LES tone is increased CNS: On CTZ, it anti-emesis Pk – crosses placenta, actions last 4-6 hrs. 17-05-2023 17
- 18. Dopamine 5-HT4 agonism 5-HT3 antagonism Inhibitory transmitter in GIT • Delay gastric emptying when food is present in stomach • Cause gastric dilatation and LES relaxation attending nausea and vomiting. • G.i.t. to enhance ACh release from myenteric motor neurons • Gastric hurrying and LES tonic • 5-HT3 receptors present on inhibitory myenteric interneurones and in NTS/ CTZ.
- 19. ADE Sedation, muscle dystonia in children, loose stools, long term use parkinsonism, galactorrhoea, gynecomastia USES 1) Antiemetic: migraine, radiation sickness, postoperative & drug- induced emesis; 2) gastro kinetic: duodenal intubation, emergency GA, Relieve gastric stasis due to vagotomy/DM; 3) Dyspepsia & hiccoughs; 4) GERD: With PPIs & H2-blockers 17-05-2023 19
- 20. • D 2 antagonist • Chemically related to haloperidol but pharmacologically related to metoclopramide • Has lower ceiling antiemetic and prokinetic actions • Poorly crosses BBB • Rare extra pyramidal side effects • Absorbed orally, but bioavailability is only 15% due to first pass metabolism • Completely metabolized and excreted in urine • t ½ is 7.5hr Domperidone Cont…
- 21. Cisapride 5-HT4 agonistic (which promotes ACh release from myenteric neurons) and 5-HT3 antagonistic (minor) action in the myenteric plexus. Little antiemetic property, because it lacks D2 receptor antagonism G a s t r i c e m p t y i n g i s a c c e l e r a t e d LES tone is improved, esophageal peristalsis augmented Enteric neuronal activation via 5-HT4 receptor also promotes cAMP-dependent Cl– secretion in the colon, increasing water content of stool Devoid of action on CTZ and does not produce extrapyramidal symptoms Primary indication of cisapride has been GERD
- 22. Ventricular arrhythmias and death, mainly among patients who took CYP3A4 inhibitors like azole antifungals, macrolide antibiotics, antidepressants, HIV protease inhibitors,. At high concentrations, cisapride blocks delayed rectifying K+ channels in heart— prolongs Q-Tc interval and predisposes to torsades de pointes/ventricular fibrillation Itopride
- 23. A 55-year-old woman with type 1 diabetes of 40 years’ duration complains of severe bloating and abdominal distress, especially after meals. Evaluation is consistent with diabetic gastroparesis. Which of the following is a prokinetic drug that could be used in this situation? (A) Alosetron (B) Cimetidine (C) Loperamide (D) Metoclopramide (E) Sucralfate
- 24. CHEMOTHERAPY INDUCED NAUSEA AND VOMITING Acute- 24 hours Delayed- 2-5 days
- 25. 5HT3 ANTAGONISTS Role of Serotonin in EMESIS Vagal,spinal visceral afferents send impulses to NTS and CTZ. Extrinsic primary afferent neurones (PAN) of the enteric nervous system (ENS). Release of 5-HT from Enterochromaffin cells 5-HT spilled into circulation reach CTZ via vascular route Substance P Bradykinin Neurokinin Cannabinoid Opioid
- 26. • Ondansetron • Granisetron, • Dolasetron • Tropisetron • Palonosetron • Higher receptor affinity • Longer t1/2,
- 27. PK Absorbed well Rapid onset of action METABOLISM T1/2 Ondansetron CYP1A2, CYP2D6, and CYP3A4 3-6 hours Granisetron- 10times more potent CYP3A4 6-9 hours Dolasetron Plasma carbonyl reductase to its active metabolite, hydrodolasetron.CYP2 D6 and CYP3A4 7-9 hrs Palonosetron CYP2D6, but also by CYP3A4 and CYP1A2. 40 hrs
- 28. CLINICAL USES Prevention and treatment of Chemotherapy-induced nausea and vomiting- Acute Palanosetron even for delayed Postoperative nausea and vomiting in adults and children Drug overdosage, g.i. disorders, uraemia Neurological injuries
- 29. ADVERSE EFFECTS Well tolerated Headache and dizziness. Mild constipation and abdominal discomfort occur in few patients. Hypotension, bradycardia, chest pain and allergic reactions are PALANOSETRON – Additive Q-T prolongation can occur when given Cisapride, moxifloxacin, erythromycin, anti- psychotics and antidepressants
- 30. NEUROKININ1 RECEPTOR ANTAGONISTS Substance P from emetogenic stimuli ActIvation of NK1 Receptor at CTZ and NTS 1. Aprepitant 2. Rolapitant 3. Netupitant DELAYED VOMITING Always with SETRONS and DEXAMETHASONE
- 31. APREPITANT • Extensively bound to plasma proteins (>95%) • Metabolized primarily by hepatic CYP3A4 • Excretion- Stools • t1/2 is 9–13hrs ROLAPITANT • t1/2 at about 180 h. • CYP3A4 to form an active metabolite, M19 (C4- pyrrolidinehydro xylated • rolapitant). • Eliminated mainly via the hepatic/biliary route. • CYP2D6 INHIBITORS NETUPITANT • T1/2-~ 80 h; • extensively metabolized by CYP3A4 (major) and CYP2C9 and CYP2D6 • (minor) to active metabolites. • Urine and faeces
- 32. THERAPEUTIC USES A/E CINV,prior to highly emetogenic drugs Neutropenia, Hiccups, Decreased appetite Dizziness Rise in liver enzymes.
- 33. CANNABINOIDS Dronabinol, Nabilone Δ9 Tetrahydrocannabinol - Cannabis indica Moderately emetogenic chemotherapy. CB1 subtype of cannabinoid receptors located on neurones in the CTZ and/ or the vomiting centre itself. Inhibits proemetic effects of endogenous compounds such as dopamine and serotonin
- 34. • Highly lipid soluble • Onset – 2 hr • Extensive first-pass metabolism with limited systemic bioavailability after single doses (only • 10%–20%). • Faeces • Large Vd . • CNS-central sympathomimetic activity. This can lead to palpitations, tachycardia, vasodilation, hypotension, and conjunctival injection (bloodshot eyes). • Abstinence syndrome (irritability, insomnia, and restlessness) • Marijuana-like “highs” Prophylactic agent in patients receiving cancer chemotherapy when other antiemetic medications are not effective. AIDS related cachexia
- 35. DEXAMETHASONE Corticosteroid Adjuvant Suppression peritumoral inflammation and prostaglandin production. Augmentation of primary antiemetic drugs like metoclopramide and ondansetron against highly emetogenic regimens. Both acute and delayed emesis.
- 36. BENZODIAZEPINES Adjuvant Relief of psychogenic component, anticipatory vomiting Lorazepam and Diazepam
- 38. ANTIEMETIC DRUGS AND RECEPTORS 1) Acetylcholine 2) Dopamine 3) Serotonin 4) Neurokinin 1 5) Histamine HYOSCINE DOMPERIDONE ONDANSETRON ROLAPITANT PROMETHAZINE 5 1 2 3 4