Antiemetics PDF

Antiemetics and Prokinetics Indika Wettasinghe Department of Pharmacology Objectives 1. Recall the - Physiology of vomiting and neuronal pathways involved Triggers that lead to nausea and vomiting Different types of neuro-receptors involved in nausea and vomiting 2. List different...

Antiemetics and Prokinetics Indika Wettasinghe Department of Pharmacology Objectives 1. Recall the - Physiology of vomiting and neuronal pathways involved Triggers that lead to nausea and vomiting Different types of neuro-receptors involved in nausea and vomiting 2. List different classes and common drugs used to treat nausea and vomiting 3. Describe the pharmacological properties of the above drugs 4. Discuss the clinical uses of the drugs “vomiting center” Is a loosely organized neuronal region within the lateral medullary reticular formation Coordinates vomiting through - cranial nerves VIII and X and neural networks in the nucleus tractus solitarius (control respiratory, salivatory, and vasomotor centers.) High concentrations of muscarinic M1, histamine H1,neurokinin 1 (NK1), and serotonin 5-HT3 receptors Four sources of afferent input to the vomiting center: 1. The “chemoreceptor trigger zone” or area postrema – located at the caudal end of the fourth ventricle, outside the BBB. Is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. The CRTZ - rich in D2 receptors and opioid receptors, and possibly serotonin 5-HT3 receptors and NK1 receptors. 2. The vestibular system Important in motion sickness Rich in muscarinic M1 and histamine H1 receptors 3. Vagal and spinal afferent nerves from the gastrointestinal tract Rich in 5-HT3 receptors. Irritation of the gastrointestinal mucosa by chemotherapy, radiation therapy, distention, or acute infectious gastroenteritis → release of mucosal serotonin and activation of these receptors, stimulate vagal afferent input to the vomiting center and CTRZ. 4. The central nervous system – plays a role in vomiting due to psychiatric disorders Stress anticipatory vomiting prior to cancer chemotherapy. There are a 101 causes for nausea and vomiting  Antiemetics 1. D2 dopamine receptor antagonists : Metoclopramide(A),Domperidone (A) 2. 5-HT3 antagonists : ondansetron (A), granisetron, dolasetron, and palonosetron 3. H1 histamine-antagonists : Cinnarizine, cyclizine, promethazine (A) 4. Phenothiazines (act via D2 antagonism): Prochlorperazine, perphenazine trifluoperazine 5. Antimuscarinic drugs: hyoscine (A) , scopolamine 6. Corticosteroids: dexamethasone (A) 7. Antagonists of neurokinin 1 (NK1): Aprepitant, netupitant, and rolapitant 8. Cannabinoid receptor agonists: dronabinol and nabilone Metoclopramide Oral, IV, IM Block dopamine D2 receptors in the CTZ - antinausea and antiemetic action Act Directly on the GI tract by enhancing Ach at muscarinic nerve endings in the gut → increase esophageal peristaltic amplitude, increase lower esophageal sphincter tone, relaxes pyloric antrum → enhance gastric emptying No effect on small intestine or colonic motility Metoclopramide also blocks dopamine receptors elsewhere in the central nervous system whereas domperidone does not readily cross BBB Domperidone Oral, rectal Block dopamine D2 receptors in the CTZ Selective peripheral activity in the upper gastrointestinal tract. The major advantage of this drug is that it does not cross the blood-brain barrier and therefore lacks the neurologic side effects of metoclopramide. Excreted in the urine, but no dose adjustment required until eGFR 10 mg once or twice daily  Clinical Uses – Metoclopramide and Domperidone 1. GORD - Metoclopramide/ domperidone. used in the Rx of symptomatic GERD , not effective in patients with erosive esophagitis. Because of the superior efficacy and safety of antisecretory agents in the treatment of heartburn, prokinetic agents are used mainly in combination with antisecretory agents in patients with regurgitation or refractory heartburn 2. Acute Migraine 3. Non-ulcer dyspepsia - symptomatic improvement in patients with chronic dyspepsia. 4. Prevention of vomiting - Prior to surgery. Pre-medication the night before and during induction. 5. Postpartum lactation stimulation 6. High-dose intravenous metoclopramide combined with dexamethasone and diphenhydramine (to counteract the dopaminergic toxicity of metoclopramide) was formerly the antiemetic regimen of choice with highly emetogenic chemotherapy Now 5HT 3 antagonists are used. Impaired gastric emptying— widely used in the Rx of delayed gastric emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis. Metoclopramide - promote advancement of NG tubes from the stomach into the duodenum. Adverse Effects - metoclopramide Central nervous system - Restlessness, drowsiness, insomnia, anxiety, and agitation Extrapyramidal effects (dystonia, akathisia, parkinsonian features) due to central dopamine receptor blockade ,occur acutely in 25% given high doses and in 5% receiving long-term therapy - especially the elderly and young females. Tardive dyskinesia, sometimes irreversible with prolonged Rx → long-term use avoided, especially in the elderly. Elevated prolactin levels (caused by both metoclopramide and domperidone) - galactorrhea, gynecomastia, impotence, and menstrual disorders Will worsen Parkinsonian motor symptoms. – Domperidone useful CI : soon after GI surgery, GI obstruction, GI haemorrhage, GI perforation  Adverse effects - Domperidone Less prone to produce central side effects – less sedation and dystonia Small increased risk of serious cardiac side-effects - serious ventricular arrhythmias or sudden cardiac death, particularly with doses > 30 mg or when used in patients > 60 years of age Use at the lowest effective dose for the shortest possible duration (max. treatment duration should not normally exceed 1 week); CI: 1. Impaired cardiac conduction – QT prolongation 2. Coadministration with drugs that prolong the QT interval or potent CYP3A4 inhibitors 3. Moderate to Severe hepatic impairment  Serotonin 5HT-3 antagonists as antiemetic Ondansetron, granisetron, dolasetron, palonosetron, tropisetron 5HT-3 receptor blocking in CNS (CTZ, VC) and peripherally T ½ : 4–9 hours and administered once daily oral or intravenous routes Extensive hepatic metabolism and eliminated by renal and hepatic excretion. (dose reduction in severe hepatic impairment. No dose adjustments are likely to be necessary in CKD as clearance by the kidney accounts for only 5% of total clearance Clinical uses 1. Chemotherapy-induced nausea and vomiting – acute, no effect in delayed, efficacy enhanced by corticosteroids (dexamethasone). Best given prophylactically. 2. Gastroenteritis 3. Postoperative and post radiation nausea and vomiting, Tx and prevention The antiemetic action is restricted to emesis attributable to vagal stimulation (eg. postoperative) and chemotherapy; Other emetic stimuli such as motion sickness are poorly controlled. 5HT-3 antagonists : adverse effects and drug interactions Well-tolerated agents , excellent safety profiles. Common - headache, dizziness, and constipation. All four agents cause a small but statistically significant prolongation of the QT interval. Serotonin Syndrome - reported in patients taking 5-HT3-receptor antagonists with other serotonergic drugs SSRIs and SNRIs CI: Long QT Syndrome H1 Antihistamines Antihistamines – No action at the CTZ Cinnarizine, cyclizine and promethazine, Meclizine, dimenhydrinate – oral Diphenhydramine and one of its salts, dimenhydrinate - first-generation histamine H1 antagonists ,have significant anticholinergic properties. Used in conjunction with other antiemetics for treatment of emesis due to chemotherapy. Meclizine - H1 antihistaminic agent - minimal anticholinergic properties, less sedation. used in prevention of motion sickness Uses prevention or treatment of motion sickness pregnancy induced vomiting  Antimuscarinics Hyoscine (scopolamine), a prototypic muscarinic receptor antagonist, is one of the best agents for the prevention of motion sickness. High incidence of anticholinergic effects when given orally or parenterally. Better tolerated as a transdermal patch AE o All the unwanted effects of antimuscarinic agents. o Dizziness, Sedation, Confusion, Dry mouth, Cycloplegia, Urinary retention Corticosteroids Dexamethasone, methylprednisolone Basis for antiemetic effect is unknown Appear to enhance the efficacy of 5-HT3-receptor antagonists Prevention of acute and delayed nausea and vomiting in patients receiving chemotherapy regimens. Neurokinin 1 (NK1)-receptor antagonists Neurokinin 1 (NK1)-receptor antagonists - antiemetic properties, mediated through central blockade in the area postrema Aprepitant, netupitant, and rolapitant - highly selective NK1-receptor antagonists , cross the blood-brain barrier and occupy brain NK1 receptors. Aprepitant, netupitant, and rolapitant : oral preparations All three agents are metabolized by the liver , primarily by the CYP3A4 pathway Fosaprepitant is an intravenous formulation that is converted within 30 minutes after infusion to aprepitant.  Clinical Uses Combined with 5-HT3- receptor antagonists and corticosteroids - prevention of acute and delayed nausea and vomiting from emetogenic chemotherapeutic regimens. Combined therapy prevents acute emesis in 80–90% of patients compared with less than 70% of patients treated without an NK1 antagonist. Prevention of delayed emesis occurs in more than 70% of patients receiving combined therapy versus 30–50% treated without an NK1 antagonist  Adverse Effects & Drug Interactions Well tolerated Low incidence of fatigue and dizziness May inhibit the metabolism of other drugs metabolized by the CYP3A4 pathway Drugs that inhibit CYP3A4 metabolism may significantly increase aprepitant plasma levels (e.g. ketoconazole, ciprofloxacin, clarithromycin, ritonavir, nelfinavir, verapamil, and quinidine). Aprepitant decreases the INR in patients taking warfarin - Aprepitant is a known inducer of CYP2C9, the main warfarin-metabolizing enzyme ANTIPSYCHOTIC AGENTS – mainly dopamine antagonists (B,C) Several classes of antipsychotic agents - antiemetic properties Phenothiazines (chlorpromazine, prochlorperazine and haloperidol) - mediated through inhibition of dopamine and muscarinic receptors. AE - Sedative properties due to antihistamine activity, extrapyramidal movement disorders Olanzapine : inhibition of dopamine D2 and serotonin 5-HT1c and 5-HT3 receptors Butyrophenones : central dopaminergic blockade (droperidol IM/IV- sedating in antiemetic doses) Side effects: EPS, hypotension, prolonged QT interval, sedation Other antiemetics (B,C) Benzodiazepines Benzodiazepines - lorazepam or diazepam , used before the initiation of chemotherapy, reduce anticipatory vomiting or vomiting caused by anxiety Cannabinoids Eg. Dronabinol, nabilone dronabinol is a psychoactive agent in marijuana medically as an appetite stimulant and as an antiemetic, the mechanisms not understood. Combination therapy with phenothiazines provides synergistic antiemetic action and attenuate the adverse effects of both agents. almost completely absorbed , undergoes significant first-pass hepatic metabolism. metabolites are excreted slowly over days to weeks in the feces and urine. Adverse effects - euphoria, dysphoria, sedation, hallucinations, dry mouth, and increased appetite. autonomic effects - tachycardia, conjunctival injection, and orthostatic hypotension  Betahistine : has complicated effects on histamine action, antagonising H3 receptors but having a weak agonist activity on H1 receptors. It is used to control the nausea and vertigo associated with Menière’s disease (C) Pro-kinetics Clinical uses - Gastroparesis : a syndrome of objectively delayed gastric emptying in the absence of a mechanical obstruction. GERD Gastrointestinal dysmotility Chemotherapy induced nausea , Vomitting 1. Metoclopramide 2. Domperidone 3. Macrolides - Erythromycin 4. Cisapride - a 5HT4 agonist, stimulates antral and duodenal motility and accelerates gastric emptying of solids and liquids  Erythromycin Erythromycin, a motilin agonist, induces high-amplitude gastric propulsive contractions that increase gastric emptying. Erythromycin also stimulates fundic contractility. Oral and IV Oral erythromycin should be administered for no longer than four weeks at a time, as the effect of erythromycin decreases due to tachyphylaxis. Adverse effects - Long QT Syndrome Selection of antiemetics by clinical situation Thank you