Antiemetics 2025 Lecture Notes PDF

Antiemetics Nissar A. Darmani Professor of Pharmacology Associate Dean Research Office Room # 2301 This is a recorded lecture Send your questions via Elentra or E-mail: [email protected] January 7, 2025 1  Objectives...

Antiemetics Nissar A. Darmani Professor of Pharmacology Associate Dean Research Office Room # 2301 This is a recorded lecture Send your questions via Elentra or E-mail: [email protected] January 7, 2025 1  Objectives 1. Why do we puke? Understand neuroanatomy of vomiting! 2. Discuss the neuroanatomy and receptor mechanisms of emetic neurotransmitters 3. Do currently used antiemetics reduce nausea? 4. Understand the pharmacology and mechanisms of antiemetic actions and clinical utilization of emetrol, antimuscarinics, antihistamines, dopamine D2 receptor antagonists, metoclopramide, cannabinoids and olanzapine. 5. Discuss the pharmacology and clinical application of first- and second-generation serotonin 5-HT3 receptor antagonist antiemetics. 6. Discuss the pharmacology and clinical application of substance P neurokinin NK1 receptor antagonist antiemetics. 7. Describe the acute and delayed phases of chemotherapy-induced nausea and vomiting and their prophylactic antiemetic therapy. 2  Nausea & Vomiting (emesis) Antiemetics Nausea Unpleasant subjective feeling of imminent vomiting Its neurochemistry and neuroanatomy are not well understood Emesis Act of forceful removal of gastrointestinal content Its neurochemistry and anatomy are better understood Both are protective mechanisms Nausea and vomiting May exist on a temporal continuum, but not always Most patients complain nausea is more common, more disabling and lasts longer Several classes of good antiemetics are available, but specific antinauseant drugs are lacking Most drugs used to treat emesis are relatively poor at preventing nausea. Nausea and vomiting can be caused by a variety of diseases, conditions, drugs. 3  Emesis Blood Gastrointestinal tract Emetic reflex Is highly complex Chemotherapy-induced nausea and vomiting (CINV) 5-HT CINV, Radiation, infectious gastroenteritis, drugs, pregnancy Vagus nerve Cause release of emetic neurotransmitters, may include: Serotonin = 5-HT, dopamine = DA, substance P = SP, prostaglandins, Leukotrienes Emetogens may cause direct or indirect activation of central/peripheral emetic loci EC cell Emetic Loci Central: Dorsal Vagal complex (DVC) in the brainstem contains: Area postrema (AP) in the chemoreceptor trigger zone (CTZ) BBB = Nucleus Tractus solitarius (NTS) is an integrative site Blood brain barrier Dorsal motor nucleus of the vagus (DMNX) sends emetic stimuli to GIT Central Pattern Generator (CPG) Higher brain centers such as cerebral cortex Direct stimulation can evoke vomiting Peripheral: Gastrointestinal tract (GIT) tissues and nerves Enterochromaffin cells (EC) contains 5-HT, SP Brainstem Vagal afferents and efferents D Splanchnic nerves V Indirect stimulation of DVC emetic nuclei by these peripheral mechanisms can evoke vomiting C Vestibular apparatus in the inner ear Darmani and Ray (2009) 4  Central & Peripheral Emetic Neurotransmitters & corresponding Receptors DVC AP in the chemoreceptor trigger zone (CTZ) contains: Serotonin 5-HT3, dopamine D2/3, acetylcholine muscarinic M1, neurokinin NK1, cannabinoid CB1 and opiate u receptors NTS contains serotonin 5-HT3, dopamine D2/3, , histamine H1, acetylcholine muscarinic, neurokinin NK1, cannabinoid CB1 and opiate -emetic receptors GIT EC cells contain 5-HT3 and other receptors Vagal afferents contain 5-HT3 and possibly NK1 receptors Nausea: the insular-, anterior cingulate-, orbitofrontal-, and prefrontal-cortices mediate nausea 5 You will not be asked questions on signaling pathways for emesis 6  Antiemetics No antiemetic is effective in all types of vomiting Choice depends on reason for nausea & vomiting Some antiemetics are agonists but majority are antagonists 1. Emetrol Oral suspension of fructose + glucose + phosphate Uses: Motion sickness, Pregnancy-induced vomiting, Drug-induced vomiting 2. Histamine H1 receptor antagonists (are really inverse agonists) Mechanisms of action Antagonist of histamine H1 receptors They Block emetic vestibular afferent activity from the inner ear going to the DVC and within the DVC Uses: Primarily motion sickness and Vertigo. Also used for prevention of Postoperative nausea and vomiting (PONV)-, Pregnancy- and Drug-induced vomiting Dimenhydrinate Most effective, but sedation and cholinergic side-effects: dry mouth Diphenhydramine blurred vision, tachycardia, urinary retention, constipation Cyclizine & Meclizine More selective H1 blockers, Less side-effects 7  Antiemetics Dopamine D2 receptor antagonists I Mechanism of action: Block dopamine D2 receptors in the CTZ in the brainstem DVC Phenothiazines: are general purpose antiemetics Promethazine also blocks histamine H1 Drowsiness, dry mouth, gastrointestinal upset, Prochlorperazine also blocks muscarinic receptors neuroleptic malignant syndrome Chlorpromazine also blocks muscarinic and H 1 receptors Extrapyramidal effects: Dystonia, tardive dyskinesia, akathisia Used for prevention of nausea and vomiting caused by uremia, radiation sickness, viral gastroenteritis, motion sickness Butyrophenones: Droperidol * Droperidol for postoperative nausea and vomiting; causes: fatal cardiac arrhythmias, sedation, Haloperidol * hypotension, extrapyramidal side-effects. Haloperidol: for cannabinoid hyperemesis Syndrome* QT prolongation, neuroleptic malignant syndrome Dystonia A movement disorder causes muscles to contract involuntarily leading to repetitive or twisting movements Tardive dyskinesia An involuntary movement disorder that mainly involves face but can also involve limbs and trunk Akathisia Feeling restlessness like you can’t sit still and need to move Dopamine D2 receptor antagonists II Metoclopramide: is a benzamide- Blocks serotonin 5-HT3 and dopamine D2 receptors oral, i.v. and i.m. preparations Can cause extrapyramidal side-effects Used for Chemotherapy-induced nausea and vomiting & vomiting due to gastroparesis Also used as a Prokinetic agent Amisulpride: Is a benzamide with D2 antagonist properties used for post operative nausea and vomiting (PONV) Contraindicated in patients with arrhythmias, congestive heart failure, ondansetron which increases QT interval Olanzapine: is a second-generation antipsychotic, blocks dopamine D1,2,3,4 and serotonin 5-HT2,3,6 receptors Used for prevention of nausea, and acute as well as delayed chemotherapy-induced vomiting Side-effects weight gain, sedation, associated with onset of diabetes mellitus Metabolized by CytP450 and more than 40% is removed by hepatic first-pass effect 9 If You Have Time, You May Read the Following Papers detailing antiemetics 10  Antiemetics Antimuscarinics Block muscarinic receptors in the DVC in the brainstem Scopolamine best agent for motion sickness Side-effects Sedation, hallucinations, dry mouth, blurred vision due to pupil dilation, tachycardia, and constipation Oral, parenteral, transdermal preparations Others: e.g., atropine Cannabinoids: Nabilone (Cesamet) is synthetic, and delta-9-tetrahydrocannabinol (9-THC = dronabinol; marinol) Are agonist antiemetics and stimulate cannabinoid CB1 receptors in the brainstem DVC and in the GIT (Darmani, 2001) Are highly lipid soluble and are readily absorbed following oral administration. High plasma protein binding They undergo extensive metabolism and have active metabolites. Mainly excreted by the biliary-fecal route and 15-25% in urine Uses: chemotherapy-induced nausea and vomiting, appetite stimulant ; adjunct analgesic for neuropathic pain Side effects: Psychoactive side-effects including hallucinations, panic and anxiety effects, loss of memory, physical and psychological dependence Palpitations, tachycardia, risk in patients with high blood pressure Cannabinoid-induced hyperemesis syndrome (CIHS) following chronic high doses 11  Antiemetics Glucocorticoids are anti-inflammatory agents Dexamethasone Useful against radiotherapy-, chemotherapy-induced nausea and vomiting, and other conditions that promote synthesis and release of inflammatory mediators such as prostaglandins, leukotrienes and other eicosanoids. Glucocorticoids suppress synthesis of prostaglandins and leukotrienes by inhibiting phospholipase A2 ( PLA2). Decrease brain tissue levels of serotonin and suppress expression of 5-HT3 receptors Used in combination with 5-HT3 and NK1 receptor antagonists against both phases of CINV Uses: Radiotherapy- and Chemotherapy-induced nausea and vomiting (CINV); postoperative nausea and vomiting (PONV) 12  Serotonin 5-HT3 receptor antagonists I Are selective antagonist of 5-HT3 receptors First generation: Ondansetron (Zofran) prototype, Granisetron (Kytril), dolasetron (Anzemet) Second generation: Palonosetron (Aloxi) has additional effects MAO: Selectively block 5-HT3 receptors on vagal afferent nerve terminals in the GIT and brainstem DVC Clinical uses: First phase of CINV; Radiotherapy; Pregnancy hyperemesis; Post-operative nausea and vomiting (PONV) Not effective against delayed phase of CINV, CIHS, motion sickness, or anticipatory nausea and vomiting. Early or immediate phase CINV Delayed-phase CINV Cisplatin 10 mg/kg i.p. Darmani et al., PBB 2015 Least shrews Cisplatin + Palonosetron (0.1 mg/k, i.p) Palonosetron 0.1 mg/kg + Cisplatin 10 mg/kg, i.p 13  Serotonin 5-HT3 receptor antagonists II Ondansetron is the prototypical drug for the first generation 5-HT3R antagonists. They attenuate the immediate-phase of CINV by 60% where serotonin is the major emetic neurotransmitter Little to no effect on delayed phase CINV where substance P is the major emetic neurotransmitter Also used for radiotherapy vomiting; Post-operative vomiting (PONV); Pregnancy-induced hyperemesis Efficacy: Palonosetron more potently attenuates both phases of CINV since it has additional effects including higher affinity, allosteric interactions and positive cooperativity, which triggers 5-HT3R internalization also inhibits 5-HT3 and neurokinin NK1 receptor cross-talk Lower oral doses of first generation 5-HT3R antagonists are used against vomiting caused by mild to moderate emetic cancer chemotherapeutics Larger doses via the i.v. route can be used against highly emetogenic cancer chemotherapeutics The antiemetic effects of 5-HT3R antagonists can be potentiated by addition of dexamethasone and NK1 receptor antagonists (i.e., the triple prophylactic therapy) against both phases of CINV Palonosetron is available in oral form combined with netupitant (a second generation NK1 receptor antagonist) as one oral tablet for prophylactic CINV antiemetic therapy (NEPA). 14  Serotonin 5-HT3 receptor antagonists III Pharmacokinetics: These drugs are well absorbed orally Ondansetron can also be given I.M. and granisetron transdermally CINV: can be given I.V. 15 min prior to treatment T1/2 Ondansetron 3-6 hr; Granisetron 5-9 hr; Dolasetron 7-9 hr, Palonosetron 40 hr Duration of action outlasts their T1/2 Plasma Protein Binding moderate, 65-76% Metabolism: Cyt P450 enzymes: Palonosetron and dolasetron primarily via CYP2D6; Granisetron by CYP1A1; Ondansetron by several CYTP450 Excreted by renal & hepatic mechanisms Drug Interactions: Serotonin syndrome occurs when 5-HT3 receptor antagonists are combined with selective serotonin reuptake inhibitors. Small prolongation of QT interval with first generation 5-HT3 antagonists due to blockade of hERG potassium channels QT interval prolongation is especially important for dolasetron and is only available in oral form. Adverse effects These drugs are well-tolerated Headache, constipation, diarrhea, abdominal pain, dizziness, asthenia Symptoms of serotonin syndrome: agitation, confusion, rapid heart rate and high blood pressure, muscle rigidity, headache, high fever and seizures 15  Neurokinin NK1 Receptor (NK1R) antagonists I Apripitant (Emend); Netupitant (when combined with palonosetron = Akynzeo); Rolapitant (Varubi) Substance P binds and activates 3 Substance P neurokinin receptors called NK1, NK2 and NK3 receptors Activation of NK1 receptors (NK1R) both in the GIT and brainstem DVC emetic nuclei evokes vomiting NK1R antagonists are most-effective against the delayed-phase of CINV where Substance P is the major emetic neurotransmitter MAO NK1R antagonists reversibly bind to NK1 receptors and prevent Substance P to excite them They suppress vomiting Addition of an NK1R antagonist to dual therapy (5-HT3R antagonist + dexamethasone) against CINV provides grater emetic protection. Cisplatin 10 mg/kg i.p. Darmani et al., PBB 2015 Least shrews Early-phase Delayed-phase Netupitant 5 mg/kg + Cisplatin 10 mg/kg, i.p Cisplatin 10 mg/kg i.p. + Netupitant 16  Neurokinin NK1R antagonists II Pharmacokinetics Aprepitant, netupitant and rolapitant are orally administered and are well absorbed from the GIT Fosaprepitant (prodrug), Fosnetupitant (prodrug) and rolapitant formulations are also for i.v. administration Netupitant and fosnetupitant are available in a fixed-dose oral combination with palonosetron (NEPA) Bioavailability Aprepitant 60%; Netupitant 60%; Rolapitant 100% T1/2 Aprepitant 9-13 hr; Netupitant 90 – 144 hr; Rolapitant 160 – 180 hr Rolapitant takes longer to achieve therapeutic concentration Remember 4 x T1/2 rule! Plasma protein binding High Aprepitant 95%; Netupitant >99%; Rolapitant 100% 17  Neurokinin NK1 Receptor antagonists III Metabolism: All NK1R antagonists undergo hepatic metabolism primarily by CYP3A4 in the liver Minor metabolism of NK1 receptor antagonists by other Cyt P450 enzymes Have one or more active metabolites Aprepitant and netupitant (but not rolapitant) inhibit CYP3A4 Thus, reduce metabolism of CYP3A4 substrates such as dexamethasone and warfarin Aprepitant is also a moderate inducer of CYP3A4 and CYP2C9 Rolapitant inhibits CYP2D6 Excretion Mainly via feces and some by the Kidney 18  Neurokinin NK1 Receptor (NK1R) antagonists IV Drug Interactions: All NK1R antagonists have the potential for drug-drug interactions Potent inhibitors of CYP3A4 (ketoconazole) would increase NK1R antagonist plasma concentration Potent inducers of CYP3A4 (rifampin) would decrease NK1R antagonist plasma concentration Aprepitant reduces the effectiveness of oral contraceptives Aprepitant can increase the QT interval and thus it is contraindicated in patients on pimozide Rolapitant inhibits CYP2D6 and thus it is contraindicated in patients receiving CYP2D6 substrates such as pimozide Rolapitant inhibits efflux transporter P-glycoprotein and thus would increase plasma concentration of drugs that are substrate for P-glycoprotein such as digoxin. 19 Neurokinin NK1 Receptor antagonists V Adverse effects: NK1R antagonists are generally safe drugs and are well-tolerated and are not associated with specific adverse events Fatigue, asthenia, headache, hiccups, and constipation Infusion site reactions following i.v. administration probably due to formulation ingredients 20 Possible emetic neurotransmitters during early and delayed phases of CINV Books and exam purposes: e.g., Hesketh et al., 2003 1. Mainly serotonin release in the gut tissue during early CINV 2. Mainly substance P Release in the brainstem during delayed phase Reality: e.g., Darmani and Ray 2009 Evidence for a re-evaluation of the neurochemical and anatomical bases of chemotherapy-induced vomiting Concomitant release of several emetic neurotransmitters including serotonin, substance P, dopamine, prostaglandins, leukotrienes, etc, during both phases of CINV both in the gut and brainstem 21 Practice Questions 1. Which one of the following best describes 2. The antiemetic olanzapine the pharmacological actions of the antiemetic drug metoclopramide given to a cancer patient 1. can reduce weight. receiving a moderate emetogenic cancer 2. Selectively binds to dopamine D2 receptors chemotherapeutic? 3. Selectively binds to serotonin 5-HT3 receptors 4. does not undergo hepatic first-pass effect 1. Selective dopamine D 2 receptor antagonist 2. Selective serotonin 5-HT3 receptor antagonist G 5. Reduces nausea and vomiting caused by chemotherapeutics* 3. Selective neurokinin NK1 receptor antagonist G4. Dopamine D2 receptor + 5-HT3 receptor antagonist* 5. 5-HT3 receptor and NK1 receptor antagonist 22 Any Question? 23