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Deciphering Emesis

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Deciphering Emesis International Journal of Pharmaceutical Chemistry and Analysis 2021;8(1):19–24 Content available at: https://www.ipinnovative.com/open-access-journals International Journal of Pharmaceutical Chemistry and Analysis Journal homepage: https://www.ijpca.org/ Review Article Deciphering emesis 1, 2 Sunil Chaudhry *, Avisek Dutta 1Bioclinitech Technologies Pvt Ltd, Mumbai & GPATTutor.com,, India 2Cognizant Aolutions, Kolkata, West Bengal, India ARTICLEINFO ABSTRACT Article history: The incidence of nausea or vomiting changes much with etiopathogenesis. Multiple neurohumoural Received 04-03-2021 pathways lead to nausea and vomiting. The various classes of antiemetics target different pro-emetic Accepted 09-03-2021 pathways to alleviate nausea and vomiting. Some drugs target more than one pathway. It is demonstrated Available online 04-05-2021 that combination therapy is more effective than single anti-emetic agent. © This is an open access article distributed under the terms of the Creative Commons Attribution Keywords: License (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and Vomiting reproduction in any medium, provided the original author and source are credited. Chemoreceptor trigger zone Aprepitant Cannabinoid receptor agonist 5 HT receptor antagonist Neurokinin receptor antagonists 1. Introduction 5. Refractory: Nausea and/or vomiting that occurs in subsequent chemotherapy cycles despite maximum Vomiting or emesis, is defined as the involuntary, forceful antiemetic protocol expulsion of the contents of stomach through the mouth and 6. Anticipatory: Nausea and/or vomiting that is sometimes from nose. triggered by sensory stimuli associated with chemotherapy administration. 1 2. Types of Vomiting Features of Cancer Chemotherapy induced nausea and 2.1. Vomiting centre vomiting: The chemoreceptor trigger zone in the Area postrema plays 1. Acute emesis: which can feature within 24 hrs of a crucial role in emesis and is one of principal areas that can treatment. induce emesis. The other sites besides the CTZ that relay 2. Delayed emesis: within 1-7 days after treatment (rare information to the vomiting center to induce emesis include & most commonly associated with cisplatin). the GI tract, the vestibular system, and the higher centers in 3. Anticipatory emesis: occurs before administration of the cortex and thalamus. chemotherapy; it reflects a conditioned response to Vomiting is through a complex series of multi- stimuli such as sight & smell. afferent neural pathways involving the some neuro- 4. Breakthrough: Nausea and/or vomiting that occurs transmitters - 5HT3, serotonin, dopamine, histamine within 7 days post chemotherapy. and acetylcholine. Drugs that block these receptors have useful anti-emetic properties. Antagonists of histamine * Corresponding author. and acetylcholine are more useful in controlling vomiting E-mail address: [email protected] (S. Chaudhry). associated with motion sickness, whereas serotonin https://doi.org/10.18231/j.ijpca.2021.004 2394-2789/© 2021 Innovative Publication, All rights reserved. 19 20 Chaudhry and Dutta / International Journal of Pharmaceutical Chemistry and Analysis 2021;8(1):19–24 Table 1: Causes of vomiting 2 Table 2: Emetogenic potential of anticancer drugs Gastroenteritis : Bacterial, Pregnancy (6th -14th Risk IV Agents Oral Agents Viral (norovirus) Week) (High >90 Cisplatin > 50mg / m2 Migraine, Vertigo, Brain Appendicitis %) tumours Streptozotocin Alcohol Labyrinthitis Cyclophosphamide > Hyperglycaemia Food Poisoning 1500mg/m2 Gall Stones, Renal Stones Hyperglycaemia, Dacarbazine Hypoglycaemia Carmustine Cancer Chemotherapy Drugs: Metronidazole, Dactinomycin NSAIDs, Calcium channel Moderate Cisplatin <50mg/m2 blockers; Erythromycin (30-90%) Stroke Oxaliplatin Pathological: Intestinal Anxiety disorders and Cytarabine >1g/m2 Pancreatitis, obstruction, depression Carboplatin Appendicitis, Cholecystitis Ifosfamide Peptic ulcer, Severe pain Cyclophosphamide Gastroesophageal reflux <1500 mg/m2 disease Doxorubicin Heart attack Daunorubicin Excessive exercise especially Epirubicin on a full stomach Idarubicin Irinotecan Low Paclitaxel Procarbazine (10-30%) Docetaxel Cyclophosphamide Mitoxantrone Etoposide Topotecan Temozolomide Etoposide Vinorelbine Pemetrexed Methotrexate Liposomal Doxorubicin Mitomycin Gemcitabine Cytabrine <100mg/m2 5 Fluorouracil Bortezomib Cetuximab Trastuzumab Minimal Bloeomycin Chlorambucil (<10%) Busulfan Hydroxyzine Fig. 1: CTZ mediated nausea and vomiting Fludarabine Methotrexate Vinca Alkaloids Capacitabine Bavacizumab Imatinib receptor antagonists (ondansetron) and dopamine receptor Geftinib antagonists (metoclopramide) are more useful in controlling chemotherapy induced emesis. 3 tractus solitarii produced emesis. 3. Antiemetic Profile Aprepitant is a highly selective antagonist of the 3.1. Substance P and antagonist G-protein coupled neurokinin-1 receptor. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and Substance P belongs to tachykinin family and acts as a corticosteroid receptors, the targets of existing therapies for neurotransmitter. Substance P is found in the gut and the chemotherapy-induced nausea and vomiting (CINV) and central nervous system, specifically the vagal afferent fibers postoperative nausea and vomiting (PONV). Neurokinin- that innervate the nucleus tractus solitarii and the area 1 receptors are present in both the central and peripheral postrema. Substance P binds to a specific neurokinin 1 nervous systems. Their primary ligand is substance P, a receptor (NK1). Substance P applied directly to the nucleus nociceptive neurotransmitter. The areas in the brainstem Chaudhry and Dutta / International Journal of Pharmaceutical Chemistry and Analysis 2021;8(1):19–24 21 Table 3: Classification of antiemetic drugs Receptor Agonists Antagonists D2 (Dopaminergic) Dopamine Metoclopramide Trimethobenzamide Prochlorperazine Droperidol D2 and D3 Domperidone H1 (Histaminic) Histamine Diphenhydramine Dimenhydrinate Meclizine Neurokinin 1 Receptors Substance P Maropitant Morpholine Aprepitant Glucocorticoid receptor Dexamethasone ENK (Encephalinergic) Met & Leu Enkaphalin Butorphanol Motilin Erythromycin 5HT3 receptor Granisetron Cannabinoid receptor - Dronabinol Palonosetron Delta-9-tetrahydrocannabinol site Nabilone Alosetron Fig. 2: Location of receptors contributing to nausea and vomiting 22 Chaudhry and Dutta / International Journal of Pharmaceutical Chemistry and Analysis 2021;8(1):19–24 thought to play critical roles in the vomiting reflex 3.3. Steroids are the central pattern generator, the nucleus tractus solitarius (NTS), and area postrema. Aprepitant (oral) and 3.3.1. Dexamethasone fosaprepitant (intravenous prodrug) are indicated for the Dexamethasone may also be used as monotherapy in prevention of nausea and vomiting. low—emetic risk chemotherapy regimens. Glucocorticoids may act via the following mechanisms: (1) anti- The recommended dose of Aprepitant is 125 mg orally inflammatory effect; (2) direct central action at the solitary 1 hour prior to chemotherapy treatment (Day 1) and 80 mg tract nucleus, (3) interaction with the neurotransmitter orally once daily in the morning on Days 2 and 3.) serotonin, and receptor proteins tachykinin NK1 and NK2, alpha-adrenaline, etc.; (4) maintaining the normal Fosaprepitant dimeglumine, is a prodrug of aprepitant, physiological functions of organs and systems; (5) was developed to provide a parenteral alternative to the regulation of the hypothalamic-pituitary-adrenal axis; and orally administered aprepitant. Fosaprepitant is rapidly (6) reducing pain and the concomitant use of opioids, converted to aprepitant via the action of ubiquitous which in turn reduces opioid-related nausea and vomiting. 6 phosphatases. Based on equivalence studies, 115 mg Dexamethasone, at intravenous doses of 10 to 20 mg, fosaprepitant seems to be the substitute for 125 mg orally improved the efficacy of high-dose metoclopramide in administrated aprepitant cisplatin-treated patients by 20%. Dose of (fosaprepitant dimeglumine) for Injection may be substituted for oral Aprepitant (125 mg) on Day 1 only 3.3.2. Dopaminergic antagonists as part of the CINV regimen. 4,5 Metoclopramide is a dopamine antagonist with a short- life and is one of the most frequently used dopamine Rolapitant is a selective and competitive antagonist antagonists. Metoclopramide is commonly used to treat of human substance P/NK1 receptors with antiemetic nausea and vomiting associated with conditions such activity. Rolapitant is indicated in combination with other as uremia, radiation sickness, cancer and the effects of antiemetic agents in adults for the prevention of delayed chemotherapy, A 10mg dose of metoclopramide has become nausea and vomiting associated with initial and repeat the most commonly used dose. courses of emetogenic cancer chemotherapy, including, Prochlorperazine is a piperazine phenothiazine but not limited to Highly emetogenic chemotherapy. The antipsychotic which block postsynaptic mesolimbic recommended dosage of rolapitant is 180 mg (two 90-mg dopaminergic receptors in the brain and has antiemetic tablets) administered orally as a single dose one to two hours effects by its antagonist actions in the D2 dopamine prior to the start of chemotherapy on day 1 with or without receptors in the chemoreceptor trigger zone. It also exhibits food. Rolapitant is well tolerated, constipation, headache, alpha-adrenergic blocking effect on α1 receptors and may fatigue, dizziness,
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