Nausea and Vomiting Lecture Notes PDF

Applied Pharmacology of the Nervous & Endocrine Systems (M33319) Year 2 Pharmacy (M33522) Nausea & Vomiting Chapter 30 Rang & Dale’s Pharmacology Chapter 30: Medical Pharmacology at a Glance 1  Learning Objec...

Applied Pharmacology of the Nervous & Endocrine Systems (M33319) Year 2 Pharmacy (M33522) Nausea & Vomiting Chapter 30 Rang & Dale’s Pharmacology Chapter 30: Medical Pharmacology at a Glance 1  Learning Objectives 1. Describe the region of the CNS involved in coordinating nausea and vomiting (N&V). 2. Describe the triggers and causes of N&V from motion sickness to drug induced and chemotherapy induced N&V. 3. Describe the mechanism of action of the anti-emetic drugs. 4. Identify and recommend the most appropriate pharmacological treatments for N&V. 2  Nausea & Vomiting Unwanted side effects of many clinically used drugs: – Cancer chemotherapy – Opioids – General anaesthetics – Digoxin – SSRI’s Indication of other underlying disease/disorder. – Motion sickness – Bacterial/viral infection – Other conditions……………. 3  Diseases and Conditions Clinically important for two reasons: 1.Symptoms of underlying conditions or diseases: drug toxicity, pregnancy, motion sickness, gastrointestinal obstruction, hepatitis, pancreatitis, myocardial infarction, renal failure, increased intracranial pressure, asthma, Zollinger-Ellison syndrome, diabetes mellitus, thyrotoxicosis, and epilepsy. 4  Importance 2. Vomiting can lead to many life-threatening consequences: aspiration pneumonia, Mallory-Weiss syndrome / tears (gastro-oesophageal sphincter), oesophageal rupture (Boerhaave’s syndrome), volume (dehydration) and electrolyte depletion, acid base imbalance malnutrition. 5  Components of Vomiting Nausea. – Extremely unpleasant discomfort, that is difficult to define, which may precede vomiting! – May occur without retching or emesis. Stimuli labyrinth stimulation, Visceral pain, Unpleasant memories and Numerous drugs. – Possibly same pathways that mediate emesis. – Mild activation of these pathways may lead to nausea – Intense activation leads to retching and/or emesis. 6 Location of Vomiting Centre and CTZ 7  Nausea and Intestinal Motility Gastric tone is reduced Gastric peristalsis is diminished or absent. The tone of the duodenum and proximal jejunum tends to be increased. Reflux of duodenal contents into the stomach is common. 8  The reflex mechanism Defensive response to remove irritating or toxic material. – Poisons – Bacterial toxins – Cytotoxic drugs Triggers release of 5-HT from the enterochromaffin cells in the intestinal mucosa. 5-HT activates vagal afferent fibres. Physical act is co-ordinated by the vomiting / emetic centre in the medulla. – Medulla receives input from chemoreceptor trigger zone (CTZ) in the area postrema. – CTZ receives inputs from the vestibular nuclei (motion sickness) Vagal afferents from the GI tract Higher cortical centres (emotional input) Blood (circulating drugs and toxins) 9  Main neurotransmitters involved Acetylcholine (M1) Histamine (H1) 5-HT (5-HT3) Dopamine (D2) Substance P (neurokinin receptors) 10  Location of Other Centres in the Medulla & Associated Phenomenal Hypersalivation. – This probably results from the close proximity of the medullary vomiting and salivary centres. Cardiac Rhythm Disturbances. – Nausea is usually accompanied by tachycardia (elevated pulse rate) and retching by bradycardia (slow pulse). – Cardiac arrhythmias (retching & vomiting) Defecation. – May accompany vomiting. – Vomiting and defecation pathways are adjacent in the area postrema of the medulla by the same stimuli. 11  Anatomy Continued Chemoreceptor Trigger Zone (CTZ) – Resides outside the blood brain barrier in the area postrema – Sensitive to drugs such as: apomorphine (emetogenic agent and treatment for ED; D2agonist) morphine (opioid analgesics) general anaesthetics (eg. Isofluorane) cardiac glycosides (digoxin) certain chemotherapeutic agents maternal hormones (HCG) – Receptors in the CTZ Dopamine (D2-receptors), 5-HT3 12 Fig. 25.5 Schematic diagram of the factors involved in the control of vomiting, with the probable sites of action of antiemetic drugs. The cerebellum may function as a second relay or gating mechanism in the link between labyrinth and chemoreceptor trigger zone (CTZ; not shown). 5-HT3, 5-hydroxytryptamine type 3; ACh, acetylcholine; D2, dopamine D2; H1, histamine H1; M, muscarinic. 13 (Based partly on a diagram from Borison H L et al. 1981 J Clin Pharmacol 21: 235–295.)  Chemical Structures of Antiemetics Acetylcholine Scopolamine/hyoscine (Muscarinic type 1 receptor antagonist) Histamine Cinnarizine Promethazine Histamine type 1 Histamine type 1 receptor antagonist) receptor antagonist) 14  Chemical Structures Metoclopramide (D2 receptor antagonist) ­Aprepitant NK1 – antagonist Substance-P ¯ Ondansetron 5-Hydroxytryptamine (5HT3 receptor antagonist) 15 Medulla oblongata a postrem Area 16 Medical Pharmacology & Therapeutics 17  Inflammation and N&V SAIDS can help with CINV. Inhibit synthesis and release of cytokines (TNFa and IL-1) 18  Neurokinin 1 (NK1) and N&V Both serotonin and substance P are agonists at NK1 receptors. NK1 receptors found in the brainstem and CTZ. 19  Emetogenic Agents Why induce vomiting – Ingested toxins but never if they are corrosive – Only in fully conscious patients Drugs used: – Ipecacuanha (emetine & cephaeline) with activated charcoal (absorbs toxins) – Copper sulphate (CuSO4) either p.o. or i.v. – Apomorphine – D2 agonist for ED 20  Antiemetics H1-receptor antagonists: – Labyrinthes (MOTION SICKNESS) and most causes nausea and vomiting. – cinnarizine, cyclizine, diphenhydramine, promethazine also anti-muscarinic activity, mild sedative action, Generally effective regardless of cause of emesis. Muscarinic receptor antagonists – Labyrinthes (Mainly MOTION SICKNESS) – hyoscine, scopolamine mild sedative action, Generally ineffective for agents acting on CTZ. Blurred vision, dry mouth, urinary retention. 21  Antiemetics continued Phenothiazines (AChM and H1 antagonists) – Uses: Cytotoxic induced N&V, Post-operative N&V – eg Chlorpromazine, trifluorphenazine, prochlorphenazine anti-histamine & anti-muscarinic action in CTZ, Can be given rectally so useful if vomiting has started. Dopamine (D2-receptor) antagonists – Uses: CINV & PONV – Metoclopramide, domperidone (phenothiazine related structurally to metoclopramide), less central side effects. – Side Effects? Extrapyramidal effects Exacerbate Parkinson's Disease spasmodic torticollis. Stimulates prolactin release resulting galactorrhoea. 22  Antiemetics continued 5-HT3-antagonists – Uses: CINV & PONV – ondansetron (Zofran; GSK) 8 mg iv infusion prior to chemotherapy; 8 mg p.o. – tropisetron (Navoban; Novartis) 5 mg iv infusion prior to chemotherapy; 5 mg p.o. – granisetron (Kytril; GSK) 3 mg iv infusion only (over 30 secs), 9 mg maximum. – Side Effects? Headache, GI upsets (motility) Depression? NK1 Antagonists (Substance P antagonist) – Delayed phase nausea in CINV – Prepitant, fosaprepitant, netupitant and rolapitant – Rolapitant t1/2 = 160 h 23  Antiemetics continued Tetrahydrocannabinol (THC) – Cannabinoid receptor agonists – CINV and PONV – nabilone (synthetic derivative) via CB1 receptors in GIT Side Effects: Drowsiness, dizziness and dry mouth. Corticosteroids: – Either alone or in combination: High dose methylprednisolone plus phenothiazine. Anticipatory nausea – benzodiazepines (sedative effect) – propranolol 24  Summary of action of common antiemetics Class Drugs Site of action Comments H1 receptors in the CNS (causing sedation) Widely effective regardless of Antihistamines Cinnarizine, cyclizine, promethazine and possibly anticholinergic actions in the vestibular apparatus cause of emesis Anticholinergic actions in the vestibular Antimuscarinics Hyoscine apparatus and possibly elsewhere Mainly MS Cannabinoids Nabilone Probably CB1 receptors in the GI tract CINV Phenothiazines: prochlorphenazine, Dopamine antagonists perphenazine, trifluorphenazine, D2 receptors in CTZ CINV, PONV, NNV, RS chlorpromazine Related drugs: droperidol, haloperidol D2 receptors in GI tract CINV, PONV, RS Metoclopramide D2 receptors in the CTZ and GI tract PONV, CINV Domperidone D2 receptors in CTZ CINV Probably multiple sites of action, including CINV; often used in combination Glucocorticoids Dexamethasone the GI tract with other drugs 5-HT3antagonists Granisteron, ondansetron, palonosetron 5-HT3 receptors in CTZ and GI tract PONV, CINV NK1 receptors in CTZ, vomiting centre and CINV; often given in combination Neurokinin-1 antagonists Aprepitant, fosaprepitant, rolapitant possibly the GI tract with another drug Abbreviations: CINV, cytotoxic drug-induced vomiting; CNS, central nervous system; CTZ, chemoreceptor trigger zone; GI, gastrointestinal; PONV, postoperative nausea and vomiting; MS, motion sickness; RS, radiation sickness. Summary 26  VOMITING During Pregnancy (Morning sickness) https://cks.nice.org.uk/topics/nausea-vomiting-in-pregnancy/ https://www.medicinesinpregnancy.org/ TREATMENT – only in severe cases as it occurs (usually) in early pregnancy. CAUTION! – For mild symptoms: Dietary and lifestyle can improve occurrence and severity. Stay hydrated, small regular meals, low fat and high carbohydrate meals. – Eat a diet rich in protein and complex carbohydrates (milk shakes, fruit juices, vegetables) – take plenty of fluids, eat in bed (crackers etc can help fight an attack). “What to expect when you’re expecting”. Eisenberg, Murkoff & Hathaway, Workman Publishing New York. ISBN 0-89480-829-X pp105-107. 27  HYPEREMESIS GRAVIDUM Like morning sickness, but becomes more severe and persists. Mother can become malnourished: – glycogen depletion and ketosis (fat metabolism) which worsens sickness, – weight loss, raised pulse, diarrhoea & sleeplessness. – If left untreated, toxaemia with elevated temp, neuritis, dim vision, memory loss, delerium convulsions & coma. 28