1. Jonathan Hsu MD Emory University Dept of Hospice and Palliative Care 5-2010

2. Disclosure Information I have no financial relationships to disclose

3. Objectives Understand the pathophysiology of nausea and vomiting Identify common causes of nausea Select antiemetic therapy based underlying physiology

4. Sample Case: P.T. is an 85-year-old farmer with diabetes, endstage heart disease, gastroesophageal reflux disorder, chronic shoulder pain from a war injury, stage 4 chronic kidney disease, and a history of alcoholism. His shoulder pain is well controlled with extended- release morphine, 30 mg PO bid, and gabapentin, 300 mg PO q HS. However, he complains of constant nausea that limits his ability to eat.

5. Nausea An unpleasant sensation vaguely referred to the epigastrium and abdomen, with a tendency to vomit.

6. Vomiting Forcible ejection of contents of stomach through the mouth.

7. Background Nearly 60% of terminally ill cancer patients reported nausea 1 And 30% of these patients experienced vomiting 33% of patients with ESRD 5 17% of patients with HIV 7 10-40% of patients treated with Opioids 6

8. Consequences Physical Dehydration, Malnutrition, Anorexia, Weight Loss, Insomnia Psychological Effects Anxiety, Depression, Anger, Nausea can be debilitating

9. Nausea is a Symptom….. In order to treat nausea….. Identify Causes Treatment of Reversible Causes Pharmacological and Non-Pharmacological Treatments

10. Pathophysiology: Physiology of Nausea: Activated by a cluster of neurons in the medulla known as the vomiting center: VC Which receives stimuli from Chemoreceptor Trigger Zone GI Tract Vestibular Apparatus in the inner ear Cerebral Cortex

11. Pathophysiology Chemoreceptor Trigger Zone: CTZ Located in the floor of the 4 th ventricle: lacks true blood brain barrier Senses fluctuation in the bloodstream: medication and its rate of uptake, metabolic disturbances, and signals from the GI tract. The CTZ triggers the VC by Neurotransmitters Serotonin Dopamine Acetylcholine Histamine

13. CausesCentersReceptors Intracranial Pressure Anxiety and memories Cerebral Cortex Motion Sickness Vestibular Disease Vestibular Apparatus Metabolic Drugs Toxins Chemoreceptor Trigger Zone Visceral (GI, etc) Chemotherapy Radiotherapy Vagus Afferents Splanchnic nerves GABA CB GABA CB H1 M1M1 M1M1 D2D2 D2D2 5HT D2D2 Vomiting Center 5HT M1M1 H1 Cannabinoids Histamine Muscarinic Dopamine Serotonin NK Neurokinin NK

14. Causes of Nausea: Cerebral Cortex Vestibular Apparatus Chemoreceptor Trigger Zone Gastrointestinal Tract Inputs to Vomiting Center Emesis

15. Causes of Nausea: “M” Metastasis Meningeal Irritation Movement Medications Mucosal Irritation Mechanical Obstruction Motility Metabolic Microbes Myocardial

16. Cortical Causes of N/V Tumor in CNS or Meninges: Neurologic Signs or MS Changes Dexamethasone, Consider palliative radiation Increased Intracranial Pressure Projectile Vomiting, HA Dexamethasone Anxiety, other conditioned responses: food, smell,etc Anticipatory nausea, predictable vomiting Counseling, Benzodiazepines Uncontrolled Pain: Pain Control

17. Vestibular/Middle Ear Vestibular Disease: Vertigo or vomiting after head motion Meclizine: H1 blocker Scopolamine: Anticholinergic (ACHm) Promethazine Middle Ear Infections Ear pain, Bulging TM Abx, decongestants Motion Sickness Travel Related nausea Scopolamine, Dimenhydrinate, Diphenhydramine

18. Chemoreceptor Trigger Zone Medication: Opioids, Digoxin, Chemotherapy, Abx, Theophylline Metabolic Renal/Liver Failure, tumor products Increase BUN/Cr/Bilirubin Rx: Haldol Hyponatremia/Hypernatremia Confusion, Low Na+ Hypercalcemia: Somnolence, delirium, high Ca++ Hydration, Pamidronate Dexamethasone Toxins: Food poisoning, Tumor Products, Ischemic Bowel, Gut Obstructions: release of serotonin by gut irritation

19. Chemically Induced Nausea Chemical Action Stimulate D2 (+/- 5HT3) in CTZ Chemotherapy  Serotonin release in GI tract  5HT3 receptors on Vagus Nerve  VC

20. Chemical/Metabolic Causes Severe Persistent Nausea Little relief from Vomiting Small volume vomitus and/or retching

21. Gastrointestinal Tract Irritation by Rx: NSAIDS, Fe, EtOH, Abx PPI/H2 blocker, Misoprostol, or stop Rx Tumor infiltration, radiation therapy of GI tract, infection Txmnt of infection

22. Gastrointestinal Tract Constipation/Impaction/Obstruction Laxative, Manual Disimpaction, Enema Metoclopromide (if no colic) Scopolamine, Glycopyrolate (ACHm) if colic Tube Feeding Reduce volume Remove tube if gag reflex Thick Secretions: Cough induced vomiting Nebulized saline expectorant Anticholinergics

23. Gastric Stasis Anticholinergic Drugs, Opioids Ascites Hepatomegaly Gastric Mecho-Receptors  Vagal Afferents  VC

24. Bowel Obstruction Intermittent/mild nausea Nausea often relieved by vomiting Large Volume Vomitus Upper GI: early satiety, vomit after meals, undigested food Lower GI: feculant vomitus, colic

25. Treat Reversible Causes!!! Drugs Hypercalcemia/Hyponatremia/Uremia Anxiety Constipation Raised Intracranial Pressure Tense Ascites Severe Pain Cough

26. Evaluation!! Detailed H+P Detailed History Severity of Nausea vs Vomiting Relief or persistence of Nausea after Vomit Timing of Vomiting and symptoms triggers (food, movement, smell, rx, etc) Frequency of vomiting and temporal association Content and volume of vomitus Sputum vs regurgitation vs vomit Associated symptoms: HA

27. Non-Rx Measures Relaxation Calm, reassuring environment Small snacks/meals, bland food Avoid odors Mouth Care Acupuncture/Acupressure P6 NG/PEG tubes Surgery/Stents Chemoradiation

28. Pharmacologic Therapy

29. CausesCentersReceptors Intracranial Pressure Anxiety and memories Cerebral Cortex Motion Sickness Vestibular Disease Vestibular Apparatus Metabolic Drugs Toxins Chemoreceptor Trigger Zone Visceral (GI, etc) Chemotherapy Radiotherapy Vagus Afferents Splanchnic nerves GABA CB GABA CB H1 M1M1 M1M1 D2D2 D2D2 5HT D2D2 Vomiting Center 5HT M1M1 H1 Cannabinoids Histamine Muscarinic Dopamine Serotonin NK Neurokinin NK

30. Prokinetic Agents Metoclopramide: Reglan Some CTZ anti-dopaminergic activity Act mostly in gut: antagonize D2 and stimulate 5HT4 receptors Stimulation of 5HT4 receptors  cause local ACH release  reversing gastroparesis High doses: blocks 5HT3 receptors in the CTZ and gut EPS Side-Effects at high doses Caution in obstructed intestine: may induce colic Increases pressure at lower esophageal sphincter

31. Antihistamine Useful for vestibular causes of nausea and vomiting Caution in constipation b/c of anticholinergic properties Diphenhydramine Meclizine (Antivert) Hydroxyzine Promethazine: watch for dystonia

32. Anticholinergics Helpful for Motion/Movement related N/V SE: dry mouth, blurred vision, confusion, constipation Hyoscine Hydrobromide: Scopolamine Glycopyrrolate May cause/worsen obstruction May be useful in colicky abdominal pain with obstruction: IE Tumor

33. Dopamine Antagonists Useful for Medication or metabolic related nausea and vomiting SE: Dystonia, IV can cause postural hypotension secondary to alpha receptor antagonism Haloperidol: Haldol SC/IV = PO (1:2) Chlorpromazine: Thorazine: more sedating IV=PO Prochlorperazine: Compazine: IV=PO Blocks D2 receptors, H1, ACH, Alpha Adenergic (chlorpromazine, prochlorperazine)

34. Serotonin 5HT3 Receptor Antagonist Useful for Post OP N/V, Chemotherapy/Radiation related N/V or 2 nd or 3 rd line rx Ondansetron: Zofran (ODT) Granisetron: Kytril/Sancuso patch Side Effect: Constipation, Headache Clinical considerations -Equal safety and efficacy at equivalent doses -Single dose regimens have equal efficacy to multidose regimens -Oral and IV routes are equivalent

35. Dexamethasone Mechanism of Action: unknown -Inhibition of prostaglandin synthesis? Decrease Inflammation -Decreased BBB permeability of chemotherapy agents -Inhibition of cortical input to vomiting center Useful in: -Brain tumor or CNS involvement -Malignant bowel obstruction -Chemotherapy induced nausea and vomiting Generally well tolerated -Fluid retention, restlessness, insomnia, hypertension -Watch blood glucose in diabetic patients

36. NK1 Receptor Antagonist Aprepitant Competitively antagonizes the NK1 receptors FDA Approved for acute or delayed onset nausea associated with chemotherapy. $$$$ Adujvant Therapy ?Mechanism of action? Dronabinol, Nabilone Adverse effects -Sedation, dizziness, hypotension, dysphoria $$$$ Cannabinoid

37. Receptor Binding Affinity (Potency) Rx D2M1H1 Scopolamine >10,0000.08>10,000 Promethazine 240212.9 Prochlorperazine 152,100100 Chlorpromazine 2513028 Metoclopramide 270>10,0001,100 Haloperiodol 4.2>10,0001,600 Peroutka and Snyder 8 Potency: the amount required to produce an effect of given intensity

38. CausesCentersReceptors Intracranial Pressure Anxiety and memories Cerebral Cortex Motion Sickness Vestibular Disease Vestibular Apparatus Metabolic Drugs Toxins Chemoreceptor Trigger Zone Visceral (GI, etc) Chemotherapy Radiotherapy Vagus Afferents Splanchnic nerves GABA CB GABA CB H1 M1M1 M1M1 D2D2 D2D2 5HT D2D2 Vomiting Center 5HT M1M1 H1 Cannabinoids Histamine Muscarinic Dopamine Serotonin NK Neurokinin NK

39. Treatment: Chemically induced Nausea: CTZ: D2, 5HT3 Haloperidol (0.5-2mg IV/SQ/PO Q4-8hrs) Prochlorperazine (5-10mg PO/PR/IV Q6-8hrs) Ondansetron (8mg TID PO/IV) Gastric Stasis: Prokinetic agents: Metoclopramide (if no colic) 10-30mg PO/PR/IV q4-6hrs Scopolamine/Glycopyrolate (if colic) (Anticholinergic) 0.2-o.6mg SL/SQ q4-8hrs (scopolamine) 0.1-0.2mg IV/SQ Q4-8hrs, 1-2mg PO q8hrs Dexamethasone 4-20mg po/IV qday Odansetron (5HT3)

40. Treatment Cortical Causes: Inc ICP, tumor, learned response Dexamethasone, Promethazine, Prochlorperazine, and benzodiazepines. Movement/Vestibular Dz Meclizine, Scopolamine, Diphenhydramine, Promethazine

41. Sample Case: P.T. is an 85-year-old farmer with diabetes, endstage heart disease, gastroesophageal reflux disorder, chronic shoulder pain from a war injury, stage 4 chronic kidney disease, and a history of alcoholism. His shoulder pain is well controlled with extended- release morphine, 30 mg PO bid, and gabapentin, 300 mg PO q HS. However, he complains of constant nausea that limits his ability to eat.

42. Summary Remember that Nausea/Vomiting are symptoms and not diseases Find and treat reversible causes of nausea. Tailor prescription accordingly to sites of action

43. Thank You

44. References 1. Reuben DB, Mor V. Nausea and vomiting in terminalcancer patients. Arch Intern Med. 1986;146(10):2021-2023. 2. Herrinton LJ, Neslund-Dudas C, Rolnick SJ, et al. Complications at the end of life in ovarian cancer. J Pain Symptom Manage. 2007;34(3):237-243. 3. Henry DH, Viswanathan HN, Elkin EP, Traina S, Wade S, Cella D. Symptoms and treatment burden associated with cancer treatment: results from a cross-sectional national survey in the U.S. [Epub ahead of print]. Support Care Cancer. Jan 17, 2008. 4. Mannix KA. Palliation of nausea and vomiting. In: Doyle D, Hanks GWC, Cherny NI, Kalman S, eds. Oxford Textbook of Palliative Medicine. 3rd ed. Oxford, England: Oxford University Press; 2005:459-468. 5. Murtagh FE, Addington-Hall J, Higginson IJ. The prevalence of symptoms in end-stage renal disease: a systematic review. Adv Chronic Kidney Dis. 2007; 14(1):82-99. 6. Baines MJ. ABC of palliative care. Nausea, vomiting, and intestinal obstruction. BMJ. 1997; 315(7116):1148-1150 7. Fantoni M, Ricci E, Del Borgo C, et al. Multicentre study on the prevalence of symptoms and symptomatic treatment in HIV infection. Central Italy PRESINT group. Journal of Palliative Care. 1997; 13(2), 9-13. 8. Peroutka, S. J. and S. H. Snyder. Antiemetics: Neurotransmitter receptor binding predicts therapeutic actions. Lancet 1982; 1(8273): 658-9

45. Mannix, Kathryn A. Palliation of Nausea and Vomiting. Oxford Textbook of Palliative Medicine. 2010; 801-812. Watson Max, Lucas Caroline, et al. Nausea and Vomiting, Oxford Handbook of Palliative Care. 2 nd edition 2009; 308-315 Sobel Jason MD, Policzer Joel MD, Management of Selected Nonpain Symptoms of Life-Limiting Illness Hospice and Palliative Care Training For Physiciains (UNIPAC U4 3 rd edition). Emanuel LL, Hauser JM, Bailey FA, Ferris FD, von Gunten CF, Von Roenn J. EPEC for Veterans: Education in Palliative and End-of-life Care for Veterans. Chicago, IL, and Washington, DC, 2010 Krakauer EL et al: Case records of the Massachusetts General Hospital. N Engl J Med 2005;352:817 References