Jonathan Hsu MD Emory University Dept of Hospice and Palliative Care

Disclosure Information I have no financial relationships to disclose

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

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.

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

Vomiting Forcible ejection of contents of stomach through the mouth.

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 % of patients treated with Opioids 6

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pharmacologic Therapy

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

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

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

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

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)

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

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

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

Receptor Binding Affinity (Potency) Rx D2M1H1 Scopolamine >10, >10,000 Promethazine Prochlorperazine 152, Chlorpromazine 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

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

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) mg IV/SQ Q4-8hrs, 1-2mg PO q8hrs Dexamethasone 4-20mg po/IV qday Odansetron (5HT3)

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

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.

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

Thank You

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