Dr. Mohammad Aljawadi PharmD, Msc, PhD Jamilah Alsaidan Msc PHCL 477 Clinical Pharmacy Department College of Pharmacy King Saud University March 2015

 The three consecutive phases of emesis are: Emesis NauseaRetchingVomiting

Inclination to vomit Feeling in throat or epigastric region alerting individual vomiting is imminent. Nausea Is the labored movement of the abdominal and thoracic muscles before vomiting Retching The forceful expulsion of gastric contents through the mouth due to GI retro- peristalsis Vomiting

 Vomiting is triggered by afferent impulses to the vomiting center, a nucleus of cells in the medulla  Impulses are received from sensory centers, such as: ◦ The chemoreceptor trigger zone (CTZ) ◦ Cerebral cortex ◦ Visceral afferents from the pharynx and GI tract

Visceral afferents from the pharynx and GI tract

 Numerous neurotransmitter receptors are located in the vomiting center, CTZ, and GI tract  Cholinergic, histaminic, dopaminergic, opiate, serotonergic, neurokinin, and benzodiazepine receptors  Three main causes of vomiting ◦ Stimulation of chemoreceptor trigger zone in the 4 th ventricle ◦ Stimulation of the GI tract ◦ Sensory input and memory

 Nausea and or / vomiting may be part of the symptom complex for a variety of gastrointestinal, cardiovascular, infectious, neurologic, metabolic or psychogenic processes

 N & V may be a  feature of such conditions as pregnancy,  may follow ◦ operative procedures ◦ administration of certain medications such as those used in cancer chemotherapy or inhalation of noxious odors

 Gastrointestinal mechanisms ◦ Mechanical obstruction:  e.g. Gastric outlet obstruction, Small bowel obstruction ◦ Functional gastrointestinal disorders: e.g.Gastroparesis, Non-ulcer dyspepsia, Chronic intestinal pseudo-obstruction, Irritable bowel syndrome ◦ Organic gastrointestinal disorders e.g Peptic ulcer disease, Pancreatitis, Pyelonephritis, Cholecystitis,Cholangitis, Hepatitis ◦ Acute gastroenteritis ( Viral, Bacterial)

 Cardiovascular diseases ◦ Acute myocardial infarction  Miscellaneous causes ◦ Pregnancy ◦ Noxious odors ◦ Operative procedures  Neurologic processes ◦ Migraine headache ◦ Vestibular disorders

 Metabolic disorders ◦ Diabetes mellitus (diabetic ketoacidosis) ◦ Renal disease (uremia)  Psychiatric causes ◦ Anxiety disorders ◦ Anorexia nervosa  Drug withdrawal ◦ Opiates ◦ Benzodiazepines  Therapy-induced causes ◦ Cytotoxic chemotherapy ◦ Radiation therapy ◦ Anticonvulsant preparations ◦ Opiates ◦ Antibiotics

 Depending on severity of symptoms, patients may present in mild to severe distress  Symptoms ◦ Simple: Self-limiting, resolves spontaneously and requires only symptomatic therapy ◦ Complex: Not relieved after administration of antiemetics; progressive deterioration of patient secondary to fluid- electrolyte imbalances; usually associated with noxious agents or psychogenic events

 Signs ◦ Simple: Patient complaint of queasiness or discomfort ◦ Complex: Weight loss; fever; abdominal pain  Laboratory tests ◦ Simple: None ◦ Complex: Serum electrolyte concentrations; upper/lower GI evaluation

 Other information ◦ Fluid input and output ◦ Medication history ◦ Recent history of behavioral or visual changes, headache, pain, or stress ◦ Family history positive for psychogenic vomiting

 Metabolic disorders ◦ Diabetes mellitus (diabetic ketoacidosis) ◦ Renal disease (uremia)  Psychiatric causes ◦ Anxiety disorders ◦ Anorexia nervosa  Drug withdrawal ◦ Opiates ◦ Benzodiazepines  Therapy-induced causes ◦ Cytotoxic chemotherapy ◦ Radiation therapy ◦ Anticonvulsant preparations ◦ Opiates ◦ Antibiotics

High Moderate Low Minimal

High (>90%)  Carmustine  Cisplatin  Cyclophosphamide ≥1,500 mg/m2  Dacarbazine  Dactinomycin  Mechlorethamine  Streptozotocin Moderate (30–90%)  Carboplatin  Cytarabine >1 g/m2 Cyclophosphamide <1,500 mg/m2  Daunorubicin  Doxorubicin  Epirubicin  Idarubicin  Ifosfamide  Irinotecan  Oxaliplatin

 Low (10–30%)  Bortezomib  Cetuximab  Cytarabine ≤1 g/m2  Docetaxel  Etoposide  Fluorouracil  Gemcitabine  Methotrexate  Mitomycin  Mitoxantrone  Paclitaxel  Pemetrexed  Topotecan  Trastuzumab  Minimal (<10%)  Bevacizumab  Bleomycin  Busulfan  2-Chlorodeoxyadenosine Fludarabine  Rituximab  Vinblastine  Vincristine  Vinorelbine

 Non-Chemotherapy Etiologies of Nausea and vomiting in cancer patients ◦ Fluid and electrolyte abnormalities  Hypercalcemia ◦ Volume depletion ◦ Adrenocortical insufficiency ◦ Drug Induced  Opiates  Antifungals  Antibiotics

 Other ◦ Uremia ◦ Metastases ◦ Gastrointestinal obstruction ◦ Increased intracranial pressure ◦ Peritonitis ◦ Radiation Therapy

 The overall goal of antiemetic therapy is to prevent or eliminate nausea and vomiting ◦ This should be accomplished without adverse events or with clinically acceptable adverse effects ◦ Simple nausea and vomiting prevention is achieved easily with treatment ◦ Patients with more complex problems require greater assistance

General Approach to Treatment Non drug Modalities Medication

 The treatment choice depends on severity of the NV and associated conditions  The management of psychogenic vomiting is greatly dependent on psychological intervention  Underlying problems are complex and must be addressed  Treatment of underlying psychological disorder with its appropriate medications  E.g. Bulimia nervosa

 Non drug modalities include Dietary, Psychological, or physical changes  Simple complaints- Avoid or intake in moderation troublesome food, beverage or odor  Behavioral interventions include relaxation biofeedback, self hypnosis, cognitive distraction, guided imagery, and systematic desensitization

 Antiemetic drugs- both non-prescription and prescription are recommended  The treatment of simple nausea and vomiting usually requires minimal therapy. Drugs are usually effective in small, infrequently administered doses.  The management of complex nausea and vomiting, for example, in patients who are receiving cytotoxic chemotherapy, may require combination therapy.

 Many treatment options for clinician to choose from  Factors that enable a clinician to discriminate between medication options: ◦ The suspected etiology of the symptoms ◦ The frequency, duration, and severity of the episodes ◦ The ability of the patient to use oral, rectal, injectable, or transdermal medications ◦ The success of previous antiemetic medication

 In relation to chemotherapy administration; Nausea or vomiting that occurs:  within 24 hours: Acute ◦ Intensity peaks after 5-6 hours  after 24 hours: Delayed  before chemo given: Anticipatory

 The distinction between acute and delayed symptoms becomes blurred with respect to time of onset after several doses and for several consecutive days  Delayed symptoms are best described with cisplatin

 Breakthrough vomiting occurs despite prophylactic treatment and /or requires additional rescue medications  Refractory emesis refers to emesis that occurs during treatment cycles when antiemetic prophylaxis and / or rescue therapy has failed in previous cycles

 Factors to consider when selecting an antiemetic for CINV include the following: 1) The emetic risk of the chemotherapy agent or regimen 2) Patient specific factors 3) Patterns of emesis after administration of specific chemotherapy agents or regimens The emetic risk of the agent is the most important and primary factor to consider when deciding IF you will administer prophylactic agents and WHICH antiemetic agent to select

 The combination of metoclopramide and dexamethasone was the most common regimen to prevent delayed nausea and vomiting before the availability of aprepitant  The combination is still used when aprepitant has not been incorporated into the initial regimen for CINV  Single agent phenothiazaine, butyrophenone, or steroids are used for mildly to moderately emetogenic regimens and for “as needed” use for prolonged symptoms (breakthrough symptoms)

 Patients receiving chemotherapy classified to be high risk should receive a combination antiemetic regimen containing three drugs on the day of chemotherapy administration (Day one)  A serotonin 5-HT 3 inhibitor (e.g. Dolasetron, Granisetron, Ondansetron, Palonosetron )  + dexamethasone  +NK 1 inhibitor ( e.g. aprepitant)

 Patients receiving regimens that are classified as being of moderate emetic risk should receive a combination antiemetic regimen containing an serotonin 5-HT 3 inhibitor plus dexamethasone on day 1.  The exception to this is patients receiving an anthracycline and cyclophosphamide should receive the triple regimen described for high emetic risk regimens  For prophylaxis prior to administration of regimens classified as low emetogenic risk dexamethasone alone is recommended

High Emetic risk  Serotonin 5-HT 3 inhibitor + dexamethasone + aprepitant Moderate Emetic risk  Anthracycline + cyclophosphamide: Serotonin 5-HT 3 inhibitor + dexamethasone + aprepitant  All other regimens of moderate emetic risk: Serotonin 5-HT 3 inhibitor + dexamethasone Low Emetic Risk  Dexamethasone Minimal risk No medication

 High Emetic Risk ◦ Serotonin 5-HT 3 inhibitor :  Dolasetron 100 mg po or 100 mg IV or 1.8 mg/kg IV  Granisetron 2 mg po or 1 mg IV or 0.01 mg/kg IV  Ondansetron 24 mg po or 8 mg IV or 0.15 mg/kg IV  Palonosetron 0.25 mg IV ◦ AND Dexamethasone 12 mg po ◦ AND Aprepitant 125 mg po

 Moderate emetic risk ◦ Anthracycline and cyclophosphamide  as before, as high emetic risk ◦ All other regimens of moderate emetic risk:  Dolasetron 100 mg po or 100 mg IV or 1.8 mg/kg IV  Granisetron 2 mg po or 1 mg IV or 0.01 mg/kg IV  Ondansetron 24 mg po or 8 mg IV or 0.15 mg/kg IV  Palonosetron 0.25 mg IV  AND Dexamethasone 8mg IV

 Low Risk ◦ Dexamethasone 8mg IV  Minimal Risk ◦ None

High Emetic Risk  Days 2 and 3 after chemotherapy: dexamethasone (8mg IV) + aprepitant (80mg PO) Moderate Emetic risk ◦ Anthracycline + cyclophosphamide: Days 2 and 3 after chemotherapy: aprepitant ( 80mg PO)  All other regimens of moderate emetic risk: Days 2–4 after chemotherapy: dexamethasone 8mg PO daily or Serotonin 5-HT 3 inhibitor: Ondansetron 8mg PO daily or twice daily Granisetron 1mg PO daily Dolasetron 100mg PO daily

 Low Emetic Risk- None  Minimal Emetic Risk- None

 The best strategy to prevent delayed CINV is to control acute CINV  Aprepitant, dexamethasone and metoclopramide have demonstrated efficacy in preventing delayed CINV  Patients receiving cisplatin and other agents are at highest risk to experience delayed NV  The management of delayed CINV caused by high risk emetogenic regimens is more well defined than moderate emetic risk regimens

 Cannabinoids are used after the failure of other regimens or to stimulate appetite  Consider using an H 2 blocker or proton pump inhibitor to prevent dyspepsia ( may mimic nausea)  Not FDA approved indications therefore doses not recommended