Nausea and Vomiting lecture 4 by Dr: Ahmed M. Ali 2018/2019

KEY CONCEPTS Nausea and vomiting may be a symptom for a variety of gastrointestinal, cardiovascular, infectious, neurologic, metabolic, or psychogenic conditions. Nausea and vomiting may be caused by a variety of medications or other noxious agents. The overall goal of treatment is to prevent or eliminate nausea and vomiting regardless of etiology. Treatment options for nausea and vomiting include drug and nondrug modalities.

Causes of Vomiting

Nausea and vomiting are SYMPTOMS of many conditions such as: Motion sickness or seasickness Drug therapy (including chemotherapy) Intense pain Food poisoning Emotional stress (e.g., fear) Infections

Overeating (gastric stretching) A reaction to certain smells or odors Myocardial infarction (heart attack) Gallbladder disease Intestinal obstruction Concussion and brain tumors الإرتجاج وأورام المخ Meningitis Some cancers Radiotherapy

Gastroparesis (paralysis of the stomach) Bulimia* Peptic ulcer disease Appendicitis Constipation Uremia Gastroparesis (paralysis of the stomach) Bulimia* Early stages of pregnancy (nausea occurs in 50-90% ; vomiting in 25-55% of pregnancies). * Bulimia is psychic disorder that involves overeating followed by self-induced vomiting.

Clinical Significance of Vomiting

Vomiting can be a sign of serious conditions such as concussion, meningitis, brain tumors, intestinal obstruction and appendicitis. Excessive vomiting may lead to DEHYDRATION especially in children who cannot detect the signs of dehydration including dry mouth and lips, sunken eyes, dry skin, elevated temperature, rapid breathing, rapid pulse and decreased urination. Recurrent severe vomiting in pregnancy can lead to “hyperemesis gravidarum”, a condition characterized by fluid and electrolyte imbalance that can endanger the life of the mother and her fetus.

Harmful Effects of Vomiting

Excessive vomiting may lead to: Dehydration (→ Fluids & Electrolytes). Alkalosis due to loss of HCl (→ NH4Cl). Hypokalemia (→ Potassium supplementation). Sodium and chloride loss (→ Saline).

Management of Vomiting

Management of vomiting includes: Control of vomiting regardless of etiology. Identification and treatment of underlying cause. Gradual intake of large amounts of clear fluids. Temporary discontinuation of oral medications and solid foods. Administration of rehydrating solutions when vomiting persists for > 24 hours. Correction of hypokalemia and metabolic alkalosis. Drug therapy.

Antiemetic Drugs

Dopamine D2-Receptor Antagonists Phenothiazines Benzamides Butyrophenones

(1) Phenothiazines These include chlorpromazine, prochlorperazine and methotrimeprazine. They are indicated in PONV, GI-induced emesis and mild CINV. The main ADRs include dystonia, tardive dyskinesia, akathisia, lowered seizure threshold and hypotension. Phenothiazines have also some antimuscarinic, antiserotonergic ( 5-HT2) and antihistaminic activity.

PONV = Postoperative nausea and vomiting. CINV = Chemotherapy-induced nausea and vomiting. RINV = Radiation-induced nausea and vomiting. PANV = Pregnancy-associated nausea and vomiting.

Dystonia Involuntary sustained or repetitive muscle contractions leading to twisting movements and abnormal fixed body postures. Dystonia is often intensified or exacerbated by physical activity, and symptoms may progress into adjacent muscles..

DYSTONIA

DYSTONIA

Dyskinesia Involuntary muscle movements associated with difficulty in initiating or controlling voluntary muscle movements. Dyskinesia can be anything from a slight tremor of the hands to an uncontrollable movement of the upper body or lower extremities.

Tardive Dyskinesia Slow-onset or late-developing, permanent involuntary repetitive body movements. Tardive dyskinesia results most frequently from long-term use (usually ≥ 3 months duration) or high-dose use of antipsychotic drugs. Repetitive involuntary movements may include grimacing تكشيرة , tongue movements, lip smackingمط الشفاة, lip puckeringكرمشة الشفاة , purse of the lipsضم الشفاة and excessive eye blinkingسرعة الرمش

Tardive Dyskinesia

Tardive Dyskinesia

Akathisia Inability to sit still Inner anxiety and a compulsive drive to move the body. A feeling of inner restlessness  restless leg syndrome.

AKATHISIA

Management of Dystonia and Dyskinesia Dose reduction or gradual withdrawal from the offending medication (use alternative). Anticholinergics e.g., trihexyphenidyl and benztropine Antispastic agents e.g., Baclofen and clonazepam. Botulinum toxin injection into the affected muscle group is an additional option for treatment. Dopamine agonists e.g., bromocriptine. Levodopa/carbidopa (peripheral dopa decarboxylase inhibitor).

(2) Benzamides These include metoclopramide (Primperan®) and domperidone (Motilium®). Metoclopramide is indicated in GI-induced emesis, gastric stasis (as in migraine), diabetic gastroparesis and CINV. Domperidone is indicated in GI-induced emesis and dopamine agonists-induced nausea. The main ADRs of metoclopramide include akathisia, dystonia and tardive dyskinesia. Dystonia occurs rarely with domperidone (penetrates the BBB poorly).

(3) Butyrophenones An example is haloperidol. Haloperidol is indicated in PONV. It blocks dopamine D2 receptors at the CTZ. It has a long half-life (18 hours). The main side effect is dyskinesia. Dose: 1–5 mg every 12 h prn (Tab, liquid, IM, IV).

Serotonin 5-HT3 Receptor Antagonists

Administration Drug Name Oral/IV Ondansetron (Zofran®) Granisetron (Kytril®) IV only Dolasetron (Anzemet®) Palonosetron (Aloxi®)

They are indicated mainly in CINV, PONV and RINV. They block presynaptic serotonin 5-HT3 receptors on sensory vagal fibers in the gut wall, effectively blocking the acute phase of CINV (they are less efficacious in preventing the delayed phase of CINV). Common ADRs include mild headache, constipation and dizziness. Palonosetron is preferred in some clinical situations because of its long half-life (approximately 40 hours) and minimal toxicity profile.

IV regimens Oral Tablets Agent Serotonin 5-HT3 Receptor Antagonists for CINV IV regimens Oral Tablets Agent 10 mcg/kg prior to chemotherapy diluted, infuse over 5 min OR undiluted over 30 seconds. 100 mg within 1 h before chemotherapy Granisetron (Kytril®) 32 mg prior to chemotherapy as a single dose (diluted, give over 15 min), or 0.15 mg/kg prior to chemotherapy, repeat at 4 and 8 h 1 mg up to 1 h prior to chemotherapy and 1 mg 12 h after the first dose, or, 2 mg up to 1 h prior to chemotherapy Tab.  8 mg 30 min prior to chemotherapy, repeat at 4 and 8 h and every 12 h for 1–2 days after chemotherapy completion Ondansetron (Zofran®) 1.8 mg/kg 30 min prior to chemotherapy undiluted, up to 100 mg over 30 min. (or diluted, over 30 min.) Dolasetron (Anzemet®) 0.25 mg 30 min prior to chemotherapy (undiluted over 30 seconds; do not repeat within 7 days) Palonosetron (Aloxi®)

Substance P Receptor Antagonists (Neurokinin NK1 -Receptor Inhibitors)

Examples include aprepitant (Emend®), fosaprepitant, netupitant, casopitant and rolapitant (t1/2 = 7 d). They act by blocking the neurokinin NK1 subtype of substance P receptors in the afferent vagal fibers innervating the nucleus tractus solitarus (NTS) and the area postrema. Indicated in chemotherapy-induced DELAYED vomiting. They improve the efficacy of standard antiemetic regimens in patients receiving multiple cycles of chemotherapy (e.g., high-dose cisplatin-based chemotherapy). Aprepitant is given as oral capsules (125 mg on day 1, 1-hour prior to chemotherapy, 80 mg on days 2 and 3).

NEPA ASCO: American Society of Clinical Oncology NEPA is an oral fixed dose combination containing 300 mg of netupitant (a highly selective NK1 receptor antagonist) and 0.5 mg of palonosetron, (a 5-HT3 receptor antagonist). NEPA was approved in the United States for prevention of CINV in October 2014 . ASCO (2015) recommends to use NEPA, in conjunction with a glucocorticoid, (as an alternative to aprepitant and fosaprepitant-containing regimens) for patients receiving highly emetogenic chemotherapy (e.g., cisplatin or combined anthracycline plus cyclophosphamide regimens). ASCO: American Society of Clinical Oncology

Anthracyclines Anticancers Daunorubicin Doxorubicin Epirubicin Idarubicin Valrubicin

Anticholinergics (Muscarinic Antagonists)

An example is hyoscine (scopolamine). It is indicated in motion sickness-induced vomiting (due to stimulation of semicircular canals in the inner ear). It is administered as the free base in the form of a transdermal patch. Common ADRs include dry mouth, blurred vision, urinary retention and constipation. Dose: 0.5 mg every 72 h prn Transdermal patch.

Histamine H1 Receptor Antagonists

These include cyclizine, promethazine, dimenhydrinate (Dramamine®), diphenhydramine, meclizine and cinnarizine. Cyclizine is indicated in PONV, motion sickness and hyperemesis gravidarum. Promethazine is indicated in motion sickness. Cinnarizine is indicated in motion sickness and hyperemesis gravidarum. Sedation and anticholinergic side effects are the most common ADRs especially in the elderly.

Steroid Receptor Agonists

Examples are dexamethasone (Decadron®) and methylprednisolone (Solu-Medrol®). Used as single agents or in combinations with 5-HT3 serotonin receptor antagonists and/or NK1 receptor antagonists.. Indicated in CINV and PONV. The most common ADRs are insomnia and mood changes. Steroid receptors may exist in the nucleus tractus solitarus (NTS) and the area postrema (which contains the CTZ). Dexamethasone:10 mg IV prior to chemotherapy, followed by 4–8 mg every 6 h for total of 4 doses. Methylprednisolone: 125–500 mg IV every 6 h for total of 4 doses.

Motilin Receptor Agonists

These include erythromycin and other macrolide antibiotics (e. g These include erythromycin and other macrolide antibiotics (e.g., azithromycin, clarithromycin and oleandomycin). They act by stimulating motilin receptors in the upper GIT. Erythromycin is indicated in diabetic gastroparesis to improve gastric emptying and prevent N& V. Rapid tolerance may develop to erythromycin’s action possibly due to down-regulation of motilin receptors. The most common ADRs include allergic reactions and GIT disturbances.

Motilin It is a 22-amino acid peptide hormone found in the gastrointestinal M cells and some enterochromaffin cells of the upper small bowel. It is a powerful contractile agent of the upper GIT →  motility Motilin receptors are found in the upper GIT.

Cannabinoid Receptor Agonists

Examples are nabilone and dronabinol. They act by stimulating the CB1 subtype of cannabinoid receptors on neurons in and around the vomiting center. Indicated in CINV when other antiemetic regimens do not provide desired efficacy. The most common ADRs include euphoria, dysphoria, sedation, depression and hypotension. Nabilone is given as capsules in a dose of 1–2 mg twice or thrice daily prn. Dronabinol is given as capsules in a dose of 5 –7.5 mg/m2 every 2–4 h prn.

Benzodiazepines

Benzodiazepines may be beneficial in patients experiencing anticipatory CINV. Benzodiazepines can be taken orally prior to chemotherapy treatment to reduce anticipatory nausea. Short acting benzodiazepines including lorazepam and midazolam can act as adjuncts to treatment of CINV, especially anticipatory, by reducing anxiety and causing sedation.

Histamine H2-RECEPTOR ANTAGONISTS

Histamine H2-receptor antagonists can be used in low doses to manage simple nausea and vomiting associated with heartburn or gastroesophageal reflux. Famotidine (10 mg), Nizatidine (75 mg), or Ranitidine (75 mg) may be used for brief periods.