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PHARMAC: ANTIEMETICS – LEEML281112

ANTIEMETICS

PHYSIOLOGY OF VOMITING
Vomiting/Emesis: Forceful expulsion of gastric contents through the mouth

Act of Vomiting
1. 2. 3. 4. 5. 6. 7. • • • Salivation and nausea (ass with pallor, rapid breathing, sweating and tachycardia) Breath held in mid-inspiration Glottis closes Reverse peristalsis empties material from upper part of small intestines into stomach Abdominal wall contract ⇒ ↑ Intra-abdominal pressure Lower esophageal sphincter and esophagus relax Gastric content ejected

Pressure of 40 cm H2O is required to lift gastric content to esophagus and mouth Cardia elevated during vomiting Abdominal part of esophagus rises to the chest

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PHARMAC: ANTIEMETICS – LEEML281112

CONTROL OF VOMITING

Vomiting Center – present in the lateral reticular formation of the medulla VC can be stimulated by different afferent pathways: 1. Chemoreceptor Trigger Zone • Located in the floor of the 4th ventricle of the brain and constitutes the area postrema (a circumventricular organ which is functionally outside the BBB) • Substances such as drugs and toxins carried in the blood can directly reach it (explains why some drugs cause or stop vomiting) • Contains dopamine D2, serotonin 5-HT3, opioid, acetylcholine and substance P receptors whose activations results in different pathways, the end result of all of which includes substance P 2. Vagus Nerve • The 10th CN gets activated when pharynx is activated causing the gag reflex 3. Vestibular system • Control the balance and sends its input to the CNS via the vestibular nerve (8th CN) • Any disturbances of balance (eg Motion sickness) can cause vomiting • Rich in Cholinergic and Histamine H1 receptors 4. Vagal and Enteric Nervous System from GIT • GIT can be irritated by chemotherapy, radiation, certain drugs, severe distension and infection • Stimulate the VC directly via vagal afferents (cholinergic receptors) and sympathetic afferents from the GIT (NA receptors) • Can also stimulate the CTZ to cause vomiting via the 5HT3 receptors and Dopamine D2 receptors present in the GIT 5. The periphery via sensory nerves • GIT irritation, myocardial infarction, renal or biliary stones via the pain receptors (H1 Receptors)

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PHARMAC: ANTIEMETICS – LEEML281112

6. Chemoreceptors and baroreceptors (5HT3 and H1 receptors) 7. CNS(Higher center – cortex, limbic system) • Can be affected by stress, certain psychiatric conditions, nauseating smells or sights

Ideal Properties Of Antiemetics
1. 2. 3. 4. 5. 6. 7. 8. Effective (different type of nausea and vomiting) Reliable Fast onset Predictable / long duration of action (good compliance) Minimal side effects No drug interaction No allergic reaction Available oral or parenteral

ANTIEMETICS

ANTIHISTAMINES
Eg. Ethanolamines – Diphenhydramine, Dimenhydrinate 1-2mg/kg Piperazines – Cyclizine (NNT 4-5), Hydroxyzine, Meclizine Uses: Prevention or treatment of motion sickness MOA: First generation H1 receptor antagonists. Ethanolamines drugs have more anticholinergic and sedating effect compared to the piperazines SE: sedation, dizziness, confusion, dry mouth, cycloplegia, and urinary retention

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ANTICHOLINERGICS
Eg. Scopolamine Transdermal patch 1.5mg – applied behind the ear (NNT 6) • • • • Uses: Prevention or treatment of motion sickness (Need to apply 4 hours before op ends or evening before) MOA: Blocks muscarinic receptor in the cerebral cortex SE: drowsiness, dry mouth, blurred vision, tachycardia, constipation CI: Pt with glaucoma dt dilation of pupils

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PHARMAC: ANTIEMETICS – LEEML281112

PHENOTHIAZINES
Eg. Promethazine (Phenergan) 12.5-25mg Chlorpromazine (Thorazine) Prochlorperazine edisylate (Compazine) 5-10mg Perphenazine (Trilafon) Uses 1. Chemotherapy-induced vomiting 2. Radiotherapy-induced vomiting 3. PONV MOA: Inhibition of central dopamine D2, muscarinic and H1 histamine receptors in CTZ SE : dry mouth, drowsiness, dizziness, hypotension, EPS (tremors, mask face, rigidity, shuffling gait) DI: CNS depression when taken with ETOH, narcotics, sedative-hypnotics and general anesthetics

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BUTYROPHENONES (antipsychotic agents)
Eg Haloperidol (Haldol) Droperidol (Inapsine) 0.625-1.25mg (NNT 4-6) MOA: Inhibition of central dopamineD2 receptors in the CTZ Uses: Rx of PONV & emesis induced by toxins, chemo and radiation therapy 1. Chemotherapy-induced vomiting 2. Radiotherapy-induced vomiting 3. PONV SE: EPS if used over extended time, hypotension Droperidol may prolong the QT interval (FDA black box warning)

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BENZAMIDES
Eg. Metoclopramide 10-50mg Domperidone Uses: 1. 2. MOA: 1. 2.

Symptomatic treatment of nausea and vomiting from any cause Prokinetic agents Antagonize dopamine D2 receptors in the CTZ to relieve N, V Antagonize the inhibitory effect of dopamine on myenteric motor neurons → Enhance coordinated GIT propulsive motility in the upper digestive tract

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PHARMAC: ANTIEMETICS – LEEML281112

3. High doses also blocks serotonin receptors Metoclopramide
Oral: tablets 10mg, Capsule SR 15mg, Syrup 1mg/ml IV/IM: solution for injection 5mg/ml Crosses BBB SE: 1. EPS (esp children and young adults at higher doses) 2. Galactorrhea by blocking the inhibitory effect of dopamine on prolactin release (infrequent)

Domperidone
Oral: Tablets 10mg, Syrup 1mg/ml Rectal supp: 30mg Does not cross BBB SE: no EPS 1. Galactorrhea

BENZODIAZEPINES
Eg. Lorazepam (Ativan), Diazepam • Uses: Given prior to the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety

SEROTONIN 5HT3 ANTAGONIST
Eg. Ondansetron (Zofran) Granisetron (Kytril) Dolasetron Tropisetron Palonosteron 4-8 mg 0.35-1.5mg 12.5 mg 2mg (t½ ≈ 4-6hrs) (t½ ≈ 5-8 hrs) (t½ ≈ 7h) (t½ ≈ 7hrs) (t½ ≈ 40hrs)

MOA • Potent antiemetics • Causes peripheral 5-HT3 receptor blockade on intestinal vagal afferents and central 5-HT3 receptor blockade in the VC and CTZ • Main antiemetic action is against emesis mediated by vagal stimulation (eg postoperative and chemotherapy) • Does not cause EPS Uses 1. Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy. 2. Postradiation nausea & vomiting 3. PONV (Vomiting NNT 6, Nausea NNT 7)

PK • High first pass metabolism

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PHARMAC: ANTIEMETICS – LEEML281112

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Excreted by liver & kidney No dose reduction in renal insufficiency but needed in hepatic insufficiency

SE • Excellent safety profile • Headache, dizziness, constipation, elevated liver enzymes • Prolongation of QT interval, but more pronounced with dolasetron

CORTICOSTEROIDS
Eg. Dexamethasone (Decadron) 4-5mg Methylprednisolone (Solu-Medrol) (NNT=4)

MOA: Various theories? o Central inhibition of PG synthesis o Decrease turnover of 5HT in the CNS Uses: Enhance efficacy of 5HT3 receptor antagonists in the treatment of chemotherapy-induced vomiting and PONV SE: Flushing, perineal itching (usually one dose not ass with SE)

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CANNABINOIDS
Eg.

- active ingredient in marijuana

Dronabinol (Marinol) Nabilone (Cesamet) Uses: For the prevention of chemotherapy-induced nausea and vomiting (unresponsive to other antiemetics) MOA: not known PK o o o Readily absorbed after oral administration Extensive first-pass metabolism with limited systemic bioavailability after single doses Metabolites are excreted primarily via the biliary-fecal route

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SE o o o Euphoria or dysphoria, sedation and hallucinations Withdrawal syndrome with abrupt withdrawal (restless, insomnia and irritability) Autonomic effects (sympathetic) in the form of tachycardia, palpitation, conjunctival injection, and orthostatic hypotension

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PHARMAC: ANTIEMETICS – LEEML281112

NK1 RECEPTOR ANTAGONIST
Eg. Aprepitant 40mg PO Casopitant Uses: 1. Preventing chemotherapy-induced nausea and vomiting 2. Aprepitant approved for PONV

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MOA: Blocks NK1 receptors in the central and peripheral nervous systems thus preventing emesis Phase 3 trial recently completed – better than ondasetron for up to 48h for vomiting but same nausea rate and rescue equipments SE: Headache, fatigue, dizziness, elevated liver enzymes Expensive

EMETICS
Drugs for Emetics
• • Given when an individual has consumed certain toxic substances that must be expelled before absorption Don’t induce vomiting if caustic substances have been ingested (eg ammonia, chlorine bleach, lye, toilet cleaners, or battery acid)→ Activated charcoal is given when emesis is CI

1. Ipecac
• • • • • • Stimulates the CTZ in the medulla and acts directly on the gastric mucosa Take with water (not milk or carbonation) Onset in 15 to 30 min (Repeat Rx if needed) Toxic if absorbed give charcoal SE: diarrhea, sedation, lethargy Toxicity: Hypotension, tachycardia, chest pain

2. Apomorphine • A morphine derived emetic • Given SC/IM • Onset 15 min

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