Prof. Hanan Hagar Pharmacology Department College of Medicine Antiemetics Prof. Hanan Hagar Pharmacology Department College of Medicine

Learning objectives Classify the main different classes of antiemetic drugs according to their mechanism of action. Know the characteristic pharmacokinetics & dynamics of different classes of antiemetic drugs. Identify the selective drugs that can be used according to the cause of vomiting. Learn the Adjuvant antiemetics. Describe the major side effects for the different classes of antiemetics.

Causes of Vomiting Nausea and vomiting may be manifestations of many conditions and may occur due to stimulation of vomiting center that respond to inputs from: Chemoreceptor trigger zone (CTZ) stimulation Disturbance of vestibular system Higher cortical centers stimulation (CNS) The periphery (Pharynx, GIT) via sensory nerves

CTZ is physiologically outside BBB. 1. Chemoreceptor trigger zone stimulation CTZ is an area of medulla that communicate with vomiting center to initiate vomiting. CTZ is physiologically outside BBB. CTZ Contains opioid receptors, D2 receptors & 5 HT3 receptors, Substance P stimulated by: Drugs (opioids, general anesthetics), Chemicals and toxins in blood, CSF. Radiation.

2. The periphery via sensory nerves GIT irritation, myocardial infarction, renal or biliay stones. 3. Disturbance of vestibular system by motion sickness 4. Higher cortical centers stimulation: emotional factors, nauseating smells or sights.

Receptors Associated with Nausea and Vomiting

Pathophysiology of Emesis Cerebral cortex chemotherapy Opioids Anesthetics Smell Sight Thought Anticipatory emesis ChemoreceptorTrigger Zone (CTZ) Vestibular nuclei Vomiting Centre (medulla) Motion sickness Muscarinic Histaminic H1 Muscarinic, 5 HT3 & Histaminic H1 (Outside BBB) 5 HT3 Dopamine D2 Opioid receptors Substance p Chemo & radio therapy Gastroenteritis Pharynx & GIT 5 HT3 receptors

Ach (Muscarinic receptors) Dopamine (D2) Chemical transmitters & receptors involved in vomiting include: Ach (Muscarinic receptors) Dopamine (D2) Histamine (Histaminergic receptors H1) Serotonin (5 -HT3) Substance P (Neurokinin receptors, NK1) Opioid (Opioid receptors)

Classification of Antiemetic Drugs 5-HT3 antagonists D2 receptor antagonists NK1 antagonists H1-receptor antagonists Muscarinic receptor antagonists Cannabinoids Glucocorticoids

5-HT3 antagonists Drugs as Ondansetron, Granisetron Orally or parenterally Potent antiemetic effects Block 5-HT3 receptor in vomiting center, CTZ and 5HT3 receptors on intestinal vagal afferents.

Uses of 5-HT3 antagonists First choice for prevention of: Chemotherapy-induced nausea and vomiting (CINV) especially cisplatin. Post-radiation NV& Post-operative NV Their effects is increased by combination with corticosteroids and NK1 antagonists. Side effects Well tolerated mild headache, dizziness and constipation minor ECG abnormalities (QT prolongation)

D2 receptor antagonists block D2 dopamine receptors in the CTZ Two types exist: Prokinetics drugs Neuroleptics (antipsychotics) Uses of D2 receptor antagonists are among the most commonly used drug for nausea and vomiting of non-specific causes. Effective against vomiting due to drugs, gastroenteritis, post-operative, toxins, uremia, radiation.

D2 receptor antagonists 1) Prokinetics drugs Drugs as metoclopramide, domperidone Both are prokinetic agents due to their 5 HT4 agonistic activity. used in GERD (gastroesophageal reflux disease), gastroparesis. Used as antiemetics (blocking D2 receptors) Metoclopramide crosses BBB but domperidone cannot (both have antiemetic effects as CTZ is outside BBB).

Side effects (only for metoclopramide): Dyskinesia (extra-pyramidal side effects), Galactorrhea, menstrual disorders, impotence. Sedation, postural hypotension.

D2 receptor antagonists Neuroleptics (Antipsychotics) Chlorpromazine (CPZ), droperidol used for postoperative vomiting and chemotherapy-induced nausea & vomiting. Side effects: extrapyramidal symptoms sedation, postural hypotension

Neurokinin1 (NK1) receptor antagonists Aprepitant Is a substance P antagonists that acts by blocking neurokinin 1 receptors. Orally Used in prevention of acute and delayed chemotherapy-induced nausea and vomiting and for prevention of postoperative nausea and vomiting. Usually combined with 5-HT3 antagonists and corticosteroids.

H1-receptor antagonists Effective for motion sickness, morning sickness in pregnancy Drugs as Diphenhydramine Meclizine - Cyclizine Promethazine: severe morning sickness of pregnancy (if only essential). Side effects: prominent sedation, hypotension, anticholinergic effects (dry mouth, dilated pupils, urinary retention, constipation.

Muscarinic receptor antagonists Hyoscine (scopolamine) Orally, injection, patches Used as transdermal patches in motion sickness (applied behind the external ear). Not in chemotherapy-induced vomiting Side effects: tachycardia, blurred vision, dry mouth, constipation, urinary retention (atropine-like actions).

Cannabinoids Nabilone, dronabinol mechanism of action not understood. act at central cannabinoid receptors. Used in vomiting due to cytotoxic anticancer drugs (adjuvant therapy). Not commonly used. Side effects: euphoria, dysphoria, sedation, hallucination.

Glucocorticoids Dexamethasone - methylprednisolone Used in chemotherapy-induced vomiting combined with 5-HT3 antagonists or NK1 receptor antagonists.

Glucocorticoids Side effects: Hyperglycemia Hypertension Cataract Osteoporosis Increased intraocular pressure Increased susceptibility to infection Increased appetite & obesity

Summary The choice of antiemetic depends on the etiology Motion sickness Muscarinic antagonists Antihistaminics Vomiting with pregnancy (morning sickness) avoid all drugs in the first trimester Pyridoxine (B6) Promethazine ( late pregnancy).

Drug- induced vomiting (CTZ) Dopamine antagonists Post operative nausea & vomiting 5-HT3 antagonists NK1 antagonists Vomiting due to cytotoxic drugs. D2- antagonists Glucocorticoids Cannabinoids

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