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Antiemetics Prof. Hanan Hagar Pharmacology Department College of Medicine.

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Presentation on theme: "Antiemetics Prof. Hanan Hagar Pharmacology Department College of Medicine."— Presentation transcript:

1 Antiemetics Prof. Hanan Hagar Pharmacology Department College of Medicine

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

3 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 Chemoreceptor trigger zone (CTZ) stimulation Disturbance of vestibular system Disturbance of vestibular system Higher cortical centers stimulation (CNS) Higher cortical centers stimulation (CNS) The periphery (Pharynx, GIT) via sensory nerves The periphery (Pharynx, GIT) via sensory nerves

4 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.

5 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.

6 Receptors Associated with Nausea and Vomiting

7 Vomiting Centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Vestibular nuclei Motion sickness Pharynx & GIT Chemo & radio therapy Gastroenteritis Chemoreceptor Trigger Zone (CTZ) (Outside BBB) chemotherapy Opioids Anesthetics Muscarinic, 5 HT 3 & Histaminic H 1 5 HT 3 receptors 5 HT 3 Dopamine D 2 Opioid receptors Substance p Muscarinic Histaminic H 1 Pathophysiology of Emesis

8 Chemical transmitters & receptors involved in vomiting include: Ach (Muscarinic receptors) Ach (Muscarinic receptors) Dopamine (D2) Dopamine (D2) Histamine (Histaminergic receptors H 1 ) Histamine (Histaminergic receptors H 1 ) Serotonin (5 -HT 3 ) Serotonin (5 -HT 3 ) Substance P (Neurokinin receptors, NK1) Substance P (Neurokinin receptors, NK1) Opioid (Opioid receptors) Opioid (Opioid receptors)

9 Classification of Antiemetic Drugs 1. 5-HT3 antagonists 2. D 2 receptor antagonists 3. NK 1 antagonists 4. H 1 -receptor antagonists 5. Muscarinic receptor antagonists 6. Cannabinoids 7. Glucocorticoids

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11 5-HT3 antagonists Drugs as Ondansetron, Granisetron Drugs as Ondansetron, Granisetron Orally or parenterally Orally or parenterally Potent antiemetic effects Potent antiemetic effects Block 5-HT3 receptor in vomiting center, CTZ and 5HT3 receptors on intestinal vagal afferents. Block 5-HT3 receptor in vomiting center, CTZ and 5HT3 receptors on intestinal vagal afferents.

12 Uses of 5-HT3 antagonists First choice for prevention of: 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 o Well tolerated o mild headache, dizziness and constipation o minor ECG abnormalities (QT prolongation)

13 D2 receptor antagonists  block D2 dopamine receptors in the CTZ  Two types exist: 1) Prokinetics drugs 2) 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.

14 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).

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

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

17 Neurokinin1 (NK1) receptor antagonists Aprepitant Is a substance P antagonists that acts by blocking neurokinin 1 receptors. Is a substance P antagonists that acts by blocking neurokinin 1 receptors.substance Psubstance P Orally Orally Used in prevention of acute and delayed chemotherapy-induced nausea and vomiting and for prevention of postoperative nausea and vomiting. Used in prevention of acute and delayed chemotherapy-induced nausea and vomiting and for prevention of postoperative nausea and vomiting. chemotherapy-induced nausea and vomitingpostoperative nausea and vomiting chemotherapy-induced nausea and vomitingpostoperative nausea and vomiting Usually combined with 5-HT 3 antagonists and corticosteroids. Usually combined with 5-HT 3 antagonists and corticosteroids.

18 H1-receptor antagonists Effective for motion sickness, morning sickness in pregnancy Effective for motion sickness, morning sickness in pregnancy Drugs as 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.

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

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

21 Glucocorticoids Dexamethasone - methylprednisolone Dexamethasone - methylprednisolone Used in chemotherapy-induced vomiting Used in chemotherapy-induced vomiting combined with 5-HT 3 antagonists or NK1 receptor antagonists. combined with 5-HT 3 antagonists or NK1 receptor antagonists.

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

23 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).

24 Drug- induced vomiting (CTZ) Dopamine antagonists Post operative nausea & vomiting Dopamine antagonists 5-HT 3 antagonists NK1 antagonists Vomiting due to cytotoxic drugs. 5-HT 3 antagonists NK1 antagonists D2- antagonists GlucocorticoidsCannabinoids

25 Thank you Questions ?


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