Antinauseants and antiemetic agents


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Antinauseants and antiemetic agents

  1. 1. Antinauseants and Antiemetic Agents By M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science
  2. 2. Nausea and Vomiting The pathologic process is coordinated by a central emesis center. It is in the mid-brainstem adjacent to the chemoreceptor trigger zone (CTZ) and the solitary tract nucleus (STN) of the vagus nerve. The lack of a blood-brain barrier allows the CTZ to monitor blood and cerebrospinal fluid constantly for toxic substances. It relays information to the emesis center to trigger nausea and vomiting.M.H.Farjoo MD, Ph.D
  3. 3. Nausea and Vomiting The emesis center also receives information from the gut, principally by the vagus nerve Two other important inputs to the emesis center come from:  the cerebral cortex in anticipatory nausea or vomiting which responds better to anxiolytic therapy than to antiemetics.  the vestibular apparatus (in motion sickness)M.H.Farjoo MD, Ph.D
  4. 4. Nausea and Vomiting The CTZ has high concentrations of receptors for serotonin (5-HT3), dopamine (D2), and opioids the STN is rich in receptors for enkephalin, histamine, and ACh, and 5-HT3 A variety of these neurotransmitters are involved in nausea and vomiting For treatment of the emesis associated with cancer chemotherapy, several antiemetic agents from different classes are used.M.H.Farjoo MD, Ph.D
  5. 5. Figure 37-4. Pharmacologists view of emetic stimuli.Myriad signaling pathways lead from the periphery to the emeticcenter. Stimulants of these pathways are noted in italics. Thesepathways involve specific neurotransmitters and their receptors (boldtype). Receptors are shown for dopamine (D2), acetylcholine(muscarinic, M), histamine (H1), and 5-hydroxytryptamine (5-HT3).Some of these receptors also may mediate signaling in the emeticcenter.
  6. 6. Nausea and Vomiting Drugs evoking vomiting include:  Analgesics  Erythromycin  Digoxin  Opiates  anti-Parkinsonian drugs  OCPsM.H.Farjoo MD, Ph.D
  7. 7. 5-HT3 Receptor Antagonists Ondansetron is the prototypical 5-HT3 Receptor Antagonist. Another agent is granisetron. There is evidence that effects at peripheral and central sites contribute to the efficacy of these agents. Optimal antiemetic effects often are obtained with a 5-HT3 antagonist combined with a glucocorticoid. Serotonin is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents.M.H.Farjoo MD, Ph.D
  8. 8. 5-HT3 Receptor Antagonists this stimulates vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. These agents are most effective in treating chemotherapy-induced nausea and in treating nausea secondary to upper abdominal irradiation. They are effective against hyperemesis of pregnancy, and to a lesser degree, postoperative nausea. They have no effect against motion sickness. the most common adverse effects is constipation or diarrhea, headache, and light-headedness.M.H.Farjoo MD, Ph.D
  9. 9. Dopamine-Receptor Antagonists Dopamine antagonists cross the blood-brain barrier and cause anxiety, dystonic reactions, galactorrhea, sexual dysfunction, and tardive dyskinesia. Phenothiazines such as chlorpromazine are among the most commonly used "general purpose" antiemetics. their principal mechanism of action is dopamine D2 receptor antagonism at the CTZ. they do not appear to be as uniformly effective in cancer chemotherapy-induced emesis.M.H.Farjoo MD, Ph.D
  10. 10. Dopamine-Receptor Antagonists Metoclopramide and domperidone are dopamine D2 receptor antagonists. Within the gastrointestinal tract activation of dopamine receptors inhibits cholinergic smooth muscle stimulation blockade of this effect is believed to be the primary prokinetic mechanism of action of these agents. They increase esophageal peristaltic amplitude, increase lower esophageal sphincter pressure, and enhance gastric emptying.M.H.Farjoo MD, Ph.D
  11. 11. Dopamine-Receptor Antagonists They have no effect on small intestine or colonic motility. Metoclopramide and domperidone also block dopamine D2 receptors in the chemoreceptor trigger zone this results in potent antinausea and antiemetic action. High-dose metoclopramide also exhibits efficacy in chemotherapy-evoked emesisM.H.Farjoo MD, Ph.D
  12. 12. Antihistamines H1-receptor antagonists act on vestibular afferents They are useful for motion sickness and postoperative emesis. Cyclizine, hydroxyzine, promethazine, and diphenhydramine are examples of this class. Cyclizine has additional anticholinergic effects that may be useful for patients with abdominal cancer.M.H.Farjoo MD, Ph.D
  13. 13. Anticholinergic Agents The most commonly used muscarinic receptor antagonist is scopolamine (hyoscine). Its principal application is in motion sickness. it has some activity in postoperative nausea and vomiting, as well. In general, anticholinergic agents have no role in chemotherapy-induced nausea.M.H.Farjoo MD, Ph.D
  14. 14. Dronabinol Dronabinol is a cannabinoid that is extracted from Cannabis sativa. The exact mechanism of the antiemetic action of dronabinol is unknown It probably stimulates the CB1 cannabinoid receptors on neurons of the vomiting center. its onset of action occurs within an hour, and peak levels are achieved within 2 to 4 hours.M.H.Farjoo MD, Ph.D
  15. 15. Cannabis crop in Afghanistan
  16. 16. cannabis plant
  17. 17. cannabis plant
  18. 18. Cannabis female flowers close-up
  19. 19. Male Cannabis pollen sacs.
  20. 20. Dronabinol Dronabinol is a useful prophylactic agent in patients receiving cancer chemotherapy when other antiemetic medications are not effective. It also can stimulate appetite and has been used in patients with acquired immunodeficiency syndrome (AIDS) and anorexia. Dronabinol causes central sympathomimetic activity which leads to palpitations, tachycardia, and conjunctival injection (bloodshot eyes). marijuana-like "highs" (e.g., euphoria, somnolence, detachment, dizziness, anxiety, nervousness, panic, etc.) can occur.M.H.Farjoo MD, Ph.D
  21. 21. Dronabinol abrupt withdrawal causes irritability, insomnia, and restlessness. Dronabinol should be prescribed with great caution to persons with a history of substance abuse (it may be abused by them)M.H.Farjoo MD, Ph.D
  22. 22. Antiinflammatory Agents Glucocorticoids such as dexamethasone can be useful adjuncts for nausea in cancer. They suppress peritumoral inflammation and prostaglandin production. A similar mechanism explains NSAIDs efficacy for vomiting induced by systemic irradiationM.H.Farjoo MD, Ph.D
  23. 23. Benzodiazepines lorazepam and alprazolam, by themselves are not very effective antiemetics their sedative, amnesic, and anti-anxiety effects can be helpful in anticipatory vomiting.M.H.Farjoo MD, Ph.D
  24. 24. Substance P Receptor Antagonists The nausea and vomiting associated with cisplatin has two components:  an acute phase that universally is experienced (within 24 hours after chemotherapy)  a delayed phase that affects only some patients (on days 2 to 5). Acute emesis is mediated by 5-HT3 pathways, whereas delayed emesis is 5-HT3-independent. 5-HT receptor antagonists are not very effective against delayed emesis.M.H.Farjoo MD, Ph.D
  25. 25. Substance P Receptor Antagonists Substance P is in vagal afferent fibers innervating the STN and area postrema. Antagonists of the NK1 receptors for substance P, such as aprepitant, have antiemetic effects in delayed nausea. they improve the efficacy of antiemetic regimens in patients receiving multiple cycles of chemotherapy.M.H.Farjoo MD, Ph.D
  26. 26. Vomiting and Pregnancy Pregnancy is the most prevalent endocrinologic cause of nausea It occurs in 70% of women in the first trimester. Hyperemesis gravidarum is a severe form of nausea of pregnancy. It can produce significant fluid loss and electrolyte disturbances.M.H.Farjoo MD, Ph.D
  27. 27. Vomiting and Pregnancy The clinician should be cautious in managing the pregnant patient with nausea. meclizine (antihistamine) and prochlorperazine (antidopaminergic) arebetter than placebo. Some obstetricians offer other therapies such as pyridoxine, acupressure, or ginger.M.H.Farjoo MD, Ph.D
  28. 28. Metabolic causes of emesis Uremia, ketoacidosis, and adrenal insufficiency, as well as parathyroid and thyroid disease, are other. Ethanol intoxication is a common toxic etiology of nausea and vomiting.M.H.Farjoo MD, Ph.D
  29. 29. Summary of Antiemetic Medications Most current drug regimens produce greater reductions in vomiting than in nausea. The most commonly used antiemetic agents act on sites within the central nervous systemM.H.Farjoo MD, Ph.D
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  31. 31. Thank you Any question?