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Antiemetic Agents

Antiemetic Agents. By: Mahmoud Mahmoud, MD, PhD. Pathophysiology of Emesis. Cerebral cortex. Cancer chemotherapy Opioids. Smell Sight Thought. Anticipatory emesis. Chemoreceptor Trigger Zone (CTZ). Vestibular nuclei. Vomiting Centre (medulla). Motion sickness.

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Antiemetic Agents

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  1. Antiemetic Agents By: Mahmoud Mahmoud, MD, PhD

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

  3. Physiology of CNS Control

  4. Pathophysiology Vomiting is present as a manifestation of different diseases and cancer chemotherapy Vomiting center (VC) of the barinstem is stimulated throughout interaction with CN VIII and X and other CNS nuclei VC is rich in the following receptors: M1, ………….acetylcholine 5HT3 , ………serotonin and H1, ……..histamine Drug combination is always recommended to control more than one mechanism

  5. VC receives input from: 1- CTZ (rich in D2, 5-HT3, opoid, neurokinin1) 2- Vestibular system 3- Irritation of pharynx (gag reflex, vagus nerve) 4- Vagal and spinal afferent Ns. Supplying GIT 5- Psychiatrically, stress Pre-treatment is recommended to control vomiting

  6. 1- Serotonin receptors antagonists(5-HT3 antagonists) MOA: Inhibit vomiting due to vagal nerve stimulation particularly due to chemotherapy, radiotherapy, anesthesia. It blocks serotonin receptors (5-HT3) in VC, CTZ and peripheral 5HT receptors Example: Ondansetron (T1/2: 6 Hr) and Palonoseyron (T1/2: 40Hr) Side effects: Well tolerated Prolong QT interval…… Arrhythmia

  7. 2- Corticosteroids MOA: unknown but it could enhance 5-HT3 antagonists. It is used injunction for preventing vomiting due to cytotoxic drug Example: dexamethasone, methylprednisolone Side effects:

  8. Side Effects - Stomach upset, increased sensitivity to stomach acid to the point of ulceration of esophagus, stomach, and duodenum, Increased appetite leading to significant weight gain - A latent diabetes mellitus often becomes manifest. Glucose intolerance is worsened in patients with preexisting diabetes. - Immunsuppressant action, particularly if given together with other immunosuppressants such as cyclosporine. Bacterial, viral, and fungal disease may progress more easily and can become life-threatening. Fever as a warning symptom is often suppressed. - Psychiatric disturbances, including personality changes, irritability, euphoria, mania - Osteoporosis under long term treatment, pathologic fractures (e.g., hip) - Muscle atrophy, negative protein balance (catabolism) - Elevated liver enzymes, fatty liver degeneration (usually reversible) - Cushingoid (syndrome resembling hyperactive adrenal cortex with increase in adiposity, hypertension, bone demineralization, etc.) - Depression of the adrenal gland is usually seen, if more than 1.5 mg daily are given for more than three weeks to a month. - Hypertension, fluid and sodium retention, edema, worsening of heart insufficiency (due to mineral corticoid activity) - Dependence with withdrawal syndrome is frequently seen. - Increased intraocular pressure, certain types of glaucoma, cataract (serious clouding of eye lenses) - Dermatologic: Acne, allergic dermatitis, dry scaly skin, ecchymoses and petechiae, erythema, impaired wound-healing, increased sweating, rash, striae, suppression of reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. - Allergic reactions (though infrequently):. (Highly unlikely, since dexamethasone is given to prevent anaphylactoid reactions.)

  9. 3- Neurokinin Receptors Antagonists (NK1 antagonists) MOA: selective inhibitors of neurokinin 1 (substance P system) Example: Aprepitant, drug combination with Dexamethazone is recommended to control vomiting Side effects: Inhibiting P450 Decrease prothrombin time in Warfarin treated patients

  10. 4- Dopamine Antagonists MOA: It inhibits D2, M1 and H1 receptors It has a sedative effect (histamine blocker) Example: Phenothiazines group: chloropromazine Butyrophenones group: haloperidole (used to treat nausea and vomiting associated with neoplastic disease, radiation sickness, opioids, cytotoxic drugs and general anesthetics) Metoclopramide(It acts on the GI tract as a pro-kinetic, and is useful in gastrointestinal disease; however, it is poor in cytotoxic or post-op vomiting) Side effects: Extrapyramidal syndrome (restless, dystonia, parkinsonism), prolong QT wave

  11. 5- Anti Histaminic MOA: It blocks H1 receptors. It has also anticholinergic effect Weak antiemetic, used for prevention of motion sickness Example: Diphenhydramine Side effect: Anticholinergic side effects: dryness of mouth, blurring of vision, sedation, dizziness, urinary retention

  12. 6- Anticholinergic MOA: It blocks M1 receptors It has minimal M1 blocker, and minimal sedation Example: Meclizine and hyoscine Meclizine: prevention of motion sickness and treatment of vertigo in labrynthine dysfunction Hyoscine: the best for motion sickness Side effects: Anticholinergic effects

  13. 7- Benzodiazepine MOA: The antiemetic effect is secondary to relieving anxiety due to binding to GABA receptors (Cl- ion channel) Example: Lorazepam and Midazolam Combination with 5-HT3 antagonists is very effective in post operative vomiting Side effects: Tolerance, addiction, CNS dysfunction, respiratory depression,

  14. 8- Cannabinoids MOA: active ingredient is THC (tetrahydrocannabinol), psychoactive in Marijuana and it is an antiemetic. Mechanism is unknown Not popular as other drugs are more efficient but they are used in patients with cachexia cytotoxic nausea, and vomiting, or who are unresponsive to other agents Example: Cannabis and Dronabinol Side effects: Euphoria, sedation, hallucination, dry mouth and increase appetite

  15. Other Trimethobenzamide; thought to work on the CTZ Ginger Emetrol also claimed to be an effective antiemetic. Syrup form (5mL) contains 1.87g of glucose, 1.87g of fructose and 21.5mg of phosphoric acid. Propofol given intravenously. It has been used in an acute care setting in hospital as a rescue therapy for emesis. Peppermintclaimed to help nausea or stomach pain when added into a tea or peppermint candies. Muscimol muscimol is a potent, selective agonist of the GABAA receptor. AjwainAjowan caraway, It is a popular spice in India, Ethiopia and Eritrea.

  16. Prokinetic Agents

  17. Control of GIT Motility Neurogenic control of GIT motility: the ENS Enteric nervous system (ENS) is a collection of nerves within the wall of the GI tract responsible for the autonomous gastrointestinal activity. It consists of connected networks of neurons: myenteric (Auerbach's) plexus, found between the circular and longitudinal muscle layers (responsible for motor control) submucosal (Meissner's) plexus, found below the epithelium (regulates secretion, fluid transport, and vascular flow). Neurons in both plexuses release acetylcholine at their terminals. Autonomic nervous system: Parasympathetic : act by releasing acetylcholine at nerve terminals. It causes contraction of muscles in the wall of the intestine and relaxation of the sphincters and increases gland secretion Sympathetic: act by releasing norepinephrine at nerve terminals. It causes relaxation of muscles in the wall of the intestine and contraction of the sphincters Types of cholinergic receptors are M2 and M3 (present in the GIT in a 4:1 ratio). M3 receptor is more important in muscle contraction.

  18. These are drugs which selectively stimulate GIT motor functions. • MOA: • Smooth muscles are under control of submucosal plexus and mesenteric plexus via sympathetic and parasympathetic NS. • Serotonin (5HT) stimulates 5HT3, 5HT1, calcitonin gene-related peptide (CGRP), motilin to induce vomiting and abdominal pain. 5HT4 stimulates release of Ach and CGRP to control motility • Dopamine inhibits gastric and intestinal contraction

  19. Strategy • We need to increase motility, enhance gastric emptying, increase peristalsis, relax sphincters. This will solve Gastropariesis • BY: • 1- Cholinomimmetics • 2- Dopamine antagonists • 3- Stimulation of motilin • 4- Chloride channel activator

  20. 1- Cholinomimmetics • MOA: Parasympathetic stimulating M3 receptors. Increasing motility. Relax sphincters and stimulates secretions • Examples: • Bethacoline… better drugs are available • Longer duration, Ach.esterase resistant • Neostigmine (cholinesterase inhibitors) • Duration 0.5-2 h • Side effects: • Cholinergic effects: salivation, nausea, vomiting diarrhea, bradycardia

  21. 2- Dopamine Receptor Antagonists • MOA: Inhibiting D2 receptors • Example: • Metoclopramide • Domperidone Does not cross BBB • It has an antiemetic effect as well and stimulates • Side effects of Metoclopramide • CNS effect and extrapyramidal syndrome • Elevation of prolactin???? infertility

  22. 1-Metoclopramide (1): Mechanisms of action (on GIT): • Dopamine receptor antagonism • 5-HT4-receptor agonist • Vagal and central 5-HT3-antagonist • Sensitization of muscarinic receptors on smooth muscle • Stimulates Prolactin secretion to induce lactation 2- Antiemetic action: Mechanism of action: Antagonize dopamine receptors in the CTZ

  23. Therapeutic Use of Metoclopramide 1- Nausea and vomiting that often accompany GI dysmotility syndromes. 2- Gastroesophageal reflux disease (symptomatic relief but not healing of esophagitis). 3-Gastroparesis where it improves gastric emptying. 4- Diagnostic procedures such as intestinal intubation or contrast radiography of the GI tract. 5- Postoperative ileus

  24. Adverse Effects:Metoclopramide 1- Extrapyramidal effects(more commonly in children and young adults and at higher doses). Tardive dyskinesia Akathisia parkinsonian-like symptoms 2- Galactorrhea by blocking the inhibitory effect of dopamine on prolactin release (infrequent)

  25. 2- Domperidone Pharmacological actions: Mechanism of action: dopamine D2 receptor antagonist Antiemetic action Mechanism of action: dopamine D2 receptor antagonist (of D2 receptors in CTZ which is outside BBB)

  26. 2- Domperidone Adverse effects: • Galactorrhea • No extrapyramidal side effects (can not cross the blood-brain barrier)

  27. 3- Macrolides • MOA: stimulates motilin receptors used for treatment of gastropariesis • Tolerance develop rapidly • Example: Erythromycin (an antibiotics) • Side effects: • Liver toxicity • Its metabolites inhibits P450

  28. 4- Chloride channel activator • MOA: stimulate opening of Cl channel (Activator) as Parasympathetic stimulants, to increase fluid secretion in small intestine to help with the passage of stool • Example: Lubiprostone (prostanoic acid derivative) • Side effect: • Delay gastric emptying • Nausea, diarrhea and abdominal pain. • The FDA approved Amitiza in April 2008 to treat women age 18 and older who have IBS with constipation. Its effectiveness in men is not proved.

  29. References • Principles of Pharmacology: Golan D, et al, Baltimore 2005 • Basic and clinical pharmacology, Katzung, 2005

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