Drugs Acting on the Gastrointestinal Tract

1. Drugs Acting on the Gastrointestinal Tract

2. Emetics and Antiemetics

3. Vomiting reflex • The vomiting reflex is a coordinated reflex controlled by a bilateral vomiting center in the dorsal portion of the lateral reticular formation in the medulla. • Pharmacologic intervention relies on inhibition of inputs or depression of the vomiting center.

4. The vomiting center receives inputs from several sources: • Chemoreceptor trigger zone (CTZ) • Vestibular nucleus • Peripheral afferents from the pharynx, gastrointestinal tract, and genitals • Psychologic input from the central nervous system (CNS) • Serotonin (5-HT3)-receptors, which are the predominant mediators of the reflex, are present in: • vomiting center • CTZ • periphery

7. Antiemetics • Def.: Agents to treat nausea and vomiting • Useful in the treatment of vomiting associated with: • motion sickness • chemotherapy

8. Cholinergic antagonists • They reduce the excitability of labyrinthine receptors and depress conduction from the vestibular apparatus to the vomiting center.

9. Cholinergic antagonists are used to: • treat motion sickness • in preoperative situations. • They are not useful in treating nausea caused by chemotherapy.

10. Scopolamine • Inhibit cholinergic and muscarinic CNS receptors. Crosses the blood-brain barrier. • More effective against motion-induced emesis. • SIDE EFFECTS: sedation, CNS excitation, dry mouth, urinary retention, blurred vision, confusion, disorientation, hallucinations

11. Histamine1 (H1)-receptor antagonists

12. Histamine1 (H1)-receptor antagonists • diphenhydramine [Benadryl] • meclizine [Antivert, Bonine] • dimenhydrinate [Dramamine] • promethazine [Phenergan]

13. These agents most likely act by inhibiting cholinergic pathways of the vestibular apparatus by receptor “crossover.” • H1-receptor antagonists are used to treat motion sickness and vertigo. • These agents produce sedation and dry mouth. • Meclizine and promethazine have minimal anticholinergic side effects and are used most often.

14. Dopamine antagonists • Metoclopramide [Reglan] • blocks receptors within the CTZ. • increases the sensitivity of the gastrointestinal tract to the action of acetylcholine (ACh) • this enhances gastrointestinal motility and gastric emptying and increases lower esophageal sphincter tone. • High doses of metoclopramide antagonize serotonin (5-HT3)-receptors in the vomiting center and gastrointestinal tract.

16. Metoclopramide is used to treat: • nausea due to chemotherapy (caused by agents such as cisplatin and doxorubicin) • narcotic-induced vomiting. • Metoclopramide produces sedation, diarrhea, extrapyramidal effects, and elevated prolactin secretion.

17. Phenothiazines and butyrophenones • Phenothiazine: prochlorperazine [Compazine] • Butyrophenone: droperidol [Inapsine].

18. Phenothiazines and butyrophenones: • block dopaminergic receptors in the CTZ • inhibit peripheral transmission to the vomiting center. • These agents are used to: • treat nausea due to chemotherapy and radiation therapy • control postoperative nausea. • Adverse effects (less pronounced with butyrophenones) include: • Anticholinergic effects (drowsiness, dry mouth, and blurred vision), • Extrapyramidal effects • Orthostatic hypotension.

19. 5-HT3 antagonists • Ondansetron [Zofran] • not effective for motion-sickness-induced nausea. • more effective against nausea induced by chemotherapy. • used in postoperative nausea. • can be administered intravenously or orally. • Side effects may include mild constipation.

20. Granisetron [Kytril] • has a greater affinity for 5-HT3 receptors. • Granisetron is longer acting and more potent than ondansetron or metoclopramide. • administered by intravenous infusion or orally. • The most common adverse effect of granisetron is headache.

21. Cannabinoids • The most commonly used in the USA is dronabinol (Δ-9-tetrahydrocannabinol) [Marinol]. • Acts by inhibiting the vomiting center, but the mechanism is unclear. • used to control nausea induced by chemotherapy. • administered as oral preparations. • adverse effect : produce sedation, psychoactive effects (“high”), dry mouth, orthostatic hypotension, and increased appetite.

22. Glucocorticoids • Dexamethasone[Decadron] • Methylprednisolone [Solu-Medrol]. • These agents can be effective as a treatment of vomiting caused by highly emetic agents. • High doses are given as an intravenous (IV) bolus or orally for delayed nausea, often combined with metoclopramide, haloperidol, diphenhydramine, or ondansetron.

23. Benzodiazepines • Lorazepam [Ativan] • Diazepam [Valium] • act as anxiolytic agents to reduce anticipatory emesis. • Diazepam is useful as a treatment of vertigo.

24. Emetrol • Emetrol is an over-the-counter (OTC) preparation containing a mixture of fructose, dextrose, and buffered orthophosphoric acid. • Emetrol is used to treat vomiting in morning sickness and in infants.

25. Neurokinin 1 (NK1) antagonist • Aprepitant [Emend] • (substance P receptor antagonist) used in delayed nausea caused by chemotherapy. • It can be used in a combination with benzodiazepines and 5-HT3 antagonists, or alone.

26. Emetics: agents that induce reflex vomiting. • Ipecac • Ipecac is a mixture of alkaloids, derived from the ipecacuanha plant.

27. Ipecac induces vomiting by stimulating the CTZ and by causing gastrointestinal irritation. • Ipecac is administered orally and is fast acting, causing vomiting in 85% of patients within 20 minutes. • Ipecac is rarely used anymore because of its low effectiveness and high side effect profile. • Cardiac toxicity caused by the emetine in ipecac is noted in abusers such as bulimics.