Drugs Acting on the Gastrointestinal Tract

1.Emetics and Antiemetics

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.

–The vomiting center receives inputs from several sources: 1.Chemoreceptor trigger zone (CTZ) 2.Vestibular nucleus 3.Peripheral afferents from the pharynx, gastrointestinal tract, and genitals 4.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

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

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

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

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

Histamine1 (H1)-receptor antagonists

diphenhydramine [Benadryl] meclizine [Antivert, Bonine] dimenhydrinate [Dramamine] promethazine [Phenergan]

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.

Dopamine antagonists 1.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.

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.

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

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.

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.

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.

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.

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.

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

–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.

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.

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

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.