Drugs Acting on the Drugs Acting on the Gastrointestinal TractGastrointestinal 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 genitals4. 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

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.