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Chapter: Basic & Clinical Pharmacology : Drugs Used in the Treatment of Gastrointestinal Diseases

Antiemetic Agents

Nausea and vomiting may be manifestations of a wide variety of conditions, including adverse effects from medications; systemic disorders or infections; pregnancy;


Nausea and vomiting may be manifestations of a wide variety of conditions, including adverse effects from medications; systemic disorders or infections; pregnancy; vestibular dysfunction; central nervous system infection or increased pressure; peritonitis; hepa-tobiliary disorders; radiation or chemotherapy; and gastrointesti-nal obstruction, dysmotility, or infections.


The brainstem “vomiting center” is a loosely organized neuronal region within the lateral medullary reticular formation and coor-dinates the complex act of vomiting through interactions with cranial nerves VIII and X and neural networks in the nucleus tractus solitarius that control respiratory, salivatory, and vasomo-tor centers. High concentrations of muscarinic M1, histamine H1, neurokinin 1 (NK1), and serotonin 5-HT3 receptors have been identified in the vomiting center (Figure 62–6).

There are four important sources of afferent input to the vomiting center:


1. The “chemoreceptor trigger zone” or area postrema is located at the caudal end of the fourth ventricle. This is outside the blood-brain barrier but is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. The chemoreceptor trigger zone is rich in dopamine D2 receptors and opioid receptors, and possibly serotonin 5-HT3 receptors and NK1 receptors.


2. The vestibular system is important in motion sickness via cra-nial nerve VIII. It is rich in muscarinic M1 and histamine H1 receptors.


3. Vagal and spinal afferent nerves from the gastrointestinal tract are rich in 5-HT3 receptors. Irritation of the gastrointestinal mucosa by chemotherapy, radiation therapy, distention, or acute infectious gastroenteritis leads to release of mucosal sero-tonin and activation of these receptors, which stimulate vagal afferent input to the vomiting center and chemoreceptor trig-ger zone.


4. The central nervous system plays a role in vomiting due to psychiatric disorders, stress, and anticipatory vomiting prior to cancer chemotherapy.


Identification of the different neurotransmitters involved with emesis has allowed development of a diverse group of antiemetic agents that have affinity for various receptors. Combinations ofantiemetic agents with different mechanisms of action are often used, especially in patients with vomiting due to chemotherapeu-tic agents.


Pharmacokinetics & Pharmacodynamics


Selective 5-HT3-receptor antagonists have potent antiemetic properties that are mediated in part through central 5-HT3-receptor blockade in the vomiting center and chemoreceptor trigger zone but mainly through blockade of peripheral 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves. The anti-emetic action of these agents is restricted to emesis attributable to vagal stimulation (eg, postoperative) and chemotherapy; other emetic stimuli such as motion sickness are poorly controlled.


Four agents are available in the USA: ondansetron, granise-tron, dolasetron, and palonosetron. (Tropisetron is anotheragent available outside the USA.) The first three agents (ondanse-tron, granisetron, and dolasetron, Figure 62–5) have a serum half-life of 4–9 hours and may be administered once daily by oral or intravenous routes. All three drugs have comparable efficacy and tolerability when administered at equipotent doses. Palonosetron is a newer intravenous agent that has greater affinity for the 5-HT3 receptor and a long serum half-life of 40 hours. All four drugs undergo extensive hepatic metabolism and are eliminated by renal and hepatic excretion. However, dose reduction is not required in geriatric patients or patients with renal insufficiency. For patients with hepatic insufficiency, dose reduction may be required with ondansetron.


5-HT3-receptor antagonists do not inhibit dopamine or mus-carinic receptors. They do not have effects on esophageal or gastric motility but may slow colonic transit.


Clinical Uses


A. Chemotherapy-Induced Nausea and Vomiting


5-HT3-receptor antagonists are the primary agents for the preven-tion of acute chemotherapy-induced nausea and emesis. When used alone, these drugs have little or no efficacy for the prevention of delayed nausea and vomiting (ie, occurring > 24 hours after chemotherapy). The drugs are most effective when given as a single dose by intravenous injection 30 minutes prior to administration of chemotherapy in the following doses: ondansetron, 8 mg; gran-isetron, 1 mg; dolasetron, 100 mg; or palonosetron, 0.25 mg. A single oral dose given 1 hour before chemotherapy may be equally effective in the following regimens: ondansetron 8 mg twice daily or 24 mg once; granisetron, 2 mg; dolasetron, 100 mg. Although 5-HT3-receptor antagonists are effective as single agents for the prevention of chemotherapy-induced nausea and vomiting, their efficacy is enhanced by combination therapy with a corticosteroid (dexamethasone) and NK1-receptor antagonist .


B. Postoperative and Postradiation Nausea and Vomiting


5-HT3-receptor antagonists are used to prevent or treat postoperative nausea and vomiting. Because of adverse effects and increased restric-tions on the use of other antiemetic agents, 5-HT3-receptor antago-nists are increasingly used for this indication. They are also effective in the prevention and treatment of nausea and vomiting in patients undergoing radiation therapy to the whole body or abdomen.


Adverse Effects


The 5-HT3-receptor antagonists are well-tolerated agents with excel-lent safety profiles. The most commonly reported adverse effects are headache, dizziness, and constipation. All four agents cause a small but statistically significant prolongation of the QT interval, but this is most pronounced with dolasetron. Although cardiac arrhythmias have not been linked to dolasetron, it should not be administered to patients with prolonged QT or in conjunction with other medica-tions that may prolong the QT interval .


Drug Interactions


No significant drug interactions have been reported with 5-HT 3-receptor antagonists. All four agents undergo some metabolism by the hepatic cytochrome P450 system but they do not appear toaffect the metabolism of other drugs. However, other drugs may reduce hepatic clearance of the 5-HT3-receptor antagonists, alter-ing their half-life.


Corticosteroids (dexamethasone, methylprednisolone) have antie-metic properties, but the basis for these effects is unknown.. These agents appear to enhance the efficacy of 5-HT3-receptor antagonists for prevention of acute and delayed nausea and vomiting in patients receiving moderately to highly emetogenic chemotherapy regimens. Although a number of corticosteroids have been used, dexame-thasone, 8–20 mg intravenously before chemotherapy, followed by 8 mg/d orally for 2–4 days, is commonly administered.


Neurokinin 1 (NK1)-receptor antagonists have antiemetic proper-ties that are mediated through central blockade in the area pos-trema. Aprepitant (an oral formulation) is a highly selective NK1-receptor antagonist that crosses the blood-brain barrier and occupies brain NK1 receptors. It has no affinity for serotonin, dopamine, or corticosteroid receptors. Fosaprepitant is an intra-venous formulation that is converted within 30 minutes after infusion to aprepitant.


The oral bioavailability of aprepitant is 65%, and the serum half-life is 12 hours. Aprepitant is metabolized by the liver, primarily by the CYP3A4 pathway.

Clinical Uses

Aprepitant is used in combination with 5-HT3-receptor antago-nists and corticosteroids for the prevention of acute and delayed nausea and vomiting from highly emetogenic chemotherapeutic regimens. Combined therapy with aprepitant, a 5-HT3-receptor antagonist, and dexamethasone prevents acute emesis in 80–90% of patients compared with less than 70% treated without aprepi-tant. Prevention of delayed emesis occurs in more than 70% of patients receiving combined therapy versus 30–50% treated with-out aprepitant. NK1-receptor antagonists may be administered for 3 days as follows: oral aprepitant 125 mg or intravenous fosa-prepitant 115 mg given 1 hour before chemotherapy, followed by oral aprepitant 80 mg/d for 2 days after chemotherapy.


Adverse Effects & Drug Interactions

Aprepitant may be associated with fatigue, dizziness, and diarrhea. The drug is metabolized by CYP3A4 and may inhibit the metabo-lism of other drugs metabolized by the CYP3A4 pathway. Several chemotherapeutic agents are metabolized by CYP3A4, including docetaxel, paclitaxel, etoposide, irinotecan, imatinib, vinblastine, and vincristine. Drugs that inhibit CYP3A4 metabolism maysignificantly increase aprepitant plasma levels (eg, ketoconazole, ciprofloxacin, clarithromycin, nefazodone, ritonavir, nelfinavir, verapamil, and quinidine). Aprepitant decreases the international normalized ratio (INR) in patients taking warfarin.


Phenothiazines are antipsychotic agents that can be used for their potent antiemetic and sedative properties . The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors. Sedative prop-erties are due to their antihistamine activity. The agents most commonly used as antiemetics are prochlorperazine, promethaz-ine, and thiethylperazine.


Antipsychotic butyrophenones also possess antiemetic proper-ties due to their central dopaminergic blockade . The main agent used is droperidol, which can be given by intra-muscular or intravenous injection. In antiemetic doses, droperidol is extremely sedating. Previously, it was used extensively for post-operative nausea and vomiting, in conjunction with opiates and benzodiazepines for sedation for surgical and endoscopic proce-dures, for neuroleptanalgesia, and for induction and maintenance of general anesthesia. Extrapyramidal effects and hypotension may occur. Droperidol may prolong the QT interval, rarely resulting in fatal episodes of ventricular tachycardia including torsades de pointes. Therefore, droperidol should not be used in patients with QT prolongation and should be used only in patients who have not responded adequately to alternative agents.


Substituted benzamides include metoclopramide (discussed pre-viously) and trimethobenzamide. Their primary mechanism of antiemetic action is believed to be dopamine-receptor blockade. Trimethobenzamide also has weak antihistaminic activity. For prevention and treatment of nausea and vomiting, metoclo-pramide may be given in the relatively high dosage of 10–20 mg orally or intravenously every 6 hours. The usual dose of trimethobenzamide is 300 mg orally, or 200 mg by intramuscular injection. The principal adverse effects of these central dopamine antagonists are extrapyramidal: restlessness, dystonias, and parkin-sonian symptoms.


As single agents, these drugs have weak antiemetic activity, although they are particularly useful for the prevention or treatment of motion sickness. Their use may be limited by dizziness, sedation, confusion, dry mouth, cycloplegia, and urinary retention. Diphenhydramine and one of its salts, dimenhydrinate, are first-generation histamine H1 antagonists that also have significant

anticholinergic properties. Because of its sedating properties, diphenhydramine is commonly used in conjunction with other antiemetics for treatment of emesis due to chemotherapy. Meclizine is an H1antihistaminic agent with minimal anticholin-ergic properties that also causes less sedation. It is used for the prevention of motion sickness and the treatment of vertigo due to labyrinth dysfunction.


Hyoscine (scopolamine), a prototypic muscarinic receptorantagonist, is one of the best agents for the prevention of motion sickness. However, it has a very high incidence of anticholinergic effects when given orally or parenterally. It is better tolerated as a transdermal patch. Superiority to dimenhydrinate has not been proved.



Benzodiazepines such as lorazepam or diazepam are used before the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety.



Dronabinol is9-tetrahydrocannabinol (THC), the major psy-choactive chemical in marijuana . After oral ingestion, the drug is almost completely absorbed but undergoes significant first-pass hepatic metabolism. Its metabolites are excreted slowly over days to weeks in the feces and urine. Like crude marijuana, dronabinol is a psychoactive agent that is used medically as an appetite stimulant and as an antiemetic, but the mechanisms for these effects are not understood. Because of the availability of more effective agents, dronabinol now is uncom-monly used for the prevention of chemotherapy-induced nausea and vomiting. Combination therapy with phenothiazines provides synergistic antiemetic action and appears to attenuate the adverse effects of both agents. Dronabinol is usually administered in a dosage of 5 mg/m2 just prior to chemotherapy and every 2–4 hours as needed. Adverse effects include euphoria, dysphoria, sedation, hallucinations, dry mouth, and increased appetite. It has some autonomic effects that may result in tachycardia, conjunctival injection, and orthostatic hypotension. Dronabinol has no signifi-cant drug-drug interactions but may potentiate the clinical effects of other psychoactive agents.


Nabilone is a closely related THC analog that has been avail-able in other countries and is now approved for use in the USA.


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