Several types of receptors are involved in the emetic response. Important among these are receptors for serotonin, glucocorticoids, substance P, neurokinin-1, dopamine, acetylcholine, and histamine. Many antiemetics, including ondansetron [Zofran], dexamethasone, aprepitant [Emend], prochlorperazine, and dimenhydrinate, act by blocking (or activating) one or more of these receptors.
Antiemetic Drugs
Several types of antiemetics are available. Their classes, trade names, and dosages are shown in Table 64.1. Uses and mechanisms are shown in Table 64.2. Properties of the principal classes are discussed next.
TABLE 64.1
Antiemetic Drugs: Classes, Trade Names, and Dosages
| Class and Generic Name | Trade Name | Adult Dosage |
| SEROTONIN ANTAGONISTS | ||
| Ondansetron | Zofran, Zuplenz | See text |
| Granisetron | Granisol, Kytril  , Sancuso | See text |
| Dolasetron | Anzemet | See text |
| Palonosetron | Aloxi | See text |
| GLUCOCORTICOIDS | ||
| Dexamethasone | Generic only | 10–20 mg IV before chemotherapy, then 4–8 mg |
| Methylprednisolone | Solu-Medrol | 2 doses of 125–500 mg IV 6 hr apart before chemotherapy |
| SUBSTANCE P/NEUROKININ-1 ANTAGONISTS | ||
| Aprepitant | Emend | 125 mg PO on day 1, then 80 mg PO on days 2 and 3 |
| Netupitant/Palonosetron | Akynzeo | 300/0.5 mg PO 1 hr before chemotherapy |
| Fosaprepitant | Emend | 115 mg IV, used in place of the first (125-mg) dose of aprepitant in the regimen above |
| Rolapitant | Varubi | 180 mg PO 1–2 hours before the start of chemotherapy |
| BENZODIAZEPINE | ||
| Lorazepam | Ativan | 1–1.5 mg IV before chemotherapy |
| DOPAMINE ANTAGONISTS | ||
| Phenothiazines | ||
| Chlorpromazine | Generic only | 10–25 mg (PO, IM, IV) every 4–6 hr PRN |
| Perphenazine | Generic only | 8–16 mg/day in divided doses (PO, IM, IV) |
| Prochlorperazine | Generic only | 5–10 mg (PO, IM, IV) 3–4 times a day PRN |
| Promethazine* | Phenergan | 12.5–25 mg (PO, IM, IV) every 4–6 hr |
| Butyrophenones | ||
| Haloperidol† | Haldol | 1–5 mg (PO, IM, IV) every 12 hr PRN |
| Droperidol | Inapsine | 0.625–2.5 mg (IM, IV) every 4–6 hr PRN |
| Others | ||
| Metoclopramide‡ | Reglan | See Table 64.3 |
| CANNABINOIDS | ||
| Dronabinol | Marinol | 5 mg/m2 PO every 2–4 hr PRN |
| Nabilone | Cesamet | 1–2 mg PO twice daily |
| ANTICHOLINERGICS | ||
| Antihistamines | ||
| Cyclizine | Cyclivert | 50 mg PO every 4–6 hr PRN |
| Dimenhydrinate | Dramamine | 50–100 mg (PO, IM, IV) every 4–6 hr PRN |
| Diphenhydramine | Benadryl | 10–50 mg (PO, IM, IV) every 4–6 hr PRN |
| Hydroxyzine | Vistaril | 25–100 mg IM every 6 hr PRN |
| Meclizine | Bonine, Antivert | 25–50 mg PO every 24 hr PRN |
| Others | ||
| Scopolamine | Transderm Scōp | 0.5 mg transdermal every 72 hr PRN |
TABLE 64.2
Antiemetic Drugs: Uses and Mechanism of Action
| Class | Prototype | Antiemetic Use | Mechanism of Antiemetic Action |
| Serotonin antagonists | Ondansetron [Zofran, Zuplenz] | Chemotherapy, radiation, postoperative | Block serotonin receptors on vagal afferents and in the CTZ |
| Glucocorticoids | Dexamethasone (generic only) | Chemotherapy | Unknown |
| Substance P/neurokinin-1 antagonists | Aprepitant [Emend] | Chemotherapy | Block receptors for substance P/neurokinin-1 in the brain |
| Dopamine antagonists | Prochlorperazine (generic only) | Chemotherapy, postoperative, general | Block dopamine receptors in the CTZ |
| Cannabinoids | Dronabinol [Marinol] | Chemotherapy | Unknown, but probably activate cannabinoid receptors associated with the vomiting center |
| Anticholinergics | Scopolamine [Transderm Scōp] | Motion sickness | Block muscarinic receptors in the pathway from the inner ear to the vomiting center |
| Antihistamines | Dimenhydrinate (generic only) | Motion sickness | Block histamine-1 receptors and muscarinic receptors in the pathway from the inner ear to the vomiting center |
Serotonin Receptor Antagonists
Serotonin receptor antagonists are the most effective drugs available for suppressing nausea and vomiting caused by cisplatin and other highly emetogenic anticancer drugs. These drugs are also highly effective against nausea and vomiting associated with radiation therapy, anesthesia, viral gastritis, and pregnancy. Four serotonin antagonists are available for treating emesis: ondansetron, granisetron, dolasetron, and palonosetron.
Ondansetron
Ondansetron [Zofran, Zofran ODT, Zuplenz] was the first serotonin receptor antagonist approved for CINV. The drug is also used to prevent nausea and vomiting associated with radiotherapy and anesthesia. In addition, the drug is used off-label to treat nausea and vomiting from other causes, including childhood viral gastritis and morning sickness of pregnancy. In all cases, benefits derive from blocking type 3 serotonin receptors (5-HT3 receptors1) located in the CTZ and on afferent vagal neurons in the upper GI tract. The drug is very effective by itself, and even more effective when combined with dexamethasone. Administration may be oral or parenteral. The most common side effects are headache, diarrhea, and dizziness. Of much greater concern, ondansetron prolongs the QT interval and hence poses a risk for torsades de pointes, a potentially life-threatening dysrhythmia. Accordingly, the drug should not be given to patients with long QT syndrome and should be used with caution in patients with electrolyte abnormalities, heart failure, or bradydysrhythmias and in those taking other QT drugs. Because ondansetron does not block dopamine receptors, it does not cause the extrapyramidal effects (e.g., akathisia, acute dystonia) seen with antiemetic phenothiazines.
Administration is by the oral (PO), intramuscular (IM), or intravenous (IV) route. For oral dosing, ondansetron is available in solution (sold as Zofran), standard tablets (sold as Zofran), orally disintegrating tablets (sold as Zofran ODT), and a soluble film (sold as Zuplenz). To prevent CINV, the recommended IV dose is 0.15 mg/kg infused slowly (over 15 minutes) beginning 30 minutes before chemotherapy; this dose is repeated 4 and 8 hours later. The dosage for patients undergoing radiation therapy is 8 mg PO (tablets, solution, or soluble film) 3 times a day. The dosage for postoperative nausea and vomiting is 16 mg PO (tablets, solution, or soluble film) 1 hour before induction of anesthesia.
Granisetron
Like ondansetron, granisetron [Granisol, Kytril 
, Sancuso] suppresses emesis by blocking 5-HT3 receptors on afferent vagal neurons and in the CTZ. The drug is approved for preventing nausea and vomiting associated with cancer chemotherapy, radiation therapy, and surgery. Principal adverse effects are headache (responsive to acetaminophen), weakness, tiredness, and either diarrhea or constipation. Administration is PO, IV, or transdermal. The recommended dosage for CINV is either (1) 10 mcg/kg IV infused over 5 minutes, starting 30 minutes before chemotherapy or (2) a single transdermal patch [Sancuso] applied 24 to 48 hours before chemotherapy and removed 24 hours after chemotherapy is completed (but no more than 7 days after application). The dosage for patients undergoing radiation therapy is 2 mg (tablets or oral solution) once daily given within 1 hour of radiation treatment. The dosage for preventing postoperative nausea and vomiting is 1 mg IV injected slowly (over 30 seconds) either before induction of anesthesia or just before reversing anesthesia.
Dolasetron
Dolasetron [Anzemet] is approved for CINV and postoperative nausea and vomiting. Administration is PO or IV. Side effects are like those of other serotonin antagonists, with one important exception: when given by IV injection in high doses, dolasetron poses a significant risk for fatal dysrhythmias. Accordingly, high-dose IV therapy should not be used. Oral therapy and low-dose IV therapy are considered safe. The recommended dosage for CINV in adults is 100 mg PO 1 hour before chemotherapy. The dosage to prevent postoperative nausea and vomiting is 100 mg PO 2 hours before anesthesia or 12.5 mg IV 15 minutes before anesthesia is stopped.
Palonosetron
Palonosetron [Aloxi], indicated for CINV and postoperative nausea and vomiting, has the same mechanism, efficacy, and side effects as other serotonin antagonists, but differs from the others in two clinically significant ways. First, palonosetron has a much longer half-life (40 hours vs. about 8 hours). Second, because of its long half-life, palonosetron is effective against delayed emesis (as well as acute emesis), whereas the others are most effective against acute emesis. Palonosetron also has much greater affinity for 5-HT3 receptors than the other serotonin antagonists, but this difference does not appear to have clinical significance. Palonosetron is available only in an IV formulation. The recommended dosage for CINV in adults is 250 mcg IV delivered over 30 seconds starting 30 minutes before chemotherapy. To prevent postoperative nausea and vomiting, the dosage is 75 mcg IV delivered over 10 seconds immediately before induction of anesthesia.
Glucocorticoids
Two glucocorticoids—methylprednisolone [Solu-Medrol] and dexamethasone—are commonly used to suppress CINV, even though they are not approved by the U.S. Food and Drug Administration (FDA) for this application. Glucocorticoids are effective alone and in combination with other antiemetics. The mechanism by which glucocorticoids suppress emesis is unknown. Both dexamethasone and methylprednisolone are administered by IV route. Because antiemetic use is intermittent and short term, serious side effects are absent. The pharmacology of the glucocorticoids is discussed in Chapter 56.
Substance P/Neurokinin-1 Antagonists
Four substance P/neurokinin-1 antagonists are currently available: aprepitant, rolapitant, netupitant, and fosaprepitant, a prodrug that undergoes conversion to aprepitant in the body. Their principal application is prevention of CINV.
Aprepitant
Actions and Use.
Aprepitant [Emend] is an important antiemetic. The drug is approved for preventing postoperative nausea and vomiting and CINV. Owing to its unique mechanism of action—blockade of neurokinin-1−type receptors (for substance P) in the CTZ—aprepitant can enhance responses when combined with other antiemetic drugs. Aprepitant has a prolonged duration of action and hence can prevent delayed CINV as well as acute CINV. Aprepitant can be used alone for managing postoperative nausea and vomiting. However, because the drug is only moderately effective, it must be combined with other antiemetic drugs—specifically, a glucocorticoid (e.g., dexamethasone) and a serotonin antagonist (e.g., ondansetron)—for managing CINV.
Pharmacokinetics.
Oral aprepitant is well absorbed, both in the presence and absence of food. Plasma levels peak 4 hours after dosing. The drug undergoes extensive hepatic metabolism—primarily by CYP3A4 (the 3A4 isoenzyme of cytochrome P450)—followed by excretion in the urine and feces. The plasma half-life is 9 to 13 hours.
Adverse Effects.
Aprepitant is generally well tolerated. Compared with patients receiving ondansetron and dexamethasone, those receiving aprepitant plus ondansetron and dexamethasone experience more fatigue and asthenia (17.8% vs. 11.8%), hiccups (10.8% vs. 5.6%), dizziness (6.6% vs. 4.4%), and diarrhea (10.3% vs. 7.5%). Aprepitant may also cause a mild, transient elevation of circulating aminotransferases, indicating possible liver injury.
Drug Interactions.
The potential for drug interactions is complex because aprepitant is a substrate for, inhibitor of, and inducer of CYP3A4, a major drug-metabolizing enzyme. Inhibitors of CYP3A4 (e.g., itraconazole, ritonavir) can raise levels of aprepitant. Conversely, inducers of CYP3A4 (e.g., rifampin, phenytoin) can decrease levels of aprepitant. By inhibiting CYP3A4, aprepitant can raise levels of CYP3A4 substrates, including many drugs used for cancer chemotherapy. Among these are docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. Also, aprepitant can raise levels of glucocorticoids used to prevent CINV. Accordingly, doses of these drugs (dexamethasone and methylprednisolone) should be reduced.
In addition to affecting CYP3A4, aprepitant can induce CYP2D6, another drug-metabolizing enzyme. As a result, aprepitant can decrease levels of CYP2D6 substrates, including warfarin (an anticoagulant) and ethinyl estradiol (found in oral contraceptives). Patients receiving warfarin should be monitored closely. Patients using oral contraceptives may need an alternative form of birth control.
Preparations, Dosage, and Administration.
Aprepitant [Emend] is available in 40-, 80- and 125-mg capsules. Dosing may be done with or without food.
For CINV, dosing is done once a day for 3 days. The first dose (125 mg) is given 1 hour before chemotherapy. The second and third doses (80 mg each) are given early on the following 2 days. As noted, aprepitant should be used in combination with dexamethasone and ondansetron.
For postoperative nausea and vomiting, treatment consists of a single 40-mg dose given within 3 hours of anesthesia induction.
Fosaprepitant
Fosaprepitant [Emend] is an intravenous prodrug that undergoes rapid conversion to aprepitant in the body. Accordingly, the pharmacology of fosaprepitant is nearly identical to that of aprepitant. Fosaprepitant is indicated only for preventing CINV. In contrast, aprepitant is approved for CINV and postoperative nausea and vomiting. For prevention of CINV, fosaprepitant is used as a substitute for aprepitant—but only for the first dose in the three-dose regimen (see earlier). Because IV fosaprepitant has greater bioavailability than PO aprepitant, the dosage for fosaprepitant is only 115 mg, compared with 125 mg for aprepitant. In addition to causing the same adverse effects as aprepitant, fosaprepitant can cause pain and induration at the infusion site.
Rolapitant
Actions and Use.
Rolapitant [Varubi] is approved for the prevention of delayed nausea and vomiting associated with chemotherapy. Like aprepitant, rolapitant works well when combined with other antiemetic agents, including dexamethasone and 5-HT3 receptor antagonists.
Pharmacokinetics.
Oral rolapitant is well absorbed, in both the presence and absence of food. Plasma levels peak 4 hours after dosing. The drug undergoes extensive hepatic metabolism—primarily by CYP3A4—followed by excretion in the urine and feces. The plasma half-life is very long—approximately 7 days.
Adverse Effects.
Rolapitant is generally well tolerated. Common adverse reactions include decreased appetite, neutropenia, dizziness, and dyspepsia. Compared with the combination of dexamethasone and a 5-HT3 receptor antagonist alone, there are no significant differences in side effects.
Drug Interactions.
Like aprepitant, concomitant use with inhibitors of CYP3A4 (e.g., itraconazole, ritonavir) can raise levels of rolapitant. Conversely, inducers of CYP3A4 (e.g., rifampin, phenytoin) can decrease levels of rolapitant.
Preparations, Dosage, and Administration.
Rolapitant [Varubi] is available in 90-mg tablets. The recommended dose is 180 mg administered 1 to 2 hours before the start of chemotherapy. Dosing should be in conjunction with prescribed dexamethasone and a 5-HT3 receptor antagonist.
Netupitant/Palonosetron
Netupitant/palonosetron [Akynzeo] is a combination drug that contains both a substance P antagonist (netupitant) and a 5-HT3 receptor antagonist (Palonosetron). The drug is approved for preventing acute and delayed nausea and vomiting associated with chemotherapy. Pharmacokinetics, adverse effects, and drug interactions are similar to the other agents that block substance P and 5-HT3 receptors. Netupitant/palonosetron [Akynzeo] is available in 300/0.5-mg capsules. Dosing can be with or without food. Patients should take one capsule approximately 1 hour before chemotherapy.
Benzodiazepines
Lorazepam [Ativan] is used in combination regimens to suppress CINV. The drug has three principal benefits: sedation, suppression of anticipatory emesis, and production of anterograde amnesia. In addition, lorazepam may help control extrapyramidal reactions caused by phenothiazine antiemetics. The basic pharmacology of lorazepam and other benzodiazepines is discussed in Chapter 27.
Dopamine Antagonists
Phenothiazines
The phenothiazines (e.g., prochlorperazine) suppress emesis by blocking dopamine-2 receptors in the CTZ. These drugs can reduce emesis associated with surgery, cancer chemotherapy, and toxins. Side effects include extrapyramidal reactions, anticholinergic effects, hypotension, and sedation. The basic pharmacology of the phenothiazines is discussed in Chapter 24.
One phenothiazine—promethazine [Phenergan]—requires comment. Promethazine is the most widely used antiemetic in young children, despite its adverse side effects (respiratory depression and local tissue injury) and despite the availability of potentially safer alternatives (e.g., ondansetron).
Black Box Warning: Promethazine
Respiratory depression from promethazine can be severe. Deaths have occurred. Because of this risk, promethazine is contraindicated in children younger than 2 years and should be used with caution in children older than 2 years.
Tissue injury can result in several ways. For example, extravasation of IV promethazine can cause abscess formation, tissue necrosis, and gangrene that requires amputation. Severe injury can also occur with inadvertent perivascular or intraarterial administration, or with administration into or near a nerve. Risk for local injury is lower with IM dosing than with IV dosing. Accordingly, when parenteral administration is needed, the IM route is preferred. Subcutaneous (subQ) promethazine is contraindicated. If IV administration must be done, promethazine should be given through a large-bore, freely flowing line, in a concentration of 25 mg/mL or less at a rate of 25 mg/min or less. Patients should be advised to report local burning or pain immediately.
Butyrophenones
Two butyrophenones—haloperidol [Haldol] and droperidol [Inapsine]—are used as antiemetics. Like the phenothiazines, the butyrophenones suppress emesis by blocking dopamine-2 receptors in the CTZ. Butyrophenones are effective against postoperative nausea and vomiting and against emesis caused by cancer chemotherapy, radiation therapy, and toxins. Potential side effects are similar to those of the phenothiazines: extrapyramidal reactions, sedation, and hypotension. The pharmacology of the butyrophenones is discussed in Chapter 24.
Black Box Warning: Droperidol
Droperidol may pose a risk for fatal dysrhythmias owing to prolongation of the QT interval. Accordingly, patients receiving the drug should undergo an electrocardiographic evaluation before administration.
Metoclopramide
Metoclopramide [Reglan] suppresses emesis through blockade of dopamine receptors in the CTZ. The drug can suppress postoperative nausea and vomiting as well as emesis caused by anticancer drugs, opioids, toxins, and radiation therapy. The pharmacology of metoclopramide is discussed later under “Prokinetic Agents.”
Cannabinoids
Two cannabinoids—dronabinol [Marinol] and nabilone [Cesamet]—are approved for medical use in the United States. Both drugs are related to marijuana (Cannabis sativa). Dronabinol (delta-9-tetrahydrocannabinol; THC) is the principal psychoactive agent in C. sativa. Nabilone is a synthetic derivative of dronabinol. A third cannabinoid preparation, sold as Sativex 
(a combination of THC and cannabidiol), is available in Canada (for treating neuropathic pain) but is not FDA approved in the United States. The basic pharmacology of THC and other cannabinoids is discussed in Chapter 33.
Therapeutic Uses
Both dronabinol and nabilone are approved for suppressing CINV. The mechanism underlying benefits is unknown but most likely results from activating cannabinoid receptors in and around the vomiting center. Because of their psychotomimetic effects and abuse potential (see later), the cannabinoids are considered second-line drugs for CINV and hence should be reserved for patients who are unresponsive to or intolerant of preferred agents.
In addition to its use in CINV, dronabinol (but not nabilone) is approved for stimulating appetite in patients with AIDS. The goal is to reduce AIDS-induced anorexia and prevent or reverse weight loss.
Adverse Effects and Drug Interactions
In theory, the cannabinoids used medically can produce subjective effects identical to those caused by smoking marijuana. Potential unpleasant effects include temporal disintegration, dissociation, depersonalization, and dysphoria. Because of these effects, cannabinoids are contraindicated for patients with psychiatric disorders. In addition to their subjective effects, cannabinoids can cause tachycardia and hypotension and therefore must be used with caution in patients with cardiovascular diseases. The cannabinoids can cause drowsiness and hence should not be combined with alcohol, sedatives, and central nervous system (CNS) depressants.
Abuse Potential
Because they can mimic the subjective effects of marijuana, cannabinoids have some potential for abuse. When first approved for medical use, both drugs were classified under Schedule II of the Controlled Substances Act (CSA)—a classification reserved for drugs with a high abuse potential. However, in 1998, the manufacturer of dronabinol petitioned the Drug Enforcement Agency (DEA) to reclassify the drug under Schedule III. Two arguments for the reduced classification were offered: (1) because of its slow onset, dronabinol does not produce the same “high” produced by smoking marijuana and (2) there is little or no interest in dronabinol on the street. Apparently, the DEA agreed: dronabinol is now classified under Schedule III. Nabilone remains under Schedule II, although its abuse potential seems no greater than that of dronabinol.
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