There is evidence that effects at peripheral and central sites contribute to the efficacy of these agents. 5-HT3 receptors are present in several critical sites involved in emesis, including vagal afferents, the STN (which receives signals from vagal afferents), and the area postrema itself (Figure 46–4). Serotonin is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents and may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. Experimentally, vagotomy has been shown to prevent cisplatin-induced emesis. However, the highest concentrations of 5-HT3 receptors in the CNS are found in the STN and CTZ, and antagonists of 5-HT3 receptors also may suppress nausea and vomiting by acting at these sites.
Pharmacokinetics. The anti-emetic effects of these drugs persist long after they disappear from the circulation, suggesting their continuing interaction at the receptor level. In fact, all of these drugs can be administered effectively just once a day.
These agents are absorbed well from the GI tract. Ondansetron is extensively metabolized in the liver by CYP1A2, CYP2D6, and CYP3A4, followed by glucuronide or sulfate conjugation. Patients with hepatic dysfunction have reduced plasma clearance, and some adjustment in the dosage is advisable. Although ondansetron clearance also is reduced in elderly patients, no adjustment in dosage for age is recommended. Granisetron also is metabolized predominantly by the liver, a process that appears to involve the CYP3A family, as it is inhibited by ketoconazole. Dolasetron is converted rapidly by plasma carbonyl reductase to its active metabolite, hydrodolasetron. A portion of this compound then undergoes subsequent biotransformation by CYP2D6 and CYP3A4 in the liver while about one-third of it is excreted unchanged in the urine. Palonosetron is metabolized principally by CYP2D6 and excreted in the urine as the metabolized and the unchanged forms in about equal proportions.
Therapeutic Use. These agents are most effective in treating chemotherapy-induced nausea and in treating nausea secondary to upper abdominal irradiation, where all three agents appear to be equally efficacious. They also are effective against hyperemesis of pregnancy, and to a lesser degree, postoperative nausea, but not against motion sickness. Unlike other agents in this class, palonosetron also may be helpful in delayed emesis, perhaps a reflection of its long t1/2.
These agents are available as tablets, oral solution, and intravenous preparations for injection. For patients on cancer chemotherapy, these drugs can be given in a single intravenous dose (Table 46–8) infused over 15 minutes, beginning 30 minutes before chemotherapy, or in 2-3 divided doses, with the first usually given 30 minutes before and subsequent doses at various intervals after chemotherapy. The drugs also can be used intramuscularly (ondansetron only) or orally. Granisetron is available as a transdermal formulation that is applied 24-48 hours before chemotherapy and worn for up to 7 days.
Adverse Effects. In general, these drugs are very well tolerated, with the most common adverse effects being constipation or diarrhea, headache, and lightheadedness. As a class, these agents have been shown experimentally to induce minor electrocardiographic changes, but these are not expected to be clinically significant in most cases.
Phenothiazines such as prochlorperazine, thiethylperazine (discontinued in the U.S.), and chlorpromazine (Chapter 16) are among the most commonly used "general-purpose" anti-nauseants and anti-emetics. Their effects in this regard are complex, but their principal mechanism of action is D2 receptor antagonism at the CTZ. Compared with metoclopramide or ondansetron, these drugs do not appear to be as uniformly effective in cancer chemotherapy–induced emesis. But they also possess antihistaminic and anticholinergic activities, which are of value in other forms of nausea, such as motion sickness.
Histamine H1 antagonists are primarily useful for motion sickness and postoperative emesis. They act on vestibular afferents and within the brainstem. Cyclizine, hydroxyzine, promethazine, and diphenhydramine are examples of this class of agents. Cyclizine has additional anticholinergic effects that may be useful for patients with abdominal cancer. For a detailed discussion of these drugs, see Chapter 32.
The most commonly used muscarinic receptor antagonist is scopolamine (hyoscine), which can be injected as the hydrobromide, but usually is administered as the free base in the form of a transdermal patch (transderm-scop). Its principal utility is in the prevention and treatment of motion sickness, although it has been shown to have some activity in postoperative nausea and vomiting tool. In general, anticholinergic agents have no role in chemotherapy-induced nausea. For a detailed discussion of these drugs, see Chapter 9.
Substance P Receptor Antagonists
The nausea and vomiting associated with cisplatin (Chapter 61) have two components: an acute phase that universally is experienced (within 24 hours after chemotherapy) and a delayed phase that affects only some patients (on days 2-5). 5-HT3 receptor antagonists are not very effective against delayed emesis. Antagonists of the NK1 receptors for substance P, such as aprepitant (and its parenteral formulation, fosaprepitant; emend), have anti-emetic effects in delayed nausea and improve the efficacy of standard anti-emetic regimens in patients receiving multiple cycles of chemotherapy.
After absorption, aprepitant is bound extensively to plasma proteins (>95%); it is metabolized avidly, primarily by hepatic CYP3A4, and is excreted in the stools; its t1/2 is 9-13 hours. Aprepitant has the potential to interact with other substrates of CYP3A4, requiring adjustment of other drugs, including dexamethasone, methylprednisolone (whose dose may need to be reduced by 50%), and warfarin. Aprepitant is contraindicated in patients on cisapride or pimozide, in whom life-threatening QT prolongation has been reported.
Aprepitant is supplied in 40-, 80- and 125-mg capsules and is administered for 3 days in conjunction with highly emetogenic chemotherapy, along with a 5-HT3 antagonist and a corticosteroid. The recommended adult dosage of aprepitant is 125 mg administered 1 hour before chemotherapy on day 1, followed by 80 mg once daily in the morning on days 2 and 3 of the treatment regimen.
Dronabinol (Δ-9-tetrahydrocannabinol; marinol) is a naturally occurring cannabinoid that can be synthesized chemically or extracted from the marijuana plant, Cannabis sativa. The exact mechanism of the anti-emetic action of dronabinol is not known but probably relates to stimulation of the CB1 subtype of cannabinoid receptors on neurons in and around the vomiting center in the brainstem (Van Sickle et al., 2001).
Pharmacokinetics. Dronabinol is a highly lipid-soluble compound that is absorbed readily after oral administration; its onset of action occurs within an hour, and peak levels are achieved within 2-4 hours. It undergoes extensive first-pass metabolism with limited systemic bioavailability after single doses (only 10-20%). Active and inactive metabolites are formed in the liver; the principal active metabolite is 11-OH-delta-9-tetrahydrocannabinol.
These metabolites are excreted primarily via the biliary-fecal route, with only 10-15% excreted in the urine. Both dronabinol and its metabolites are highly bound (>95%) to plasma proteins. Because of its large volume of distribution, a single dose of dronabinol can result in detectable levels of metabolites for several weeks.
Therapeutic Use. Dronabinol is a useful prophylactic agent in patients receiving cancer chemotherapy when other anti-emetic medications are not effective. It also can stimulate appetite and has been used in patients with acquired immunodeficiency syndrome (AIDS) and anorexia. As an anti-emetic agent, it is administered at an initial dose of 5 mg/m2 given 1-3 hours before chemotherapy and then every 2-4 hours afterward for a total of four to six doses. If this is not adequate, incremental increases can be made up to a maximum of 15 mg/m2 per dose. For other indications, the usual starting dose is 2.5 mg twice a day; this can be titrated up to a maximum of 20 mg per day.
Adverse Effects. Dronabinol has complex effects on the CNS, including a prominent central sympathomimetic activity. This can lead to palpitations, tachycardia, vasodilation, hypotension, and conjunctival injection (bloodshot eyes). Patient supervision is necessary because marijuana-like "highs" (e.g., euphoria, somnolence, detachment, dizziness, anxiety, nervousness, panic, etc.) can occur, as can more disturbing effects such as paranoid reactions and thinking abnormalities. After abrupt withdrawal of dronabinol, an abstinence syndrome (irritability, insomnia, and restlessness) can occur. Because of its high affinity for plasma proteins, dronabinol can displace other plasma protein-bound drugs, whose doses may have to be adjusted as a consequence. Dronabinol should be prescribed with great caution to persons with a history of substance abuse (alcohol, drugs) because it also may be abused by these patients.
Nabilone (cesamet) is a synthetic cannabinoid with a mode of action similar to that of dronabinol.
Pharmacokinetics. Nabilone, like dronabinol, is a highly lipid-soluble compound that is rapidly absorbed after oral administration; its onset of action occurs within an hour, and peak levels are achieved within 2 hours. The t1/2 is ~2 hours for the parent compound and 35 hours for metabolites. The metabolites are excreted primarily via the biliary-fecal route (60%), with only ~25% excreted in the urine.
Therapeutic Use. Nabilone is a useful prophylactic agent in patients receiving cancer chemotherapy when other anti-emetic medications are not effective. A dose (1-2 mg) can be given the night before chemotherapy; usual dosing starts 1-3 hours before treatment and then every 8-12 hours during the course of chemotherapy and for 2 days following its cessation.
Adverse Effects. The adverse effects are largely the same as for dronabinol, with significant CNS actions in >10% of patients. Cardiovascular, GI, and other side effects are also common and together with the CNS actions limit the usefulness of this agent.
Glucocorticoids and Anti-Inflammatory Agents
Glucocorticoids such as dexamethasone can be useful adjuncts (Table 46–7) in the treatment of nausea in patients with widespread cancer, possibly by suppressing peritumoral inflammation and prostaglandin production. A similar mechanism has been invoked to explain beneficial effects of NSAIDs in the nausea and vomiting induced by systemic irradiation. For a detailed discussion of these drugs, see Chapters 34 and 42.
Benzodiazepines, such as lorazepam and alprazolam, by themselves are not very effective anti-emetics, but their sedative, amnesic, and anti-anxiety effects can be helpful in reducing the anticipatory component of nausea and vomiting in patients. For a detailed discussion of these drugs, see Chapter 17.
Phosphorated Carbohydrate Solutions
Aqueous solutions of glucose, fructose, and phosphoric acid (emetrol, nausetrol) are available over the counter to relieve nausea. Their mechanism of action is not well established. They may be safely taken for a short period (1 hour with a dose every 15 minutes).