Serotonin S₃ receptor blockers (5-HT3 antagonists) (ondansetron, granisetron, dolasetron, palonesetron) have proved effective in the prevention of both acute and delayed chemotherapy-induced nausea and vomiting. When the drugs are used alone, complete prevention of acute nausea and vomiting is achieved in about 40% to 50% of patients; more than 70% have no vomiting, but some nausea. When they are combined with a program of acute glucocorticoid therapy (e.g., dexamethasone), their prophylactic efficacy rises to 90% for prevention of emesis and to 70% for prevention of both nausea and vomiting. The first three listed above are similar in regard to efficacy and side effects, which include constipation, headache (occasionally severe), mild dizziness, and a transient, clinically insignificant prolongation of electrocardiographic intervals. The fourth, palonosetron, is only available IV and is longer lasting so it is useful for patients with nausea despite use of the other agents.

These drugs can be administered IV or orally. Ondansetron is the most commonly used of the oral preparations (one to four 8-mg doses are administered orally prior to chemotherapy (or the equivalent IV dose can be given as appropriate), and then one 8-mg dose can be given every 8 hours as needed). The use of one or the other of these agents depends on familiarity of the oncologist with the agent(s) and cost issues. As new 5-HT3 antagonists with different properties are introduced, it is important to consider the potential value of these properties in making decisions about using one agent or another in a specific situation.

Glucocorticoids have proved effective, especially in the prevention of delayed nausea and vomiting (perhaps because of their anti-inflammatory effects). In controlled trials, they have outperformed phenothiazines in the prevention of acute emesis and work well in combination with 5-HT3 antagonists, which make them particularly attractive. They also do not have the sedative effects seen with most other antinausea medications (except the 5-HT3 antagonists). However, they can cause restlessness or difficulty with sleep. A typical program is a 4- to 10-mg oral dose of dexamethasone given just before chemotherapy, followed by three more doses given every 6 hours with a small amount of food, often with the last dose given many hours before bedtime.

Metoclopramide blocks both dopaminergic and serotonin receptors, which accounts for its antiemetic action and its side effects.

Given parenterally in high doses just before chemotherapy, it too can suppress emesis, but to a considerably lesser degree than the serotonin receptor blockers (42% complete suppression vs. 75%). It is frequently used at lower doses given more frequently in combination with other agents, especially to prevent delayed emesis. Its dopaminergic blocking effect promotes gastric emptying and gastroesophageal sphincter closure but also leads to dystonia in young patients and mental confusion in older patients. It is usually given orally although it can also be administered IV.

Phenothiazines, such as prochlorperazine (Compazine), are well established as a treatment for mild nausea and vomiting associated with other conditions, but they are less effective in chemotherapy if used alone. However, when combined with other antiemetic agents, they may help provide additional prophylaxis. Similar to metoclopramide, phenothiazines act centrally, blocking serotonin and dopamine receptors in the chemoreceptor trigger zone. Sedation accompanies their use and is often desired, but extrapyramidal symptoms may also ensue. They are available in oral, suppository, and parenteral forms. The route of administration has little influence on effectiveness. On the day of treatment, a prochlorperazine capsule or suppository is given 4 to 8 hours before the administration of chemotherapy and again on a regularly scheduled basis for the next 24 hours. The main drawback to phenothiazine therapy is the precipitation of extrapyramidal symptoms, which are most likely to occur when daily doses exceed 50 mg. Their onset necessitates discontinuation of therapy. Haloperidol, a major tranquilizer that is not a phenothiazine, is similar to prochlorperazine in antiemetic and extrapyramidal effects. It blocks dopaminergic receptors. Side effects are similar to those of metoclopramide.

The identification of substance P receptors in the central sites triggering emesis has led to the investigation of agents that block such receptors and inhibit substance P-mediated effects. Substance P blockers (e.g., aprepitant) in combination with 5-HT3 blockers and dexamethasone have significant additional benefit, especially in the prevention of delayed emesis. This improves prevention of delayed emesis especially for highly emetogenic regimens, such as those containing high-dose cisplatin. Aprepitant is either given orally for 3 days beginning the day chemotherapy is started or else as a single dose intravenously prior to chemotherapy administration.

Benzodiazepines potentiate the activities of the central inhibitory neurotransmitter γ-aminobutyric acid and can enhance the antiemetic effects of other agents. They also cause a desirable degree of mild amnesia. A short-acting preparation such as lorazepam is commonly given both before chemotherapy and then on an ongoing basis. It too is best used as part of a combination program. Some prescribe an antihistamine (e.g., diphenhydramine) in place of a benzodiazepine although this is not usually quite as effective. Psychogenic vomiting that occurs in anticipation of chemotherapy responds to sublingual, oral, or IV lorazepam or oral alprazolam in conjunction with behavioral desensitization therapy; however, the best treatment is prevention of emesis at the outset of chemotherapy. This latter point cannot be emphasized too strongly.

Cannabinoids and marijuana have some antinausea and appetitestimulant effects. Purified tetrahydrocannabinol (dronabinol) can be utilized in combination with other agents to prevent or
decrease nausea or vomiting. Side effects include somnolence and confusion (usually mild but can be bothersome especially in older patients). There is no convincing evidence that smoking marijuana provides greater antinausea effect although there may be differences in time of onset depending on route of administration.

Hyoscine (scopolamine) used as a transdermal patch applied every 72 hours has some antinausea effects against chemotherapy. Although not as effective as some of the other agents and therefore reserved for settings where they are insufficient to control nausea, it can sometimes help provide some relief in difficult-to-treat cases.

A few treatable causes need to be considered when a patient presents with refractory emesis. Persistent vomiting can be a manifestation of bowel obstruction or severe ileus, which responds to decompression by nasogastric suctioning. Hypercalcemia and hypokalemia may be causes as well as consequences of vomiting; monitoring of electrolytes and correction of any imbalances can help lessen the anorexia, nausea, and vomiting that sometimes accompany them.