Antinausea medications and cancer

ATC CODE: A04A

DEFINITION: Antinausea agents, or antiemetics, encompass a range of drug classes that act on the peripheral and central nervous systems to prevent nausea and vomiting. In patients with cancer, antiemetics are used to control acute, delayed, and anticipatory nausea and vomiting that result from chemotherapy.

Cancers treated: Indirectly used in the treatment of many cancers to control nausea and vomiting associated with many chemotherapy regimens.

Subclasses of this group: Serotonin-3 antagonists, substituted benzamides, corticosteroids, phenothiazines, benzodiazepines, butyrophenones, cannabinoids, neurokinin-1 antagonists

Delivery routes: Administered to inpatients and outpatients as oral tablets, capsules, or liquids; as intravenous or solutions; or as rectal suppositories

How these drugs work: Nausea and vomiting, or emesis, are the most common chemotherapy-associated toxicities, affecting more than 75 percent of patients, especially with the development of combination regimens. The effective use of antinausea agents to improve chemotherapy tolerance is one of the most important advances in supportive cancer care. Among the first of the agents to deter emesis was metoclopramide, a substituted benzamide that acts as a dopamine receptor antagonist and, at higher doses, as an additional serotonin receptor antagonist. Although the exact mechanisms of nausea and vomiting reflexes have not been determined, neurotransmitter blockade at dopaminergic, serotonergic, neurokinin-1, and other receptors in the central nervous system or peripherally in the gastrointestinal tract successfully controls the reactions. Like metoclopramide, phenothiazines such as chlorpromazine and butyrophenones such as haloperidol also prevent nausea and vomiting by dopaminergic blockade. Dopamine antagonism from these three subclasses provides relief of moderate emesis.

The more newly developed serotonin-3 (5HT-3) receptor antagonists work peripherally, especially in the small intestine, and are extremely effective for the treatment and prevention of acute emesis. Ondansetron, granisetron, and dolasetron are equivalent in efficacy and may provide total receptor blockade, as evidenced by their dose-related efficacy plateaus. Palonsetron is longer acting than others in the subclass. Because acute emesis is associated with peripheral control and delayed emesis is associated with central control, 5HT-3 antagonists are more effective in treating acute nausea and vomiting, which occurs in the first twenty-four hours after chemotherapy is administered.

Benzodiazepines such as lorazepam have some activity by blocking cortical input to the emetic center but are more useful for their sedative and anxiolytic effects, which make the agents ideal for combination regimens. In addition, these drugs induce retrograde amnesia, which is successful in preventing anticipatory nausea and vomiting that may occur with repeat chemotherapy administration.

Neurokinin-1 (NK-1) receptors are more recently studied targets of nausea mechanisms. The first approved agent in the NK-1 antagonist class was aprepitant. Because NK-1 mediates substance P activation of NK-1 receptors in the brain stem, aprepitant’s NK-1 receptor antagonism is useful for the treatment of delayed emesis, which is more centrally mediated. Aprepitant successfully prevents acute and delayed nausea and vomiting when combined with serotonin antagonists and corticosteroids. By the mid-2020s, three other NK-1 antagonists were approved: Fosaprepitant, Casopitant, and Rolapitant.

Corticosteroids, especially dexamethasone, methylprednisolone, and prednisone, have a confirmed effect, alone or in combination, against moderate nausea and vomiting despite an unknown mechanism of action and a lack of receptor blockade. Corticosteroids are often the second drug in a combination regimen with dopamine, serotonin, or NK-1 receptor antagonists.

Cannabinoids such as dronabinol act centrally with psychotropic activity to provide limited but affirmed antinausea activity. They can be used for patients with moderate emesis and poor tolerance or response to other agents or for patients who need control of breakthrough pain.

Medical researchers continued to bring new antinausea medications to the market as the twenty-first century progressed. Olanzapine, a psychiatric medication, showed promise in providing relief to cancer patients, and especially those seeking end-of-life comfort care. Aprepitant, another NK-1 antagonist, also showed promise for its antinausea effects. Finally, Dexamethasone, a steroid, showed success in reducing nausea related to the treatment of some cancers.

Side effects: Each subclass of antinausea agents is associated with different side effects; successful combination regimens provide greater efficacy without overlapping drug toxicities. Metoclopramide side effects are primarily related to dopamine antagonism and include extrapyramidal reactions, including acute dystonic reactions. Akathisia, or restlessness, is common and may persist for hours. Drowsiness and diarrhea are also possible. Phenothiazines and butyrophenones also cause dopamine-related drowsiness, diarrhea, and extrapyramidal reactions. In addition, constipation, dizziness, and hypotension have been noted. Lorazepam is associated with sedation in addition to amnesia, confusion, transient enuresis, and blurred vision. Serotonin antagonists all have similar side effects of mild to moderate headache in 20 to 30 percent of patients and mild, uncommon occurrences of constipation or diarrhea. Corticosteroids may cause insomnia, hyperglycemia, gastrointestinal upset, and, rarely, psychosis. NK-1 antagonism leads to fatigue, dizziness, headache, and gastrointestinal disturbances. Side effects of dronabinol include dysphoria, hallucinations, dizziness, dry mouth, sedation, and disorientation.

Bibliography

Grunberg, S. M. “Antiemetic Activity of Corticosteroids in Patients Receiving Cancer Chemotherapy: Dosing, Efficacy, and Tolerability Analysis.” Annals of Oncology, vol. 18, no. 2, Feb. 2007, pp. 233-240.

Jordan, K., H. J. Schmoll, and M. S. Aapro. “Comparative Activity of Antiemetic Drugs.” Critical Reviews in Oncology/Hematology 61, no. 2 (Feb., 2007): 162-175.

“Olanzapine Reduces Nausea Caused by Advanced Cancer.” National Cancer Institute, 12 June 2020, www.cancer.gov/news-events/cancer-currents-blog/2020/olanzapine-reduces-nausea-advanced-cancer. Accessed 11 June 2024.

Roila, F., S. Fatigoni, and G. Ciccarese. “Daily Challenges in Oncology Practice: What Do We Need to Know About Antiemetics?” Annals of Oncology, vol. 17, suppl. 10, Sept. 2006, pp. 90-94.

Stoutenburg, John P, and Harry Raftopoulos. “Antiemetic studies on the NK1 receptor antagonist aprepitant.” Journal of the National Comprehensive Cancer Network : JNCCN, vol. 2,5, 2004, pp. 491-7. doi:10.6004/jnccn.2004.0038.