Antiemetic Agents

July 1, 2007

FDA-Approved Drugs: 5-HT3 receptor antagonists Zofran (ondansetron), Kytril (granisetron), Anzamet (dolasetron), Aloxi (palonosetron); NK-1 receptor antagonist: Aprepitant (Emend)

FDA-Approved Drugs: 5-HT3 receptor antagonists Zofran (ondansetron), Kytril (granisetron), Anzamet (dolasetron), Aloxi (palonosetron); NK-1 receptor antagonist: Aprepitant (Emend)

Investigational Drugs: Casopitant mesylate (GW679769)

Mechanism of Action

Chemotherapy stimulates the vomiting center in the medulla of the brain. In addition, serotonin and substance P (which binds to NK-1 receptors), are released from the enterochromafin cells in the gut, and both stimulate the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center, causing vomiting. By administering antiemetics prior to chemotherapy administration, 5-HT3 receptor and substance P receptor antagonists block the serotonin and NK-1 receptors in the gastrointestinal mucosa and CTZ, thus preventing chemotherapy-related nausea and vomiting. These agents may be given with Decadron (dexamethasone), which is believed to act as an anti-inflammatory, thus increasing the antiemetic protection.

Metabolism

5-HT3 receptor antagonists are metabolized by the P-450 enzyme system in the liver, and excreted in the urine. Half-lives vary with the drug (Aloxi 40 hr, Kytril 9 hr, Anzamet 7.3 hr, Zofran 3-4 hr). Emend is highly protein-bound, and also is metabolized by the P-450 enzyme system, primarily CYP3A4, with a terminal half-life of 9-13 hours.

Indications

According to the American Society of Clinical Oncology (2006), 5-HT3 receptor and substance P receptor antagonists are recommended for patients receiving highly and moderately emetogenic chemotherapy, in combination with dexamethasone.

FDA indications are as follows:

Zofran: prevention of 1) chemotherapy-related nausea and vomiting (moderately and highly emetogenic),
2) postoperative nausea and/or vomiting, 3) radiation-associated nausea and vomiting (oral Zofran).

Kytril: prevention of 1) chemotherapy-related nausea and vomiting including that caused by high-dose cisplatin, 2) post-operative nausea and vomiting (IV), 3) radiation-associated nausea and vomiting.

Anzamet: prevention of 1) chemotherapy-related nausea and vomiting including high-dose cisplatin, 2) prevention and treatment of postoperative nausea and/or vomiting.

Aloxi: prevention of 1) chemotherapy-related acute nausea and vomiting (moderately and highly emetogenic), 2) delayed nausea and vomiting (moderately emetogenic).

Emend: in combination with decadron and a 5-HT3 receptor antagonist, for the prevention of 1) chemotherapy-related acute and delayed nausea and vomiting (moderately and highly emetogenic), 2) postoperative nausea and/or vomiting.

Interactions

Aprepitant:

1) drugs that are metabolized by CYP3A4 microenzyme system can increase serum aprepitant levels (ketoconazole, itraconazole, nefazodone, clarithromycin, ritonavir, nelfinavir [Viracept], diltiazem) so should be combined cautiously;

2) dexamethasone and methylprednisolone levels are increased, so each should be reduced to 50% of the dose;

3) drugs that strongly induce the CYP3A4 microenzyme system can lower aprepitant serum levels (rifampin, carbamazepine, phenytoin), so assess for efficacy of aprepitant and need for dose increase.

Special Considerations

Antiemetic agent should be administered prior to chemotherapy with enough time to saturate receptors, eg, 1 hour if given orally, and 15-30 minutes if given intravenously.

Contraindications/Precautions

5-HT3 receptor antagonists may cause constipation, so assess bowel elimination status carefully when patient is receiving concomitant opioids.