NK1-receptor antagonists are used in combination with 5-HT3receptor antagonists and corticosteroids for the prevention of acute and delayed nausea and vomiting from highly emetogenic chemotherapeutic regimens. Combined therapy with an NK1-receptor antagonist, a 5-HT3-receptor antagonist, and dexamethasone prevents acute emesis in 80–90% of patients compared with less than 70% of patients treated without an NK1 antagonist. Prevention of delayed emesis occurs in more than 70% of patients receiving combined therapy versus 30–50% treated without an NK1 antagonist. Oral NK1-receptor antagonists may be administered as follows: aprepitant 125 mg given 1 hour before chemotherapy, followed by oral aprepitant 80 mg/d for 2 days after chemotherapy; rolapitant 180 mg; or netupitant 300 mg/palonosetron 0.5 mg given as a single dose 1–2 hours before chemotherapy. For patients unable to tolerate oral therapy, intravenous fosaprepitant 115 mg may be given as a single intravenous dose 1 hour before chemotherapy. The addition of the antipsychotic agent olanzapine 10 mg on days 1–4 further decreases the incidence of acute and delayed nausea and vomiting with highly emetogenic chemotherapeutic regimens by 15–30%.
The NK1-receptor antagonists are well tolerated with a low incidence of fatigue and dizziness. The drugs are metabolized by CYP3A4 and may inhibit the metabolism of other drugs metabolized by the CYP3A4 pathway. Several chemotherapeutic agents are metabolized by CYP3A4, including docetaxel, paclitaxel, etoposide, irinotecan, imatinib, vinblastine, and vincristine. Drugs that inhibit CYP3A4 metabolism may significantly increase aprepitant plasma levels (eg, ketoconazole, ciprofloxacin, clarithromycin, nefazodone, ritonavir, nelfinavir, verapamil, and quinidine). Aprepitant decreases the international normalized ratio (INR) in patients taking warfarin.
ANTIPSYCHOTIC AGENTS (PHENOTHIAZINES, BUTYROPHENONES, & THIENOBENZODIAZEPINES)
Several classes of antipsychotic agents can be used for their anti-emetic and sedative properties (see Chapter 29). The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors. Sedative properties are due to their antihistamine activity. The agents most commonly used as antiemetics are prochlorperazine, promethazine, and thiethylperazine. The antiemetic properties of olanzapine (a thienobenzodiazepine) may be attributable to inhibition of dopamine D2 and serotonin 5-HT1c and 5-HT3 receptors.