Neurokinin 1 (NK₁) receptors are distributed across the GI tract, vagal afferents, and key CNS regions including the central vomiting center and chemoreceptor trigger zone (CTZ) Chemotherapy agents stimulate enterochromaffin cells in the gastrointestinal (GI) tract to release large amounts of substance P (SP). SP is a neuropeptide released by specific sensory nerves in response to many different stressors, including those in the GI mucosa affected by chemotherapy. SP binds and activates these NK₁ receptors leading to the nausea and vomiting associated with chemotherapy.

NK₁-receptor antagonists, like aprepitant (Emend), netupitant (Akynzeo), and rolapitant (Varubi), have been developed to counteract this physiological response. These drugs cross the blood-brain barrier, selectively bind to NK₁ receptors, and inhibit the binding of substance P, thereby preventing chemotherapy-induced nausea and vomiting (CINV).

CINV typically has two phases: the acute phase, which develops within hours of chemotherapy, and the delayed phase, which occurs between two and five days post-treatment. While most anti-emetic drugs effectively control the acute phase of CINV, NK₁-receptor antagonists are particularly effective in inhibiting the delayed phase. For optimal results, they are typically used with a 5-HT₃ antagonist and dexamethasone.

These antagonists are metabolized primarily through the liver's CYP3A4 pathway. However, they can suppress the hepatic metabolism of anti-cancer agents like docetaxel (Taxotere), paclitaxel (Taxol), and imatinib (Gleevec). Adverse effects may include fatigue, abdominal pain, diarrhea, hiccups, and, uncommonly, neutropenia.