What is an example of an NK antagonist?

October 13, 2025 •

4 min read

According to the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO), NK antagonists are strongly recommended for preventing chemotherapy-induced nausea and vomiting (CINV). A primary and widely used example of an NK antagonist is aprepitant, a medication that targets specific receptors in the brain to block the vomiting reflex.

Quick Summary

This article discusses neurokinin-1 (NK1) receptor antagonists, a class of antiemetic drugs exemplified by aprepitant. It explains their mechanism of action in blocking substance P, their primary use for preventing chemotherapy-induced and postoperative nausea and vomiting, and provides insight into other examples like fosaprepitant, netupitant, and rolapitant.

Key Points

Aprepitant is a prime example: Aprepitant is a well-known NK1 receptor antagonist, used orally and via its IV prodrug fosaprepitant, primarily for preventing nausea and vomiting from chemotherapy.
Mechanism is unique: These drugs block the NK1 receptor, which prevents Substance P from initiating the vomiting reflex, a pathway distinct from other antiemetics like serotonin antagonists.
Effective against delayed symptoms: NK antagonists are particularly valuable for controlling delayed-phase chemotherapy-induced nausea and vomiting (CINV), which is difficult to manage with older antiemetics alone.
Part of combination therapy: For maximum efficacy, NK antagonists are often used in combination with other antiemetics, such as 5-HT3 antagonists and corticosteroids, especially for highly emetogenic chemotherapy.
Drug interactions can occur: Because many NK antagonists are metabolized by CYP3A4, they can have significant interactions with other medications processed by this enzyme, requiring careful dose adjustments.
Other examples exist: Beyond aprepitant, other notable NK antagonists include fosaprepitant (IV prodrug), netupitant, and rolapitant, each with distinct pharmacological properties.

Understanding Neurokinin-1 (NK1) Receptor Antagonists

Neurokinin-1 (NK1) receptor antagonists are a class of antiemetic drugs that play a crucial role in preventing nausea and vomiting associated with cancer chemotherapy (CINV) and postoperative recovery (PONV). Unlike older antiemetics that target serotonin or dopamine receptors, NK1 antagonists offer a distinct and complementary mechanism of action by blocking the NK1 receptor. This makes them particularly effective against the delayed phase of nausea and vomiting, which other antiemetic classes often fail to control adequately.

At the core of their function is the blocking of Substance P, a neuropeptide that binds to NK1 receptors in the central nervous system, particularly in the brainstem's vomiting centers. By blocking this interaction, NK1 antagonists effectively interrupt the emetic signal pathway and suppress the vomiting reflex. This central site of action is what gives these agents their broad-spectrum antiemetic properties, targeting both centrally and peripherally acting emetogenic stimuli.

Aprepitant: A key example of an NK antagonist

Aprepitant is one of the most prominent examples of an NK antagonist, first approved by the FDA in 2003. It is a potent, selective, and non-peptide antagonist of the human NK1 receptor. Administered orally, it is used in combination with other antiemetics to prevent both acute and delayed CINV. Its antiemetic effects last for approximately 40 hours, providing sustained protection against nausea and vomiting, especially in the delayed phase. Aprepitant has little to no affinity for other receptors like serotonin, dopamine, or corticosteroids, which contributes to its targeted action.

Formulations of Aprepitant

To address different patient needs and administration preferences, aprepitant is available in several forms:

Oral capsules: Taken once daily for a few days following chemotherapy.
Intravenous injection (as fosaprepitant): Fosaprepitant is a water-soluble prodrug that is rapidly converted to aprepitant in the body. It offers the benefit of single-dose intravenous administration for patients who cannot tolerate oral medication.

Other notable NK antagonists

While aprepitant is a cornerstone, other NK antagonists have also been developed and are used in clinical practice:

Fosaprepitant: An intravenous prodrug of aprepitant, it offers convenience for patients who are unable to take oral medications. It converts to aprepitant within about 30 minutes of infusion.
Netupitant: Often used in a fixed-dose oral combination with the serotonin antagonist palonosetron (as NEPA), netupitant is a newer NK1 antagonist with a longer half-life than aprepitant.
Rolapitant: Approved by the FDA in 2015, rolapitant is another selective NK1 antagonist known for its very long half-life of up to 160 hours. It is administered as a single oral dose before chemotherapy.

Therapeutic applications

The primary application of NK antagonists is in the prevention of chemotherapy-induced nausea and vomiting, but their pharmacological profile also suggests other uses. Some of these are still under investigation.

Chemotherapy-induced nausea and vomiting (CINV)

NK1 antagonists are a cornerstone of modern CINV management, particularly for regimens that are considered moderately to highly emetogenic. Guidelines from organizations like the NCCN recommend using a triple regimen that includes an NK1 antagonist, a 5-HT3 antagonist, and a corticosteroid like dexamethasone to maximize protection against both acute and delayed CINV.

Postoperative nausea and vomiting (PONV)

NK1 antagonists can also be effective in preventing PONV, especially in patients with a very high risk of vomiting after surgery. Studies have shown that some NK1-RAs can be as effective as 5-HT3 antagonists and are more potent in preventing vomiting specifically.

Chronic pruritus (itching)

Some exploratory studies have investigated the potential use of NK1 antagonists for treating severe chronic pruritus that is refractory to other treatments. While some anecdotal cases have shown promise, the data remains conflicting, and further studies are needed to determine their role in dermatological conditions.

Comparison of key NK antagonists


Feature	Aprepitant (Emend)	Fosaprepitant (Ivemend)	Netupitant (in Akynzeo)	Rolapitant (Varubi)
Administration	Oral capsule	Intravenous (IV)	Oral capsule (with palonosetron)	Oral tablet
Primary Use	Prophylaxis of CINV and PONV	Prophylaxis of CINV	Prophylaxis of CINV	Prophylaxis of delayed CINV
Mechanism	NK1 receptor antagonist	Prodrug of aprepitant	NK1 receptor antagonist	NK1 receptor antagonist
Half-life	9-13 hours	Converts to aprepitant	~90 hours	~160 hours

Conclusion: The growing importance of NK antagonists

NK antagonists represent a significant advance in supportive care, particularly in managing the challenging symptoms of nausea and vomiting from chemotherapy. By targeting the Substance P/NK1 receptor pathway, they offer a powerful and selective mechanism that complements other antiemetic strategies, providing effective relief for both acute and delayed symptoms. As exemplified by aprepitant, these drugs have reshaped treatment guidelines, improving the quality of life for cancer patients undergoing aggressive chemotherapy regimens. The availability of different formulations and drugs within this class allows for tailored treatment plans, ensuring better patient compliance and outcomes. Continued research will likely uncover more about their potential in other conditions, but their primary legacy remains in advancing antiemetic care. For more information on supportive care in cancer, including antiemetic guidelines, consult authoritative resources such as the National Comprehensive Cancer Network (NCCN).

Frequently Asked Questions

Unlike other antiemetics that target serotonin or dopamine, NK antagonists specifically block the Neurokinin-1 (NK1) receptor, preventing the binding of the natural substance P. This distinct mechanism makes them highly effective against the delayed phase of nausea and vomiting, complementing the action of other antiemetic classes.

No, fosaprepitant is a water-soluble prodrug that is administered intravenously. Once in the body, it is converted into the active form, aprepitant. It offers a convenient intravenous option for patients who cannot take oral medications.

The primary use of NK antagonists is for the prevention of chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). They are often included in a multi-drug regimen for patients receiving moderately to highly emetogenic chemotherapy.

Common side effects of NK antagonists can include fatigue, headache, hiccups, and constipation. Other less common or drug-specific side effects can occur, such as infusion-site reactions with fosaprepitant due to its intravenous administration.

While effective, NK antagonists are typically used in combination with other antiemetics, such as 5-HT3 receptor antagonists and corticosteroids. This multi-drug approach is standard practice, especially for highly emetogenic chemotherapy, to maximize control over both acute and delayed symptoms.

The mechanism of NK antagonists, which targets the Substance P/NK1 receptor pathway, is particularly effective at controlling the delayed phase of CINV. This pathway plays a crucial role in the later stages of the emetic response, distinguishing these drugs from other antiemetics.

Beyond their primary use as antiemetics, NK antagonists have been explored for other conditions. Some studies have investigated their potential for treating chronic pruritus (itching) and have shown mixed but promising results.

Aprepitant has a shorter half-life compared to netupitant and rolapitant. Netupitant is typically co-administered with a 5-HT3 antagonist in a fixed-dose capsule, while rolapitant is known for its exceptionally long half-life, allowing for single-dose administration.