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PATHOGENESIS OF EMESIS
APREPITANT – MOA
Other NK1 Receptor antagonists
Aprepitant is a neurokinin 1(NK1) receptor antagonist
approved by FDA in 2003 for the prevention of acute and
delayed chemotherapy-induced nausea and vomiting (CINV).
PATHOGENESIS OF EMESIS
Emesis is a defense mechanism controlled by the area
postrema of the medulla oblongata. There are various sources
of input to the vomiting center.
Receptors on the floor of the fourth ventricle of the brain
represent the chemoreceptor trigger zone.
The chemoreceptor trigger zone contains dopamine D2
receptors, 5-HT3 receptors, opioid receptors, acetylcholine
receptors, and receptors for substance P.
Stimulation of different receptors are involved in different
pathways leading to emesis. In the final common pathway,
substance P, which activates the NK-1 receptor, appears to be
Additionally, the vagal and enteric nervous system inputs
transmit information regarding the state of the
gastrointestinal system. Irritation of the GI mucosa by
chemotherapy, radiation, distention, or acute infectious
gastroenteritis activates the 5-HT3 receptors of these inputs.
Cytotoxic agents cause a detectable increase in blood levels
of serotonin and its major metabolite, 5-
Hydroxyindoleacetic acid (5-HIAA).
The presence of these chemicals in the blood activate
5-HT3 receptors in the chemoreceptor trigger zone, in turn
releasing substance P, which activates NK1 receptors to
cause an emetic response.
Substance P belongs to the tachykinin family of peptides.
Substance P is present in the central nervous system,
where it is a neurotransmitter and in the GIT, where it
may play a role as a transmitter in the enteric nervous
system and as a local hormone.
Substance P - behavior, anxiety, depression, nausea, and
It is a potent arteriolar vasodilator, mediated by release
of nitric oxide from the endothelium.
Also known to stimulate cell growth in culture.
The actions are mediated by three G protein-coupled
tachykinin receptors designated NK1, NK2, and NK3
Substance P is the preferred ligand for the NK1 receptor,
the predominant tachykinin receptor in the human brain.
NK1 is a G protein-coupled receptor located in the
central and peripheral nervous system.
It is found in high concentrations in the vomiting
center of the brain
also plays a key part in the transmission of pain impulses
from the peripheral receptors to CNS
EMETOGENIC POTENTIAL OF ANTICANCER DRUGS
Aprepitant is a highly selective NK1 antagonist approved by US-FDA
in march 2003 for the treatment of chemotherapy induced
nausea and vomiting.
inhibit both the acute and delayed emesis induced by cytotoxic
drugs by blocking Substance P in the brain's neurons.
selectively antagonize NK1 receptors, while having very low
affinity to other common receptors such as serotonin, dopamine,
It has also been shown to increase the efficacy of the 5HT3
receptor antagonists and corticosteroids.
Bioavailability of 60 - 65% ; unaffected by food
Half life 9-13hrs
95% bound to plasma proteins
Metabolism in Liver (CYP3A4)
Excreted in urine(50%) and in faeces(50%)
- Chemotherapy induced nausea and vomiting (CINV)
- Post operative nausea and vomiting (PONV)
- Cyclic vomiting syndrome
CINV - 125 mg on day1 (before chemotherapy) and then 80mg on
days 2 and 3 (after chemotherapy)
PONV – 40mg within 3hrs prior to induction
Should be given with a 5HT3 antagonist and Dexamethasone
Dose of dexamethasone should be reduced by 50%
Elevation of Liver Enzymes
Cases of angioedema, urticaria, SJS
C/I – Patients on cisapride/pimozide- QT prolongation
Aprepitant is metabolized primarily by CYP3A4 with minor
metabolism by CYP1A2 and CYP2C19.
As a moderate inhibitor of CYP3A4, aprepitant may inhibit the
metabolism of other drugs metabolized by the CYP3A4 pathway.
Drugs that inhibit CYP3A4 metabolism increase aprepitant
Aprepitant decreases INR in patients taking warfarin.
Specific interaction has been demonstrated with oxycodone,
where aprepitant both increased the efficacy and worsened the
side effects of oxycodone.
Other NK1 Receptor Antagonists…
Fosaprepitant – prodrug ; I/V infusion
Casopitant – Phase 3 trial for CINV
Vestipitant – antiemetic /anxiolytic under trial for tinnitus
Maropitant – under trial for motion sickness and vomiting
Aprepitant – a clear cut therapeutic advance
Good Safety profile
Effective in Breast cancer patients
(cyclophosphamide/anthracycline based chemotherapy)
Potential for drug interactions
High cost of the drug