Ondanov Mechanism of Action

Pharmacology: Pharmacodynamics: Ondansetron is a potent, highly selective 5HT3 receptor antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex.
Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the 4th ventricle, and this may promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3-receptors on neurons located both in the peripheral and central nervous system. The mechanisms of actions in postoperative nausea and vomiting are not known but there may be common pathways with cytotoxic-induced nausea and vomiting. Ondansetron does not alter plasma protein concentrations.
Pharmacokinetics: Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first-pass metabolism. Peak plasma concentrations are attained approximately 1.5 hrs after dosing. For doses >8 mg, the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect reduction in first-pass metabolism at higher oral doses.
Bioavailability is slightly enhanced by the presence of food but unaffected by antacids. The disposition of ondansetron following oral, IM or IV dosing is similar with a terminal elimination half-life of about 3 hrs and steady-state volume of distribution of about 140 L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron. Ondansetron is not highly protein bound (70-76%). Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2DB (the debrisoquine polymorphism) has no effect on the ondansetron's pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing. Studies in healthy elderly volunteers have shown slight, but clinically significant age-related increases in both oral bioavailability and half-life of ondansetron.
Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).