Ondrin 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 fourth ventricle, and this may also 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 action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting. Ondansetron does not alter plasma prolactin concentrations. The role of Ondansetron in opiate-induced emesis is not yet established.
Pharmacokinetics: The pharmacokinetic properties of ondansetron are unchanged on repeat dosing. A direct correlation of plasma concentration and anti-emetic effect has not been established.
Absorption: Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (Bioavailability is about 60%.). Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids.
A 4 mg intravenous infusion of ondansetron given over 5 minute's results in peak plasma concentrations of about 65 ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25 ng/ml are attained within 10 minutes of injection.
Distribution: The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a steady state volume of distribution of about 140 L. Equivalent systemic exposures is achieved after IM and IV administration of ondansetron.
Ondansetron is not highly protein bound (70-76%).
Metabolism: Ondansetron is cleared from the systemic circulation redominantly by hepatic metabolism through multiple enzymatic pathways. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron's pharmacokinetics.
Elimination: Less than 5% of the absorbed dose is excreted unchanged in the urine. Terminal half-life is about 3 hours.
Elderly persons: Slight age-related increases in both oral bioavailability (65%) and half-life (5 hours).
Renal impairment: In patients with renal impairment (creatinine clearance 15-60 ml/min), both systemic clearance and volume of distribution are reduced following IV administration of ondansetron, resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4 h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged following IV administration.
Hepatic impairment: Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.
Gender differences: 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).