Vaxcel Granisetron Mechanism of Action

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT₃) antagonists. ATC code: A04AA02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Serotonin is the main neurotransmitter responsible for emesis after chemo- or radiotherapy. Serotonin receptors of the 5-HT₃ type are located peripherally in vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT₃ receptors. This invokes vagal afferent discharge, inducing vomiting. Granisetron is a potent antiemetic and highly selective antagonist of 5-hydroxytryptamine (5-HT₃) receptors. Radioligand binding studies have demonstrated that Granisetron has negligible affinity for other receptor types including 5-HT and dopamine D₂ binding sites.
Chemotherapy - and radiotherapy-induced nausea and vomiting: Granisetron administered intravenously has been shown to prevent nausea and vomiting associated with cancer chemotherapy in adults and children 2 - 16 years of age.
Post-operative nausea and vomiting: Granisetron administered intravenously has been shown to be effective for prevention and treatment of post-operative nausea and vomiting in adults. Efficacy in children has not been established in controlled clinical trials.
Pharmacokinetics: Absorption: Absorption of granisetron is rapid and complete.
Distribution: Granisetron is extensively distributed, with a mean volume of distribution of approximately 3 L/kg. Plasma protein binding is approximately 65%.
Metabolism: Biotransformation pathways involve N-demethylation and aromatic ring oxidation followed by conjugation. In-vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily.
Elimination: Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged granisetron averages 12% of dose while that of metabolites amounts to about 47% of dose. The remainder is excreted in feces as metabolites. Mean plasma half-life in patients by the intravenous route is approximately 9 hours, with a wide inter-subject variability. The pharmacokinetics of intravenous granisetron demonstrate no marked deviations from linear pharmacokinetics at oral doses up to 2.5-fold and intravenous doses up to 4-fold the recommended clinical dose. The results of a study in healthy male volunteers have demonstrated that systemic delivery of 3mg granisetron from an intramuscular injection is slower than from a 5 minute intravenous infusion (as indicated by lower Cmax and later Tmax). In other respects, the pharmacokinetics of granisetron are virtually indistinguishable when administered by these two different routes.
Special Populations: Renal failure: Data indicate that pharmacokinetic parameters in patients with severe renal failure after a single intravenous dose are generally similar to those in normal subjects.
Hepatic impairment: Total plasma clearance of an intravenous dose in patients with hepatic impairment due to neoplastic liver involvement, was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage adjustment is necessary.
Elderly: In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects.
Pediatrics: After single intravenous doses, pharmacokinetics in children are similar to those in adults when appropriate parameters (volume of distribution, total plasma clearance) are normalized for body weight.