Onzet Mechanism of Action

Pharmacology: Pharmacodynamics: Tablet: Mechanism of Action: Ondansetron is a potent, highly selective 5-HT3 receptor antagonist.
Its precise antiemetic and antinauseal mechanism of action is not known. Chemotherapeutic agents and radiotherapy may cause release of 5-HT3 in the small intestine initiating a vomiting reflex by activating vagal afferents via 5-HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5-HT3 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 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.
Injection: In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or a small intestinal transit time. In another study in six normal male volunteers, a 16 mg dose infused over 5 minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram (ECG). However, no thorough QT study has been conducted with ondansetron. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations.
In a gender-balanced pharmacodynamic study (n = 50), ondansetron 4 mg administered intravenously or intramuscularly was dynamically similar in the prevention of nausea and vomiting using the ipecacuanha model of emesis.
Mechanism of Action: Ondansetron is a selective 5-HT₃ receptor antagonist. While ondansetron's mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist.
Pharmacokinetics: Tablet: Peak plasma concentrations of Ondansetron occur about 1.5 hours after an oral dose of 8 mg, and about 6 hours after a rectal dose. The absolute bioavailability may be somewhat higher (65%) and clearance lower, presumably due to reduced hepatic first-pass metabolism.
Ondansetron is extensively distributed in the body; about 70 to 75% of the drug is protein bound.
It is metabolized in the liver through multiple enzymatic pathways; Ondansetron is a substrate for cytochrome P450 isoenzymes, primarily CYP3A4, but also CYP1A2 and CYP2D6. Less than 5% of a dose is excreted unchanged in the urine.
Injection: In normal adult volunteers, the following mean pharmacokinetic data have been determined following a single 0.15 mg/kg intravenous dose. (See Table 1.)

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Absorption: A study was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of single 4 mg dose administered as a 5 minute infusion compared to a single intramuscular injection. Systemic exposure as measured by mean AUC were equivalent, with values of 156 (95% CI 136, 180) and 161 (95% CI 137, 190) ng/h/mL for intravenous and intramuscular groups, respectively. Mean peak plasma concentrations were 42.9 (95% CI 33.8, 54.4) ng/mL at 10 minutes after intravenous infusion and 31.9 (95% CI 26.3, 38.6) ng/mL at 41 minutes after intramuscular injection. In normal volunteers (19 to 39 years old, n = 23), the peak plasma concentration was 264 ng/mL following a single 32 mg dose administered as a 15 minute intravenous infusion.
Distribution: Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, over the pharmacologic concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.
Metabolism: Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.
Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. The metabolites are observed in the urine.
In vitro metabolism studies have shown that ondansetron is a substance for multiple human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 plays a predominant role while formation of the major in vivo metabolites is apparently mediated by CYP1A2. The role of CYP2D6 in ondansetron in vivo metabolism is relatively minor. The pharmacokinetics of intravenous ondansetron did not differ between subjects who were poor metabolisers of CYP2D6 and those who were extensive metabolisers of CYP2D6, further supporting the limited role of CYP2D6 in ondansetron disposition in vivo.
Elimination: In normal volunteers (19 to 39 years old, n = 23), following a single 32 mg dose administered as a 15 minute intravenous infusion, the mean elimination half-life was 4.1 hours. Systemic exposure to 32 mg ondansetron was not proportional to dose as measured by comparing dose-normalized AUC values to an 8 mg dose. This is consistent with a small decrease in systemic clearance with increasing plasma concentrations.
In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no difference in the multidose pharmacokinetics over a 4 day period.
Geriatrics: A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusion in that age group. No dosage adjustment is recommended in the elderly.
Pediatrics: In general, surgical and cancer pediatric patients younger than 18 years tend to have a higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher volume of distribution in this age group.
In a study of 21 pediatric cancer patients (4 to 18 years of age) who received three intravenous doses of 0.15 mg/kg of ondansetron at 4 hour intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic parameters similar to those adults.
Renal Impairment: Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron mean plasma clearance was reduced by about 41% in patients with severe renal impairment (creatinine clearance < 30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in those without hepatic impairment. In patients with severe hepatic (Child-Pugh score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in 2 year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per day, respectively (approximately 2.5 and 3.8 times the recommended human intravenous dose of 32 mg/day, based on body surface area).
Ondansetron was not mutagenic in standard test for mutagenicity.
Oral administration of ondansetron up to 15 mg/kg per day (approximately 3.8 times the recommended human intravenous dose, based on body surface area) did not affect fertility or general reproductive performance of male and female rats.