Ondansetron

Mechanism

Mechanism of action

Cytotoxic chemotherapy agents and radiation induce massive release of serotonin (5-HT) by enterochromaffin cells of the small intestinal epithelium. The released serotonin directly stimulates the 5-HT₃ receptors located on the afferent fibers of the abdominal extrinsic vagus nerve, transmitting powerful afferent impulses to the vomiting center in the medulla oblongata.

In parallel, free serotonin stimulates the 5-HT₃ receptors present in the brain area postrema of the chemoreceptor trigger zone (ZGQ).

Ondansetron selectively blocks these receptors both at the peripheral level (myenteric junctions of the vagus) and at the level of the central nervous system (ZGQ), preventing the transmission of emetogenic signals to the executing structures of the brain stem in an optimal manner.

Pharmacokinetics

Pharmacokinetics

• Absorption: Complete oral absorption after administration of standard or oral lyophilized tablets. Bioavailability of 60% due to a moderate hepatic first pass metabolism.
• Distribution: Apparent volume of distribution of 1.8 to 2.4 L/kg. Moderately crosses the blood-brain barrier. Plasma protein binding of 70% - 76%.
• Metabolism: Extensive hepatic through microsomal hydroxylation and subsequent conjugation with glucuronic acid or sulfates. The metabolic enzymes involved are mainly CYP2D6, CYP3A4 and CYP1A2.
• Excretion: Low kidney. Less than 5% of the administered dose is eliminated in unchanged free form in the urine. Elimination is completed via the fecal and biliary route as conjugated inactive metabolites.
• Half-life: 3.5 to 5.5 hours in young adults. It can be prolonged up to 8-12 hours in the elderly with compromised clearance or in cases of Child-Pugh C liver disease.

Indicators and dose

Approved indications

• Prevention and treatment of acute nausea and vomiting induced by moderate or highly emetogenic chemotherapy.
• Prevention and treatment of nausea and vomiting induced by total body or fractionated abdominal radiotherapy.
• Treatment and prevention of immediate postoperative nausea and vomiting in adults and pediatric patients over one month of age.

Dosage and Clinical Adjustment

Adults:

• Prevention of emesis due to severe chemotherapy: 8 mg to 24 mg orally or 8 mg to 16 mg slowly intravenously (over 15 minutes) before administration of the cytotoxic agent.
• Postoperative nausea prophylaxis: 4 mg intravenously as a slow bolus at the time of anesthetic induction, or 4 mg orally one hour before the procedure.

Adjustment in Renal Failure: No dose modification is required in renal failure of any degree.

Adjustment in Liver Failure: In patients with severe advanced liver failure (Child-Pugh C / decompensated liver cirrhosis), plasma clearance is extremely reduced, prolonging the half-life to more than 18 hours. A strict maximum dose of 8 mg per day should be applied by any route.

Security

QT Interval Prolongation and Serotonin Syndrome Alert

Like other compounds in its class, ondansetron dose-dependently blocks myocardial potassium hERG channels, demonstrably prolonging the electrocardiographic QTc interval. Its rapid intravenous administration, especially in doses greater than 16 mg, increases the risk of serious ventricular arrhythmias of the Torsion de Pointes type. Furthermore, its coadministration with serotonergic stimulating agents (SSRIs, SNRIs) can trigger an acute serotonin syndrome with fatal consequences.

Contraindications

• Absolute: Concomitant coadministration of apomorphine (causally associated with profound cardiovascular collapse and severe fatal hypotension mediated by centralized dopamine receptors). Known hypersensitivity to ondansetron or other class antagonists (granisetron, palonosetron).
• Relative: Congenital long QT syndrome. Severe electrolyte abnormalities (uncorrected severe hypokalemia).

Adverse effects (ADRs)

• Frequent (>1/100): Transient marked headache, sensation of facial flushing or heat, severe constipation (due to inhibiting the serotonergic stimulus of colonic peristalsis mediated by 5-HT₃ receptors).
• Uncommon / Rare: Transient hypotension, asymptomatic elevation of hepatic transaminases, transient blurred vision, QTc prolongation, episodic dizziness.

Drug interactions

• Potent CYP3A4 inducers: Rifampicin, phenytoin or carbamazepine can accelerate the clearance of ondansetron and reduce its effective therapeutic plasma levels by half.
• Drugs that prolong the QT interval: Synergy of severe arrhythmic risk in coadministration with amiodarone, sotalol, erythromycin or atypical antipsychotics.

Safety of Use in Pregnant Women

Pregnancy (Orofacial Malformation Alert): Although historically used extensively off-label for the treatment of hyperemesis gravidarum, recent large-scale epidemiological studies have revealed a slight increase in the risk of congenital orofacial malformations (cleft lip and palate) when administered during the first trimester of gestation. Its use is categorically discouraged during the first 12 weeks of embryonic development.