Ondansetron

BRAND NAMES

ZOFRAN: Zofran has two strengths in film-coated tablets: 4 mg and 8 mg. It is used to lessen nausea and vomiting brought on by chemotherapy, cancer, and surgery.

ZUPLENZ: Zuplenz oral soluble film dosage recommendations for adults are 24 mg administered as three 8 mg films spaced 30 minutes apart before the start of a single-day chemotherapy regimen, one 8 mg film spaced three times a day during radiation therapy, or 16 mg administered as two 8 mg films spaced one hour apart prior to anesthesia induction.

MECHANISM OF ACTION

Ondansetron is a selective 5-HT3 serotonin receptor antagonist with antiemetic effects. It is one of the four FDA-approved 5-HT3 serotonin receptor antagonists used to control nausea and vomiting, along with granisetron, dolasetron, and the second-generation medication, palonosetron.

Ondansetron prevents and treats nausea and vomiting via both central and peripheral mechanisms. Central effects are mediated by the inhibition of 5HT-3 serotonin receptors in the posttrauma region. The "chemoreceptor trigger zone" is found in the posttrauma region on the fourth ventricle floor. This zone detects neurotransmitters such as serotonin, toxins, and other signals and aids in the sensation of nausea and subsequent vomiting. Ondansetron also has peripheral effects, operating on the vagus nerve. It targets the 5-HT3 receptors located in the vagus nerve terminals. The vagus nerve detects nausea and vomiting stimuli within the gastrointestinal system, such as stomach irritants. It creates synapses in the brainstem's nucleus tractus solitarius, which is another crucial area for vomiting. Ondansetron's antiemetic effects are assumed to be mostly due to its peripheral activities.

PHARMACOKINETICS

Absorption:

After taking 8 mg orally once, ondansetron is quickly absorbed from the digestive tract and reaches its maximal plasma concentration (Tmax) around 1.5 hours later. Following oral therapy, ondansetron's absolute bioavailability is between 50 and 70 percent. The first-pass metabolism is the cause of the decreased bioavailability. Because the first-pass metabolism is saturated at doses of 8 mg, 16 mg, 32 mg, and 64 mg, ondansetron's systemic bioavailability increases nonlinearly. The bioavailability of ondansetron is much higher in cancer patients (85%–87%) compared to healthy individuals (50%–70%), most likely as a result of metabolic variations.

Distribution:

Tissues contain large amounts of ondansetron and its metabolites. At a steady condition, the apparent volume of distribution (Vd) is around 1.8 L/kg. In human volunteers, ondansetron passes the blood-brain barrier to a lesser degree; its CSF concentration is only 10%–15% of plasma concentration.

Metabolism:

The main location for metabolism is the liver. Oxidation is the main metabolism-related process. The predominant ondansetron is 8-hydroxy ondansetron, accounting for 40% of the total, followed by 7-hydroxy ondansetron (< 20%) and 6-hydroxy ondansetron (< 5%). N-demethylation, which produces N-dimethyl ondansetron, is another mode of minor metabolism. 8-hydroxy ondansetron is the active metabolite of ondansetron. It is quickly broken down in the liver to form glucuronide and sulfate conjugates, which results in low blood concentrations and a negligible effect on ondansetron's antiemetic properties. Ondansetron metabolism involves cytochrome P-450 enzymes, such as CYP1A2, CYP2D6, and CYP3A4. When it comes to ondansetron metabolism in humans, CYP1A1/2 is the most important enzyme, while CYP2D6 is just slightly involved. At greater ondansetron concentrations, CYP3A4 plays a crucial role.

Elimination:

Ondansetron clearance is almost entirely due to hepatic metabolism, with less than 5% eliminated unaltered in the urine. Ondansetron's clearance and elimination half-lives vary with age. The elimination half-life of an 8 mg oral or intravenous dosage is around 3-4 hours in humans, but 5.5 hours in the elderly.

PHARMACODYNAMICS

With a modest affinity for dopamine receptors, ondansetron is a highly selective antagonist of the serotonin 5-HT3 receptor. Both centrally in the chemoreceptor trigger zone of the region postrema in the medulla and peripherally on vagal nerve terminals are sites of 5-HT3 receptor presence. In reaction to chemotherapeutic drugs, the small intestine's enterochromaffin cells produce serotonin, which may activate vagal afferents (via 5-HT3 receptors) and cause the vomiting reflex. The antiemetic effect of ondansetron is believed to be mostly mediated by antagonistic interactions with vagal afferents, with a small amount of antagonism with central receptors.

DOSAGE AND ADMINISTRATION

The routes of administration are oral, intramuscular (IM), and intravenous (IV). Oral formulations come in tablet and soluble film formats. Ondansetron pills should be taken 1-2 hours before radiation, 30 minutes before chemotherapy, and one hour before anesthetic induction. Both oral and intravenous versions have been demonstrated to be equally effective in treating emetogenic chemotherapy.

The etiology and administration route have an impact on dosage. However, because of the possibility of QTc prolongation and arrhythmias, the maximum recommended single dosage is 16 mg per IV injection. The usual dosage for preventing nausea and vomiting after surgery is 8 mg taken orally every 12 hours or 4 mg intravenously. For patients with renal impairment receiving medication orally or by IV, no dose modifications are required. The maximum daily dosage is lowered to 8 mg IV or 8 mg oral in patients with severe hepatic impairment, although the same applies to those with mild to moderate hepatic impairment. Weight-based pediatric dosage is administered at a maximum of 16 mg per dose, or 0.15 mg/kg.

CONTRAINDICATIONS

Ondansetron is not recommended for people who are hypersensitive to the medicine or any of its components. Severe hypersensitivity responses, including anaphylaxis, have been documented. Ondansetron should not be used if you are already on apomorphine. Concurrent use of ondansetron with apomorphine can result in severe hypotension and loss of consciousness, with ondansetron amplifying the hypotensive effects of apomorphine.

DRUG INTERACTIONS

Ondonsetran should not be used with any of the following. 

• Apomorphine
• Certain drugs for fungal infections, such as fluconazole, itraconazole, ketoconazole, posaconazole, and voriconazole. 
• Cisapride
• Dronedarone
• Pimozide
• Thioridazine

SIDE EFFECTS

The most common side effects of ondonsetran

• Tiredness
• Constipation
• Fast heartbeat
• Agitation
• Weakness
• Headache
• drowsiness

Severe side effects of ondonsetran

• Fever
• Stomachache
• Joint pains
• Sweating
• Confusion
• Muscle twitching, stiffness or tremor

TOXICITY

There is no known antidote for ondansetron, hence overdose is treated with supportive measures. A case study presents a child who overdosed on ondansetron and had convulsions, QTc prolongation, hepatotoxicity, and serotonin syndrome. To treat his seizures, the patient needed endotracheal intubation, supportive care, and lorazepam.