Vomikind Oral Solution

Indications

• Food preservative
• Treatment of urea cycle disorders
• Metabolic disorders involving benzoyl-CoA

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines based on condition.

Adults: Refer to the BNF for specific dosing guidelines based on condition.

Mechanism of action

Benzoate acts mainly by inhibiting the growth of bacteria and fungi through its ability to lower the pH, creating an environment that is less favorable for microbial growth. It is also involved in metabolic pathways where it helps in the conjugation of toxic substances, facilitating their excretion from the body.

Pharmacodynamics

Benzoate is known for its antimicrobial properties, which are particularly effective against a wide range of fungi and bacteria. Its efficacy as a preservative is due to its ability to penetrate microbial cell membranes and disrupt their metabolic processes. Additionally, it has been observed to modulate various metabolic pathways, particularly those associated with aromatic compound degradation.

Pharmacokinetics

After ingestion, benzoate is rapidly absorbed in the gastrointestinal tract. It is metabolized primarily in the liver, where it undergoes conjugation with glycine to form hippurate, which is then excreted in the urine. The half-life of benzoate varies depending on individual metabolic rates but is generally short due to its efficient conversion and excretion.

Pregnancy

There is limited data on the use of benzoate in pregnancy. Consultation with healthcare professionals is advised before use.

Breast-feeding

Limited data is available on the excretion of benzoate in breast milk. Caution is recommended when administering to nursing mothers.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Indications

• Prevention of nausea and vomiting associated with cytotoxic chemotherapy
• Prevention of postoperative nausea and vomiting
• Management of nausea and vomiting induced by radiotherapy

Dosage

Adults: For adults, ondansetron is typically administered as 8 mg before chemotherapy or surgery, followed by an additional 8 mg dose 12 hours later if necessary. The maximum total dose should not

Mechanism of action

Ondansetron selectively antagonizes the serotonin receptor subtype 5-HT3. Cytotoxic chemotherapy and radiotherapy cause serotonin release from enterochromaffin cells in the small intestine, leading to the stimulation of 5-HT3 receptors on vagal afferents, which can initiate the vomiting reflex. By blocking these receptors, ondansetron interrupts this pathway, thus preventing nausea and vomiting. Additionally, it may influence the central nervous system by affecting the chemoreceptor trigger zone in the area postrema.

Pharmacodynamics

Ondansetron is a highly specific and selective 5-HT3 receptor antagonist with minimal activity at other serotonin receptors and low affinity for dopamine receptors. Its pharmacodynamic properties are characterized by its ability to inhibit the 5-HT3-mediated vomiting reflex, which is triggered by the release of serotonin due to the gastrointestinal effects of emetogenic drugs. The drug has a significant role in controlling nausea and vomiting without major sedative effects.

Pharmacokinetics

Ondansetron is well-absorbed after intravenous or oral administration, with peak plasma concentrations reached within 1-2 hours. It has a bioavailability of approximately 60% when taken orally. The drug is extensively metabolized in the liver, primarily by CYP3A4, CYP2D6, and CYP1A2 enzymes. Its elimination half-life ranges from 3 to 6 hours, and it is primarily excreted in urine as metabolites, with less than 5% of the dose excreted unchanged. Patients with hepatic impairment may require dose adjustments due to altered metabolism.

Adverse effects

• Extrapyramidal symptoms
• QT interval prolongation
• Serotonin syndrome
• Dystonia
• Appetite decreased
• Dry mouth
• Flushing
• Generalised oedema
• Vertigo

Interactions

• Mitotane - Unknown (decreases exposure)

Precautions

• Caution in hepatic impairment
• Avoid in pregnancy
• Avoid during breastfeeding

Pregnancy

Manufacturer advises to avoid use during pregnancy.

Breast-feeding

Avoid – no information available.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Powder for solution for infusion
• Solution for injection
• Tablets
• Transdermal patch

Mechanism of action

Ondansetron is a selective antagonist of the serotonin receptor subtype, 5-HT3. Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin (5-HT) from enterochromaffin cells of the small intestine, presumably initiating a vomiting reflex through stimulation of 5-HT3 receptors located on vagal afferents. Ondansetron may block the initiation of this reflex. Activation of vagal afferents may also cause a central release of serotonin from the chemoreceptor trigger zone of the area postrema, located on the floor of the fourth ventricle. Thus, the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT3 receptors on neurons located in either the peripheral or central nervous systems, or both. Although the mechanisms of action of ondansetron in treating postoperative nausea and vomiting and cytotoxic induced nausea and vomiting may share similar pathways, the role of ondansetron in opiate-induced emesis has not yet been formally established.

Pharmacodynamics

Ondansetron is a highly specific and selective serotonin 5-HT₃ receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors,. The serotonin 5-HT₃ receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema,. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents, suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract,. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT₃ receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting,. Moreover, the effect of ondansetron on the QTc interval was evaluated in a double-blind, randomized, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron was tested at single doses of 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, prolongation of the Fridericia-corrected QTc interval (QT/RR0.33=QTcF) was observed from 15 min to 4 h after the start of the 15 min infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 19.6 (21.5) msec at 20 min. At the lower tested dose of 8 mg, QTc prolongation was observed from 15 min to 1 h after the start of the 15-minute infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 5.8 (7.8) msec at 15 min. The magnitude of QTc prolongation with ondansetron is expected to be greater if the infusion rate is faster than 15 minutes. The 32 mg intravenous dose of ondansetron must not be administered. No treatment-related effects on the QRS duration or the PR interval were observed at either the 8 or 32 mg dose. An ECG assessment study has not been performed for orally administered ondansetron. On the basis of pharmacokinetic-pharmacodynamic modelling, an 8 mg oral dose of ondansetron is predicted to cause a mean QTcF increase of 0.7 ms (90% CI -2.1, 3.3) at steady-state, assuming a mean maximal plasma concentration of 24.7 ng/mL (95% CI 21.1, 29.0). The magnitude of QTc prolongation at the recommended 5 mg/m2 dose in pediatrics has not been studied, but pharmacokinetic-pharmacodynamic modeling predicts a mean increase of 6.6 ms (90% CI 2.8, 10.7) at maximal plasma concentrations. In healthy subjects, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects. Ondansetron has no effect on plasma prolactin concentrations.