, Volume 52, Issue 5, pp 773–794


A Review of its Pharmacology and Preliminary Clinical Findings in Novel Applications


  • Michelle I. Wilde
    • Adis International Limited
  • Anthony Markham
    • Adis International Limited
Drug Evaluation

DOI: 10.2165/00003495-199652050-00010

Cite this article as:
Wilde, M.I. & Markham, A. Drugs (1996) 52: 773. doi:10.2165/00003495-199652050-00010



The use of ondansetron, a selective serotonin 5-HT3 receptor antagonist, is well established in patients with nausea and vomiting associated with cancer chemotherapy, radiotherapy or anaesthesia and surgery. The wide distribution of 5-HT3 receptors in the body and the role of these receptors in disease have provided the rationale for investigation of ondansetron in novel applications.

Preliminary data have shown ondansetron to have clinical benefit in patients with nausea and vomiting associated with drug overdosage or poisoning, anti-infective or antidepressant therapies, uraemia or neurological trauma, and in patients with pruritus. Patients with gastrointestinal motility disorders (e. g. carcinoid syndrome, irritable bowel syndrome, diarrhoea associated with cryptosporidiosis or diabetes, and chronic refractory diarrhoea) have also shown some improvement when treated with ondansetron, as have patients with certain pain or CNS-related disorders [e. g. alcohol (ethanol) dependence, opiate withdrawal, vertigo, cerebellar tremor and Parkinson’s disease treatment-related psychosis].

In contrast to conventional antiemetics, ondansetron is generally well tolerated with a lower incidence of sedation and only isolated case reports of extrapyramidal reactions. Furthermore, unlike dopamine receptor-blocking neuroleptics, ondansetron does not appear to worsen the symptoms of Parkinson’s disease.

Thus, in addition to its established indications, preliminary results suggest that ondansetron may be beneficial in a number of novel applications. This drug may represent a treatment alternative in patients with refractory disease, or an effective treatment of conditions for which current therapies are either poorly tolerated or not available. Further investigation of ondansetron in a range of potential new applications appears to be warranted.

Pharmacodynamic Properties

Ondansetron, a carbazole derivative, is a competitive and selective antagonist of serotonin 5-HT3 receptors. 5-HT3 receptors are present in both the central and peripheral nervous systems and are associated with several serotonin-mediated physiological and pathological processes.

The mechanisms by which ondansetron produces its clinical effects in the novel applications reviewed are not fully understood. Effects related to the peripheral nervous system are thought to involve inhibition of 5-HT3 receptor-induced depolarisation of vagal afferent nerves and inhibition of myenteric neurons and 5-HT3 receptor-mediated nociceptive responses. Blockade of 5-HT3 receptors at central sites (including the area postrema, nucleus tractus solitarius, amygdala and dorsal raphe nucleus) and blockade of dopamine release/cell firing in the nucleus accumbens (via 5-HT3 receptor antagonism) are possible mechanisms of CNS-related effects of ondansetron.

In animal studies, ondansetron has been shown to delay or increase gastric emptying, increase gastric mucosal blood flow and basal acid and sodium secretion, prevent or reduce stress- or alcohol (ethanol)-induced gastric mucosal damage, inhibit fluid loss and inflammation in small bowel obstruction, and reduce abdominal responses to rectal distension and viscerosensitive changes during experimental colitis. In healthy volunteers, ondansetron did not significantly affect gastric emptying, distension or compliance. However, colonic transit times were significantly longer with ondansetron than with placebo, and ondansetron inhibited tonic colonic postprandial responses. Duodenal motility, small intestinal transit and mouth to caecum transit times were unaffected.

The drug had no significant effects on basal cognitive performance and/or scopolamine-induced cognitive and/or behavioural effects in elderly or young healthy volunteers. However, ondansetron has been shown to have favourable effects on cognitive performance in animal studies.

In general, alcohol (ethanol) consumption was either reduced or unaffected by ondansetron in animal models of alcohol dependence. Ondansetron had no significant effects on self-administration of cocaine, heroin or nicotine, or on nicotine hypersensitivity in animals. However, ondansetron reduced withdrawal symptoms and had varied effects on behaviour associated with chronic alcohol, cocaine, benzodiazepine or nicotine administration in animals. Pretreatment with intravenous ondansetron did not modify the effects of alcohol in 2 studies of social drinkers. However, oral ondansetron significantly attenuated the pleasurable effects of alcohol in social drinkers and decreased their desire to drink.

Ondansetron inhibited or reduced raised mesolimbic dopamine activity and antagonised increased locomotor activity caused by dopamine excess in animals; dopamine metabolism was unaffected. Ondansetron has shown variable anxiolytic activity in animal models of anxiety. Data on the effects of ondansetron on the development of tolerance to or withdrawal from benzodiazepines in animals are varied. Ondansetron did not impair psychomotor and/or driving performance in healthy volunteers or patients with anxiety.

Pharmacokinetic Properties

In healthy adults, oral ondansetron (8mg in single or multiple doses) is completely and rapidly absorbed with a mean maximum plasma concentration (Cmax) of 20 to 48 μg/L, area under the plasma concentration-time curve of 101 to 351 μg/L • h and time to Cmax of 1 to 2.1 hours. Bioavailability is only approximately 60% as a result of significant first-pass metabolism. There is no evidence of accumulation after repeated oral doses, and coadministration with food or antacids does not appear to affect absorption. Oral ondansetron has a terminal elimination half-life of ≈ 2.5 to 5.4 hours.

Oral ondansetron has a volume of distribution of approximately 135 to 160L and binds only moderately to plasma proteins (70 to 76%). CSF concentrations are < 15% of plasma concentrations.

Ondansetron undergoes extensive hepatic oxidative metabolism. Metabolites contribute little to the activity of the drug and are excreted in the urine and faeces; renal clearance accounts for less than 5% of total unaltered ondansetron clearance.

Cytochromes P450 IA2, 2D6 and 3A are involved in the hydroxylation of ondansetron; therefore, drug interactions between ondansetron and agents that compete for these enzymes could potentially occur. However, no significant pharmacokinetic differences for ondansetron were observed in poor or extensive debrisoquine metabolisers.

The overall pharmacokinetics of ondansetron in children appear to be similar to those in adults. Ondansetron clearance is reduced in patients with hepatic impairment; dosage adjustments may be necessary, especially in patients with severe hepatic impairment (see Dosage and Administration summary).

Clinical Findings in Novel Applications

The wide distribution of 5-HT3 receptors throughout the body, the ability of ondansetron to act at multiple sites and the promising findings from animal studies and studies in healthy volunteers have provided the rationale for investigation of this drug in several novel applications. However, much of the available data on ondansetron in these applications is of a preliminary nature. Reports to date have involved only a small number of patients, most with refractory disease, and current treatments for many of the applications reviewed are minimally effective, poorly tolerated or nonexistent.

Single or multiple doses of intravenous ondansetron 5 to 10mg (or 0.14 or 0.15 mg/kg) or oral ondansetron 8mg relieved or improved nausea and/or vomiting associated with the following: theophylline, paracetamol (acetaminophen), colchicine or baclofen overdosage or poisoning and/or their antidotes/treatments; anti-infective and antidepressant therapies; uraemia; and neurological trauma.

Some clinical improvement in gastrointestinal symptoms with oral or intravenous ondansetron 8 to 16mg 2 or 3 times daily has been observed in patients with carcinoid syndrome or other gastrointestinal motility disorders including diarrhoea associated with cryptosporidiosis or diabetes and chronic refractory diarrhoea. Data from 2 placebo-controlled studies in patients with irritable bowel syndrome indicate that ondansetron significantly improved stool consistency (and stool frequency in 1 study); however, there were no between-treatment differences for a number of other clinical parameters in these studies. No beneficial effect was seen in patients with gastric stasis syndrome or diabetic gastroparesis.

Single or multiple doses of intravenous and/or oral ondansetron 4 or 8mg relieved or reduced pruritus in patients with cholestatic disease, terminal uraemia or itching following intrathecal morphine administration. This effect was significant compared with placebo in a small number of patients with cholestatic disease.

Various doses/dosages of ondansetron have also shown clinical benefit in some pain or CNS-related disorders (including nonsevere alcohol dependence, opiate withdrawal, intractable vertigo, cerebellar tremor and Parkinson’s disease treatment-related psychosis). Anxiety was not reduced by this agent in the one available study to date.

Tolerability and Drug Interactions

Tolerability data on ondansetron in potential new applications are limited. According to available clinical reports, headache and constipation were the adverse events most commonly observed in patients with nausea and vomiting associated with anti-infective therapy or in patients with cerebellar tremor, vertigo or Parkinson’s disease treatment-related psychosis.

These findings are supported by tolerability data from postoperative nausea and vomiting trials involving a total of 1900 patients. Headache (14%), dizziness (12%) and drowsiness/sedation (2%) were the most commonly reported adverse effects; their incidence was similar with ondansetron and placebo.

In contrast to conventional antiemetics, ondansetron has been associated with a lower incidence of sedation and only isolated case reports of extrapyramidal reactions. There have been reports (>20 cases to date) of anaphylactoid/ anaphylactic reactions associated with intravenous ondansetron.

Abnormalities in liver function tests have been associated with ondansetron therapy. No adverse cardiovascular events have been reported.

Dosage and Administration

Specific dosage recommendations for the use of ondansetron in potential new applications are not available at present. Oral and intravenous dosages of ondansetron have ranged widely in the available literature. In patients with severe hepatic impairment, the dosage of ondansetron should be ≤8mg once daily. Dosage adjustments do not appear to be required in the elderly, in patients with renal impairment or on the basis of gender alone.

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© Adis International Limited 1996