Ondansetron

Ondansetron
Systematic (IUPAC) name
9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3-dihydro-1H-carbazol-4(9H)-one
Identifiers
CAS number	99614-02-5
ATC code	A04AA01
PubChem	4595
DrugBank	APRD00481
ChemSpider	4434
Chemical data
Formula	C18H19N3O
Mol. mass	293.4 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	~60%
Protein binding	70%-76%
Metabolism	Hepatic (CYP3A4, CYP1A2, CYP2D6)
Half life	5.7 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	B1(AU) B(US)
Legal status	Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes	Oral, rectal, IV, IM
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Ondansetron (INN) (pronounced /ɒnˈdænsɛtrɒn/) or GlaxoSmithKline's Zofran is a serotonin 5-HT₃ receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy. Its effects are thought to be on both peripheral and central nerves. Ondansetron reduces the activity of the vagus nerve, which activates the vomiting center in the medulla oblongata, and also blocks serotonin receptors in the chemoreceptor trigger zone. It has little effect on vomiting caused by motion sickness, and does not have any effect on dopamine receptors or muscarinic receptors.

History

Ondansetron was developed around 1984 by scientists working at Glaxo's laboratories in London. It is in both the Imidazole and Carbazole families of heterocyclic compounds. After several attempts the company successfully filed for U.S. patent protection for the drug in 1986. U.S. Patent 4,695,578 was granted in September 1987 while U.S. Patent 4,753,789 was granted in June 1988. U.S. Patent 5,578,628, a divisional patent of U.S. Patent 4,753,789, was granted in November 26, 1996. Ondansetron was granted Food and Drug Administration (FDA) approval as Zofran in January 1991. Glaxo did pediatric research on Zofran's uses, and gained patent extension as a result. Consequently U.S. exclusivity ended December 24, 2006. The FDA subsequently approved the first generic versions in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals. It is currently marketed by GlaxoSmithKline (GSK) under the trade name Zofran; other manufacturers include Cipla Ltd. (Emeset), Gedeon Richter Ltd. (Emetron), Korea United Pharmaceuticals (Emodan), Zentiva a.s. (Ondemet) and Novell Pharmaceutical Laboratories (Ondavell). On May 29, 2006, Baxter Healthcare received tentative approval^[1] to market its own label of Ondansetron Injection, USP, 8 mg/50 mL and 32 mg/50 mL iso-osmotic sodium chloride solution, after GSK's patent expired on December 24, 2006.

Clinical uses

The 5-HT₃ receptor antagonists are the primary drugs used to treat and prevent chemotherapy-induced nausea and vomiting (CINV). Many times they are given intravenously about 30 minutes before beginning therapy. Ondansetron is also effective in controlling post-operative nausea and vomiting (PONV) and post-radiation nausea and vomiting, and is a possible therapy for nausea and vomiting due to acute or chronic medical illness or acute gastroenteritis.

Although it is highly effective, its high cost had limited its use to controlling PONV and CINV- although it is now available in cheaper generic forms. It is also used off-label to treat hyperemesis gravidarum in pregnant women, but there is no conclusive data available on its safety in pregnancy, especially during the first trimester. It is also often used to treat cyclic vomiting syndrome; although there have been no formal trials to confirm efficacy, case reports suggest it can be helpful in some cases. The drug is administered 1–3 times daily, depending on the severity of nausea and/or vomiting. The normal oral dose for adults and children over the age of 12, is 8 mg initially, followed by a second dose of 8 mg, eight hours later. The drug is then administered once every 12 hours, usually not for more than 2-3 days. Following oral administration, it takes about 1.5–2 hours to reach maximum plasma concentrations. This drug is removed from the body by the liver and kidneys.

The clinical effect of ondansetron (and other drugs from the same group) can be potentiated by combining it with dexamethasone.

Investigational and off-label

Schizophrenia

A 2006 double-blind, randomized controlled trial indicated that ondansetron may have value in the treatment of schizophrenia, as an adjunct to haloperidol. The study found the combination to significantly improve negative schizophrenia symptoms, and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol;^[2] an earlier, smaller, open-label trial had found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia, and the study patients also showed significant improvement in the disease's symptoms.^[3][4]

Sleep apnea

US patent 6,548,082 B1

Parkinson's disease

Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinson's disease.^[5] Its ability to be of benefit despite lacking any significant antagonistic properties at dopamine receptors or the 5-HT2A receptor raises interesting questions about the etiology of psychosis.

Alcoholism

Ondansetron lowers the cravings for alcohol, especially in early-onset alcoholics. In one cognitive-behavioral therapy study, ondansetron patients with early-onset alcoholism had fewer drinks per day and reported more days without drinking at all, compared to the other groups in the study.^[6][7]

Opioid addiction

Researchers at the Stanford University School of Medicine have demonstrated that ondansetron might be useful and effective for treating withdrawal symptoms of opioid addictions.^[8] Unlike the existing treatments methadone and buprenorphine, it is not itself an opioid.^[8] And it doesn't require continued supervision like treatment with clonidine.^[8]

The original experiment used mice who were injected with increasing doses of morphine, assayed with naloxone and then underwent haplotypic analysis to isolate a gene candidate.^[9] HTR3A which codes for the 5-HT₃ receptor emerged as the primary candidate, which suggested 5-HT₃ antagonist ondansetron as a possible treatment.^[9] The researchers were then able to show using an acute morphine administration model the efficacy in withdrawal symptom control in humans.^[9]

Irritable bowel syndrome

Ondansetron blocks the 5-HT3 receptor in the enteric nervous system, and thereby reduces colonic contractions, sensory perception, and motility. A large number of drugs in this category, 5-HT3 antagonist, have been shown to have this effect, which positively impacts irritable bowel syndrome with diarrhea (IBS-D). Thus, ondansetron has been effective in treating diarrhea-predominant IBS in initial studies, and is being used off label for this exact effect.^[10]

Postanesthetic shivering

Two small, placebo-controlled trials have been conducted to assess the efficacy of ondansetron for postanesthetic shivering, a common occurrence after surgery. Ondansetron was found to be as effective as pethidine (meperidine, Demerol) when given as a single IV dose before anesthesia.^[11]

Adverse effects

Ondansetron is a well-tolerated drug with few side effects. Constipation, dizziness and headache are the most commonly reported side effects associated with its use. There have been no significant drug interactions reported with this drug's use. It is broken down by the hepatic cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system.

See also

• Granisetron
• Dolasetron
• Alosetron (not an antiemetic but another 5-HT₃ antagonist investigated for controlling irritable bowel syndrome)
• 5-HT₃ receptor antagonist: Drug discovery and development

References