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5-HT3 antagonists

Created: 1/9/2005
Updated: 6/11/2009
 

[i] Ondansetron

Structure:

The structure of Ondansetron

Uses

Used in the prevention and treatment of postoperative nausea and vomiting. Widely used in the management of nausea and vomiting induced by chemotherapy and radiotherapy.

Chemical

Synthetic carbazole

Presentation

1) As a clear, colourless, aqueous solution in 2/4 ml glass-free ampoules containing 2 mg/ml ondansetron hydrochloride dehydrate (iv/im).
2) Tablets (4/8 mg)
3) Suppository (16 mg)
4) Oral melt wafers (bioequivalent to tablets).
5) Syrup

Mode of action

There are four types of serotonergic (5-HT) receptors (5-HT1-4). 5-HT1 receptors are subdivided further (5-HT1A etc). A high density of 5-HT3 receptors is found in the area postrema and nucleus tractus solitarius, most likely on the vagus nerve terminals. Receptors have also been found on peripheral sections of the vagus nerve in the gastrointestinal tract. Ondansetron is a highly selective antagonist at 5-HT3 receptors; it has an affinity 250-1000 times greater for the 5-HT3 receptor than for any other receptor. The drug antagonises 5-HT3 receptors both centrally and peripherally. Emetogenic stimuli result in the release of 5-HT in the small intestine and initiate a vomiting reflex (via vagal afferents, via 5-HT3 receptors). Peripheral 5-HT3 receptors have been identified on parasympathetic nerve afferents in the myenteric nerve plexus of the intestinal wall. Thus, ondansetron blocks the initiation of this reflex. Vagal afferents may also result in the release of 5-HT in the area postrema; ondansetron may also therefore have a central effect in anti-emesis. Chemo- or radiotherapy may cause the release of 5-HT from enterochromaffin cells. The cytotoxic agent cisplatin may induce nausea and vomiting by the release of 5-HT from damaged intestinal mucosa.

Dose

The adult dose is 8 mg 8 hourly orally or 4 mg iv/im per 24 hours. The paediatric dose is 0.1 mg/kg iv per 24 hours (>2 years of age).

Effects

No demonstrable effects on the cardiovascular system (although rapid iv bolus may cause bradycardia), respiratory system or central nervous system. The drug may increase large bowel transit time (no effect on gastric motility).

Toxicity

Constipation, headache and flushing may occur.

Absorption

Bioavailability 60%. Rapid oral absorption.

Distribution

76% protein bound. Volume of distribution 2 L/kg.

Metabolism

Hydroxylation/N-demethylation of the indole nucleus, then conjugation with glucuronic acid or sulphate. Metabolites are inactive.

Excretion

<5% excreted unchanged in the urine. Clearance is 6 ml/min/kg. Elimination half life is 3 hours. Hepatic impairment prolongs the half life, hence limit dose to 8 mg/day. Excretion is not affected by renal impairment.


[ii] Granisetron, tropisetron and dolasetron

Closely related drugs with a similar spectrum of activity. Granisetron is not licensed in paediatric patients. Studies suggest that tropisetron has less effect than ondansetron and granisetron. Dolasetron has recently been introduced into the US market. Only dose-ranging and placebo-controlled studies have been carried out to date.

References

[i] Ondansetron: a review of its use as an antiemetic in children.
Culy CR et al.
Paediatr Drugs 2001; 3(6): 441-79

[ii] Ondansetron compared with metoclopramide in the treatment of established postoperative nausea and vomiting. The French Ondansetron Study Group.
Diemunsch P et al.
Br J Anaesth 1997; 79(3): 322-6

[iii] Prophylactic antiemetic therapy with ondansetron, tropisetron, granisetron and metoclopramide in patients undergoing laparoscopic cholecystectomy: a randomized, double-blind comparison with placebo.
Naguib M et al.
Can J Anaesth 1996; 43(3): 226-31

[iv] A randomized controlled trial of the antiemetic effect of three doses of ondansetron after strabismus surgery in children .
Bowhay AR et al.
Paediatr Anaesth 2001; 11(2): 215-21



ArticleDate:20050901
SiteSection: Article
 
   
    
                                            
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