Ondansetron, Promethazine, and Droperidol – What are the warnings about?

All of the anti-emetics listed above are great at controlling nausea and vomiting.  However, they all have side effects that have caused a lot of scrutiny.  Ondansetron (Zofran) is a serotonin 5-HT3 receptor antagonist that likely works on central and peripheral causes of nausea.  The exact mechanism is unknown, but most sources think it blocks vagal afferent nerves.  Normally the vagal afferent signal will result in serotonin release in the chemoreceptor trigger zone in the area postrema near the third and fourth ventricles, resulting in nausea.  Ondansetron theoretically blocks both the vagal afferent and the serotonin effects, resulting in decreased nausea.  Several reports of increased in QTc were reported in the past, resulting in the FDA issuing a Medwatch Safety Alert on September 15 of this year for patients with long QT syndrome.  The FDA also is making the manufacture investigate the QT prolongation further.  I would expect many well designed studies to be performed in the next few years investigating this issue, but for now the drug still appears to be safe unless you think they have history of congenital long QT syndrome.

Promethazine (Phenergan) is a phenothiazine medication that blocks H1 receptors as well as having moderate anti-cholinergic effects, which likely accounts for the anti-emetic properties.   For parenteral use, most people use this medication IV even though it is recommended for IM use.  In 2009, a woman had IV push phenergan given, resulting in gangrene and loss of her arm.  The FDA then added a black box warning making subcutaneous administration contraindicated and recommending IM use.  However, no black box warning was made for IV use.  Remember, you can always give it PO or PR!

Droperidol has been used for over 30 years for nausea and vomiting.  Mechanism of action is unknown, but it is theorized that it blocks the post-synaptic GABA receptors in the chemoreceptor trigger zone.  It may also block dopaminergic receptors in the caudate nucleus and nucleus accumbens, resulting in an anti-emetic effect.  A black box warning was issued in 2001 due to prolongation of the QTc in 273 patients in one study; only 73% of these patients were from the US and the dose used were very high (25-250mg).  Only 5 of the 273 cases were given 2.5mg of droperidol resulting in VT/torsades.  Therefore, the black box warning is to use caution in patients with risk of prolonged QT and a contraindication in patients with history of prolonged QT.  The rules for use are as follows: -12 lead EKG prior to use

-Do not give if QTc >440ms in males or > 450 ms in females

-Keep on monitor during use and 2-3 hours after

-Use lowest dose necessary to achieve effect

-See blackboxrx.com under droperidol, which lists the conditions that places a patient at higher risk

Halloran K, Barash P.  Inside the black box:  current policies and concerns with the United States Food and Drug Administration’s highest drug warning system.  Curr Opin Anaesthesiol.  2010.  23:  423-27.


Goldfrank’s Manual of Toxicologic Emergencies, 8th Ed.

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