Numerous conditions (i.e., infection, pregnancy, vestibular dysfunction, increased intracranial pressure) and exposures to various pharmaceuticals agents – including inhalational anesthetics – can cause nausea and vomiting.
This complex series of reflexes is coordinated by the brainstem vomiting center, located in the lateral medullary reticular formation, and propagated chiefly via cranial nerves VIII and X and through pathways within the nucleus tractus solitaris, which control respiration, salivation, and vasomotor centers. (1)
Several sources of afferent input are known to stimulate the vomiting center, including the chemoreceptor trigger zone (CTZ), located near the area postrema on the floor of the fourth ventricle, where the blood brain barrier is not as developed, making it readily accessible to emetogenic stimuli in the blood and cerebrospinal fluid (CSF). This area is rich in a number of different receptor classes, including: dopamine D2, serotonin 5-HT3, and opioid receptors. Other afferent fibers are activated by the vestibular system (important in motion sickness) through CN VIII, which is rich in muscarinic and histamine H1 receptors; vagal and enteric afferent fibers in the mucosa of the GI tract are also rich in 5-HT3 receptors. (2)
As a consequence, numerous selective 5-HT3 receptor antagonists have been developed that demonstrate potent antiemetic properties. Their mechanism is thought to be mediated mainly through peripheral receptors located in intestinal vagal afferents.
The first of this class of drugs (-setrons) to be developed was ondansetron (Zofran), a carbazole derivative developed by Glaxo in 1984. Its efficacy was first established in 1987 and it was approved by the United States Food and Drug Administration in 1991. (3,4)
Pharmacokinetics: Ondansetron is widely distributed (VD ~ 160 L) and binds moderately (70-76%) to plasma proteins; the elimination half-life averages approximately 3.8 +/- 1 hours. Clearance occurs by hepatic metabolism (95%) through hydroxylation on the indole ring followed by glucuronide or sulfate conjugation. (5)
Side Effects: While the 5-HT3 receptor antagonists are well-tolerated, commonly reported side effects include: fever, headache, dizziness, and constipation. On 15 September 2011, the U.S. Food and Drug Administration (FDA) informed the public of an ongoing safety review of the anti-nausea drug Zofran (ondansetron, ondansetron hydrochloride and their generics): Ondansetron may increase the risk of developing abnormal changes in the electrical activity of the heart, which can result in a potentially fatal abnormal heart rhythm, specifically, torsades de pointes.
It is important to emphasize that in the hospital setting, numerous risk factors for drug-induced QT interval prolongation – potentially leading to torsades de pointes – do exist, including: hypokalemia, hypomagnesemia, bradycardia, genetic predisposition, associated heart disease, female gender, and use of drugs that either prolong the QT interval or disrupt the metabolism or distribution of QT-prolonging drugs. (6-9)
Over the past two decades, the single most common cause of withdrawal or restriction of a medication that has already entered the market has been prolongation of the QT interval associated with polymorphic ventricular tachycardia or torsades de pointes. (10) While case reports have been published documenting the proarrhythmic potential of -setrons in both adults and children, overall electrocardiographic data have been conflicting. (11,12)
Presently, only two prospective studies, conducted by the same investigators, have evaluated the effect of ondansetron, droperidol, and a combination of these agents on prolongation of the QT interval corrected for heart rate (QTc) at various time points following administration. (13,14) In both studies, ondansetron was associated with a statistically significant increase in mean maximal QTc lengthening of about 17–20 msec (p < 0.0001); however, these findings were documented in patients who were either healthy volunteers or postoperative patients without additional risk factors for QTc prolongation (defined as >450 msec for men and >470 msec for women).
As per the Center for Education and Research at the University of Arizona: Ondansetron is a member of the risk category of “possible drugs” that could prolong the QTc interval, leading to torsades de pointes.
In patients admitted for either heart failure or acute coronary syndromes with at least one additional risk factor for torsades de pointes, we found that this effect could be seen at least 120 minutes following drug exposure. When considering using ondansetron for long-term administration in the inpatient setting, patients with cardiovascular disease who are at high risk for drug-induced torsades de pointes should at least be monitored via telemetry. From a patient safety perspective, ondansetron should be added to the clinician’s list of drugs that can possibly prolong the QTc interval. (15)
- A D Miller, R A Leslie The area postrema and vomiting. Front Neuroendocrinol: 1994, 15(4);301-20
- R M Hagan, A Butler, J M Hill, C C Jordan, S J Ireland, M B Tyers Effect of the 5-HT3 receptor antagonist, GR38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of the rat brain. Eur. J. Pharmacol.: 1987, 138(2);303-5
- B Costall, S J Gunning, R J Naylor, M B Tyers The effect of GR38032F, novel 5-HT3-receptor antagonist on gastric emptying in the guinea-pig. Br. J. Pharmacol.: 1987, 91(2);263-4
- F Roila, A Del Favero Ondansetron clinical pharmacokinetics. Clin Pharmacokinet: 1995, 29(2);95-109
- Drew et al. American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology, the Council on Cardiovascular Nursing, and the American College of Cardiology Foundation Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. Circulation: 2010, 121(8);1047-60
- Charbit et al. Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study. Anesthesiology: 2008, 109(2);206-12
- Charbit et al. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology: 2005, 102(6);1094-100
- Nathan et al. Implications of anesthesia in children with long QT syndrome. Anesth. Analg.: 2011, 112(5);1163-8
- Brian J Barnes, James M Hollands Drug-induced arrhythmias. Crit. Care Med.: 2010, 38(6 Suppl);S188-97
- Donald R Miller Arrhythmogenic potential of antiemetics: perspectives on risk-benefits. Can J Anaesth: 2003, 50(3);215-20
- W A Baguley, W T Hay, K P Mackie, F W Cheney, B F Cullen Cardiac dysrhythmias associated with the intravenous administration of ondansetron and metoclopramide. Anesth. Analg.: 1997, 84(6);1380-1