Introduction
Prolonged QT interval reflects prolonged myocyte repolarization due to ion channel malfunction and gives rise to early
after-depolarizations.1
Prolonged QTc is defined as > 470 msec in males and > 480 msec in females.1
The danger of a prolonged QTc interval is a life-threatening polymorphic ventricular rhythm known as Torsades de Pointes
(TdP), the risk of TdP is 2-3 times higher when QTc is > 500 msec.1
Multiple factors can contribute to QTc prolongation including advancing age, bradyarrhythmias, underlying cardiac
disease, electrolyte abnormalities (e.g. hypokalemia, hypomagnesaemia, hypocalcemia), and medications (e.g.
antiarrhythmics, antidepressants, antimicrobials, antipsychotics, and many others).1-2
Medication induced QT prolongation is dose and route related, with higher doses and IV administration being associated
with more QT prolongation
Clinical Detail
| Medication | Ondansetron (Zofran) | Promethazine (Phenergan) | Metoclopramide (Reglan) | Prochlorperazine (Compazine) |
|---|---|---|---|---|
| Dose | 4 mg | 12.5 mg | 5 to 10 mg | 5 to 10 mg |
| Route of Administration | PO (ODT + Tab), IV, IM | PO, IV, IM, Rectal | PO, IV, IM | PO, IV, IM, Rectal |
| PK/PD | Onset: ~30 min; Half-life: 3-6 hours; Metabolism: Extensive hepatic, CYP1A2/2D6/3A4; Excretion: Urine (44-60%), feces (~25%) | Onset: PO/IM ~20 min, IV ~5 min; Duration: 4-6 hours; Metabolism: Hepatic, CYP2D6/2B6; Excretion: Urine & feces as inactive metabolites | Onset: PO 30-60 min, IV 1-3 min, IM 10-15 min; Duration: 1-2 hours; Metabolism: Hepatic, CYP2D6; Excretion: Urine (~85%), feces | Onset: PO 30-40 min, IM 10-20 min, rectal 60 min; Duration: 3-4 hours; Metabolism: Primarily hepatic; Excretion: Feces |
| Adverse Effects | Headache, fatigue, malaise, constipation | Injection reactions (vesicant), CNS depression | Flushing (common w/ high IV doses), injection reactions, dystonic reactions, restlessness | Anticholinergic effects, extrapyramidal symptoms, risk of aspiration |
| Drug Interactions and warnings | CYP3A4 inducers, QT prolongating medications, serotonin syndrome, caution in hepatic disease (Child-Pugh class C) | BBW: Severe tissue injury (including gangrene) with injection administration (IM preferred over IV) | CNS depressants, anticholinergics; BBW: Tardive dyskinesia (dose & duration related), CYP2D6 inhibitors, serotonin modulators, anti-Parkinson agents, CNS depression, extrapyramidal symptoms | BBW: Elderly patients with dementia (increased risk of death; CNS depression), orthostatic hypotension, caution in seizure disorders |
| Crediblemeds Classification | Known risk of TdP | Possible risk of TdP | Conditional risk of TdP | No classification |
Evidence
| Author, year | Design / sample size | Intervention & Comparison | Outcome |
|---|---|---|---|
| Li, 2018 | Prospective, observational study (n=20) | IV ondansetron 4 mg | A single administration of ondansetron was associated with a mean QTc increase of 16.2 msec (p=0.01). Zero related cardiac events reported. |
| Moffett, 2016 | Prospective, observational study (n=22) | IV ondansetron 4 mg | A single administration of ondansetron was associated with a mean QTc increase of 20 msec. Zero related cardiac events reported. |
| Owczuk, 2009 | Prospective, double-blind, randomized study (n=40) | IV promethazine 25 mg vs IV midazolam 2.5 mg | Promethazine had a statically significant increase in QTc interval compared to midazolam at 5, 10, 15, & 20 min (p<0.001). Significantly higher number of patients with a QTc > 450 in the promethazine group compared to the midazolam group (11 vs 7; p=0.007). No cardiac events were reported. |
| Charbit, 2008 | Prospective, double-blind, randomized study (n=16) | IV droperidol 1 mg vs IV ondansetron 4 mg vs IV droperidol 1 mg + ondansetron 4 mg vs placebo | Compared to placebo both droperidol and ondansetron significantly prolonged the QTc interval by 25 msec and 17 msec respectably (p=0.014). Droperidol and ondansetron combined prolonged the QTc by 28 msec compared to placebo. |
| Ellidokuz, 2003 | Prospective, double-blind, cross-over (n=10) | IV metoclopramide 10 mg | Metoclopramide administration resulted in steeper QT/RR slopes compared with the pre-drug values (0.0037 ± 0.004 vs 0.064 ± 0.012, p=0.041). The QT variance increased after metoclopramide administration (46 ± 9 vs 164 ± 27, p=0.003). No cardiac events were reported. |
| Czekalla, 2001 | Four controlled, double-blind, randomized controlled trials (N=2700) | olanzapine 5-15 mg vs placebo | Olanzapine 15 ± 2.5 mg/day dose group had increase of QTc of 8.44 msec vs 4.71 msec in placebo group (p=0.038); no difference in olanzapine group dosing < 15 mg/day. No cardiac events were reported in post marketing data. |
Conclusions
- Commonly used antiemetics, including ondansetron, promethazine, metoclopramide, and prochlorperazine, can prolong the QTc interval, with the magnitude of effect being dose- and route-related (higher doses and IV administration carrying greater risk).
- By CredibleMeds classification, ondansetron carries a known risk of Torsades de Pointes, promethazine a possible risk, and metoclopramide a conditional risk, so agent selection should weigh each drug’s relative QT risk for the individual patient.
- Across the studies reviewed, single doses of these antiemetics produced measurable but generally modest QTc increases (on the order of roughly 16-25 msec) with no related cardiac events reported, suggesting the absolute risk is low in otherwise low-risk patients.
- ECG monitoring and attention to QTc are most warranted when antiemetics are combined with other QT-prolonging medications or given to patients with additional risk factors such as advancing age, bradyarrhythmia, underlying cardiac disease, or electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia).
References
Drew BJ, et al. Circulation. 2010 Mar 2;121(8):1047-60.
Viskin S et al. Lancet. 1999;354:1625-33.
Chan A et al. An International J of Med. 2007. 100(10):609.
Drew BJ, et al. Circulation. 2010; 121:1047.
Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed May 22, 2019.
Kai Li, Kathy, et al. J of Health-System Pharm. 2018; 75(5):276-282.
Moffett P, et al. Acad Emerg Med. 2016; 23(1):102-5.
Owczuk R, et al. Anaesthesia. 2009; 64(6):609-614.
Charbit B, et al. Anesthesiology. 2008; 109:206-12.
Czekalla J et al. J Clin Psychiatry. 2001 Mar;62(3):191-8.
Ellidokuz E. Aliment Pharmacol Ther. 2003 Jul 1;18(1):151-5.
A short weekly clinical Pearl for acute care pharmacists.
Get the Friday Pearl email
Get a short weekly clinical Pearl for acute care pharmacists. No spam.
Free forever. Unsubscribe anytime. No spam.