Risk of Ventricular Arrhythmias and Association with Ondansetron

Moeller, Jaclyn R.; Gummin, David D; Nelson, Tom; Drendel, Amy L.; Shah, Breanne K.; Berger, Stuart

doi:10.1016/j.jpeds.2016.08.058

Cited by 15 publications

(7 citation statements)

References 13 publications

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“…A second potentially important clinical implication is that I KAS blockade is a new mechanism for diLQTS. Because I KAS is not an important repolarization current in normal ventricles (7,8,29), ondansetron is proarrhythmic only in patients with organic heart diseases (11,19,21). Potential exceptions could include chronic ventricular pacing, hypokalemia (4), bradycardia, and heart block (34) when I KAS is upregulated to compensate for reduced repolarization reserve.…”

Section: Discussionmentioning

confidence: 99%

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca²⁺-activated K⁺ channels

Guo

Hassel

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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Apamin-sensitive small-conductance Ca-activated K (SK) current ( I) is encoded by Ca-activated K channel subfamily N ( KCNN) genes. I importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that I inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT receptor antagonist ondansetron blocks I. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca sensitivity, increasing I density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced I inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca sensitivity and I density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent I blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT receptor antagonist, blocks small-conductance Ca-activated K (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of drug-induced long QT syndrome.

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Section: Discussionmentioning

confidence: 99%

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca²⁺-activated K⁺ channels

Guo

Hassel

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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“…Among pediatric population, no signi cant QTc prolongation following administration of standard doses of ondansetron (0.15 mg/kg) has been observed in several studies, and the risk of ventricular dysrhythmias has been estimated to be 3 in 100,000 [22,32]. Among the adult population, on the other side, several studies have reported dysrhythmias and QTc prolongation after IV ondansetron administration [30,[33][34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Single dose intravenous ondansetron induces QTc prolongation in adult emergency department patients: is it predictable and persistent? A prospective observational study

Rukerd

Shahrbabaki

Movahedi

et al. 2023

Preprint

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Background Ondansetron is one of the most routinely used drugs in the emergency department (ED) for treating nausea and vomiting, particularly in intravenous (IV) form. Nevertheless, it has been shown to prolong QT interval and increase the risk of fatal ventricular dysrhythmias. The accurate prediction of QTc interval prolongation induced by just a single-dose IV ondansetron in the ED remains unclarified in the literature. This study further evaluated the associations between IV ondansetron dosage and subsequent QTc prolongation.Methods In this prospective observational study, a total number of 106 patients presenting to the ED in a 3-month period with nausea and vomiting treated with IV ondansetron were enrolled. QTc intervals were measured at baseline (QTc0), 30 minutes (QTc30) and 60 minutes (QTc60) following a single-dose administration of ondansetron at 4 or 8 mg doses.Results In the multivariable logistic regression, ondansetron IV dose and QTc0 were independently associated with QTc60 > 480msec. The area under curves (AUC) for prediction of prolonged QTc60 were 0.71 and 0.64 for dosage and QTc0, respectively. There was a 100% sensitivity for QTc0 = 400msec to predict QTC60 < 480msec, while QTc0 > 460msec predicted QTC60 > 480msec with 98% specificity. Each msec increment in QTc0 increased the likelihood of prolonged QTc60 by 3%, while increasing the single dose of 4mg to 8mg increased prolonged QTc60 odds by 33%.Conclusions Based on our results, single doses of up to 8 mg ondansetron could be safely injected for patients with no risk factors for QTc prolongation and initial QTc of 400msec or less. Above this QTc cutoff, using the 4mg dose instead of 8mg as a precaution may be advisable if the baseline QTc is not prolonged and ondansetron administration is necessary.

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“…Ondansetron is contraindicated in infants younger than 6 months of age and in children with cardiac disease, as it is associated with QT prolongation. A large retrospective study with 37,794 children observed seven cases of ventricular arrhythmia in children with a previous congenital cardiac conduction abnormality or other major cardiac diseases [89]. Nevertheless, routine electrocardiogram and electrolyte screening are not recommend [90].…”

Section: Management Of Dies In Childrenmentioning

confidence: 99%

Drug-Induced Enterocolitis Syndrome in Children

Filippo

Venanzi

Ciarelli

et al. 2023

IJMS

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Drug-Induced Enterocolitis Syndrome (DIES) is a drug-induced hypersensitivity reaction non-IgE mediated involving the gastrointestinal system that occurs 2 to 4 h after drug administration. Antibiotics, specifically amoxicillin or amoxicillin/clavulanate, represent the most frequent drugs involved. Symptoms include nausea, vomiting, abdominal pain, diarrhea, pallor, lethargy, and dehydration, which can be severe and result in hypovolemic shock. The main laboratory finding is neutrophilic leukocytosis. To the best of our knowledge, 12 cases of DIES (9 children-onset and 3 adult-onset cases) were described in the literature. DIES is a rare clinically well-described allergic disease; however, the pathogenetic mechanism is still unclear. It requires to be recognized early and correctly treated by physicians.

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Risk of Ventricular Arrhythmias and Association with Ondansetron

Cited by 15 publications

References 13 publications

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca²⁺-activated K⁺ channels

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca²⁺-activated K⁺ channels

Single dose intravenous ondansetron induces QTc prolongation in adult emergency department patients: is it predictable and persistent? A prospective observational study

Drug-Induced Enterocolitis Syndrome in Children

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Risk of Ventricular Arrhythmias and Association with Ondansetron

Cited by 15 publications

References 13 publications

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca2+-activated K+ channels

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca2+-activated K+ channels

Single dose intravenous ondansetron induces QTc prolongation in adult emergency department patients: is it predictable and persistent? A prospective observational study

Drug-Induced Enterocolitis Syndrome in Children

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Product

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Ondansetron blocks wild-type and p.F503L variant small-conductance Ca²⁺-activated K⁺ channels

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca²⁺-activated K⁺ channels