Phenytoin in Treatment of Methadone-Induced Torsades de Pointes: A Case Report

Altheeb, Zaid; Alziadat, Moayyad; Shamoon, Fayez

doi:10.1097/mjt.0000000000000523

Cited by 3 publications

(2 citation statements)

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“…There are little data available comparing modern AADs with phenytoin and in recent years, usage of phenytoin as an AAD has been limited to some case reports of refractory arrhythmias [48][49][50]. Based on new evidence from animal studies that phenytoin can stabilise Ca 2+ leak form abnormally phosphorylated RyR2s in heart failure [6], it is worth reconsidering the use of phenytoin as an AAD.…”

Section: Discussionmentioning

confidence: 99%

Antiarrhythmic Properties of Phenytoin

Mahmoodi

Brienesse

Boyle

et al. 2021

Preprint

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BACKGROUND: Phenytoin has long been used to treat epilepsy and for some time as an antiarrhythmic drug (AAD). It is known that the diastolic calcium leakage through dysfunctional cardiac ryanodine receptors (RyR2) is a mechanism for arrhythmias in heart failure. Recent evidence suggests that phenytoin inhibits dysfunctional RyR2, reduces the calcium leak during diastole in heart failure, and may improve cardiac systolic function. This indicates the potential for repurposing phenytoin as an AAD in patients with heart failure.METHODS: A systematic search of MEDLINE, Embase, and the Cochrane Library databases was performed in March 2019. The search was limited to the studies published in the English language from 1946 to 2019. Studies on the antiarrhythmic effects of phenytoin in adults compared to no treatment or other AADs were included. Studies were excluded if there was insufficient clinical data regarding antiarrhythmic effects, dosing and administration of phenytoin and other ADDs. Conference abstracts, editorials, case studies and review articles were also excluded. RESULTS: A total of 157 non-duplicate titles were screened, and 25 articles underwent full-text review. 13 studies met the inclusion criteria, representing a total of 985 patients. Phenytoin was found to be effective in treating arrhythmias associated with digitalis toxicity, and in suppressing premature ventricular contractions (PVCs). In a recent animal study, phenytoin inhibited diastolic calcium leak through dysfunctional RyR2 in failing sheep hearts and improved cardiac systolic function without affecting normal functional RyR2.CONCLUSION: Phenytoin has an acceptable safety profile when used as an AAD. It has some utility in treating digitalis-induced arrhythmias and suppressing PVCs, however, further study is needed to determine its efficacy as an antiarrhythmic in heart failure patients given new evidence of its RyR2 stabilising properties.TRIAL REGISTRATION NUMBER: PROSPERO database (CRD42019129125).

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Section: Discussionmentioning

confidence: 99%

Antiarrhythmic Properties of Phenytoin

Mahmoodi

Brienesse

Boyle

et al. 2021

Preprint

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“…Phenytoin and lidocaine as class Ib drugs mildly shorten the QT C and have been used for the treatment of druginduced TdP. 30,31 Encainide exhibits little effect on JT interval 32 and has no TdP reported.…”

Section: Procainamidementioning

confidence: 99%

Utility of Normalized TdP Score System in Drug Proarrhythmic Potential Assessment: A Blinded in vitro Study of CiPA Drugs

Liu

Lü

et al. 2020

Clin Pharma and Therapeutics

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Drugs that prolong QT may cause torsade de pointes (TdP). However, translation of nonclinical assessment of QT prolongation or hERG channel, targeted by QT-prolonging drugs, into clinical TdP risk has been insufficient to date. In this blinded study, we confirmed the utility of a Normalized TdP Score System in predicting drug-induced TdP risks among 34 drugs, including 28 with low, intermediate, and high TdP risks under the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative plus six compounds with names blinded to the investigators, using the rabbit ventricular wedge assay. Concentration-dependent TdP scores were determined by drug-induced changes in QT, T p-e , and proarrhythmias. Disclosure of the names and testing concentrations was made after completion of the experiments and report to the sponsors. Drugs' normalized TdP scores were calculated thereafter based on their respective free clinical maximum concentration (C max ). Drugs' normalized TdP scores were calculated and ranked for 33 drugs, excluding 1 investigational drug, and the TdP risks of the 28 CiPA drugs were correctly distinguished according to their respective categories of low, intermediate, and high TdP risks under the CiPA initiative. Accordingly, we are able to propose the cutoff values of the normalized TdP scores at 1 × C max : ≤ 0, > 0 to < 0.65 and ≥ 0.65, respectively, for low, intermediate, and high risk. This blinded study supports utility of our Normalized TdP Score System in predicting drug-induced TdP risks in 33 drugs, including 28 used for characterization of other assays under the CiPA initiative. However, these results need to be replicated in other laboratories.Torsades de pointes (TdP) is defined as a life-threatening polymorphic ventricular tachycardia that specifically occurs in the setting of QT prolongation. 1 Clinically encountered QT prolongation leading to TdP is largely caused by drug treatment particularly in the presence of pathological conditions like electrolyte imbalance, a variety of cardiomyopathies, etc. 2,3 Two key international regulatory guidelines were then established by International Committee/Council for Harmonisation (ICH) for

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Methadone

2017

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Phenytoin in Treatment of Methadone-Induced Torsades de Pointes: A Case Report

Cited by 3 publications

References 4 publications

Antiarrhythmic Properties of Phenytoin

Antiarrhythmic Properties of Phenytoin

Utility of Normalized TdP Score System in Drug Proarrhythmic Potential Assessment: A Blinded in vitro Study of CiPA Drugs

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