Antipsychotic-related QTc prolongation,torsade de pointes and sudden death

Sudden unexpected deaths have been reported with antipsychotic use since the early 1960s. In some cases the antipsychotic may be unrelated to death, but in others it appears to be a causal factor. Antipsychotics can cause sudden death by several mechanisms, but particular interest has centred on torsade de pointes (TdP), a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and sudden death. The QTc interval is a heart rate-corrected value that represents the time between the onset of electrical depolarisation of the ventricles and the end of repolarisation. Prolongation of the QTc interval is a surrogate marker for the ability of a drug to cause TdP. In individual patients an absolute QTc interval of >500 msec or an increase of 60 msec from baseline is regarded as indicating an increased risk of TdP. However, TdP can occur with lower QTc values or changes. Concern about a relationship between QTc prolongation, TdP and sudden death applies to a wide range of drugs and has led to the withdrawal or restricted labelling of several. Among antipsychotics available in the UK, sertindole was voluntarily suspended, droperidol was withdrawn, and restricted labelling introduced for thioridazine and pimozide. The degree of QTc prolongation is dose dependent and varies between antipsychotics reflecting their different capacity to block cardiac ion channels. Significant prolongation is not a class effect. Among currently available agents, thioridazine and ziprasidone are associated with the greatest QTc prolongation. Virtually all drugs known to cause TdP block the rapidly activating component of the delayed rectifier potassium current (I(kr)). Arrhythmias are more likely to occur if drug-induced QTc prolongation coexists with other risk factors, such as individual susceptibility, presence of congenital long QT syndromes, heart failure, bradycardia, electrolyte imbalance, overdose of a QTc prolonging drug, female sex, restraint, old age, hepatic or renal impairment, and slow metaboliser status. Pharmacodynamic and pharmacokinetic interactions can also increase the risk of arrhythmias. Further research is needed to quantify the risk of sudden death with antipsychotics. The risk should be viewed in the context of the overall risks and benefits of antipsychotic treatment. It seems prudent, where possible, to select antipsychotics that are not associated with marked QTc prolongation. If use of a QTc-prolonging drug is warranted, then measures to reduce the risk should be adopted.     

Psychotropic drugs,cardiac arrhythmia,and sudden death

A variety of drugs targeted towards the central nervous system are associated with cardiac side effects, some of which are linked with reports of arrhythmia and sudden death. Some psychotropic drugs, particularly tricyclic antidepressants (TCAs) and antipsychotic agents, are correlated with iatrogenic prolongation of the QT interval of the electrocardiogram (ECG). In turn, this is associated with the arrhythmia (TdP). This review discusses the association between psychotropic agents, arrhythmia and sudden death and, focusing on TCAs and antipsychotics, considers their range of cellular actions on the heart; potentially pro-arrhythmic interactions between psychotropic and other medications are also considered. At the cellular level TCAs, such as imipramine and amitriptyline, and antipsychotics, such as thioridazine, are associated with inhibition of potassium channels encoded by In many cases this cellular action correlates with ECG changes and a risk of TdP. However, not all psychotropic agents that inhibit HERG at the cellular level are associated equally with QT prolongation in patients, and the potential for QT prolongation is not always equally correlated with TdP. Differences in risk between classes of psychotropic drugs, and between individual drugs within a class, may result from additional cellular effects of particular agents, which may influence the consequent effects of inhibition of repolarizing potassium current.     

QTc interval prolongation and antipsychotic drug treatments: focus on sertindole

Since the 1960s, physicians have been aware of electrocardiographic (ECG) abnormalities and cases of sudden death associated with the use of antipsychotic drugs in patients with schizophrenia. Explanations for such deaths have traditionally focused on drug-induced prolongation of the QT interval leading to the development of life-threatening ventricular arrhythmias such as torsade de pointes (TdP). It is now apparent that most conventional and atypical antipsychotics can cause dose-related prolongation of the corrected QT interval (QTc), although there are important differences in the potency of individual agents. This review discusses potential mechanisms underlying QTc prolongation and arrhythmogenesis and examines the evidence for a relationship between antipsychotic drugs and prolongation of the QTc interval. New electrophysiological and epidemiological data are presented which suggest there may not be a clear-cut cause-effect relationship between QTc prolongation and the development of ventricular tachyarrhythmias for all atypical antipsychotics. For at least one of these agents (sertindole), counterbalancing mechanisms may act to reduce the risk of proarrhythmic activity arising as a result of QTc prolongation.     

Sudden cardiac death secondary to antidepressant and antipsychotic drugs

A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use.     

Assessing QT interval prolongation and its associated risks with antipsychotics

Several antipsychotics are associated with the ventricular tachycardia torsade de pointes (TdP), which may lead to sudden cardiac death (SCD), because of their inhibition of the cardiac delayed potassium rectifier channel. This inhibition extends the repolarization process of the ventricles of the heart, illustrated as a prolongation of the QT interval on a surface ECG. SCD in individuals receiving antipsychotics has an incidence of approximately 15 cases per 10,000 years of drug exposure but the exact association with TdP remains unknown because the diagnosis of TdP is uncertain. Most patients manifesting antipsychotic-associated TdP and subsequently SCD have well established risk factors for SCD, i.e. older age, female gender, hypokalaemia and cardiovascular disease. QT interval prolongation is the most widely used surrogate marker for assessing the risk of TdP but it is considered somewhat imprecise, partly because QT interval changes are subject to measurement error. In particular, drug-induced T-wave changes (e.g. flattening of the T-wave) may complicate the measurement of the QT interval. Furthermore, the QT interval depends on the heart rate and a corrected QT (QTc) interval is often used to compensate for this. Several correction formulas have been suggested, with Bazett's formula the most widely used. However, Bazett's formula overcorrects at a heart rate above 80 beats per minute and, therefore, Fridericia's formula is considered more appropriate to use in these cases. Several other surrogate markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled in its measurement. A QT interval >500?ms markedly increases the risk for TdP and SCD, and should lead to discontinuation of the offending drug and, if present, correction of underlying electrolyte disturbances, particularly serum potassium and magnesium derangements. Before prescribing antipsychotics that may increase the QTc interval, the clinician should ask about family and personal history of SCD, presyncope, syncope and cardiac arrhythmias, and recommend cardiology consultation if history is positive.     

Acquired QT interval prolongation and HERG: implications for drug discovery and development

Putative interactions between the Human Ether-a-go-go Related Gene (HERG), QT interval prolongation and Torsades de Pointes (TdP) are now integral components of any discussion on drug safety. HERG encodes for the inwardly rectifying potassium channel (I_Kr), which is essential to the maintenance of normal cardiac function. HERG channel mutations are responsible for one form of familial long QT syndrome, a potentially deadly inherited cardiac disorder associated with TdP. Moreover, drug-induced (acquired) QT interval prolongation has been associated with an increase in the incidence of sudden unexplained deaths, with HERG inhibition implicated as the underlying cause. Subsequently, a number of non-cardiovascular drugs which induce QT interval prolongation and/or TdP have been withdrawn. However, a definitive link between HERG, QT interval prolongation and arrhythmogenesis has not been established. Nevertheless, this area is subject to ever increasing regulatory scrutiny. Here we review the relationship between HERG, long QT syndrome and TdP, together with a summary of the associated regulatory issues, and developments in pre-clinical screening.     

药物致Q-T间期延长的文献分析

近年来,临床实践有许多药物都会导致Q-T间期延长甚至尖端扭转型室性心律失常（TdP）。本文通过对1979年-2013年国内医药期刊公开报道的药物致Q-T间期延长的个案进行统计和分析,总结了56个病例的一般情况、引起Q-T间期延长的药物、发生时间及转归等,致Q-T间期延长药物中排在前三位的分别为抗心律失常药、抗微生物药、抗组胺药。大部分患者在用药后一个月内出现,停药及对症治疗后好转。临床医师应正确地认识药物致Q-T间期延长发生机制和易感因素,才能保证临床安全有效地使用药物。     

Investigation of the potential of clozapine to cause torsade de pointes

Antipsychotics are frequently associated with QTc interval prolongation, a proposed marker for vulnerability to fatal ventricular arrhythmias, e.g. torsade de pointes (TdP). Little has been published on this topic in relation to clozapine. The objectives of this review were to: (i) calculate the frequency of QTc interval prolongation, T-wave abnormalities, TdP, ventricular tachycardia/fibrillation and sudden unexplained death in patients treated with clozapine and thioridazine from clinical trial and post-marketing reports; (ii) to compare these data with published findings for haloperidol, risperidone, olanzapine, sertindole and ziprasidone; and (iii) to correlate these clinical data with results from preclinical tests presently considered to be of predictive value for a compound's potential to cause QTc interval prolongation and TdP. A review of the global Novartis databases for clozapine and thioridazine and a Medline/Internet search for information on these cardiac events and for preclinical effects on the human ether-a-go-go related gene channels, action potential duration, and QT interval changes produced by the selected antipsychotics were performed. The clozapine database (2.8 million patient-years spanning 27 years) demonstrated that at therapeutic doses all but three reports of QTc interval prolongation and both of TdP were confounded by relevant co-medication/comorbidity. The literature review revealed that all antipsychotics considered except clozapine induced TdP and/or QTc interval prolongation at therapeutic doses. Preclinical in vitro tests appear to overestimate the risk of clozapine, haloperidol and risperidone to prolong QTc interval in patients and underestimate such a risk for sertindole and ziprasidone. Extrapolation of in vitro results to clinical events requires qualified interpretation.     

QT prolongation and safety in the Indian population

The QT interval in electrocardiogram (ECG) reflects the total duration of ventricular myocardial depolarization and repolarization. It has been well recognized that many condition may cause QT interval prolongation. Unfortunately, numbers of cardiac and non-cardiac drug prolong the QT interval and cause a distinctive polymorphic ventricular tachycardia termed torsade de pointes (TdP). TdP can degenerate into ventricular fibrillation, which leads to sudden cardiac death. Recently various regulatory and clinical bodies of Europe, USA, Canada and Australia have made their focus on the drugs that induce prolongation of QT interval. Committee for Proprietary Medicinal Products (CPMP) of the European Agency issued a document entitled 'Points to Consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products' [1, 2]. In addition, USFDA adopted the guideline 'Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-anti arrhythmic drugs' [3]. These documents and guidelines are primarily concern with development of novel agents and the new use or new dose of already approved drugs. The scope of this guideline is to study the effect of drugs on QT prolongation and give idea of evaluation of drug's effects on QT prolongation. Today more than 50 available drugs (both old and new) have been identify, which prolong the QT interval [1]. Several drugs have been withdrawn from many countries on this basis but many of these drugs are still available in Indian market and potentially creating life-threatening arrhythmias. This article will focus on recommendation of study on the normal limits of QT interval in Indian population and preparation of the database, which can be helpful in withdrawal of drugs from the market that produces QT prolongation.     

Antidepressants: their effects on cardiac channels, QT prolongation and Torsade de Pointes

The cardiovascular side effects of older antidepressants, such as tricyclic antidepressants, are well established and are known to be linked to their capacity to inhibit cardiac and vascular ion channels. Newer compounds, such as selective serotonin reuptake inhibitors, mirtazapine and venlafaxine, have been reported to have a more benign cardiovascular profile, although they also share antagonistic properties with regard to voltage-dependent ion channels in different tissues. The electrophysiological effects that antidepressants exert on ion channels may affect the cardiac action potential (AP), lengthening both depolarization and repolarization phases, widening the QRS complex, prolonging the QT interval or causing Brugada-like electrocardiogram patterns. Lengthening of the depolarization phase can slow conduction through the His-Purkinje system and myocardium, while slowing repolarization can lead to early after depolarizations and Torsade de Pointes (TdP). In this review, we discuss data from experimental animal models regarding the effects of antidepressants on the cardiac AP, as well as antidepressant-induced QT prolongation in humans and sudden death in patients treated with antidepressants. It appears that although various experimental studies may lead to an understanding of the mechanisms involved in the modulation of cardiac electrical activity, there are significant discrepancies between in vitro data describing the action of antidepressants on the AP, data from clinical trials on QT prolongation by antidepressants and risk of TdP. The role of genetic polymorphisms of potassium-channel-encoding genes in determining the individual risk of cardiac arrhythmias and the limits of QT use as a marker of risk are discussed. Extensive pharmacokinetic and pharmacodynamic studies are required to determine the doses and plasma ranges of each drug that are associated with the greatest risk of arrhythmic complications.     

氟喹诺酮类药物所致尖端扭转型室性心动过速

氟喹诺酮类常用药物中左氧氟沙星、环丙沙星、加替沙星和莫西沙星等可以引起尖端扭转型室性心动过速(TdP).TdP的临床表现为眩晕、昏厥甚至心搏停止,心电图可见QT间期延长及TdP.其发生机制尚不明确,可能与抑制心肌细胞K<'+>离子通道,使K<'+>外流受阻有关.氟喹诺酮类常用药物所致TdP的危险因素有女性、高龄、器质性心脏病(特别是充血性心力衰竭、QT间期延长、心动过缓)、肝肾功能损害、低钾低镁血症,以及合用可以引起QT间期延长的药物等.一旦患者出现QT间期延长及TdP应立即停药,补充钾和镁抑制早期后除极,也可采用人工临时心脏起搏或异丙肾上腺素提高基础心率.意识丧失和心室颤动者,可进行体外电复律.     

QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system

BACKGROUND: Recent case series have associated the synthetic opioid, methadone, with QT prolongation and torsades de pointes (TdP) ventricular arrhythmia. STUDY OBJECTIVE: To review and analyze adverse events (QT prolongation and TdP) reported to the Food and Drug Administration (FDA) to determine the patient characteristics, dosages of methadone, and outcomes of methadone-treated patients. METHODS: The study design was a retrieval and retrospective analysis of reports of adverse events associated with methadone voluntarily reported to the FDA MedWatch program from 1969 to October 2002. Reports were accessed via QSCAN (DrugLogic, Reston, VA), a commercially available software interface. RESULTS: In a total of 5,503 reports of adverse events associated with methadone, 43 (0.78%) noted the occurrence of TdP and 16 (0.29%) QT prolongation. Doses were reported in 42/59 (71%) of cases; mean dose was 410 +/- 349 mg/day (median 345, range 29-1680). The dosages for 10 of the 42 cases (29%) were within the recommended range for methadone maintenance treatment, 60-100 mg/day. Female gender, interacting medications, hypokalemia, hypomagnesemia, and structural heart disease, risk factors previously identified with other drugs known to cause TdP, were found in 44 (75%) cases. Most adverse events required hospitalization or resulted in prolonged hospitalization (28/59, 47%) and 5/59 (8%) were fatal. CONCLUSIONS: Cases of TdP associated with methadone have been reported to the FDA MedWatch system. Analysis of the cases provides evidence that prolonged QT and TdP can occur over a wide range of dosages including those usually recommended for addiction treatment.     

Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin

Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis. A multi-scale mechanistic modeling framework consisting of physiologically based pharmacokinetics (PBPK) simulations of clinically relevant drug exposures combined with Quantitative Systems Toxicology (QST) models of cardiac electro-physiology could bridge this gap. We illustrate this PBPK-QST approach in cardiac risk assessment as exemplified by moxifloxacin, an anti-tuberculosis drug with abundant clinical cardiac safety data. PBPK simulations of moxifloxacin concentrations (systemic circulation and estimated in heart tissue) were linked with in vitro measurements of cardiac ion channel inhibition to predict the magnitude of QT prolongation in healthy individuals. Predictions closely reproduced the clinically observed QT interval prolongation, but no arrhythmia was observed, even at ×10 exposure. However, the same exposure levels in presence of physiological risk factors, e.g., hypokalemia and tachycardia, led to arrhythmic event in simulations, consistent with reported moxifloxacin-related TdP events. Application of a progressive PBPK-QST cardiac risk assessment paradigm starting in early development could guide drug development decisions and later define a clinical “safe space” for post-approval risk management to identify high-risk clinical scenarios.     

Safety of droperidol in behavioural emergencies

By the year 2000, droperidol had become a standard drug for the treatment of behavioural emergencies in both psychiatric and medical settings. In 2001, the US FDA issued a ‘black box’ warning, citing cases of QT prolongation and/or torsades de pointes. As a result, the use of droperidol has been sharply circumscribed. The authors will review the literature on antipsychotic medications in general, focusing on droperidol in particular, with regard to QT interval prolongation, dysrhythmia, and sudden death. In addition, the mechanism of drug-induced QT interval prolongation will be discussed. The authors will then review their extensive experience with droperidol. The authors conclude that, while in theory droperidol may prolong the QT interval to an extent similar to thioridazine, its long history of clinical use has shown no pattern of sudden deaths analogous to those that provoked the FDA warning. Although the numbers presented by the FDA initially appear alarming, after further evaluation it is clear that more definitive studies should have been carried out. Droperidol is safe, extremely effective, and now underused as a treatment for severely agitated or violent patients.     

Safety of droperidol in behavioural emergencies

By the year 2000, droperidol had become a standard drug for the treatment of behavioural emergencies in both psychiatric and medical settings. In 2001, the US FDA issued a 'black box' warning, citing cases of QT prolongation and/or torsades de pointes. As a result, the use of droperidol has been sharply circumscribed. The authors will review the literature on antipsychotic medications in general, focusing on droperidol in particular, with regard to QT interval prolongation, dysrhythmia, and sudden death. In addition, the mechanism of drug-induced QT interval prolongation will be discussed. The authors will then review their extensive experience with droperidol. The authors conclude that, while in theory droperidol may prolong the QT interval to an extent similar to thioridazine, its long history of clinical use has shown no pattern of sudden deaths analogous to those that provoked the FDA warning. Although the numbers presented by the FDA initially appear alarming, after further evaluation it is clear that more definitive studies should have been carried out. Droperidol is safe, extremely effective, and now underused as a treatment for severely agitated or violent patients.     

ILSI-HESI cardiovascular safety subcommittee initiative: evaluation of three non-clinical models of QT prolongation

INTRODUCTION: Drugs that delay cardiac repolarization pose potential safety risks to patients and cause serious regulatory concern because of the link between QT interval prolongation and the potentially fatal arrhythmia torsades de pointes (TdP). Predicting which drugs will cause TdP is an inexact and difficult science. The utility of non-clinical assays was not well understood due in part to variability in methods, species, and consistency in the assays reported in the literature. The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) outlined a set of studies to determine how well selected commonly used non-clinical assays identified compounds known to cause TdP and prolong QT interval in humans. METHODS: Compounds known to prolong ventricular repolarization and compounds considered safe by years of clinical use were tested in three assays: HERG ionic current, Purkinje fiber repolarization, and in vivo QT studies in conscious telemeterized dogs. RESULTS: The data from each of these assays demonstrate that compounds that may pose a proarrhythmia risk for patients can be distinguished from those that are considered safe. DISCUSSION: Taken collectively, the in-vitro and in-vivo preclinical results can be integrated to develop an accurate preclinical risk assessment to support clinical safety.     

Prevalence of Torsades de Pointes inducing drugs usage among elderly outpatients in North Jordan Hospitals

Background

Torsade de Pointes (TdP) is an abnormal cardiac rhythm associated with a prolongation of QT interval. Although in most cases it spontaneously returns to the normal rhythm, TdP can lead to sudden cardiac death. Medications are the main cause of QT-prolongation and subsequent TdP flare, even though the exact mechanism of why some people evoke TdP but others do not is still unknown. It is evident that elderly patients are more susceptible to experience drug's side effects especially with chronically used medications.

Antipsychotic drugs and QT prolongation

Antipsychotic drugs (AD) are effective and frequently prescribed to more females than males. AD may cause serious cardiovascular side-effects, including prolonged QT interval, eventually leading to torsades de pointes (TdP) and sudden death. Epidemiologic data and case-control studies indicate an increased rate of sudden death in psychiatric patients taking AD. This review summarizes current knowledge about the QT prolonging effects of AD and gives practical suggestions. Amisulpride, clozapine, flupenthixol, fluphenazine, haloperidol, melperone, olanzapine, perphenazine, pimozide, quetiapine, risperidone, sulpiride, thioridazine and ziprasidone cause a QT prolongation ranging from 4 ms for risperidone to 30 ms for thioridazine. Our knowledge about the QT-prolonging effects of many AD is still limited. Females are under-represented in most studies. Many studies were conducted or supported by pharmaceutical companies. To avoid prodysrhythmia caused by QT prolongation, other factors influencing QT interval have to be considered, such as other drugs affecting the same pathway, hypokalemia, hypomagnesemia, bradycardia, increased age, female sex, congestive heart failure and polymorphisms of genes coding ion channels or enzymes involved in drug metabolism. Because the response of a patient to AD is individual, an electrocardiogram recording the QT interval has to be performed at baseline, after AD introduction and after occurrence of any factor that might influence the QT interval.