西酞普兰：潜在的心律失常危险

西酞普兰属选择性5羟色胺重摄取抑制剂（SSRI）类抗抑郁药。FDA认为西酞普兰安全剂量为每日不超过40 mg,否则心电活动有异常。60岁以上患者应服更低剂量。不推荐遗传性长QT综合征患者、近期有心肌梗死或不能代偿的心力衰竭者及服用其他延长QT间期药物者使用西酞普兰。对肝损害、60岁以上、服用甲氰咪呱或其他CYP2C19抑制剂患者,西酞普兰加大推荐剂量为每天20mg。     

美FDA要求西酞普兰最高日治疗剂量不得超出40mg

2011年10月,美国FDA发出安全性通告：因西酞普兰（citalopram）会以剂量依赖性方式延长用药者、特别是存在基础心脏疾病和处在低钾血症或低镁血症风险中的患者的QT间期,故其最高日治疗剂量不得超出40mg。FDA称：西酞普兰说明书的相关部分已作了相应修改,以免引致潜在致命的尖端扭转型心律失常。     

艾司西酞普兰与米氮平治疗抑郁症的临床疗效分析

目的探讨艾司西酞普兰与米氮平治疗抑郁症的临床疗效。方法100例抑郁症患者,随机分为艾司西酞普兰与小剂量米氮平组和艾司西酞普兰与大剂量米氮平组,各50例。艾司西酞普兰与小剂量米氮平组给予艾司西酞普兰与小剂量米氮平联合治疗,艾司西酞普兰与大剂量米氮平组给予艾司西酞普兰与大剂量米氮平联合治疗。比较两组疗效、治疗前后的汉密尔顿抑郁量表(HAMD)评分、蒙哥马利抑郁评定量表评分、生活质量(QOL)评分、副作用发生情况及药物开始起效时间。结果艾司西酞普兰与大剂量米氮平组治疗总有效率为100.00%,高于艾司西酞普兰与小剂量米氮平组的80.00%,差异有统计学意义(P<0.05)。治疗后,两组HAMD评分、蒙哥马利抑郁评定量表评分、QOL评分均较治疗前改善,且艾司西酞普兰与大剂量米氮平组HAMD评分、蒙哥马利抑郁评定量表评分均低于艾司西酞普兰与小剂量米氮平组,QOL评分高于艾司西酞普兰与小剂量米氮平组,差异均有统计学意义(P<0.05)。艾司西酞普兰与大剂量米氮平组药物开始起效时间(5.41±0.53)d短于艾司西酞普兰与小剂量米氮平组的(7.21±0.56)d,差异有统计学意义(P<0.05)。艾司西酞普兰与大剂量米氮平组副作用发生率为46.00%(23/50),高于艾司西酞普兰与小剂量米氮平组的24.00%(12/50),差异有统计学意义(χ^2=5.319,P<0.05)。结论抑郁症患者应用艾司西酞普兰与大剂量米氮平治疗的效果确切,但不良反应较多。     

麻醉药物与围术期心电监测

摘要：心电监测是围术期患者必不可少的监测项目,可协助麻醉医生实施高效的麻醉管理与麻醉规划,其具有的及时、个体化、显著、易于识别等优势还可用于指导麻醉用药方案。围术期心电监测结果受到多种因素的影响,术中麻醉药物对心电图的影响也多种多样。局部麻醉药物引起PQ间期延长、QRS波延长、HR减慢,布比卡因可导致心律失常发生率升高;瑞芬太尼引起HR减慢、PR间期、QRS时限和QTc间期缩短,大剂量时造成心肌显著抑制,舒芬太尼仅引起HR减慢;氯胺酮导致HR增快、RR间期延长、QRS间期延长;非甾体抗炎药引起ST-T改变与R波脉搏波传导增快;丙泊酚诱导时引起HR减慢、Tp-e与QTc间期延长;硫喷妥钠引起QTc间期明显延长、HR升高;右美托咪定导致HR明显减慢、QT间期延长、QTc间期缩短与Tpe/QT比值减小;琥珀胆碱引起HR减慢,发生严重高钾血症时出现QT间期缩短、QRS波增宽等;阿曲库铵、罗库溴铵、米库氯铵、泮库溴铵与氧化亚氮均引起HR增快;新斯的明和舒更葡糖钠均引起HR减慢,舒更葡糖钠还可导致QT间期延长;高浓度七氟烷引起HR减慢、QTc间期延长与Tp-e/QT比值降低;异氟烷、地氟烷均可引起HR增快、QTc间期延长;氟烷可引起HR减慢、QTc间期延长。     

艾司西酞普兰与氢溴酸西酞普兰治疗抑郁症的对照观察

目的：探讨艾司西酞普兰对抑郁症患者的疗效和安全性。方法：68例符合CCMD-3抑郁发作的门诊患者随机分为艾司西酞普兰组和氢溴酸西酞普兰组，艾司西酞普兰剂量10～20mg·d^-1，氢溴酸西酞普兰20-50mg·d-^1，疗效采用汉密尔顿抑郁量表（HAMD）焦虑量表（HAMA），不良反应和安全性用TESS和实验室检查评定。观察时间为期6周。结果：艾司西酞普兰组有效率70．6％，治愈率47．1％，氢溴酸西酞普兰组有效率61．8％，治愈率41．2％，两组比较差异无显著性。艾司西酞普兰主要不良反应为食欲下降（11．8％）、恶心（8．8％）、头晕（5．9％）、口干（5．9％）等，与氢溴酸西酞普兰无差异。脱落率和失访率各为11．8％和14．7％，无显著差异。结论：艾司西酞普兰治疗抑郁症患者安全有效，疗效与氢溴酸西酞普兰相当，但起效快于氢溴酸西酞普兰。     

药物诱发的QT间期延长和尖端扭转型室性心动过速研究进展

许多药物可引起QT间期延长和尖端扭转型室性心动过速(TdP),导致心源性猝死。引起QT间期延长和TdP的药物包括心血管药物和非心血管药物,其机制与药物阻滞延迟整复钾离子电流的快速部分有关。最近研究表明一些患者应用药物后引起QT间期延长和TdP与基因异常有关。在临床应用中,应熟悉常见引起QT间期延长和TdP的药物,在使用时加强心电图检测。     

药物警戒快讯

美国FDA更新高剂量西酞普兰引起心率异常的安全性信息2011年8月24日,美国食品药品监督管理局(FDA)向医疗专业人员和患者发布信息称,由于有引发心脏电活动异常变化的风险,氢溴酸西酞普兰的剂量不可高于40mg/日。研究结果显示,高于40mg/日的剂量对抑郁症的治疗并不存在更多的效益。     

西酞普兰合并针灸治疗抑郁症的临床效果分析

目的探讨西酞普兰合并针灸治疗抑郁症的临床效果。方法选择我院100例2016年9月至2018年4月抑郁症患者。按照治疗分组,西酞普兰单一治疗组采取西酞普兰治疗,西酞普兰联合针灸治疗组则采取西酞普兰联合针灸治疗。比较两组疗效;抑郁的改善时间;治疗前后患者抑郁的指标评分情况、生活质量情况;不良反应。结果西酞普兰联合针灸治疗组疗效较高,P <0.05;西酞普兰联合针灸治疗组抑郁的改善时间更好,P <0.05;治疗前两组抑郁的指标评分情况、生活质量情况接近,P> 0.05;治疗后西酞普兰联合针灸治疗组抑郁的指标评分情况、生活质量情况改善的程度更大,P <0.05。西酞普兰联合针灸治疗组不良反应和西酞普兰单一治疗组接近,P> 0.05。结论西酞普兰联合针灸治疗抑郁症的疗效好,可更好改善抑郁的指标评分情况、生活质量情况。     

舍曲林与西酞普兰治疗帕金森病合并抑郁的差别的临床研究

目的：研究舍曲林、西酞普兰治疗帕金森病合并抑郁的疗效及安全性。方法帕金森病合并抑郁患者随机分为舍曲林治疗组及西酞普兰治疗组,采用抑郁自评量表（SDS）在治疗前、治疗6周及治疗12周评价疗效。结果西酞普兰组早期起效快于舍曲林组,但12周后有效率无明显差别,两组均未见严重不良反应。结论常规剂量的舍曲林和西酞普兰治疗帕金森病伴发抑郁均安全有效。     

长期应用SSRIs类抗抑郁药对老年抑郁症患者ST-T及QT间期影响的研究

目的了解长期应用SSRIs类抗抑郁药对老年抑郁症患者ST-T及QT间期的影响。方法 256例患者根据药物种类分为帕罗西汀组、西酞普兰及艾司西酞普兰组、盐酸舍曲林和氟伏沙明组。每组均按年龄(50～64岁;≥65岁)分为两组。结果四组药物在不同年龄段不同用药时间ST-T改变,P>0.05,无统计学差异。四组药物在不同年龄段,不同用药时间段均未有QTc≥440 ms病例。结论 SSRIs类抗抑郁药物在老年抑郁症患者中应用相对安全,但也并不是绝对安全,在长期用药过程中还需要定期检查心电图,以调整用药,保证用药安全性。     

Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses

AIMS: To develop a pharmacokinetic-pharmacodynamic model describing the time-course of QT interval prolongation after citalopram overdose and to evaluate the effect of charcoal on the relative risk of developing abnormal QT and heart-rate combinations. METHODS: Plasma concentrations and electrocardiograph (ECG) data from 52 patients after 62 citalopram overdose events were analysed in WinBUGS using a Bayesian approach. The reported doses ranged from 20 to 1700 mg and on 17 of the events a single dose of activated charcoal was administered. The developed pharmacokinetic-pharmacodynamic model was used for predicting the probability of having abnormal combinations of QT-RR, which was assumed to be related to an increased risk for torsade de pointes (TdP). RESULTS: The absolute QT interval was related to the observed heart rate with an estimated individual heart-rate correction factor [alpha = 0.36, between-subject coefficient of variation (CV) = 29%]. The heart-rate corrected QT interval was linearly dependent on the predicted citalopram concentration (slope = 40 ms l mg(-1), between-subject CV = 70%) in a hypothetical effect-compartment (half-life of effect-delay = 1.4 h). The heart-rate corrected QT was predicted to be higher in women than in men and to increase with age. Administration of activated charcoal resulted in a pronounced reduction of the QT prolongation and was shown to reduce the risk of having abnormal combinations of QT-RR by approximately 60% for citalopram doses above 600 mg. CONCLUSION: Citalopram caused a delayed lengthening of the QT interval. Administration of activated charcoal was shown to reduce the risk that the QT interval exceeds a previously defined threshold and therefore is expected to reduce the risk of TdP.     

The role of adenosine receptors and endogenous adenosine in citalopram-induced cardiovascular toxicity

Aim:

We investigated the role of adenosine in citalopram-induced cardiotoxicity.

Materials and Methods:

Protocol 1: Rats were randomized into four groups. Sodium cromoglycate was administered to rats. Citalopram was infused after the 5% dextrose, 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; A₁ receptor antagonist), 8-(-3-chlorostyryl)-caffeine (CSC; A_2a receptor antagonist), or dimethyl sulfoxide (DMSO) administrations. Protocol 2: First group received 5% dextrose intraperitoneally 1 hour prior to citalopram. Other rats were pretreated with erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; inhibitor of adenosine deaminase) and S-(4-Nitrobenzyl)-6-thioinosine (NBTI; inhibitor of facilitated adenosine transport). After pretreatment, group 2 received 5% dextrose and group 3 received citalopram. Adenosine concentrations, mean arterial pressure (MAP), heart rate (HR), QRS duration and QT interval were evaluated.

Results:

In the dextrose group, citalopram infusion caused a significant decrease in MAP and HR and caused a significant prolongation in QRS and QT. DPCPX infusion significantly prevented the prolongation of the QT interval when compared to control. In the second protocol, citalopram infusion did not cause a significant change in plasma adenosine concentrations, but a significant increase observed in EHNA/NBTI groups. In EHNA/NBTI groups, citalopram-induced MAP and HR reductions, QRS and QT prolongations were more significant than the dextrose group.

Conclusions:

Citalopram may lead to QT prolongation by stimulating adenosine A₁ receptors without affecting the release of adenosine.KEY WORDS: Adenosine receptor, citalopram toxicity, endogenous adenosine, QT prolongation, rat     

Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers

1 Sparfloxacin, a new fluoroquinolone, slightly increases the duration of the QT interval. Reverse rate-dependence of QT interval prolongation has been shown for many agents that are known to prolong QT interval duration, and QT prolongation at slow heart rates may be a risk factor for torsades de pointes.
2 A double-blind, randomized, placebo controlled, crossover study was performed in 15 healthy volunteers to determine the effects of single oral doses of sparfloxacin (200 and 400  mg) on the QT interval at various heart rates.
3 12-lead ECGs were recorded at rest and during exercise tests 5  h after sparfloxacin or placebo administration. QT intervals were calculated at predetermined RR intervals (1000, 800, 700, 600, 500 and 400 ms) after individual QT-RR curve fitting.
4 Sparfloxacin at both doses induced prolongation of the QT interval which was around 4% greater than placebo. No significant reverse rate-dependence of QT interval prolongation was observed.
5 Oral administration of sparfloxacin appears unlikely to be associated with marked QT interval prolongation.     

Antipsychotic medications and sudden cardiac death

The objectives of this paper are to: 1) discuss practical aspects of antipsychotic induced QT prolongation, torsades de pointes (TdP) and sudden cardiac death, 2) discuss its possible mechanisms, 3) review data for each antipsychotic medication or class of medications and, 4) present recommendations from the literature. We performed computerized searches of the biomedical literature utilizing MEDLINE and PsycINFO computer databases (1966-2001), and by reviewing bibliographies to identify all pertinent case reports, case series, and formal studies using the following search terms: antipsychotics, sudden cardiac death, and QT prolongation. QT prolongation is a dynamic phenomena affected by various factors (mood, disease states, gender, medication, etc.). Sudden cardiac death attributable to antipsychotic medications seems to occurs in a step-wise fashion beginning with QT prolongation, leading to TdP, which can progress to cardiac arrest. Blocking the rapidly-acting potassium rectifier current appears be the primary mechanism of QT prolongation in drugs known to cause TdP and sudden cardiac death. All antipsychotic medications have been shown to cause QT prolongation, however, the degree to which this occurs and the risk of TdP varies. The risk of sudden cardiac death increases with higher doses of medications, use of phenothiazines or intravenous butyrophenones, and in patients with certain medical illnesses, especially cardiac disease. In order to prevent sudden death from antipsychotic medications, we recommend obtaining screening electrocardiograms in all at-risk patients, follow-up electrocardiograms after the initiation of medication, and using the lowest effective dose of medication. If QT prolongation occurs, the risks and benefits of therapy should be considered and medication adjustments made if warranted.     

Comparative toxicity of citalopram and the newer antidepressants after overdose

OBJECTIVE: To compare the toxicity of citalopram, venlafaxine, mirtazapine, and nefazadone after overdose. METHODS: Two-year retrospective review of consecutive patients admitted to the toxicology unit of Edinburgh Royal Infirmary. Outcome measure included physiological variables, ECG recordings, peak creatine kinase, development of arrhythmias, seizure, tremor or agitation, and the need for admission to a critical care facility. RESULTS: A total of 225 patients were studied. Venlafaxine was associated with a significantly higher pulse rate (p < 0.0001) and tremor (p = 0.007) than other antidepressants. Citalopram was associated with a significantly longer QT interval on ECG recording (p < 0.0001) but mean QTc durations were not significantly different between all drugs studied. No arrhythmias were recorded. Only venlafaxine and citalopram caused seizures and were associated with the need for admission to Intensive Care, but there was no significant difference between them. CONCLUSIONS: Mirtazapine and nefazadone appear safe in overdose and were associated with minimal features of neurological or cardiovascular toxicity. Citalopram is more likely to cause QT prolongation but other features of cardiovascular toxicity were uncommon. Both citalopram and venlafaxine are proconvulsants. Venlafaxine also causes more frequent features of the serotonin syndrome.     

No evidence of QT prolongation with supratherapeutic doses of aleglitazar

Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist in clinical development, designed to offer a balanced activation of PPAR-α and PPAR-γ. A phase 2 trial has demonstrated improvements in dyslipidemia and glycemic control and reduction of cardiovascular risk markers in patients with type 2 diabetes mellitus treated with aleglitazar. This study evaluated whether supratherapeutic doses of aleglitazar affect cardiac repolarization, as detected by changes in the QT interval.Healthy subjects were randomized to receive single oral doses of placebo, 300 μg aleglitazar, 3000 μg aleglitazar, and 400 mg moxifloxacin, in 1 of 4 sequences. Triplicate 12-lead electrocardiogram measurements were recorded predose and regularly (0.75-72 hours) after each treatment. The primary outcome was measurement of QT interval using a study-specific correction factor for heart rate.Administration of aleglitazar (300 μg and 3000 μg) did not cause any significant QT prolongation and after aleglitazar treatment any mean increases from placebo were <5 msec, at all time points. There was a trend for aleglitazar to cause a small dose-dependent decrease in QT interval using a study-specific correction factor for heart rate. The incidence of adverse events was similar with aleglitazar (18%-20%) and placebo (26%).Single supratherapeutic doses of aleglitazar are not associated with prolongation of the QT interval corrected for heart rate.     

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.     

Citalopram overdose: Late presentation of torsades de pointes (TdP) with cardiac arrest

Introduction

Citalopram overdose may produce bradycardia, QT prolongation, and torsades de pointes (TdP). A cardiotoxic metabolite may be responsible for the delayed onset of cardiotoxicity. Although some authorities recommend a minimum of 24 hours of observation following citalopram overdose, a recent analysis suggested that dysrhythmias rarely occur beyond 13 hours post-ingestion. We present a case of citalopram overdose with a substantially delayed onset of cardiac toxicity.

Case Report

A 36-year-old woman complained of shakiness, numbness in the arms, and palpitations that began approximately 32 hours after ingesting 50 (20-mg) tablets of citalopram. Her initial vital signs were: blood pressure, 84/44 mmHg; pulse, 102–150/minute; respirations, 17/min; temperature, 99.3° F (37.3° C). Her initial ECG showed sinus rhythm with a prolonged corrected QT interval (572 msec) with paroxysmal, self-limited runs of wide-complex tachycardia that appeared multifocal in nature. Approximately 20 minutes after presentation, she experienced self-terminating TdP, with transient hypotension and loss of consciousness. Her serum citalopram concentration (33 hours post-ingestion) was 477 ng/mL (therapeutic: 40–110 ng/mL); desmethylcitalopram concentration was 123.2 ng/mL (therapeutic: 14–40 ng/mL). She was treated with magnesium and lidocaine, and her corrected QT interval remained abnormal for 24 hours after presentation.

Discussion

Citalopram overdose can produce life-threatening cardiac toxicity with a clinical onset that may be delayed beyond a routine observation period of 6 hours. Once the QT interval is prolonged, it seems prudent to prolong the observation period.     

Drug- and non-drug-associated QT interval prolongation

Sudden cardiac death is among the most common causes of cardiovascular death in developed countries. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia following repolarization disturbances. An important risk factor for repolarization disturbances is use of QT prolonging drugs, probably partly explained by gene–drug interactions. In this review, we will summarize QT interval physiology, known risk factors for QT prolongation, including drugs and the contribution of pharmacogenetics. The long QT syndrome can be congenital or acquired. The congenital long QT syndrome is caused by mutations in ion channel subunits or regulatory protein coding genes and is a rare monogenic disorder with a mendelian pattern of inheritance. Apart from that, several common genetic variants that are associated with QT interval duration have been identified. Acquired QT prolongation is more prevalent than the congenital form. Several risk factors have been identified with use of QT prolonging drugs as the most frequent cause. Most drugs that prolong the QT interval act by blocking hERG-encoded potassium channels, although some drugs mainly modify sodium channels. Both pharmacodynamic as well as pharmacokinetic mechanisms may be responsible for QT prolongation. Pharmacokinetic interactions often involve drugs that are metabolized by cytochrome P450 enzymes. Pharmacodynamic gene–drug interactions are due to genetic variants that potentiate the QT prolonging effect of drugs. QT prolongation, often due to use of QT prolonging drugs, is a major public health issue. Recently, common genetic variants associated with QT prolongation have been identified. Few pharmacogenetic studies have been performed to establish the genetic background of acquired QT prolongation but additional studies in this newly developing field are warranted.     

Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology

Methadone is used as the pharmacologic mainstay for substitution for illegal opiates and as analgesic for chronic or cancer-related pain. Given the benefits of methadone substitution for illicit opioids, the finding of an association between methadone and prolongation of cardiac depolarization (QT prolongation) and torsades de pointes is of great concern. QT prolongation can occur with many drugs and is a potentially lethal adverse drug reaction, necessitating risk monitoring and therapeutic alternatives in some patients. Recent studies suggest that QT prolongation with methadone is context dependent: occurrence is more frequent with high doses of methadone, concomitant administration of CYP3A4 inhibitors, hypokalemia, hepatic failure, administration of other QT prolonging drugs and pre-existing heart disease. The valued benefit of methadone substitution therapy on the one hand and the increased cardiovascular risk in particular situations on the other illustrate the difficulties in dealing with drug-induced QT prolongation in general.