QT-Interval prolonging drugs: Mechanisms and clinical relevance of their arrhythmogenic hazards

Zehender, Manfred; Hohnloser, Stefan H.; Just, Hanjörg

doi:10.1007/bf03029779

Cited by 76 publications

(33 citation statements)

References 188 publications

(241 reference statements)

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“…Of these, one had right bundle branch block and four were taking other drugs which might affect QT interval (dothiepin, imipramine, thioridazine, sotalol), the doses of which were not altered during the study, and five had cardiovascular disease (cerebrovascular disease (three), coronary artery disease (one), and hypertension (one)). Electrocardiograms of two patients receiving terodiline were collected after only 8 made when patients were not receiving treatment. There was a positive correlation between absolute values of QTc and QTd in patients receiving terodiline (r = 0 70, P < 0 005) and between terodiline induced increases in QTc and QTd (r = 0-88, P < 0O001).…”

Section: Discussionmentioning

confidence: 99%

Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence.

Thomas¹,

Higham²,

Hartigan-Go³

et al. 1995

Heart

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Objective-Terodiline, an antimuscarinic and calcium antagonist drug, was used to treat detrusor instability but was withdrawn in 1991 after provoking serious ventricular arrhythmias associated with increases in the corrected QT interval (QTc). This research was performed to relate drug induced electrocardiographic changes in asymptomatic recipients to plasma concentrations of the R( +) and S(-) terodiline enantiomers. (443 (33) and 42 (17) ms'12, paired t tests, P < 0-002 and P < 0 01 respectively) in the 12 patients in sinus rhythm. The mean (95% confidence interval) drug induced increases were 48 (23 to 74) Ms112 for QTc and 42 (13 to 70) ms'12 for QTd. These increases correlated with total plasma terodiline (QTc: r = 0-77, P < 0-006, QTd: r = 0*68, P < 0.025) and with plasma concentrations of both terodiline enantiomers.Conclusions-Terodiline increases QTc and QTd in a concentration dependent manner. It is not clear whether this is a stereoselective effect and, if so, which enantiomer is responsible. The results suggest that drug induced torsade de pointes is a type A (concentration dependent) adverse drug reaction. (Br HeartJ7 1995;74:53-56)

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Section: Discussionmentioning

confidence: 99%

Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence.

Thomas¹,

Higham²,

Hartigan-Go³

et al. 1995

Heart

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“…[14][15][16] Male Japanese white rabbits weighing 2.0 to 2.5 kg were anesthetized with intravenous pentobarbital sodium (40 mg/kg). The free running Purkinje fibers, right ventricular free wall, left atrium, and right atrial tissue including sinoatrial node region were quickly dissected from the hearts and placed in an organ bath containing modified physiological salt solution of the following composition (mM): NaCl 135, KCl 5, CaCl 2 2, MgCl 2 1, NaHCO 3 15, and glucose 5.5 (gassed with 95% O 2 /5% CO 2 , pH 7.4, 37°C). Purkinje fibers, right ventricular muscles, and left atria were driven by external electrical stimulation with bipolar platinum electrodes and rectangular current pulses (5-ms duration, about 1.2ϫthreshold strength) at a constant frequency (1 Hz) generated by an electronic stimulator (Nihon Kohden, SEN-3201).…”

Section: Microelectrode Recording Of Action Potential Configurationmentioning

confidence: 99%

Lack of Action Potential-Prolonging Effect of Terfenadine on Rabbit Myocardial Tissue Preparations

Masumiya

Saito

Ito

et al. 2004

Biological & Pharmaceutical Bulletin

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It is well recognized that both cardiovascular and noncardiovascular drugs may promote arrhythmia.1) Clinical treatment with class I and class III antiarrhythmic agents as well as non-cardiovascular drugs such as terfenadine, cisapride, and haloperidol has been associated with QT prolongation and serious ventricular arrhythmia including torsades de pointes.2-6) Studies with animal myocardium have demonstrated that these drugs are able to prolong action potential duration (APD) through inhibition of the rapid component of the delayed rectifier potassium current (IKr). 2,7,8) Since then, the assessment of the risks incurred with noncardiovascular therapeutic agents for cardiac function has received great attention. Some researchers and organizations have postulated that analysis of APD in rabbit Purkinje fibers is the most adequate method for evaluation.9) This appeared reasonable because rabbit Purkinje fibers had been shown to be highly sensitive to drugs with APD-prolonging activity.

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“…It ranges from 0.5% when atrial fibrillation is treated to 4% in high-dose conversion therapy of atrial fibrillation and up to 2&28% in the treatment of malignant forms of ventriculararrhythrmas. 12 In the two cases described, high-dosed quinidine therapy was administered. Conspicuous in contrast to earlier statements in the literature is the Occurrence of torsade de pointes associated with a drop in heart rate and an abrupt prolongation of QT at the time of conversion to sinus rhythm.…”

Section: Case No Andtherapy With Amiodmne (Class Iii)mentioning

confidence: 99%

Torsade de pointes complicating drug treatment of low‐malignant forms of arrhythmia: Four case reports

Faber

Zehender

Loo

et al. 1994

Clinical Cardiology

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Summary:In patients with malignant ventricular arrhythmias, antiarrhythniic therapy is known to c x y a substantial risk of proarrhythmia. This risk is usually considered to be low when supraventricular arrhythmias or benign ventricular arrhythmias are considered. We were able to collect data on four patients without a history of life-threatening arrhythmias. in whom witiarrhythmic therapy was used and resulted in documented ventriculx fibrillation or torsade de pointes. In Cases No. 1 and 2.amal fibrillation was treated with either quinidine or quinidine and sotalol in combination. In both patients Holter monitoring, 4-I2 h :]tier conversion to sinus rhythm, documented the spmtaneous Occurrence of toixade de pointes degenerating into ventriculm fibrillation and requiring DC shock for termination. In Case No. 3, atrial fibrillation was treated with sotalol and amiodarone for 2 months when incessant episodes of torsade de pointes were documented. In Case No. 4, frequent but unsustained ventricular arrhythmias were treated with amiodarone in a patient sutfering dilative cardiomyopathy. After 6 days of treatment at a hem rate of 54 beats/inin, a mdrked QT increase was associated with the occurrence of repetitive episodes of polymorphic ventricular tachycardia degenerating into ventricular fibrillalion. None of the patients presented significant electrolyte abnormalities in the laboratory. A pathologic increase of' the QTc-lime was documented in Cases No. 1,3, and 4. In all pati en r s an ti m h yt hmic therapy was withdrawn after the proarrhythmic event and the patient became free of malignant tachyan-hythnuas. Antiarrhythmic therapy also carries a considerable risk of proarrhythmia when "benign" cardiac mhythtnias are treated. The risk seems to be lower than in patients with malignant arrhythmias, however it includes the occurrence of lethal tachyarrhythmias. Special attention should be paid to the selection ofantiarrhythmic agents when used in combination.

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QT-Interval prolonging drugs: Mechanisms and clinical relevance of their arrhythmogenic hazards

Cited by 76 publications

References 188 publications

Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence.

Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence.

Lack of Action Potential-Prolonging Effect of Terfenadine on Rabbit Myocardial Tissue Preparations

Torsade de pointes complicating drug treatment of low‐malignant forms of arrhythmia: Four case reports

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