© 2001 European Society of Cardiology
Torsades de pointes caused by Mibefradil
Unfallkrankenhaus Berlin, Department of Internal Medicine Warener Strasse 7, D-12683 Berlin, Germany
* Corresponding author. Tel.: +49-30-5681-3601; fax: +49-30-5681-3603. E-mail address: franz-xaverk{at}ukb.de (F.X. Kleber)
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Abstract |
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 Top Abstract 1. Introduction2. Case report3. DiscussionReferences |
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We report a case of symptomatic Torsades de pointes due to QTc prolongation by Mibefradil, which potentially explains unexpected deaths related to this drug. Multiple episodes of Torsades de pointes were documented in a 76-year-old woman with significant QTc prolongation of 0.53 s. After discontinuation of Mibefradil QTc intervals normalized and no further ventricular tachyarrythmias were observed. We conclude that Mibefradil can cause QTc prolongation and life threatening ventricular dysrhythmias.
Key Words: Mibefradil • Calcium channel blocker • Torsades de pointes • Ventricular tachycardias
Received February 2, 2001; Revised February 2, 2001; Accepted April 26, 2001
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1. Introduction |
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TopAbstract1. Introduction2. Case report3. DiscussionReferences |
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In early June 1998 Mibefradil was withdrawn from the market, approximately 1 year after it had been approved in Europe and the US. The withdrawal was due to reports of multiple interactions with other drugs. However, no causal links to deaths have been established.
The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs and its clinical and regulatory implications has been highlighted by a policy conference of the European Society of Cardiology in June 1999 [1]. Mibefradil primarily acts by blocking T-type calcium channels, and considerably less of L-type channels. It was available for treatment of chronic stable angina pectoris and hypertension. Despite case reports of induced bradyarrythmias under Mibefradil, no reports documenting significant ventricular tachyarrythmias have been published.
We report a case with symptomatic Torsades de pointes due to QTc prolongation by Mibefradil, which potentially explains unexpected deaths on this drug.
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2. Case report |
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TopAbstract1. Introduction2. Case report3. DiscussionReferences |
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A 76-year-old woman was admitted to the emergency room from another hospital where she was admitted one day earlier with complete AV block following a syncope. Prior history revealed arterial hypertension, gout and varicosis for more than 10 years.
On admission we saw a woman (158 cm, 91 kg) with bilateral peripheral pitching oedema, low-grade mesosystolic crescendo–decrescendo murmur in the third left intercostal space, blood pressure of 130/56 mmHg and a regular bradycardia (45 bpm).
She was on Digitoxin 0.07 mg qid, Captopril 12.5 mg bid, Mibefradil 50 mg qid, Allopurinol 300 mg qid, Spironolacton 50 mg bid, and Furosemide 20 mg bid. The Mibefradil medication had been initiated 6 months earlier. Digitoxin and Mibefradil were stopped on admission.
Chest X-ray was inconspicuous except bilateral accentuated pulmonary vascular appearance.
Results of laboratory studies on admission showed a potassium of 4.2 mmol/l, sodium 142 mmol/l, calcium 2.58 mmol/l, creatinin 100 µmol/l, glucose 8.5 mmol/l, white blood cells 16.5 Gpt/l, hemoglobin 8.2 mmol/l, platelets 310 Gpt/l, TSH 0.96 mU/l, and Digitoxin 8.4 µg/l (normal range 13–25 µg/l). The magnesium level was not determined.
Echocardiography showed normal atrial and ventricular diameters, left ventricular hypertrophy (interventricular septum=12 mm, left ventricular wall thickness=12 mm) and unimpaired left ventricular systolic function (ejection fraction=85%). At the aortic valve, a mean gradient of 30 mmHg and thickening of the leaflets with mild regurgitation were described.
Non-invasive results were confirmed by cardiac catheterization. A mild coronary disease with stenoses not exceeding 50% was found. Mean pulmonary artery pressure was 20 mmHg, left ventricular ejection fraction was normal (73%) and left ventricular end-diastolic pressure was elevated to 21 mmHg.
ECG studies, 2 years prior to admission, showed sinus rhythm with a heart rate of 73 bpm, PQ interval of 0.157 s, QRS interval of 0.1 s and QTc interval of 0.43 s.
Seven months prior to admission, Holter monitoring revealed sinus rhythm (heart rate 63 bpm) and ventricular arrhythmia (LOWN IVa). Electrocardiography on admission showed a heart rate of 41 bpm, third degree AV block, right bundle branch block, QT interval 0.62 s, a QTc interval 0.53 s and negative T waves V1–V4 (see Fig. 2). The ECG, 24 h after admission, showed a QTc interval of 0.52 s. The further course of QTc interval normalization is documented in Fig. 1.
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Multiple episodes of Torsades de pointes were documented in the first 24 h after hospitalization. The longest one lasted for 25 beats (Fig. 3). Torsades de pointes tachycardias were not seen later than 24 h after the last drug ingestion, but short runs of non-sustained VTs of 5 beats persisted for several days (see Fig. 3). Ten days after admission persistent third degree AV block, 5 couplets and few bigemini, but no VTs were found. The symptomatic bradycardia of 40–50 bpm was persistant.
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Fourteen days after admission, a DDD pacemaker was implanted for treatment of symptomatic bradycardia. Five days later the patient was discharged without any cardiac complaints.
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3. Discussion |
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TopAbstract1. Introduction2. Case report3. DiscussionReferences |
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Due to various drug interactions, Roche Pharma withdrew Mibefradil from the market on 8 June 1998. Interactions were mainly described for drugs interfering with cytochrom P 450 3A4 oxidation [2].
Mibefradil has been reported to cause changes in the appearance of T and U waves, involving a decrease in amplitude of the T wave and increased amplitude of the U wave [3], sinus bradycardia in 3–14% of patients and first degree AV block in 0–12% of patients [4–6]. Severe AV node suppression with consecutive bradycardia was reported in 36 cases [3], mostly occurring in elderly patients taking concomitant β-blocker therapy. Only a few cases with second degree AV block, usually appearing as a Wenckebach rhythm, were reported. A single case with third degree AV block was observed in a patient taking 150 mg [7]. There were no reports of significant ventricular arrhythmia.
Our patient showed symptomatic Torsades de pointes and a relevant QTc prolongation. QTc prolongation with Mibefradil has not been reported so far. One group reported shortened action potential duration by blocking T-type channels and QTc interval decrease [3].
Mibefradil at supratherapeutic concentrations induces a sustained increase of cytosolic Ca2+ in cultured rat cardiac fibroblasts and human platelets [8]. As a consequence of raising cytoplasmatic Ca2+, spontaneous mechanical and electrical oscillations occur, which can lead to arrhythmias through the development of delayed post-depolarisation and triggered activity.
Experimental studies on cloned cardiac cells showed sufficient blockage of HERG and KvLQT1/IsK potassium channels at therapeutic concentrations of Mibefradil comparable with effects caused by Verapamil (HERG) and Bepridil (HERG and KvLQT1/IsK) [9,10]. These effects might cause or contribute to prolongation of QTc interval and ventricular arrhythmia.
In our case the presence of bradycardia, complete heart block, right bundle branch block, left ventricular hypertrophy and female sex are significant factors modulating repolarization and increasing the risk of ventricular arrhythmia [1]. The normalization of the QTc interval and the disappearance of Torsade de pointes tachycardias following the discontinuation of Mibefradil, demonstrate that Mibefradil probably contributes significantly to this life-threatening ventricular tachyarrhythmia. In view of the persistence of the complete heart block after Mibefradil discontinuation, this arrhythmia must be determined as spontaneous.
We conclude that Mibefradil, under unfavorable circumstances, can cause QTc prolongation and life threatening ventricular dysrhythmias.
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References |
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TopAbstract1. Introduction2. Case report3. DiscussionReferences |
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- Haverkamp W., Breithardt A., Camm A.J., et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Eur Heart J (2000) 21:1216–1231.
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- Eberhard M., Miyagawa K., Hermsmeyer K., Erne P. Effects of mibefradil on intracellular Ca2+ release in cultured rat cardiac fibroblasts and human platelets. Naunyn Schmiedebergs Arch Pharmacol (1995) 353(1):94–101.[Web of Science][Medline]
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[Abstract/Free Full Text] - Chouabe C., Drici M.-D., Romey G., Barhanin J. Effects of calcium channel blockers on cloned cardiac K+ channels Ikr and Iks. Therapie (2000) 55:195–202.[Web of Science][Medline]
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