Tizanidine (Zanaflex): A Muscle Relaxant That May Prolong the QT Interval by Blocking IKr

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Tizanidine (Zanaflex) is a centrally acting imidazoline muscle relaxant that is structurally similar to clonidine (α2-adrenergic agonist) but not to other myorelaxants such as baclofen or benzodiazepines. Interestingly, cardiac arrhythmias and QT interval prolongation have been reported with tizanidine.


To evaluate the effects of tizanidine on cardiac ventricular repolarization.


(1) Whole-cell patch-clamp experiments: HERG- or KCNQ1+KCNE1-transfected cells were exposed to tizanidine 0.1-100 μmol/L (n = 29 cells, total) to assess drug effect on the rapid (IKr) and slow (IKs) components of the delayed rectifier potassium current. (2) Langendorff retroperfusion experiments: isolated hearts from male Hartley guinea pigs (n = 6) were exposed to tizanidine 1 μmol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD90). (3) In vivo wireless cardiac telemetry experiments: guinea pigs (n = 6) implanted with radio transmitters were injected a single intraperitoneal (ip) dose of tizanidine 0.25 mg/kg and 24 hours electrocardiography (ECG) recordings were made.


(1) Patch-clamp experiments revealed an estimated IC50 for tizanidine on IKr above 100 μmol/L Moreover, tizanidine 1 μmol/L had hardly any effect on IKs (5.23% ± 4.54% inhibition, n = 5 cells). (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, tizanidine 1 μmol/L prolonged MAPD90 by 8.22 ± 2.03 (6.7%) and 11.70 ± 3.08 ms (8.5%), respectively (both P < .05 vs baseline). (3) Tizanidine 0.25 mg/kg ip caused a maximal 11.93 ± 1.49 ms prolongation of corrected QT interval (QTc), 90 minutes after injection.


Tizanidine prolongs the QT interval by blocking IKr. Patients could be at risk of cardiac proarrhythmia during impaired drug elimination, such as in case of CYP1A2 inhibition during drug interactions.

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