title: Tizanidine (Zanaflex): a muscle relaxant that may prolong the QT interval by blocking IKr.
abstract: BACKGROUND
  Tizanidine (Zanaflex) is a centrally acting imidazoline muscle relaxant that is structurally similar to clonidine (α(2)-adrenergic agonist) but not to other myorelaxants such as baclofen or benzodiazepines. Interestingly, cardiac arrhythmias and QT interval prolongation have been reported with tizanidine.
  
  
  OBJECTIVE
  To evaluate the effects of tizanidine on cardiac ventricular repolarization.
  
  
  METHODS
  (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 (I(Kr)) and slow (I(Ks)) 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 (MAPD(90)). (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.
  
  
  RESULTS
  (1) Patch-clamp experiments revealed an estimated IC(50) for tizanidine on I(Kr) above 100 µmol/L. Moreover, tizanidine 1 µmol/L had hardly any effect on I(Ks) (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 MAPD(90) 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.
  
  
  CONCLUSIONS
  Tizanidine prolongs the QT interval by blocking I(Kr). Patients could be at risk of cardiac proarrhythmia during impaired drug elimination, such as in case of CYP1A2 inhibition during drug interactions.
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC Canada.
authors.forename: Nisrin
authors.initials: N
authors.lastname: Kaddar
authors.forename: Patrick
authors.initials: P
authors.lastname: Vigneault
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pilote
authors.forename: Dany
authors.initials: D
authors.lastname: Patoine
authors.forename: Chantale
authors.initials: C
authors.lastname: Simard
authors.forename: Benoit
authors.initials: B
authors.lastname: Drolet
mesh_terms: D000818:Animals; D016466:CHO Cells; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D057809:HEK293 Cells; D006321:Heart; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology* / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000633:toxicity; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D009125:Muscle Relaxants, Central; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C023754:tizanidine; D003000:Clonidine