Chemical formula: C₉H₈ClN₅S Molecular mass: 253.711 g/mol PubChem compound: 5487
Tizanidine is a centrally acting skeletal muscle relaxant. Its principal site of action is the spinal cord, where the evidence suggests that, by stimulating presynaptic alpha2-receptors, it inhibits the release of excitatory aminoacids that stimulate N-methyl-D-aspartate (NMDA) receptors. Polysynaptic signal transmission at spinal interneuron level, which is responsible for excessive muscle tone, is thus inhibited and muscle tone reduced.
Tizanidine has no direct effect on skeletal muscle, the neuromuscular junction or on monosynaptic spinal reflexes. In addition to its muscle-relaxant properties, tizanidine also exerts a moderate central analgesic effect. In humans, tizanidine reduces pathologically increased muscle tone, including resistance to passive movements and alleviates painful spasms and clonus.
Tizanidine is rapidly absorbed, reaching peak plasma concentration in approximately 1 hour after dosing.
Tizanidine is only about 30% bound to plasma proteins and, in animal studies, was found to readily cross the bloodbrain barrier. Mean steady-state volume of distribution (VSS) following i.v. administration is 2.6 L/kg.
Although tizanidine is well absorbed, first pass metabolism limits plasma availability to 34% of that of an intravenous dose. Tizanidine undergoes rapid and extensive metabolism in the liver. Tizanidine is mainly metabolized by cytochrome P450 1A2 in vitro.
The metabolites are primarily excreted via the renal route (approximately 70% of the administered dose) and appear to be inactive. Renal excretion of the parent compound is approximately 53% after a single 5 mg dose and 66% after dosing with 4 mg three times daily. The elimination half-life of tizanidine from plasma is 2-4 hours in patients.
Tizanidine has linear pharmacokinetics over the dose range 4 to 20 mg. The low intraindividual variation in pharmacokinetic parameters (Cmax and AUC) enables reliable prediction of plasma levels following oral administration.
The pharmacokinetic parameters of tizanidine are not affected by gender. In patients with renal insufficiency (creatinine clearance <25 mL/min), maximal mean plasma levels were found to be twice as high as in normal volunteers, and the terminal half-life was prolonged to approximately 14 hours, resulting in much higher (approximately 6-fold on average) AUC values.
Concomitant food intake has no clinically significant influence on the pharmacokinetic profile of tizanidine tablets.
Tizanidine possesses a low order of acute toxicity. Sign s o f overdose were seen after single dose s >40 m g/kg in animals and are related to the pharmacological action of the substance.
The toxic effects of tizanidine are mainly related to its pharmacological action. At doses of 24 and 40 m g/kg per day in subchronic and chronic rodent studies, the α2-agonist effects resulted in central nervous system stimulation, e.g. motor excitation, aggressiveness, tremor and convulsions.
Signs related to centrally mediated muscle relaxation, e.g. sedation and ataxia, were frequently observed at lower dose levels in subchronic and chronic oral studies with dogs. Such signs, related to the myotonolytic activity of the substance, were noted at 1 to 4 m g/kg per day in a 13-week dog study, and at 1.5 m g/kg per day in a 52-week dog study.
Prolongation of the QT interval and bradycardia were noted in chronic toxicity studies in dogs at doses of 1.0 m g/kg per day and above.
Retinal atrophy and corneal opacity have been observed in chronic toxicity studies in the rat. The no observed adverse effect load in the rat was below 1 m g/kg/day.
Slight increases in hepatic serum transaminases were observed in a number of toxicity studies at higher dose levels. They were not consistently associated with histopathological changes in the liver.
Various in vitro assays as well as in vivo assays produced no evidence of mutagenic potential of tizanidine.
No evidence for carcinogenicity was demonstrated in two long-term dietary studies in mice (78 weeks) and rats (104 weeks), at dose levels up to 9 m g/kg per day in rats and up to 16 m g/kg per day in mice. At these dose levels, corresponding to the maximum tolerated dose, based on reductions in growth rate, no neoplastic or pre-neoplastic pathology, attributable to treatment, was observed.
No embryo toxicity or teratogenicity occurred in pregnant rats and rabbits at dose levels up to 30 m g/kg per day of tizanidine. However, doses of 10-100 m g/kg per day in rats were maternally toxic and resulted in developmental retardation of foetuses as seen by lower foetal body weights and retarded skeletal ossification.
In female rats, treated prior to mating through lactation or during late pregnancy until weaning of the young, a dose-dependent (1 0 and 3 0 mg/kg per day) prolongation of gestation time and dystocia occurred, resulting in an increased foetal mortality and delayed development. These effects were attributed to the pharmacological effect of tizanidine. No developmental effects occurred at 3mg/kg per day although sedation was induced in the treated dams.
Passage of tizanidine and/or its metabolites in to milk of rodents is known to occur.
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