Description
Tizanidine is a centrally-acting muscle relaxant useful in the treatment of muscle
spasms and a variety of spastic conditions.
Originator
Sandoz (Switzerland)
Uses
Labeled Tizanidine, intended for use as an internal standard for the quantification of Tizanidine by GC- or LC-mass spectrometry.
Uses
Tizanidine could have therapeutic use as a SARS-CoV-2 main protease inhibitor.
Definition
ChEBI: 2,1,3-Benzothiadiazole substituted at C-4 by a Delta1-imidazolin-2-ylamino group and at C-4 by a chloro group. It is an agonist at alpha2-adrenergic receptor sites.
Manufacturing Process
14 ml of benzoyl chloride are added to a solution of 11.5 g of ammonium
thiocyanate in 150 ml of acetone in an ice bath and the mixture is then stirred
for 10 min. This solution is heated to the boil at reflux together with 19 g of
4-amino-5-chloro-2,1,3-benzothiadiazole. The solution is cooled to room
temperature and diluted with a 4-fold quantity of water. The precipitate is
filtered off and rapidly brought to a boil together with 150 ml of a 2 N
aqueous sodium hydroxide solution and kept at the boil for 5 min. The
solution is cooled to room temperature, is acidified weakly with glacial acetic
acid, the precipitate is filtered off, washed with ether and recrystallized from
methanol. The N-(5-chloro-2,1,3-benzothiadiazol-4-yl)thiourea, obtained and
this is boiled for 1 h together with 9 g of methyl iodide in 150 ml of methanol.
After concentrating by evaporation, crude S-methyl-N-(5-chloro-2,1,3-
benzothiadiazol-4-yl)isothiuronium iodide is obtained. 9.8 g of S-methyl-N-(5-
chloro-2,1,3-benzothiadiazol-4-yl)isothiuronium iodide are heated to the boil
at reflux for 1 h together with 50 ml of methanol and 1.8 ml of ethylene
diamine. The solvent is then removed by evaporation and the moist residue is
boiled at reflux for 1 h together with 20 ml of n-amyl alcohol. The mixture is
subsequently shaken with 50 ml of chloroform and 150 ml of water until all
the material is dissolved. 40 ml of a 2 N aqueous sodium hydroxide solution
are added to the aqueous phase and extraction is effected with 200 ml of
chloroform. The organic phase is dried and concentrated by evaporation. After
recrystallizing the residue from methanol with the addition of some active
charcoal, 4-(2-imidazolin-2-yl-amino)-5-chloro-2,1,3-benzothiadiazole, having a melting point of 221-223°C, is obtained.
The 4-(2-imidazolin-2-yl-amino)-5-chloro-2,1,3-benzothiadiazole hydrochloride
may be obtained by the teaction of 4-(2-imidazolin-2-yl-amino)-5-chloro-
2,1,3-benzothiadiazole with hydrochloric acid.
Therapeutic Function
Muscle relaxant, Spasmolytic
Mechanism of action
Tizanidine is a centrally active muscle relaxant analogue of clonidine that is approved for use in reducing spasticity associated with cerebral or spinal cord
injury. Its mechanism of action for reducing spasticity suggests presynaptic inhibition of motor neurons at the α2-adrenergic receptor sites, reducing the release of
excitatory amino acids and inhibiting facilitatory ceruleospinal pathways, thus resulting in a reduction in spasticity. Tizanidine only has a small fraction of the
antihypertensive action of clonidine, presumably because of action at a selective subgroup of α2C-adrenoceptors, which appear to be responsible for the analgesic and
antispasmodic activity of imidazoline α2-agonists(20).
Clinical Use
Tizanidine is a centrally acting adrenergic α2 receptor agonist used to treat chronic muscle
spasticity conditions, such as multiple sclerosis.
Side effects
Postulated mechanisms include α2 receptor-mediated decreased release of norepinephrine and
serotonin from spinal interneurons. Tizanidine is structurally related to the α2 agonist
clonidine that is used to treat hypertension; however, the blood pressure–lowering potency of
tizanidine is approximately 10 to 20% that of clonidine. Nevertheless, patients may experience
hypotension with tizanidine, together with muscle weakness, that may result in dizziness and falls
in mobile patients. Tizanidine is rapidly and almost completely absorbed from the gastrointestinal
tract; however, the estimated bioavailability is only 10 to 15% because of extensive first-pass
metabolism, mainly by CYP1A2, which results in oxidative degradation of the imidazoline ring
and hydroxylation of the aromatic system. Elevated liver enzyme values are not frequent
with tizanidine use. Hepatic injury and death because of liver failure have been reported,
however, and this complication should be considered in view of its marginal antispasmodic
efficacy. Other frequently reported side effects of tizanidine are drowsiness and dry
mouth. Clonidine also has been used to treat spasticity; however, even less high-quality clinical
study data are available for this agent.
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: enhanced muscle relaxant effect
with procainamide.
Antibacterials: concentration increased by
ciprofloxacin - avoid; concentration possibly
increased by norfloxacin; concentration possibly
reduced by rifampicin.
Antidepressants: concentration increased by
fluvoxamine - avoid.
Antihypertensives: enhanced hypotensive effect.
Oral contraceptives: clearance of tizanidine reduced
by 50
%.
Metabolism
Tizanidine undergoes rapid and extensive first pass metabolism in the liver mainly via the cytochrome P450 isoenzyme CYP1A2. The metabolites (mainly inactive) constitute 70
% of the administered dose and are excreted via the renal route.
