Tizanidine

253.71

253.71

610-648-1

6AI06C00GW

DTXSID9023679

M03BX02|M - Musculo-skeletal system

2934999090

90.4

1.4

white solid

1.82 g/cm3

221-223 °C

391.2ºC at 760 mmHg

190.4ºC

H2O: ~29 mg/mL

This product should be stored at room temperature. It should be kept in a tightly closed container.

LD50 orally in mice: 235 mg/kg (Sayers)

7.48None

7.48

149.4 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

3

22-36/37/38

26-36

DK9910000

Xn

This material is stable if stored as directed.

|Warning|H302+H332 (66.67%): Harmful if swallowed or if inhaled [Warning Acute toxicity, oral; acute toxicity, inhalation]|P201, P202, P261, P264, P270, P271, P281, P301+P312, P304+P312, P304+P340, P308+P313, P312, P330, P405, and P501|Aggregated GHS information provided by 3 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

**LD50 information** Oral LD50 (rat): 414 mg/kg; Subcutaneous LD50 (rat): 282 mg/kg; Oral LD50 (mouse): 235 mg/kg [MSDS] **Use in pregnancy** Animal studies have determined that this drug causes fetal harm. Studies have not been performed in humans, and it is advisable to ensure that tizanidine use in pregnant women should be reserved for cases in which possible benefit clearly outweighs the possible risk to mother and unborn child. **Use in breastfeeding** In studies of rat models, this tizanidine was found excreted in the breastmilk with a milk-to-blood ratio of 1.8:1. In young nursing rats, abnormal results were obtained in tests indicative of central nervous system function. Various developmental changes that may have been attributable to the drug were observed. It is unknown whether tizanidine is excreted in human milk. It is a lipid-soluble drug, however, and likely to be excreted into breast milk. **Carcinogenesis and mutagenesis** No signs of carcinogenicity were observed in two dietary studies performed in rodent models. Tizanidine was given to mice for 78 weeks at doses reaching a maximum 16 mg/kg (equivalent to twice the maximum recommended human dose). In addition, the drug was given to rats for 104 weeks at doses reaching 9 mg/kg (equivalent to 2.5 times the maximum recommended human dose). There was a lack of a statistically significant increase in the occurrence of tumors in either study group. Tizanidine was not found to be mutagenic or clastogenic in several laboratory essays, including the bacterial Ames test, the mammalian gene mutation test, in addition to the chromosomal aberration test in Chinese hamster cells and several other assays.

Transient and asymptomatic elevations in serum ALT greater than 3 times the upper limit of normal occur in ~5% of patients taking tizanidine compared to 0.4% of subjects on placebo. Reports of severe hepatotoxicity, acute liver failure and death have been mentioned in review articles on tizanidine, but few case reports have been published. In these reports, the latency to onset of jaundice has ranged from 2 to 14 weeks and the enzyme elevations have been both cholestatic and hepatocellular (Case 1). Immunoallergic and autoimmune features have not been mentioned. Recovery was complete after 1 to 2 months.

About 30% bound to plasma proteins.

Tizanidine is indicated for the relief of muscle spasticity, which can interfere with daily activities. The general recommendation is to reserve tizanidine use for periods of time when there is a particular need for relief, as it has a short duration of action.|FDA Label

Tizanidine is a commonly used muscle relaxant that has been linked to rare instances of acute liver injury, a few of which have been fatal.

Autonomic Agents: Muscle Relaxants, Central

**A note on spasticity** Spasticity is an increase in muscle accompanied by uncontrolled, repetitive contractions of skeletal muscles which are involuntary. The patient suffering from muscle spasticity may have reduced mobility and high levels of pain, contributing to poor quality of life and problems performing activities of personal hygiene and care. **General effects** Tizanidine is a rapidly acting drug used for the relief of muscle spasticity when it is required for performing specific activities. It acts as an agonist at Alpha-2 adrenergic receptor sites and relieves symptoms of muscle spasticity, allowing the continuation of normal daily activities. In animal models, tizanidine has not been shown to exert direct effects on skeletal muscle fibers or the neuromuscular junction, and has shown no significant effect on monosynaptic spinal reflexes (consisting of the communication between only 1 sensory neuron and 1 motor neuron). The frequency of muscle spasm and clonus are shown to be decreased by tizanidine. Tizanidine shows a stronger action on polysynaptic reflexes, which involve several interneurons (relay neurons) communicating with motor neurons stimulating muscle movement. **Effects on blood pressure and heart rate** This drug decreases heart rate and blood pressure in humans. Despite this, rebound hypertension and tachycardia along with increased spasticity can occur when tizanidine is abruptly discontinued.

Compounds capable of relieving pain without the loss of CONSCIOUSNESS. (See all compounds classified as Analgesics.)|Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)|Agents that inhibit the actions of the parasympathetic nervous system. The major group of drugs used therapeutically for this purpose is the MUSCARINIC ANTAGONISTS. (See all compounds classified as Parasympatholytics.)|Compounds that bind to and activate ADRENERGIC ALPHA-2 RECEPTORS. (See all compounds classified as Adrenergic alpha-2 Receptor Agonists.)|A heterogeneous group of drugs used to produce muscle relaxation, excepting the neuromuscular blocking agents. They have their primary clinical and therapeutic uses in the treatment of muscle spasm and immobility associated with strains, sprains, and injuries of the back and, to a lesser degree, injuries to the neck. They have been used also for the treatment of a variety of clinical conditions that have in common only the presence of skeletal muscle hyperactivity, for example, the muscle spasms that can occur in MULTIPLE SCLEROSIS. (From Smith and Reynard, Textbook of Pharmacology, 1991, p358) (See all compounds classified as Muscle Relaxants, Central.)

This drug undergoes significant first-pass metabolism. After the administration of an oral dose, tizanidine is mostly absorbed. The absolute oral bioavailability of tizanidine is measured to be about 40%. **Effect of food on absorption** Food has been shown to increase absorption for both the tablets and capsules. The increase in absorption with the tablet (about 30%) was noticeably higher than the capsule (~10%). When the capsule and tablet were administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. It is therefore advisable to take this drug with food for increased absorption, especially in tablet form.|This drug is mainly eliminated by the kidney.|Extensively distributed throughout the body. The average steady-state volume of distribution is 2.4 L/kg.|**A note on renal impairment** Tizanidine clearance is found to be decreased by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. This drug should be used with caution in patients with renal impairment.

About 95% of the ingested dose of tizanidine is metabolized. The main enzyme involved in the hepatic metabolism of tizanidine is CYP1A2.|Tizanidine has known human metabolites that include 2-[(5-chloro-2,1,3-benzothiadiazol-4-yl)amino]-4,5-dihydro-1H-imidazol-4-ol.

Approximately 2.5 hours.

Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites. This drug is centrally acting and leads to a reduction in the release of excitatory amino acids like glutamate and aspartate, which cause neuronal firing that leads to muscle spasm. The above reduction and excitatory neurotransmitter release results in presynaptic inhibition of motor neurons. The strongest effect of tizanidine has been shown to occur on spinal polysynaptic pathways. The anti-nociceptive and anticonvulsant activities of tizanidine may also be attributed to agonist action on Alpha-2 receptors. Tizanidine also binds with weaker affinity to the Alpha-1 receptors, explaining its slight and temporary effect on the cardiovascular system.

5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiadiazole

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients