Pharmacology
DrugBankDescription
Tizanidine is a fast-acting drug used for the management of muscle spasm, which may result from the effects of multiple sclerosis, stroke, an acquired brain injury, or a spinal cord injury . It may also be caused by musculoskeletal injury . Regardless of the cause, muscle spasticity can be an extremely painful and debilitating condition. Initially approved by the FDA in 1996, tizanidine is an Alpha-2 adrenergic receptor agonist reducing spasticity by the presynaptic inhibition of excitatory neurotransmitters that cause firing of neurons promoting muscle spasm .
Mechanism of Action
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 .
Pharmacodynamics
**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 .
Metabolism
About 95% of the ingested dose of tizanidine is metabolized. The main enzyme involved in the hepatic metabolism of tizanidine is CYP1A2 .
Absorption
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.
Toxicity
**LD50 information** Oral LD50 (rat): 414 mg/kg; Subcutaneous LD50 (rat): 282 mg/kg; Oral LD50 (mouse): 235 mg/kg **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).
Indication
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, F4471.
Elimination
This drug is mainly eliminated by the kidney .
Volume of Distribution
Extensively distributed throughout the body. The average steady-state volume of distribution is 2.4 L/kg .
Clearance
**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 .
Tolerance & Pharmacokinetics
drugs.wikiTolerance Decay
Experience Report Analysis
ErowidDemographics
Gender Distribution
Age Distribution
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Real-World Dose Distribution
62K DosesFrom 6 individual dose entries