Tizanidin

Uses

It is used in the symptomatic treatment of painful muscle spasm associated with musculoskeletal conditions and as an adjunct in the management of spasticity associated with multiple sclerosis or spinal cord disorders.

Tizanidin is also used to associated treatment for these conditions: Acute Low Back Pain, Drug Withdrawal Headache, Insomnia, Migraine, Pain, Seizures, Spasticity, Muscle, Withdrawal From Addictive Substance; Detoxification

How Tizanidin works

Tizanidin 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. Tizanidin also binds with weaker affinity to the Alpha-1 receptors, explaining its slight and temporary effect on the cardiovascular system .

Dosage

Tizanidin dosage

The usual initial daily dose is 2 mg as a single dose. The daily dose may be increased thereafter according to response in steps of 2 mg at intervals of at least 3 to 4 days, usually up to 24 mg daily given in 3 to 4 divided doses. The maximum recommended dose is 36 mg daily.

Side Effects

Tizanidin Hydrochloride may cause drowsiness, fatigue, dizziness, dry mouth, nausea, gastrointestinal disturbances, hypotension. Bradycardia, insomnia, hallucinations and altered liver enzymes, and rarely acute hepatitis have also been reported.

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. Tizanidin 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 .

Tizanidin 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 .

Precaution

Patients with impaired kidney or liver function; when patients drive a vehicle or operate machinery.

Interaction

Alcohol or other CNS depressants may enhance the CNS effects of Tizanidin. There may be an additive hypotensive effect when Tizanidin is used in patients receiving antihypertensive therapy.

Food Interaction

• Avoid alcohol.
• Take with or without food. Maintain the same schedule with regard to meals, as concentrations increase in the fasted state and decrease in the fed state.

Tizanidin Alcohol interaction

[Moderate]

The sedative effect of tizanidine may be potentiated by concomitant use of other agents with central nervous system (CNS) depressant effects.

In addition, tizanidine and many of these agents (e.g., alcohol, anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, muscle relaxants) also can exhibit hypotensive effects, which may be additive during coadministration and may increase the risk of symptomatic hypotension and orthostasis, particularly during initiation of therapy or dose escalation.

Tizanidin itself is a central alpha-2 adrenergic agonist.

Pharmacologic studies have found tizanidine to possess between 1/10 to 1/50 of the potency of clonidine, a structurally similar agent, in lowering blood pressure.

In a single-dose study where blood pressure was monitored closely after dosing, two-thirds of patients treated with an 8 mg dose had a 20% reduction in either the diastolic or systolic blood pressure.

The reduction was seen within 1 hour after dosing, peaked 2 to 3 hours after dosing, and was associated at times with bradycardia, orthostatic hypotension, lightheadedness, dizziness, and rarely, syncope.

The hypotensive effect of tizanidine is dose-related and has been measured following single doses of 2 mg or more.

Caution is advised and more gradual dose titration may be appropriate when tizanidine is used with other substances that can cause CNS depression and/or hypotension, particularly in elderly or debilitated patients.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to avoid rising abruptly from a sitting or recumbent position.

Patients should contact their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or excessive CNS effects that interfere with their normal activities.

Tizanidin Drug Interaction

Major: escitalopram, metoprolol, acetaminophen / hydrocodoneModerate: zolpidem, diphenhydramine, duloxetine, pregabalin, albuterol, topiramate, alprazolam, ondansetron, cetirizineUnknown: amphetamine / dextroamphetamine, omega-3 polyunsaturated fatty acids, montelukast, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Tizanidin Disease Interaction

Major: hepatotoxicity, hypotension, renal dysfunctionModerate: psychoses

Volume of Distribution

Extensively distributed throughout the body. The average steady-state volume of distribution is 2.4 L/kg .

Elimination Route

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.

Half Life

Approximately 2.5 hours .

Clearance

A note on renal impairment

Tizanidin 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 .

Elimination Route

This drug is mainly eliminated by the kidney .

Pregnancy & Breastfeeding use

Tizanidin has no teratogenic effects in rats and rabbits. As there have been no controlled studies in pregnant women, it should not be used during pregnancy unless the benefit clearly outweighs the risk. Although only small amounts of Tizanidin are excreted in animal milk, lactating women should not take Tizanidin.

Contraindication

Tizanidin Hydrochloride is contraindicated to the patients who have known hypersensitivity to this drug and in case of severe hepatic impairment.

Acute Overdose

Children: Experience in children is limited and the use of Tizanidin in this patient group is not recommended.

Elderly: Renal clearance in the elderly may in some cases be significantly decreased. Caution is therefore indicated when using in elderly patients.

Storage Condition

Store in a cool & dry place, protected from light & moisture. Do not freeze. Keep all medicines out of the reach of children.

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