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Definition
Tizanidine is a centrally-acting alpha-2 adrenergic agonist used as a muscle relaxant. It is commonly used to treat muscle spasms caused by multiple sclerosis, stroke, or spinal cord injury.
Mechanism of Action
Tizanidine's muscle relaxant effects are primarily mediated through its agonistic action at central alpha-2 adrenergic receptors, particularly the alpha-2A subtype. Activation of these receptors inhibits the release of excitatory neurotransmitters, such as glutamate, resulting in reduced neuronal activity within the spinal cord and brainstem. This ultimately leads to decreased muscle tone and spasticity. Additionally, tizanidine may possess some inhibitory effects on voltage-gated calcium channels, further contributing to its muscle relaxant properties.
Pharmacokinetics
Tizanidine is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1-2 hours. It undergoes extensive first-pass metabolism, resulting in an absolute bioavailability of approximately 20%. Tizanidine is primarily metabolized by the liver via cytochrome P450 enzymes, and its metabolites are excreted mainly in the urine. The elimination half-life of tizanidine is approximately 2-4 hours.
Absorption
Tizanidine is rapidly absorbed from the gastrointestinal tract after oral administration, with peak plasma concentrations typically occurring within 1-2 hours. The extent of absorption is approximately 20%, due to extensive first-pass metabolism in the liver. Tizanidine's absorption is not significantly affected by food intake, allowing for flexible dosing regardless of mealtimes.
Distribution
Tizanidine is widely distributed throughout the body after absorption, with a volume of distribution of approximately 2.7 L/kg. It is highly lipophilic and readily crosses the blood-brain barrier, achieving significant concentrations in the central nervous system. Tizanidine is approximately 30% bound to plasma proteins, primarily albumin. The drug's distribution into tissues is influenced by regional blood flow and the presence of alpha-2 adrenergic receptors.
Metabolism
Tizanidine undergoes extensive metabolism in the liver, primarily via cytochrome P450 enzymes. The major metabolic pathways involve hydroxylation and glucuronide conjugation. The primary metabolite is 4-hydroxytizanidine, which is further metabolized to 4-hydroxy-N-glucuronide tizanidine. These metabolites are pharmacologically inactive and are excreted primarily in the urine. Tizanidine's metabolism may be affected by factors such as hepatic function, age, and co-administered medications.
Excretion
Tizanidine and its metabolites are primarily excreted in the urine, with approximately 70% of the administered dose being recovered in the urine within 24 hours. The elimination half-life of tizanidine is approximately 2-4 hours. Renal impairment can significantly affect tizanidine's excretion, leading to increased plasma concentrations and prolonged elimination. Therefore, dose adjustments may be necessary in patients with renal dysfunction.
Uses
Tizanidine is indicated for the treatment of muscle spasms caused by multiple sclerosis, stroke, or spinal cord injury.
Muscle spasms
Tizanidine is effective in reducing the frequency and severity of muscle spasms associated with multiple sclerosis, stroke, or spinal cord injury. It is thought to work by reducing the activity of excitatory neurotransmitters in the spinal cord and brainstem, leading to decreased muscle tone and spasticity. Tizanidine has been shown to improve mobility, reduce pain, and enhance overall function in patients with these conditions.
Multiple sclerosis
In patients with multiple sclerosis, tizanidine is used to manage muscle spasms and spasticity, which can significantly impact mobility, daily activities, and quality of life. Tizanidine's ability to reduce muscle tone and improve muscle control can enhance overall function, reduce pain, and facilitate rehabilitation efforts. By alleviating muscle spasms, tizanidine can help patients with multiple sclerosis maintain independence and improve their overall well-being.
Stroke
Tizanidine is used to treat muscle spasms and spasticity following a stroke. These symptoms can hinder rehabilitation efforts and affect mobility, daily activities, and overall recovery. Tizanidine's ability to reduce muscle tone and improve muscle control can facilitate physical therapy, enhance functional outcomes, and improve the patient's quality of life. By alleviating muscle spasms, tizanidine can help stroke survivors regain independence and reintegrate into their daily routines.
Acquired brain injury
Tizanidine is used to manage muscle spasms and spasticity resulting from acquired brain injury. These symptoms can significantly impact motor function, daily activities, and overall rehabilitation. Tizanidine's ability to reduce muscle tone and improve muscle control can facilitate physical therapy, enhance functional outcomes, and improve the patient's quality of life. By alleviating muscle spasms, tizanidine can help individuals with acquired brain injury regain independence and reintegrate into their daily routines.
Spinal cord injury
Tizanidine is used to treat muscle spasms and spasticity associated with spinal cord injury. These symptoms can hinder rehabilitation efforts, affect mobility, and impact overall quality of life. Tizanidine's ability to reduce muscle tone and improve muscle control can facilitate physical therapy, enhance functional outcomes, and improve the patient's independence. By alleviating muscle spasms, tizanidine can help individuals with spinal cord injury regain mobility, participate in daily activities, and improve their overall well-being.
Dosage and Administration
Tizanidine is administered orally, typically in divided doses throughout the day.
Adults
The recommended starting dose of tizanidine for adults is 2 mg, taken three times daily. The dose may be gradually increased by 2-4 mg every 3-7 days, as tolerated, to achieve optimal symptom control. The maximum recommended daily dose is 36 mg, divided into three or four equal doses. Tizanidine should be taken with food to reduce the risk of side effects, particularly hypotension.
The safety and efficacy of tizanidine in children have not been established. Therefore, tizanidine is not recommended for use in pediatric patients.
Side Effects
Tizanidine is generally well-tolerated, but some side effects may occur.
Common
The most common side effects of tizanidine include⁚
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Less common
Less common side effects of tizanidine include⁚
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Rare
Rare side effects of tizanidine include⁚
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Precautions
Tizanidine should be used with caution in patients with certain medical conditions.
Hepatic impairment
Tizanidine is metabolized in the liver, so caution should be exercised when administering it to patients with hepatic impairment; Reduced liver function can lead to increased plasma concentrations of tizanidine, potentially increasing the risk of side effects. The dose of tizanidine may need to be reduced in patients with severe hepatic impairment.
Renal impairment
Tizanidine is primarily excreted by the kidneys, so caution should be exercised when administering it to patients with renal impairment. Reduced kidney function can lead to increased plasma concentrations of tizanidine, potentially increasing the risk of side effects. The dose of tizanidine may need to be reduced in patients with severe renal impairment.
Pregnancy
The safety of tizanidine during pregnancy has not been established. Animal studies have shown some evidence of fetotoxicity at high doses. Therefore, tizanidine should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Lactation
Tizanidine is excreted in human milk. The effects of tizanidine on breastfed infants are not known. Therefore, tizanidine should be used during lactation only if the potential benefit outweighs the potential risk to the infant.
Children
The safety and efficacy of tizanidine in children have not been established. Therefore, tizanidine is not recommended for use in pediatric patients.
Contraindications
Tizanidine is contraindicated in certain individuals.
Hypersensitivity
Tizanidine is contraindicated in individuals with known hypersensitivity to the drug or any of its components.
Severe hepatic impairment
Tizanidine is contraindicated in individuals with severe hepatic impairment (Child-Pugh class C).
Drug Interactions
Tizanidine may interact with certain medications.
CYP1A2 inhibitors
CYP1A2 inhibitors, such as fluvoxamine, cimetidine, and propranolol, can increase tizanidine plasma concentrations. This may increase the risk of side effects. Therefore, caution should be exercised when co-administering tizanidine with CYP1A2 inhibitors.
CYP3A4 inhibitors
CYP3A4 inhibitors, such as ketoconazole, itraconazole, and erythromycin, can increase tizanidine plasma concentrations. This may increase the risk of side effects. Therefore, caution should be exercised when co-administering tizanidine with CYP3A4 inhibitors.
CYP3A4 inducers
CYP3A4 inducers, such as rifampin, phenytoin, and carbamazepine, can decrease tizanidine plasma concentrations. This may reduce the effectiveness of tizanidine. Therefore, caution should be exercised when co-administering tizanidine with CYP3A4 inducers.
Other muscle relaxants
Co-administration of tizanidine with other muscle relaxants, such as baclofen or dantrolene, may increase the risk of excessive muscle relaxation and side effects. Therefore, caution should be exercised when combining tizanidine with other muscle relaxants.
Sedatives
Co-administration of tizanidine with sedatives, such as benzodiazepines or opioids, may increase the risk of excessive sedation and side effects. Therefore, caution should be exercised when combining tizanidine with sedatives.
Hypnotics
Co-administration of tizanidine with hypnotics, such as zolpidem or zaleplon, may increase the risk of excessive sedation and side effects. Therefore, caution should be exercised when combining tizanidine with hypnotics;
Alcohol
Co-administration of tizanidine with alcohol may increase the risk of excessive sedation and side effects. Therefore, caution should be exercised when combining tizanidine with alcohol.
Overdosage
Overdosage of tizanidine can lead to serious consequences.
Symptoms
Symptoms of tizanidine overdosage may include⁚
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Treatment
Treatment of tizanidine overdosage may include⁚
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Storage
Tizanidine should be stored at room temperature, protected from light and moisture.
Patient Information
Tizanidine is used to treat muscle spasms.
Instructions for use
Take tizanidine exactly as prescribed by your doctor. Do not take more or less of it, and do not take it more often than prescribed. Tizanidine can be taken with or without food, but it is best to take it with food to reduce the risk of side effects, particularly hypotension. If you miss a dose of tizanidine, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses at once.
Side effects to watch for
The most common side effects of tizanidine include⁚
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Less common side effects include⁚
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Rare side effects include⁚
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If you experience any of these side effects, especially the rare ones, stop taking tizanidine and contact your doctor immediately.
Precautions to take
Before taking tizanidine, tell your doctor if you have any of the following conditions⁚
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Tizanidine can cause drowsiness, so it is important to avoid driving or operating machinery until you know how it affects you. Tizanidine can also interact with other medications, so it is important to tell your doctor about all the medications you are taking;
