Tizanidine

BRAND NAMES

Zanaflex: It contains active ingredient tizanidine with available strengths of 2 mg and4 mg.

MECHANISM OF ACTION

Tizanidine is an imidazoline derivative that acts as a central alpha-2 receptor agonist. Tizanidine prevents the release of excitatory amino acids such as glutamate and aspartate from spinal interneurons. As a result, tizanidine increases the presynaptic inhibition of motor neurons. Tizanidine has a strong effect on spinal polysynaptic networks.

Overall, these effects diminish the facilitation of spinal motor neurons. Similarly, alpha-2 receptor-mediated suppression of inter-neuronal activity appears responsible for tizanidine's additional anti-nociceptive and anticonvulsant properties. Tizanidine also reduces the frequency of spasms and clonus. Tizanidine has a lower affinity for alpha-1 receptors than clonidine, which may explain its milder and more transient action on the cardiovascular system despite their structural and molecular similarities.

PHARMACOKINETICS

Absorption

Tizanidine undergoes considerable first-pass hepatic metabolism, having an oral bioavailability of 20% to 34%. Tizanidine reaches a steady-state concentration within 24 to 48 hours of treatment. There is no significant change in its pharmacokinetic behavior with repeated ingestion.

Distribution

Tizanidine is widely distributed in tissues, with a volume of 2.4 L/kg. Tizanidine binds around 30% of plasma proteins.

Metabolism

Tizanidine is extensively metabolized in the liver by cytochrome P450-1A2 into inactive metabolites.

Elimination

Tizanidine has a 2.5-hour elimination half-life, follows linear pharmacokinetics, and is eliminated 60% in urine and 20% in feces.

PHARMACODYNAMICS

Tizanidine is a fast-acting medication used to relieve muscular stiffness when necessary for certain tasks. It works as an agonist at alpha-2 adrenergic receptor sites, relieving muscular stiffness symptoms and allowing patients to resume regular daily activities. In animal models, tizanidine was found to have no direct effects on skeletal muscle fibers or the neuromuscular junction, as well as no substantial effect on monosynaptic spinal reflexes. Tizanidine has been demonstrated to lessen the frequency of muscular spasms and clonus. Tizanidine has a stronger effect on polysynaptic reflexes, which include several interneurons (relay neurons) interacting with motor neurons to stimulate muscle movement.

DOSAGE AND ADMINISTRATION

Oral administration of tizanidine is available in 2 mg, 4 mg, and 6 mg capsules or 2 mg and 4 mg tablets. Oral dosage should begin at 2 mg and be repeated every 6 to 8 hours as needed. The dosage may be increased incrementally by 2 to 4 mg per dose for 1 to 4 days until a statistically significant reduction in spasticity is observed. The maximum dosage is 36 milligrams per day or three dosages per 24 hours.

Tizanidine should be tapered gradually if it is taken for more than nine weeks or at higher dosages than 20 to 36 mg per day. It is advised to taper the dosage to 2-4 mg per day to lower the chance of rebound hypertension, tachycardia, and increased spasticity.

CONTRAINDICATIONS

• Tizanidine should not be used if you have a hypersensitivity to it or its constituents.
• Tizanidine should be used with care in individuals with hepatic impairment. Tizanidine review papers describe cases of severe hepatotoxicity, abrupt liver failure, and death.
• Tizanidine should be used with caution in individuals with renal impairment, as stated in the product labeling. In such cases, lower the dosage. If greater dosages are required, increase the individual dosage rather than the frequency.

DRUG INTERACTIONS

• Because of potential drug interactions, tizanidine should not be combined with other CYP1A2 inhibitors such as oral contraceptives containing Ethinyl oestradiol and gestodene, dronedarone, pimozide, saquinavir, cimetidine, famotidine, acyclovir, or ticlopidine.
• If tizanidine is therapeutically indicated, start with 2 mg and gradually increase to 2 to 4 mg daily, dependent on the patient's reaction to therapy.
• Tizanidine should be used with caution in individuals using other alpha-2 adrenergic receptor agonists.
• The concurrent use of tizanidine with fluvoxamine or ciprofloxacin is prohibited because of substantial hypotension and increased psychomotor impairment.
• The concurrent use of tizanidine with fluvoxamine or ciprofloxacin is prohibited because of substantial hypotension and increased psychomotor impairment.

SIDE EFFECTS

The common side effects of tizanidine include

• Nervousness
• Rhinitis
• Constipation
• Asthenia
• Hallucination
• Blurred vision
• Dizziness
• Dyskinesia

Severe side effects of tizanidine include

• Severe hypotension
• Anaphylaxis
• QT interval prolongation
• Exfoliative dermatitis
• Severe hepatotoxicity and liver failure

TOXICITY

There is no remedy for tizanidine toxicity. A tizanidine overdose is treated by closely monitoring the airways and administering intravenous fluids and vasopressors as needed. The pediatric case report documented a tizanidine overdose resulting in spastic quadriplegia and toxicity with multiple organ failure in the absence of infection. A recent case report showed a changed mental state and hemodynamic instability caused by tizanidine overdose, and naloxone 10 mg IV treatment improved the Richmond Agitation-Sedation Scale score. The study concluded that naloxone might be administered in tizanidine overdose in emergency conditions, although naloxone did not reverse the hemodynamic characteristics.