Tizigesic tablets 4mg

Indications

• Spasticity associated with multiple sclerosis
• Spasticity due to spinal cord injury or disease

Dosage

Children: Refer to the BNF for Children for specific dosing guidance.

Adults: Initially 2 mg daily, increased in steps of 2 mg at intervals of 1 to 4 days, with a maximum of 36 mg per day in divided doses.

Mechanism of action

Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons through agonist actions at Alpha-2 adrenergic receptor sites. This central action decreases the release of excitatory amino acids like glutamate and aspartate, which are involved in muscle spasm. The primary effect occurs on spinal polysynaptic pathways, and it may also exhibit anti-nociceptive and anticonvulsant effects through its action on Alpha-2 receptors.

Pharmacodynamics

Tizanidine is effective in reducing muscle spasticity, characterized by increased muscle tone and involuntary contractions, which can significantly impair mobility and quality of life. By acting as an agonist at Alpha-2 adrenergic receptors, Tizanidine allows for the relief of muscle tightness and spasms, enabling individuals to engage more comfortably in daily activities. It does not exert direct effects on skeletal muscle fibers or the neuromuscular junction and shows minimal impact on monosynaptic spinal reflexes.

Pharmacokinetics

Tizanidine is rapidly absorbed after oral administration, with peak plasma concentrations typically occurring within 1 to 2 hours. It has a relatively short half-life, necessitating multiple daily doses for effective management of spasticity. The drug is extensively metabolized in the liver, primarily by the cytochrome P450 system, and caution is advised in patients with hepatic impairment due to the potential for altered drug levels. Renal impairment may also influence its pharmacokinetics.

Contra-indications

• Brain damage
• Coma
• Epilepsy
• Myasthenia gravis
• Pre-coma

Adverse effects

• Angioedema
• Anxiety
• Bradycardia
• Confusion
• Conjunctivitis
• Dizziness
• Drowsiness
• Dyspepsia
• Fever
• Flushing
• Headache
• Hepatic disorders
• Hypotension
• Insomnia
• Leukopenia
• Memory loss
• Nasal congestion
• Nausea
• Seizures
• Skin reactions
• Syncope
• Taste disturbance
• Metallic taste
• Vertigo
• Vision disorders
• Vomiting

Interactions

• Combined hormonal contraceptives: Severe (increases exposure)
• Mexiletine: Severe (increases exposure)
• Osilodrostat: Severe (increases exposure)
• Ciprofloxacin: Severe (increases exposure)
• Rucaparib: Severe (increases exposure)
• Fluvoxamine: Severe (increases exposure)
• Vemurafenib: Severe (increases exposure)
• Givosiran: Moderate (increases exposure)
• Axitinib: Unknown (increases exposure)
• Ritonavir: Unknown (decreases exposure)

Precautions

• Caution in hepatic impairment (risk of increased half-life)
• Caution in renal impairment
• Drowsiness may affect performance of skilled tasks (e.g., driving); effects may be enhanced by alcohol

Pregnancy

Avoid in the first trimester; thereafter, sufficient use only if potential benefit outweighs risk (no information available).

Breast-feeding

Avoid-no information available.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Tablets: 2 mg, 3 mg, 4 mg
• Oral suspension: 36 mg per day

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. Despite this, rebound hypertension and tachycardia along with increased spasticity can occur when tizanidine is abruptly discontinued.