What is the mechanism of action of tizanidine?

Mechanism of Action of Tizanidine

Tizanidine is a centrally acting α2-adrenergic receptor agonist that reduces spasticity by increasing presynaptic inhibition of motor neurons in the spinal cord. 1

Primary Mechanism

• Tizanidine acts as an agonist at α2-adrenergic receptor sites, reducing spasticity through increased presynaptic inhibition of motor neurons. 1
• The drug has no direct effect on skeletal muscle fibers or the neuromuscular junction, and produces no major effect on monosynaptic spinal reflexes. 1
• The greatest effects occur on polysynaptic pathways, with the overall result being reduced facilitation of spinal motor neurons. 1

Specific Receptor Targets and Spinal Mechanisms

• Tizanidine binds to both α2-adrenoreceptors and imidazoline (I) receptors, with the α2A subtype and I receptors primarily mediating the antispasticity effect, while α2B receptors are not involved. 2
• The drug reinforces three distinct inhibitory mechanisms: presynaptic inhibition, Ia reciprocal inhibition (postsynaptic), and Ib nonreciprocal inhibition (postsynaptic). 3
• Tizanidine markedly reduces flexor reflexes and corrects multiple pathophysiologic abnormalities in spasticity. 3
• The broad spectrum of activity—reinforcing both presynaptic and Ib nonreciprocal inhibition—allows tizanidine to reduce both brisk tendon jerks and muscle hypertonia. 3

Structural and Comparative Pharmacology

• The imidazoline chemical structure of tizanidine is related to the antihypertensive drug clonidine and other α2-adrenergic agonists. 1
• Tizanidine has one-tenth to one-fiftieth (1/10 to 1/50) the potency of clonidine in lowering blood pressure, explaining its more favorable cardiovascular profile. 1

Site of Action

• The antispasticity effect involves both spinal and potentially supraspinal sites, targeting α2A receptors present on spinal neurons, primary afferents, and activated astrocytes. 2
• In intact animals, tizanidine likely removes tonic facilitation of spinal neurons by descending noradrenergic fibers through presynaptic autoinhibition of locus coeruleus neurons. 4
• Immunofluorescence studies demonstrate upregulation of α2A receptors in activated astrocytes in spastic spinal cord tissue. 2

Clinical Relevance

• This mechanism explains tizanidine's FDA approval for treating spasticity associated with upper motor neuron syndromes such as stroke, multiple sclerosis, and spinal cord injury. 5
• The drug's action on spinal interneurons deprived of normal monoaminergic descending innervation accounts for its efficacy in conditions with disrupted supraspinal control. 3