Tizanidine -Zanaflex
Tizanidine -Zanaflex®
Classification:
Musculoskeletal Agents
- Skeletal Muscle Relaxants
- Central-acting adrenergic agents
Description: Tizanidine is an oral agent used to reduce muscle tone associated with spasticity related to cerebral or spinal cord injury, multiple sclerosis, or other spastic disorders. The imidazoline chemical structure of tizanidine is related to that of clonidine and other central-acting alpha2-adrenergic agonists. Tizanidine significantly reduces muscle tone and frequency of spasms in patients with spasticity due to spinal cord injury; but does not reduce muscle strength. Both tizanidine and baclofen inhibit spinal interneuron firing, however, tizanidine’s effects are mediated by alpha2-receptors whereas baclofen acts directly on neuronal membrane polarization. The efficacy of tizanidine in the treatment of spasticity is comparable to baclofen. Tizanidine produces more drowsiness and sedation than baclofen, but tizanidine is not associated with the muscle weakness which may occur with baclofen therapy. Tizanidine was approved by the FDA on December 3, 1996.
Mechanism of Action: Tizanidine is a central-acting alpha2-adrenergic agonist which acts at presynaptic receptors. It is structurally and pharmacologically related to clonidine, but has only 2-10% of clonidine’s antihypertensive potency. The antispasmodic activity of tizanidine results from agonism at central pre-synaptic alpha2-receptors. The response to agonism at these receptors is a decrease in the release of excitatory amino acids which in turn leads to inhibition of spinal motor neurons. In animal models, tizanidine has no direct effect on skeletal muscle fibers or the neuromuscular junction, and no major effect on monosynaptic spinal reflexes. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons.
Pharmacokinetics: Tizanidine is administered orally as capsules or tablets. Tizanidine is well-absorbed, with an absolute oral bioavailability of 40% due to extensive first pass metabolism in the liver; the tablets and capsules are bioequivalent under fasted conditions, but not under fed conditions. Following oral administration of the tablet or capsule in the fasted state, peak plasma concentrations of tizanidine occur in about 1 hour. Food increases the Cmax of the tablets by about 30% and delays the time to peak concentration by approximately 25 minutes. When the capsules are given with food, the Cmax is decreased by 20% and the Tmax is increased by 2-3 hours. As a result, the Cmax of the capsules is about two-thirds the Cmax for the tablet when given with food. Food also increases the extent of absorption of both the tablets and capsules; the increase is approximately 30% for the tablets and about 10% for the capsules. Sprinkling the contents of the capsule on applesauce results in a 15-20% increase in Cmax and AUC of tizanidine and a 15-minute decrease in the time to peak concentration. Once absorbed, tizanidine is widely distributed throughout the body. The intrapatient effects of tizanidine on muscle tone are correlated with plasma concentrations; adverse effects are dose-related. Tizanidine is approximately 30% bound to plasma proteins.
Approximately 95% of an oral dose of tizanidine is metabolized, presumably to inactive metabolites with half-lives ranging from 20 to 40 hours. The half-life of tizanidine is approximately 2 hours. Following single and multiple oral dosing, about 60% and 20% of the tizanidine dose is recovered in the urine and feces, respectively.
Tizanidine clearance is reduced in elderly subjects and in renally impaired patients, but is not influenced by gender. A cross-study comparison of pharmacokinetic data following single-dose tizanidine showed that younger subjects cleared the drug four times faster than elderly subjects. Tizanidine clearance is reduced by more than 50% in elderly patients with renal impairment (CrCl < 25 ml/min) compared to healthy elderly subjects. Gender had no influence on tizanidine pharmacokinetics. It is not known whether tizanidine is significantly removed by hemodialysis. The effects of race, hepatic disease, or pediatric age on tizanidine disposition have not been studied.
[ Revised 10/10/2005 10:14:00 AM ]
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