Important points of the pharmacodynamics and pharmacokinetics of tizanidine are as follows:
Pharmacology. Tizanidine is an agonist at alpha2-agonist receptor sites and presumably reduces spasticity by increasing presynaptic inhibition of 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. The main clinical effects are a reduction in tonic stretch and polysynaptic reflexes. Tizanidine remains a useful medication for patients suffering from spasticity caused by multiple sclerosis, traumatic brain injury, or spinal cord injury.
The imidazoline chemical structure of tizanidine is related to that of the antihypertensive drug clonidine and other alpha2-adrenergic agonists. Pharmacological studies in animals show similarities between the two compounds, but tizanidine was found to have one-tenth to one-fiftieth the potency of clonidine in lowering blood pressure.
Pharmacokinetics. The essential features are the following:
| • Following oral administration, tizanidine is essentially completely absorbed and has a half-life of approximately 2.5 hours. |
| • There are ethnic differences in clearance of tizanidine. The metabolic clearance of tizanidine 5.9 l/h/kg in Japanese subjects is lower in than rate of 8.1 to 10.9 l/h/kg in Caucasians (13). |
| • Peak plasma concentration is reached at 1.5 hours after dosing. Food increases the maximum concentration by approximately one-third and shortens time to peak concentration by approximately 40 minutes, but the extent of tizanidine absorption is not affected. Tizanidine has linear pharmacokinetics over a dose of 1 to 20 mg. |
| • The absolute oral bioavailability of tizanidine is approximately 40% due to extensive first-pass metabolism in the liver. Approximately 95% of an administered dose is metabolized. Tizanidine metabolites are not known to be active. |
| • Tizanidine is widely distributed throughout the body; mean steady-state volume of distribution is 2.4 L/kg following intravenous administration in healthy adult volunteers. Following single and multiple oral dosing of 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively. |
| • Tizanidine is approximately 30% bound to plasma proteins, independent of concentration over the therapeutic range. |
Formulations. A pharmacokinetic study of tizanidine showed that the tablet and capsule formulations were bioequivalent in the fasting state, but action of the capsule was delayed if taken with food. A pharmacokinetic study to compare two proprietary preparations of tizanidine concluded that each Tizanidine 4 mg tablet from Pharma International Company is bioequivalent to Sirdalud® 4 mg tablet from Novartis (02).
The bioavailability of the tizanidine intranasal formulation is higher than that of tizanidine oral tablets (19). A nasal formulation of tizanidine is being considered for phase II clinical trials.
Because of the short half-life of oral tizanidine given as tablets requiring frequent administration, efforts are being made to develop sublingual formulations that improve bioavailability as shown in clinical trials. One clinical trial has shown that tizanidine, encapsulated in a chitosan lactate wafer for buccal delivery, increases the bioavailability of tizanidine 2.27-fold (06).
A drug-in-adhesive patch of tizanidine is prepared by employing ion-pair and permeation enhancer to increase drug-polymer miscibility and drug release (22). A new generation of amphiphilic vesicles known as aspasomes are potential carriers for transdermal delivery of tizanidine. Skin irritancy tests confirmed that the vesicles were noninvasive and safe for the skin. Based on the results obtained, the optimized aspasomes formula represents a promising Nano platform for tizanidine to be administered transdermally, thus, improving the therapeutic efficacy of this important muscle relaxant (09).
Drug monitoring. Tizanidine is not prohibited by the World Anti-Doping Agency but, for therapeutic purposes, can only be obtained via a nominative temporary use authorization. It is possible to test for tizanidine in head hair specimens collected from international racing cyclists, and evidence is provided by using liquid chromatography-tandem mass spectrometry and confirmation by liquid chromatography-high-resolution mass spectrometry. However, it is not possible to interpret the data in terms of doses and frequency of use due to a lack of controlled study (10).
