Several alpha2-adrenoceptor agonists have been evaluated recently as adjuncts to anesthesia [1-5]. The beneficial properties of these drugs include sedative, analgesic, and, possibly, also anxiolytic effects. They also improve sympathoadrenal and hemodynamic stability during and after anesthesia and surgery, and reduce the requirements for volatile anesthetics, opioids, and benzodiazepines [3-9]. In spite of this, they are used relatively rarely in clinical anesthesia because of their hemodynamic side effects. Excessive bradycardia and hypotonia, and even sinus arrest, have been described after the administration of these compounds [1,8,10].
Tizanidine is an orally active alpha2-adrenoceptor agonist and is used clinically mainly as a centrally acting muscle relaxant for painful muscular spasms [11,12]. Its well known side effects include sedation and reduced salivation . Tizanidine has a relatively short duration of action . It may also possess less cardiovascular side effects than other alpha2-adrenoceptor agonists . These features make tizanidine a potentially interesting drug for anesthetic use.
The present study was undertaken to characterize the sedative, hemodynamic, sympatholytic, and other pharmacodynamic effects of tizanidine in healthy volunteers, and to determine an equipotent dose of tizanidine to 150 micro gram of clonidine, to be used in subsequent clinical studies in surgical patients.
The subjects were six healthy male volunteers, who participated after written, informed consent (mean age 21 yr, range 21-23 yr; mean weight 76 kg, range 68-83 kg; mean height 179 cm, range, 168-187 cm). They had taken no medications during the 2 wk preceding this study. The health of the subjects was ascertained by detailed medical history, physical examination, clinical chemistry tests, and electrocardiogram. The protocol was approved by the Ethics Committee of Turku University Hospital. Alcoholic beverages were not allowed for 24 h prior to each session, and the subjects had fasted since 10:00 PM on the preceding night. The subjects were allowed to drink one glass of water on the morning of the test day. Smoking was prohibited on the test day.
The subjects arrived at the laboratory at 8:00 AM. An intravenous cannula was inserted for blood sampling and it was kept open with a dilute solution of heparin. The experiments were performed in a quiet, dimly lit room. The subjects had a light standard meal and were allowed a lavatory visit at 180 min after drug administration. Otherwise they remained supine throughout the sessions. The subjects were permitted to leave the laboratory 6 h after drug administration.
The study was double-blind and placebo controlled, and followed a randomized, complete block design. Each subject received three different single doses (4, 8, and 12 mg) of tizanidine (Sirdalud Registered Trademark; Sandoz, Basel, Switzerland), one single dose (150 micro gram) of clonidine, and placebo. The doses were given between 8.45 and 9.30 AM and the drugs were ingested with 150 mL of water after a minimum of 30 min supine rest. The interval between each session was at least 5 days.
Arterial blood pressure and heart rate were measured noninvasively with an automated oscillometric device. Impairment of vigilance was assessed objectively with the critical flicker fusion threshold test , and with the Maddox Wing test , where an increasing degree of exophoria (in diopters) indicates the impairment of extraocular muscle balance.
Visual analog scales, 10 cm long, were used to report subjective sedation (extremes, "fully alert" to "almost asleep") . Nonstimulated saliva secretion was measured by placing three preweighed dental cotton rolls at the orifices of the parotid ducts and under the tongue for 2 min and then recording the weight of the rolls.
Blood samples to determine human growth hormone (GH) and norepinephrine levels were collected into chilled K3 EDTA tubes at 1 min before drug administration and at 30, 60, 90, 120, 180, 240, and 360 min after the administration. Plasma was separated within 30 min of sampling at +4 degrees C, and the samples stored at -70 degrees C until analyzed. Blood samples to determine the drug concentration from serum were collected at the same time points. Human GH concentrations were determined using radioimmunoassay (Spectria Registered Trademark HGH125 I; Orion Diagnostica, Espoo, Finland), and norepinephrine levels by high-performance liquid chromatography with electrochemical detection . Serum tizanidine concentrations were measured using a radioreceptor assay, described earlier . Tritiated clonidine was used as the labeled ligand. Tizanidine displaced clonidine over two log units of concentration, and the Hill slope of the displacement curve was close to unity.
The subjects were asked to report any possible drug-related subjective sensations, and a standardized questionnaire was completed at 1-h intervals during each session.
The data were analyzed using repeated-measures analysis of variance (ANOVA) followed by one-way ANOVA and Fisher's test for individual comparisons. The growth hormone values were converted logarithmically to correct the skewness in distribution. A significance level of less than 0.05 was considered statistically significant. Minitab statistical package (Minitab Inc., State College, PA) was used for computing the tests. All reported results are means +/- SE.
The drugs were well tolerated, with no distinctly unpleasant experiences. The most common side effect was dryness of the mouth, which was usually considered to be "mild." Two of the subjects mentioned dryness of mouth to be "moderate," both after administration of clonidine 150 micro gram. The subjective experience of sedation was rather modest after all drug doses, but tended to be most marked after clonidine 150 micro gram. Neither the visual analog scale nor the Maddox Wing readings revealed any statistically significant differences between the treatments Table 1. Drug-induced impairment of critical flicker fusion ratings was statistically significant Table 1, Figure 1, but further analysis with one-way ANOVA or Fisher's test did not reveal any significant differences between the drug doses.
Both clonidine and tizanidine decreased arterial blood pressure Table 1. The maximum reductions in diastolic blood pressure for clonidine, tizanidine 12 mg, tizanidine 8 mg, tizanidine 4 mg, and placebo were 19%, 13%, 13%, 7%, and 5%, respectively. For systolic blood pressure (SBP) the maximal reductions were 8%, 10%, 12%, 9%, and 5%, respectively. Drug effects on SBP were largest 90 min after drug administration, when statistically significant differences in SBP (P < 0.05) were observed between placebo and tizanidine 8 mg (108 +/- 3.7 vs 98 +/- 3.0 mm Hg), placebo and tizanidine 12 mg (108 +/- 3.7 vs 98 +/- 3.0 mm Hg), and between placebo and clonidine (108 +/- 3.7 vs 97.1 +/- 3.0 mm Hg). Diastolic blood pressure was most markedly reduced at 2 h after drug administration, when statistically significant differences (P < 0.05) were seen between placebo and clonidine 150 micro gram (62.8 +/- 1.1 vs 56.3 +/- 2.1 mm Hg), placebo and tizanidine 8 mg (62.8 +/- 1.1 vs 56.3 +/- 2.0 mm Hg), and between placebo and tizanidine 12 mg (62.8 +/- 1.1 vs 55.5 +/- 1.4 mm Hg).
Both clonidine and the two larger doses of tizanidine reduced basal salivation. The effect of clonidine lasted clearly longer than the effect of tizanidine Table 1 and Figure 2 (P < 0.05 at 6 h).
The concentration of norepinephrine in plasma was clearly reduced after clonidine and the two higher doses of tizanidine Figure 3. Two hours after drug administration, both tizanidine 12 mg and clonidine 150 micro gram plasma norepinephrine concentrations were statistically significantly different from placebo (0.68 +/- 0.07 nmol/L vs 1.06 +/- 0.08 nmol/L and 0.64 +/- 0.14 nmol/L vs 1.06 +/- 0.08 nmol/L, respectively), but by the end of the session the norepinephrine concentration had returned to the baseline level after tizanidine 12 mg. Clonidine 150 micro gram was still, at 6 h after administration, statistically significantly different (P < 0.05) from all other treatments in terms of plasma norepinephrine levels (0.57 +/- 0.09 nmol/L vs 1.06 +/- 0.1 nmol/L for placebo).
Both clonidine 150 micro gram and tizanidine 12 mg tended to increase plasma, human GH levels, but the changes did not reach statistical significance after logarithmic transformation Table 1, Figure 4.
Tizanidine serum concentrations showed high inter- and intraindividual variability, and did not allow the calculation of exact pharmacokinetic parameters. The peak concentrations were reached in 30-90 min after drug administration.
Recently, alpha2-adrenoceptor agonists have gained wide attention as potentially useful pre- or perianesthetic drugs. Tizanidine has not been evaluated in this paradigm. In this study, we sought to determine an equally sedative and sympatholytic dose of tizanidine to 150 micro gram clonidine.
Carabine et al.  have reported that oral clonidine in a dose of 200 micro gram had anxiolytic activity with no marked hemodynamic effects. The dose of clonidine used by us, 150 micro gram, is suitable for premedication, since it does not delay recovery from anesthesia . The effects of the largest dose of tizanidine studied by us, 12 mg, closely resembled those of clonidine 150 micro gram in quality and magnitude, but were of shorter duration. Both drugs had relatively modest sedative effects, they reduced arterial blood pressure, salivation, and plasma norepinephrine concentrations to a similar extent, and both tended to stimulate GH secretion. These effects are typical for alpha2-adrenoceptor agonists with relatively rapid penetration into the central nervous system [4-6,23,24]. Plasma norepinephrine concentrations were used here as an indicator of presynaptic sympathetic activity, and growth hormone as a marker for pharmacological effects mediated by alpha2-adrenoceptors in brain.
Our results show that the effects of 12 mg of tizanidine orally resemble those of 150 micro gram of clonidine. This dose of tizanidine is comparable with that normally used in the treatment of spasticity (4-6 mg three times a day). Pharmacokinetic studies performed with tizanidine indicate that serum concentrations increase proportionally to dosage, that peak serum concentrations are usually achieved in 60 minutes, and that the elimination of tizanidine is relatively rapid (t1/2 three hours) [14,15]. Clonidine has a longer duration of action than tizanidine, and the onset of its actions may also be slower. The short duration of action of tizanidine may make it desirable as a drug for premedication.
We want to express our gratitude to Mrs. Tuire Olli-Lahdesmaki, BM, Miss Eija Lehtovirta, and Mrs. Taina Lehti for skillful technical assistance.
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© 1996 International Anesthesia Research Society
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