Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Antispastic with a spinal site of attack: (ATC Code: M03B X01).
Baclofen depresses both monosynaptic and polysynaptic reflex transmission in the spinal cord by stimulating the GABAß receptors. Baclofen is a chemical analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
Neuromuscular transmission is not affected by baclofen. Baclofen exerts an antinociceptive effect. In neurological diseases associated with spasm of the skeletal muscles, the clinical effects of baclofen take the form of a beneficial action on reflex muscle contractions and of marked relief from painful spasm, automatism, and clonus. Baclofen improves the patient's mobility, makes it easier for him/her to manage without aid, and facilitates physiotherapy.
Consequent important gains include improved ambulation, prevention and healing of decubitus ulcers, and better sleep patterns due to elimination of painful muscle spasms. In addition, patients experience improvement in bladder and sphincter function and catheterization is made easier, all representing significant improvements in the patient's quality of life. Baclofen has been shown to have general CNS depressant properties, causing sedation, somnolence, and respiratory and cardiovascular depression.
Baclofen when introduced directly into the intrathecal space, permits effective treatment of spasticity with doses at least 100 times smaller than those for oral administration.
Intrathecal bolus:
The onset of action is generally half an hour to one hour after administration of a single intrathecal dose. Peak spasmolytic effect is seen at approximately 4 hours after dosing, the effect lasting 4 to 8 hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms and the method and speed of drug administration.
Continuous infusion:
Baclofen's antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion.
Maximum efficacy is observed within 24 to 48 hours.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Because of the slow CSF circulation and the baclofen concentration gradient from the lumbar to the cisternal CSF the pharmacokinetic parameters observed in this fluid and as described below should be interpreted considering a high inter- and intra-patients variability.
Absorption
Direct infusion into the spinal subarachnoid space by-passes absorption processes and allows exposure to the receptor sites in the dorsal horn of the spinal cord.
Distribution
After single intrathecal bolus injection/short-term infusion the volume of distribution, calculated from CSF levels, ranges from 22 to 157 ml.
With continuous intrathecal infusion daily doses of 50 to 1200 micrograms result in lumbar CSF concentrations of baclofen as high as 130 to 1240 ng/ml at steady state. According to the half-life measured in the CSF, CSF steady-state concentrations will be reached within 1-2 days.
During intrathecal infusion the plasma concentrations do not exceed 5ng/ml, confirming that baclofen passes only slowly across the blood-brain barrier.
Elimination
The elimination half-life in the CSF after single intrathecal bolus injection/short-term infusion of 50 to 136 micrograms baclofen ranges from 1 to 5 hours. Elimination half-life of baclofen after having reached steady-state in the CSF has not been determined.
After both single bolus injection and chronic lumbar subarachnoid infusion using an implantable pump system, the mean CSF clearance was about 30 ml/h.
At steady-state conditions during continuous intrathecal infusion, a baclofen concentration gradient is built up in the range between 1.8 : 1 and 8.7 : 1 (mean: 4 : 1) from lumbar to cisternal CSF. This is of clinical importance insofar as spasticity in the lower extremities can be effectively treated with little effect on the upper limbs and with fewer CNS adverse reactions due to effects on the brain centers.
Special populations
Elderly Patients
No pharmacokinetic data is available in elderly patients after administration of Baclofene Bioindustria L.I.M. 10 mg/5 ml. When a single dose of the oral formulation is administered, data suggest that elderly patients have a slower elimination but a similar systemic exposure to baclofen compared to young adults.
However, the extrapolation of these results to multi-dose treatment suggests no significant pharmacokinetics difference between young adults and elderly patients.
Pediatrics
In pediatric patients, respective plasma concentrations are at or below 10 ng/ml.
Hepatic impairment
No pharmacokinetic data is available in patients with hepatic impairment after administration of Baclofene Bioindustria L.I.M. 10 mg/5 ml. However, as liver does not play a significant role in the disposition of baclofen it is unlikely that its pharmacokinetics would be altered to a clinically significant level in patients with hepatic impairment.
Renal impairment
No pharmacokinetic data is available in patients with renal impairment after administration of Baclofene Bioindustria L.I.M. 10 mg/5 ml. Since baclofen is majorly eliminated unchanged through thekidneys, accumulation of unchanged drug in patients with renal impairment cannot be excluded.