CLINICAL PHARMACOLOGY
Tablets
The precise mechanism of action of baclofen is not fully
known. Baclofen is capable of inhibiting both monosynaptic
and polysynaptic reflexes at the spinal level, possibly
by hyperpolarization of afferent terminals, although actions
at supraspinal sites may also occur and contribute to
its clinical effect. Although baclofen is an analog of
the putative inhibitory neurotransmitter gamma-aminobutyric
acid (GABA), there is no conclusive evidence that actions
on GABA systems are involved in the production of its
clinical effects. In studies with animals, baclofen has
been shown to have general CNS depressant properties as
indicated by the production of sedation with tolerance,
somnolence, ataxia, and respiratory and cardiovascular
depression. Baclofen is rapidly and extensively absorbed
and eliminated. Absorption may be dose-dependent, being
reduced with increasing doses. Baclofen is excreted primarily
by the kidney in unchanged form and there is relatively
large intersubject variation in absorption and/or elimination.
Injection
The precise mechanism of action of baclofen as a muscle
relaxant and antispasticity agent is not fully understood.
Baclofen inhibits both monosynaptic and polysynaptic reflexes
at the spinal level, possibly by decreasing excitatory
neurotransmitter release from primary afferent terminals,
although actions at supraspinal sites may also occur and
contribute to its clinical effect. Baclofen is a structural
analog of the inhibitory neurotransmitter gamma-aminobutyric
acid (GABA) and may exert its effects by stimulation of
the GABAB, receptor subtype.
Baclofen injection when introduced directly into the
intrathecal space permits effective CSF concentrations
to be achieved with resultant plasma concentrations 100
times less than those occurring with oral administration.
In people, as well as in animals, baclofen has been shown
to have general CNS depressant properties as indicated
by the production of sedation with tolerance, somnolence,
ataxia, and respiratory and cardiovascular depression.
Pharmacodynamics of Baclofen Injection
Adult Patients: The onset of action is
generally one-half hour to one hour after an intrathecal
bolus. Peak spasmolytic effect is seen at approximately
four hours after dosing and effects may last four to eight
hours. Onset, peak response, and duration of action may
vary with individual patients depending on the dose and
severity of symptoms.
Pediatric Patients: The onset, peak,
and duration of action is similar to those seen in adult
patients.
Continuous Infusion: Baclofen injection's
antispastic action is first seen at 6 to 8 hours after
initiation of continuous infusion. Maximum activity is
observed in 24 to 48 hours.
No additional information is available for pediatric
patients.
Pharmacokinetics of Baclofen Injection
The pharmacokinetics of CSF clearance of baclofen injection
calculated from intrathecal bolus or continuous infusion
studies approximates CSF turnover, suggesting elimination
is by bulk-flow removal of CSF.
Intrathecal Bolus: After a bolus lumbar
injection of 50 or 100 mcg baclofen injection in seven
patients, the average CSF elimination half-life was 1.51
hours over the first four hours and the average CSF clearance
was approximately 30 ml/hour.
Continuous Infusion: The mean CSF clearance
for baclofen injection was approximately 30 ml/hour in
a study involving ten patients on continuous intrathecal
infusion.
Concurrent plasma concentrations of baclofen during intrathecal
administration are expected to be low (0-5 ng/ml).
Limited pharmacokinetic data suggest that a lumbar-cisternal
concentration gradient of about 4:1 ia established along
the neuroaxis during baclofen infusion. This is based
upon simultaneous CSF sampling via cisternal and lumbar
tap in 5 patients receiving continuous baclofen infusion
at the lumbar level at doses associated with therapeutic
efficacy; the inter-patient variability was great. The
gradient was not altered by position.
Six pediatric patients (age 6-18 years) receiving continuous
intrathecal baclofen infusion at doses of 77-400 mcg/day
had plasma baclofen levels near or below 10 ng/mL.
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