Baclofen
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🧬 Receptor activity
Mechanism of action
The exact mechanism of action of baclofen is unclear. Baclofen is an agonist at the beta subunit of gamma-aminobutyric acid (GABA) receptors expressed on pre- and post-synaptic neurons. Upon binding to GABA<sub>B</sub> receptors, baclofen causes an influx of potassium into the neuron, leading to hyperpolarization of the neuronal membrane and decreased calcium influx at presynaptic nerve terminals. This results in a decreased rate of action potential threshold being reached by presynaptic neurons and reduced action potential of postsynaptic motor neurons that innervate the muscle spindles. Baclofen thereby inhibits the transmission of both mono- and polysynaptic reflexes at the spinal cord, relaxing spasticity. Baclofen may act on some voltage-gated calcium channels; however, the clinical significance of this is unclear.
Pharmacodynamics
Baclofen is an antispasmodic agent that induces muscle relaxation. It reduces the release of excitatory neurotransmitters in the pre-synaptic neurons and stimulates inhibitory neuronal signals in the post-synaptic neurons. Oral formulations of baclofen are the most commonly used form of the drug. In one cross-section study, intrathecal baclofen was more effective than oral baclofen in relieving spasticity directly at the level of the spinal cord. Baclofen has CNS depression properties and can cause sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression. Baclofen also mediates some antinociceptive effects and stimulates gastric acid secretion. Baclofen exhibits anti-inflammatory and neuroprotective activities: it inhibits the release of pro-inflammatory cytokines from microglia and astrocytes, and decreases oxidative stress in rats.
Pharmacokinetics
Half-life
The half-life is 2-6 hours after oral administration and 1-5 hours following intrathecal administration. The apparent elimination half-life of baclofen oral suspension or granules is about 5.6 hours.
Absorption
Baclofen has an oral bioavailability of 70% to 85%. Following oral administration, it is rapidly absorbed through the gastrointestinal tract with peak plasma concentrations being reached two to three hours after ingestion. Peak effect is observed about four hours after intrathecal administration. The absorption is dose-dependent and increases with higher doses. There is intersubject variation in absorption. Administration of oral baclofen suspension with a high-fat meal resulted in 9% decrease in AUC and 33% decrease in Cmax compared to the fasted state.
About 70-80% of baclofen is eliminated in an unchanged form by renal excretion within 72 hours of administration. About 5% of the dose is excreted via the kidneys as metabolites. There is intersubject variation in elimination.
The volume of distribution of baclofen is 0.7 L/kg. As baclofen is mainly water-soluble, it does not readily cross the blood-brain barrier. Drug concentrations of baclofen in the cerebrospinal fluid are approximately 8.5 times lower than in the plasma.
The systemic clearance (CL/F) was 180 mL/min and the renal clearance was 103 mL/min following oral administration.
Metabolism
Approximately 15% of the oral dose is metabolized in the liver, mainly by deamination. Deamination yields the main metabolite, β-(p-chlorophenyl)-4-hydroxybutyric acid, which is pharmacologically inactive.
~ 15% of the dose is metabolized in the liver, primarily by deamination. 70-80% of the dose is excreted unchanged or as metabolites in urine and the remainder is excreted in feces. Oral Baclofen is readily absorbed from the gastrointestinal tract. After oral administration, baclofen appears in the blodd within half an our. It is fairly distributed in most organs and body tissues. After oral administration of baclofen, about 85% is excreted unchanged in the urine and feces and the remainder is oxidatively dearninated in the liver to produce beta-(p-chlorophenyl)-gamma-hydroxybutyric acid as a major metabolite. (L1322).
Route of Elimination: In a study using radiolabeled baclofen, approximately 85% of the dose was excreted unchanged in the urine and feces.
Baclofen is excreted primarily by the kidney as unchanged drug; 70 - 80% of a dose appears in the urine as unchanged drug. The remainder is excreted as unchanged drug in the feces or as metabolites in the urine and feces.
Half Life: 2.5-4 hours
Protein binding
The protein binding is approximately 30%.
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