Baclofen

Baclofen (brand names Kemstro and Lioresal) is a derivative of gamma-aminobutyric acid, and is an agonist specific to mammalian but not fruit fly (Drosophila) GABAB receptors. It is used for the treatment of spastic movement, especially in instances of spinal cord injury, spastic diplegia, multiple sclerosis, amyotrophic lateral sclerosis (Lou Gehrig's Disease) and trigeminal neuralgia. Its beneficial effects result from actions at spinal and supraspinal sites. Baclofen can also be used to treat hiccups.

Description of compound
Baclofen is a white to off-white, odorless or practically odorless crystalline powder, with a molecular weight of 213.66 g/mol. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.

Routes of administration
Baclofen can be administered either orally or intrathecally (directly into the spinal fluid). Intrathecal administration is often indicated in spasticity patients, as very little of the oral dose actually reaches the spinal fluid.

Intrathecal administration is particularly used in patients with multiple sclerosis who have severe painful spasms which are not controllable by oral baclofen, or patients with spastic diplegia in whom managament of spasticity is made easier by regular self-ministering of the drug through its pump. A test dose is given to assess the effect, and if successful a chronic intrathecal catheter is inserted and connected to a computer-controlled implanted pump. The reservoir in the pump can be replenished by percutaneous injection. These pump systems are quite sophisticated and expensive, so careful patient selection is required.

History
Historically Baclofen was designed to be a drug for epilepsy in the 1920’s, and was derived from GABA. The effect on epilepsy was disappointing but it was found that in certain patients spasticity decreased. Baclofen was and is still given orally with variable effects. In severely affected children, the oral dose is so high that side effects appear and the treatment loses its benefit. How and when baclofen came to be used in the spinal sac is not really clear but this is now an established method for the treatment of spasticity in many conditions.

How Baclofen works
Baclofen affects the spinal cord, which is the main connection between the brain and the rest of the body. The spinal cord plays a role as a reflex system that functions as a feedback loop. Our most obvious reflex is the withdrawal of our appendages from extreme heat. Baclofen works on this reflex circuit's Renshaw cells. These cells are very sensitive to a neurotransmitter produced by the nervous system, GABA (gamma-amino-butyric-acid), which slows this reflex circuit down. Baclofen mimics the effects of GABA. The dose of intrathecal Baclofen necessary to slow down the reflex circuit is variable but is generally one thousand times (three orders of magnitude) smaller than the oral dose.

Baclofen is a direct agonist of GABAB receptors, which upon activation utilize a G-protein coupled mechanism to increase transmembrane potassium conductance through specific ion channels. Since potassium has a positive charge, and since intracellular potassium concentrations are normally at least ten times that of the extracellular environment, opening potassium channels has an inhibitory, hyperpolarizing effect on a cell's resting electrochemical potential. This tends to decrease the rate of neuronal action potentials, which accounts for Baclofen's anti-spastic effects.

Pharmacokinetics
The drug is rapidly absorbed after oral administration and is widely distributed throughout the body. Biotransformation is low and the drug is predominantly excreted in the unchanged form by the kidneys.

Overdose
Symptoms of a baclofen overdose include vomiting, weakness, drowsiness, slow breathing, seizures, unusual pupil size, and coma.

Underdose
Symptoms of baclofen underdose (via intrathecal delivery) include itching, hypotension, paresthesias, fever, and altered mental state (including delusions and hallucinations).