Baclofen

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.

Toxicity

The oral LD50 in rats is 145 mg/kg.
Baclofen withdrawal symptoms typically occur within hours to days following interruption of either oral or intrathecal drug formulations. Abrupt discontinuation of baclofen is not advised. Clinical manifestations of baclofen overdose may include altered mental status, somnolence, seizure, hypothermia, respiratory depression, and coma. Overdose from baclofen oral tablets resulted in vomiting, lightheadedness, drowsiness, muscular hypotonia, accommodation disorders, coma, respiratory depression, and seizures. Most overdose symptoms are neurological but uncommon cardiovascular effects such as hypertension, bradycardia, and tachycardia may be observed. In case of overdose, symptomatic treatment and gastric decontamination should be initiated. When the patient is alert, gastric emptying should be performed by inducing emesis and then performing lavage while maintaining an adequate airway and respiration. Emesis should not be induced in unconscious patients.

Chemical properties

Off-White Solid

Originator

Lioresal,Ciba Geigy,Switz.,1971

The Uses of Baclofen

Baclofen may be used as a pharmaceutical secondary reference standard for the determination of the analyte in plasma samples by liquid chromatography tandem mass spectrometry and tablet formulations by UV spectroscopy, respectively.

The Uses of Baclofen

Specific GABA-B receptor agonist. Muscle relaxant (skeletal)

The Uses of Baclofen

(±)-Baclofen has been used as γ-aminobutyric acid receptor B GABA_B?receptor agonist:

• as well as control GABAergic drug to test its protective effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic toxicity
• to test its effects on in vivo motor function tests and performance of mutant mice
• to test its excitability effect on dopaminergic (DA) neurons of the ventral tegmental area (VTA)
• to test its effect in reducing dendritic excitability in Purkinje neurons

Background

Baclofen is a gamma-aminobutyric acid (GABA) agonist used as a skeletal muscle relaxant. Although originally designed in 1962 to treat epilepsy, baclofen was not effective in treating this condition but instead was shown to reduce spasticity in selected patients. Baclofen was reintroduced in 1971 as a treatment for spasticity and was later approved by the FDA in 1977. Baclofen is used to manage severe muscle spasms of cerebral or spinal cord origins, including multiple sclerosis and traumatic brain injury.
Baclofen was investigated for use in alcohol dependence and withdrawal; however, evidence is limited and there is inconsistent evidence to suggest its clinical efficacy in managing alcohol dependence or withdrawal symptoms.

What are the applications of Application

(±)-Baclofen is a selective agonist of the GABAB receptor

Indications

Oral baclofen is indicated for the treatment of spasticity resulting from multiple sclerosis and is particularly useful for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. It may also be used to treat patients with spinal cord injuries and other spinal cord diseases. Baclofen should not be used to treat skeletal muscle spasms resulting from rheumatic disorders.
Intrathecal baclofen is also indicated for the management of severe spasticity of the cerebral or spinal original in patients 4 years of age and older. It is reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable central nervous system side effects at effective doses. For use in spasticity due to traumatic brain injury, baclofen should be considered after at least one year of injury.

Definition

ChEBI: A monocarboxylic acid that is butanoic acid substituted by an amino group at position 4 and a 4-chlorophenyl group at position 3. It acts as a central nervous system depressant, GABA agonist and muscle relaxant.

Manufacturing Process

42.45 g of β-(p-chlorophenyl)glutaric acid imide are stirred into a solution of 8.32 g of sodium hydroxide in 200 ml of water. The mixture is heated for 10 minutes at 50°C, and the solution thus formed is cooled to 10° to 15°C. At this temperature there are then added dropwise a solution of 40.9 g of sodium hydroxide in 200 ml of water and then, in the course of 20 minutes, 38.8 g of bromine. When all has been dropped in, the batch is stirred for 8 hours at 20° to 25°C. The reaction solution is then cautiously adjusted with concentrated hydrochloric acid to pH 7, whereupon finely crystalline γ-amino- β-(p-chlorophenyl)butyric acid settles out. To purify it, it is recrystallized from water. Melting point is 206°to 208°C.

brand name

Kemstro (Schwarz Pharma); Lioresal (Medtronic); Lioresal (Novartis).

Therapeutic Function

Muscle relaxant

Biological Functions

Baclofen (Lioresal) is the parachlorophenol analogue of the naturally occurring neurotransmitter γ-aminobutyric acid (GABA).

General Description

Odorless or practically odorless white to off-white crystalline powder.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Baclofen is an amine. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

Health Hazard

SYMPTOMS: Symptoms of exposure to Baclofen via ingestion may include drowsiness, insomnia, dizziness, weakness, mental confusion, nausea, constipation, anorexia, urinary retention, impotence, nystagmus, diplopia and incoordination. Ingestion may lead to cholinergic effects and lassitude. It may also lead to ataxia. Other symptoms due to ingestion may include impaired renal function, fatigue, headache, hypotension, urinary frequency, rash, pruritis, ankle edema, excessive perspiration, weight gain, nasal congestion, and rarely, euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, tremor, rigidity, dystonia, blurred vision, strabismus, miosis, mydriasis, dysarthia, epileptic seizure, dyspnea, palpitation, chest pain, syncope, dryness of the mouth, taste disorder, abdominal pain, vomiting, diarrhea, blood in the stools, enuresis, dysuria, inability to ejaculate, nocturia and hematuria. Overexposure through ingestion may result in seizures, and coma with respiratory depression. Aspiration pneumonia is a frequent complication of coma with respiratory depression. Other symptoms due to overdosage may include vomiting, muscular hypotonia, drowsiness, and accommodation disorders. Cyanosis has been reported. Chronic ingestion may result in drowsiness, depression, weakness, anxiety, ataxia, headaches, blurred vision, gastric upset and pruritic skin rashes characterized by urticaria or erythematous macular eruptions. Sudden withdrawal after chronic ingestion may cause auditory and visual hallucinations, anxiety and tachycardia. Seizures may also occur after sudden withdrawal. Abuse may lead to drug dependence.

Fire Hazard

Flash point data for Baclofen are not available. Baclofen is probably combustible.

Biological Activity

Selective GABA B receptor agonist. Skeletal muscle relaxant.

Biochem/physiol Actions

Baclofen, a γ-aminobutyric acid (GABA) analog, possesses myorelaxant properties Being a γ-aminobutyric acid receptor B (GABAB) agonist, baclofen may be involved in the potentiation of dendritic potassium K+?channels. It may be useful in blocking transient lower esophageal sphincter relaxation (TLESR)?in gastroesophageal reflux disease (GERD). Baclofen may also have scope for treating addictive especially, in alcohol use disorder (AUD).

Mechanism of action

Baclofen appears to affect the neuromuscular axis by acting directly on sensory afferents, γ-motor neurons, and collateral neurons in the spinal cord to inhibit both monosynaptic and polysynaptic reflexes. The principal effect is to reduce the release of excitatory neurotransmitters by activation of presynaptic GABAB receptors. This seems to involve a G protein and second-messenger link that either increases K⁺ conductance or decreases Ca⁺⁺ conductance.

Pharmacokinetics

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.

Clinical Use

Baclofen is an agent of choice for treating spinal spasticity and spasticity associated with multiple sclerosis. It is not useful for treating spasticity of supraspinal origin. Doses should be increased gradually to a maximum of 100 to 150 mg per day, divided into four doses.

Side Effects

Side effects are not a major problem, and they can be minimized by graduated dosage increases.They include lassitude, slight nausea, and mental disturbances (in including confusion, euphoria, and depression). The drowsiness is less pronounced than that produced by diazepam—an important therapeutic advantage. Hypotension has been noted, particularly following overdose. Elderly patients and patients with multiple sclerosis may require lower doses and may display increased sensitivity to the central side effects. Baclofen may increase the frequency of seizures in epileptics.

Safety Profile

Poison by ingestion,subcutaneous and intravenous routes. Human systemiceffects by ingestion: blood pressure lowering, coma,muscle weakness, pulse rate decrease, respiratorydepression. When heated to decomposition it emits toxicfumes of Cl^-

Synthesis

Baclofen, 4-amino-3-(4-chlorophenyl)butyric acid (15.3.5), is synthesized in two ways. According to the first, 4-chlorobenzaldehyde is condensed with two moles of acetoacetic ester, giving the product (15.3.1), which initially undergoes alkaline hydrolysis and decarboxylation forming 3-(4-chlorphenyl)glutaric acid (15.3.2). Dehydration of this gives 3-(4-chlorophenyl)glutaric acid anhydride (15.3.3), and further treatment with ammonia gives the corresponding glutarimide (15.3.4). Reacting this with an alkaline solution of a halogen (Hofmann rearrangement) gives baclofen (15.3.6).

Veterinary Drugs and Treatments

Baclofen may be useful to decrease urethral resistance in dogs to treat urinary retention. It is not recommended for cats.

in vitro

(±)-baclofen dampened cell growth in human hepatocellular carcinoma (hcc) cells in a dose-dependent manner. (±)-baclofen also caused cell cycle arrest at g0/g1 phase without inducing cell death. additionally, (±)-baclofen-evoked hcc cells proliferation was associated with down-regulation of the intracellular camp level, up-regulation of p21waf1 protein expression and its phosphorylation level, which could be reversed by pretreatment with the gabab antagonist, phaclofen, indicating that (±)-baclofen-evoked growth blockade was exerted in a gabab-dependent fashion [1].

in vivo

the mice, subcutaneously injected with bel-7402 cells, were given an intraperitoneal injection of (±)-baclofen 30 mg/kg every day for 30 days. compared with the control, (±)-baclofen remarkably blocked the bel-7402 xenograft tumor growth without causing toxic effects via measuring the relative tumor volume and the mean body weight change in (±)-baclofen-treated groups, which could make (±)-baclofen as an effective and relatively safe potential drug for the treatment of hcc [1].

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: enhanced muscle relaxant effect with procainamide.
Antidepressants: enhanced muscle relaxant effect with tricyclics.
Antihypertensives: enhanced hypotensive effect. Lithium: use with caution.

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.

Metabolism

Baclofen is rapidly and effectively absorbed after oral administration. It is lipophilic and able to penetrate the blood-brain barrier.Approximately 35% of the drug is excreted unchanged in the urine and feces.

storage

Room temperature

References

[1]. wang, t., huang, w., & chen, f. baclofen, a gabab receptor agonist, inhibits human hepatocellular carcinoma cell growth in vitro and in vivo. life sciences. 2008; 82(9-10): 536-541.