GABA and glutamate pharmacology

Vigabatrin

Irreversibly inhibits GABA transaminase.
increases the amount of GABA available for release
enhances GABA effect at synapses

Tiagbine

inhibitor of GABA metabolism

Competitive inhibitor of GABA transporters.
Increased synaptic and extrasynaptic GABA concentrations
Nonspecific agonism of GABA receptors
Oral medication (rapidly absorbed, 90% bioavailability)
Used in the treatment of epilepsy

y-Vinyl GABA (Vigabatrin)

inhibitor of GABA metabolism

“suicide inhibitor” of GABA transaminase. (Blocks degradation of GABA)
High intracellular GABA concentrations
Increased synaptic GABA release
Nonspecific agonism of GABA receptors
Used in the treatment of epilepsy

Benzodiazepines

GABAa receptor modulators

-Have sedative, hypnotic, amnestic and anxiolytic effects.
-At high doses can cause hypnosis and stupor.
-When used alone, rarely cause fatal CNS depression

Barbiturates

GABAa receptor modulators

First introduced mid-twentieth century.
Can be used to treat epilepsy, as a general anesthetic induction agent and for
control of intercranial hypertension

Diazepam and Alprazolam

Benzodiazepines

chronic severe anxiety and anxiety associated with depression and
schizophrenia

Triazolam and Quazepam

Benzodiazepines

treatment of insomnia via facilitation of sleep onset and duration. (alter sleep
stages)

Clonazepam

Benzodiazepines

Antiepiletic

Zolpidem

Benzodiazepines

used to treat insomnia can cause sleepwalking, sleep-driving and sleep-eating

Anesthetic barbiturates

GABAa receptor agonists and enhances of receptor responses to GABA

Anticonvulsant barbiturates

Influence GABAA receptors at barbiturate- specific sites on the β subunit

Thiopental and Pentobarbital

for inducing general anesthesia. (rapid brain entry)
*High concentrations leads to death

Ethanol

Nonprescription drugs that alter GABA physiology

-Acts as an anxiolytic and sedative via CNS depression.
-Enhances GABAA mediated Cl- influx and inhibits excitatory effects of
glutamate at NMDA receptors (see later).
-Synergist with sedatives, hypnotics, antidepressants, anxiolytics,
anticonvulsants and opioids.
-Tolerance and dependence associated with altered GABAA receptor function

Chloral hydrate

Nonprescription drugs that alter GABA physiology

rarely used old sedative for treatment of insomnia.
Illegally used to incapacitate individuals: a “mickey finn”

y-hydroxybutyric acid

Nonprescription drugs that alter GABA physiology

GABA isomer – sedative and treatment for narcolepsy
“date-rape” drug

Flunitrazepam

Nonprescription drugs that alter GABA physiology

Rohypnol – fast acting benzodiazepine leading to amnesia. “date-rape” drug

Memantine

-Excitotoxicity from excessive glutamate implicated in dementia in Alzheimer’s.
-noncompetitive NMDA receptor antagonist

Amantadine

-In Parkinson’s disease decrease dopaminergic transmission results in over
activation of glutamatergic synapses in the CNS.
-noncompetitive NMDA receptor antagonist in combination with
levodopa can help reduce dyskinesia in Parkinson’s (≈60%)