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GABA Inhibitors

GABA Inhibitors

Article Author:
Kevin George
Article Editor:
Nazia Sadiq
9/6/2020 1:16:35 PM
For CME on this topic:
GABA Inhibitors CME
PubMed Link:
GABA Inhibitors


Gamma-aminobutyric acid (GABA) inhibitors, or GABA antagonists, are drugs that inhibit the action of GABA, the primary inhibitory neurotransmitter of the central nervous system. They predominantly work at the GABA receptor. GABA receptors categorize into the GABA-A receptor and GABA-B receptor subtypes.[1] There also exists a GABA-C receptor, but it is typically classified as a subtype of GABA-A receptors and named GABA-A-rho.[2] While GABA-A receptors are ionotropic receptors that gate chloride channels, GABA-B receptors are metabotropic G-protein coupled receptors. The receptor subtypes can also be differentiated based on their selectivity to agonists and antagonists: GABA-A receptors are antagonized by bicuculline and insensitive to baclofen, whereas GABA-B receptors are agonized by baclofen and insensitive to bicuculline. The potency of most GABA-A receptor antagonists is mostly independent of receptors subunit composition, in contrast to GABA-A receptor agonists.[3]

Examples of GABA-A receptor antagonists include flumazenil, bicuculline, picrotoxin/picrotoxinin, gabazine, suramin, sepranolone, salicylidene salicylhydrazide (SCS), bilobalide, RU5135, and 4-(3-biphenyl-5-(4-piperidyl)-3-isoxazole (3-biphenyl-4-PIOL).[3] Examples of GABA-C receptor antagonists include 1,2,5,6-Tetrahydropyridin-4-methylphosphinic acid (TPMPA).[4]

Examples of GABA-B receptor antagonists include 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP).[4]

Issues of Concern

Mechanism of Action

The mechanism of action of GABA receptor antagonists depends on the drug itself. Bicuculline is a competitive antagonist at GABA-A receptors; it binds to GABA-A receptors and thus inhibits the binding of GABA. Picrotoxinin, the active component of picrotoxin, acts as a non-competitive antagonist at GABA-A receptors, binding to GABA ionophores.[5] Picrotoxin also acts on GABA-C receptors, glycine, and 5-HT3 receptors, binding in the pore region of these ligand-gated ion channels.[3] Gabazine acts as a competitive antagonist at GABA-A receptors.[6] Salicylidene salicylhydrazide (SCS) acts as an inhibitor of the activation of GABA-A receptors containing the beta-1 subunit.[7] RU5135, a steroid derivative, acts as a competitive antagonist with a common site of action as bicuculline but is much more potent than bicuculline. RU5135 also acts as a glycine antagonist.[8] 3-biphenyl-4-PIOL acts as a selective GABA-A receptor antagonist.[9] Suramin is a competitive antagonist selective to GABA-A receptors, specifically the alpha-1-beta-2-gamma-2 GABA-A receptor. Suramin is also a non-selective antagonist of purinergic receptors.[10]

Flumazenil acts as a specific benzodiazepine antagonist at GABA-A receptors. However, research has shown that flumazenil also has partial positive allosteric modulatory activity at GABA-A receptors containing the alpha-6 subunit.[11] Some research suggests that the action of flumazenil can vary depending on the presence of other GABA-A receptor modulators. When given at low doses and in the presence of a benzodiazepine, flumazenil acts as a low efficacy GABA-A receptor antagonist. On the other hand, when given at high doses or in the presence of a GABA-A agonist that acts at a site other than the benzodiazepine site, flumazenil acts as a low efficacy GABA-A receptor partial agonist.[12]

Clinical Significance

GABA receptor antagonists produce convulsant and stimulant effects and mainly have a use for research purposes. For example, bicuculline and gabazine are frequently used to dissect GABA-A receptor components in neurons functionally. These GABA receptor antagonists act as subtype-selective compounds and help to study the behavioral effects of the different GABA-A receptor subtypes.[7]

Not all GABA-A receptor antagonists are convulsants, however, such as the drug bilobalide, derived from Ginkgo biloba. Bilobalide instead acts as an anticonvulsant and neuroprotectant by reducing the release of L-glutamate and reducing excitation, as well as inhibiting GABA synthesis via inhibition of glutamate decarboxylase.[3]

Some GABA receptor antagonists, such as flumazenil, are used for the management of suspected benzodiazepine overdoses and reversal of benzodiazepine sedative effects associated with general anesthesia. Flumazenil is a benzodiazepine GABA-A receptor antagonist, preventing benzodiazepines from binding to the benzodiazepine binding site on GABA-A receptors and preventing the influx of chloride ions and resulting hyperpolarization, thus preventing the GABA-ergic inhibitory effects.[13] In this manner, flumazenil is the antidote when a benzodiazepine overdose is suspected or during procedures that use benzodiazepines as anesthetic agents. Flumazenil can also be useful in the treatment of benzodiazepine dependence and the management of benzodiazepine withdrawal syndrome. It has been shown to alleviate persistent withdrawal symptoms, reduce benzodiazepine craving, and decrease post-detoxification relapse rates.[12]

There has been further research in the clinical indications of flumazenil, with one study finding that flumazenil may improve the features of Parkinson disease.[14] There is also some interest in using GABA receptor antagonists, such as flumazenil, for the treatment of idiopathic hypersomnia, a rare disorder of hypersomnolence that can be distinguished from narcolepsy by the absence of rapid eye movement sleep disturbances. Given that GABA-A receptors regulate sleep and wakefulness, Rye et al. proposed that an excess of GABA signaling may be responsible for idiopathic hypersomnia, and thus, flumazenil may be able to treat the condition. They found flumazenil improved psychomotor vigilance and sleepiness in all patients are roughly 2 hours after administration.[15]

Suramin is an anti-parasitic drug used to treat African human trypanosomiasis or sleeping sickness. However, research has shown that suramin may be used in the treatment of autism by normalizing the hyperactive response of the hypothalamus-pituitary-adrenal (HPA) axis by antagonizing GABA-A receptors.[10]

One study found that sepranolone, a GABA-A receptor modulating steroid antagonist to the progesterone metabolite allopregnanolone, significantly reduced negative mood in women with the premenstrual dysphoric disorder (PMDD).[16]


Nursing, Allied Health, and Interprofessional Team Interventions

Given the full range of clinical applications of GABA receptor antagonists, interprofessional communication, and care coordination is essential when using these medications. For example, physicians, nurses, pharmacists, and other health professionals all must be knowledgeable about treating benzodiazepine overdoses with flumazenil. However, flumazenil’s effects are inconsistent, and not all patients may respond. Additionally, anesthesiologists carry a significant responsibility to be well-versed with GABA receptor antagonists as they may be used to reverse the effects of anesthesia. Further, as research into different GABA receptor antagonists continues to expand their clinical utility, all health professionals must keep up to date on the literature to provide the highest quality of care to their patients. An interprofessional team that prioritizes communication, collaboration, and shared decision making through an integrated, patient-centered approach can enhance outcomes and team performance, which leads to improved patient safety. Each member of the interprofessional team is responsible for identifying complications with the treatment of GABA receptor antagonists and responding appropriately and promptly to ensure the best possible prognosis and outcome.

Nursing, Allied Health, and Interprofessional Team Monitoring

In a healthcare setting, when a patient receives intravenous benzodiazepines, a nurse dedicated to the monitoring of the patient is essential. Also, resuscitative equipment, including flumazenil, must be available in the room even before starting the procedure.


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