Updated StatPearls Info, Sep/21: GABA Receptor Positive Allosteric Modulators

"GABA Receptor Positive Allosteric Modulators"

https://www.ncbi.nlm.nih.gov/books/NBK554443/#article-2.s2

Excerpt:

Indications

The GABA-positive allosteric modulators used in clinical practice fall under four categories: benzodiazepines, barbiturates, ethanol, and induction anesthetics. There are also drugs used to treat insomnia, e.g., zolpidem. Generally, these drugs will cause sedation, anticonvulsant, anxiolytic, and muscle relaxant effects. The specific indications of each drug appear in outline form below. Benzodiazepines consist of drugs such as alprazolam, lorazepam, diazepam, etc. Most of these agents are recognizable by the suffixes -zolam and -pam.[1][2]

These drugs are now recommended for short-term management of insomnia, panic disorder, and anxiety due to the risk of physical and psychological tolerance and dependence. They are also helpful as abortive medications for generalized clonic-tonic seizures and seizure prophylaxis in alcohol withdrawal. Midazolam and lorazepam are also used for light sedation in short outpatient or interventional radiology procedures. Drugs in this class exert their action by increasing the effects of an agonist when they achieve potentiation.[1]

Most general anesthetics are positive allosteric modulators of GABA-A receptors. Positive allosteric modulators work by increasing the frequency with which the chlorine channel opens when an agonist binds to its own site on the GABA receptor. This action results in an increase in the chloride ion concentration in the postsynaptic neuron and causes immediate hyperpolarization of this neuron, making it less excitable and thus inhibiting the possibility of an action potential. Drugs that act like GABA agonists, the benzodiazepines, are widely used to manage seizures, muscle spasms, insomnia, delirium, and anxiety.[3][4]

Barbiturates were once used to induce sedation but are now used for short-term management of insomnia, seizure prophylaxis, and euthanasia. Phenobarbital specifically can be used in neonatal jaundice. It is also a recognized drug of misuse. Ethanol is a potential drug of abuse. It has a specific application in the septal ablation of patients with symptomatic hypertrophic obstructive cardiomyopathy (HOCM). Intravenous anesthetics such as etomidate, propofol, midazolam, and thiopental are useful for inducing sedation in surgical procedures.[3][5][6][4]

Mechanism of Action

The target of GABA-positive allosteric modulators (PAM) is the GABA-A receptor. The GABA-A receptor is commonly composed of two α (alpha) subunits, two β (beta) subunits, and one γ (gamma) subunit that form a pentamer around the ligand-gated chloride channel. Depending on where the GABA-A receptor is in the CNS, the composition of the subunits in the GABA-A receptor will vary.[1]

The GABA-A receptor is activated when its ligand, GABA, binds to the ligand-binding site. GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the central nervous system. When GABA binds to the ligand site of the GABA-A receptor, the channel opens to allow chloride into the cell. This action results in hyperpolarization of the cell and subsequently diminished action potential, preventing the release of excitatory neurotransmitters.[1]

Drugs in this class exert their action by increasing the effects that an agonist has when achieving potentiation. Most general anesthetics are PAMs of GABA-A receptors. Positive allosteric modulators operate by increasing the frequency with which the chlorine channel opens when an agonist binds to its own site on the GABA receptor. This action results in an increase in the Cl- ion concentration in the postsynaptic neuron and causes immediate hyperpolarization of this neuron, making it less excitable and thus inhibiting the possibility of an action potential. Drugs that act like GABA agonists, the benzodiazepines, are widely used to manage seizures, muscle spasms, insomnia, delirium, and anxiety.[1][6][4]

Most general anesthetics are positive allosteric modulators (PAM) of the GABA-A receptor. Positive allosteric modulators presumably work by enhancing the frequency of opening of the chloride channel when an agonist binds to its own receptor site on the GABA neurons. This change increases the concentration of Cl- ions in the postsynaptic neurons, which results in immediate hyperpolarization of the neuron. The result is that the neuron is less excitable and thus, unable to generate an action potential.[1][6][4]

Alcohol (ethanol) appears to be a GABA-A receptor agonist. GABA is one of the significant inhibitory neurotransmitters in the central nervous system, and GABA-like drugs are often used therapeutically to decrease muscle spasms. The belief is that alcohol mimics the actions of GABA in the brain by binding to GABA-A receptors and inhibiting the generation of nerve action potentials/neuronal signaling.[1]

Benzodiazepines work by increasing the frequency of chloride channel opening, which facilities GABA-A receptor potential, which reduces neuronal firing. Barbiturates work by increasing the duration of time chloride channels are opening, which facilitates GABA-A receptor potential, reducing neuronal firing. Ethanol helps potentiate GABA receptors.[1][2][6]

Administration

GABA-positive allosteric modulators are available for administration in a variety of different dosage forms. Benzodiazepine administration can be oral, parenteral, or rectally. Barbituates can be administered orally, parenterally, or rectally. An ethanol blood alcohol concentration of 20 to 50 mg/dL leads to diminished fine motor coordination. A blood alcohol concentration of 400 mg/dL can cause respiratory depression. Anesthetics such as etomidate and thiopental can be administered intravenously.[1][3][7][8]

Adverse Effects

Benzodiazepine GABA-positive allosteric modulators can cause sedation, dizziness, weakness, unsteadiness, and dependence. Paradoxical agitation may occur in geriatric populations. Barbiturate GABA-positive allosteric modulators can cause sedation, respiratory depression, cardiovascular depression, and dependence. Ethanol GABA-positive allosteric modulators can cause sedation, slurred speech, respiratory depression, cardiovascular depression, and dependence.[9][10]

Contraindications

Benzodiazepine GABA-positive allosteric modulators are contraindicated in patients who have had prior hypersensitivity reactions. Lorazepam contraindications include patients with acute narrow-angle glaucoma. Alprazolam is contraindicated with ketoconazole and itraconazole because of inhibiting the metabolism of alprazolam. Barbiturate GABA-positive allosteric modulators are contraindicated in patients who have had prior hypersensitivity reactions to barbiturate medications. They are also contraindicated in patients with latent porphyria or severe liver and or respiratory disease.[2][8]