What is the mechanism of action of benzodiazepines (BZDs)?

From the Guidelines

Benzodiazepines work by enhancing the effect of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, by binding to a specific site on the GABA-A receptor complex, which increases the frequency of chloride ion channel opening, producing sedative, anxiolytic, muscle relaxant, and anticonvulsant effects. This mechanism of action is supported by the most recent and highest quality study available, which highlights the importance of understanding the pharmacodynamics of benzodiazepines in order to optimize their use and minimize potential harms 1.

Key Points

• Benzodiazepines bind to the GABA-A receptor complex, increasing the frequency of chloride ion channel opening, which hyperpolarizes neurons and makes them less excitable 1.
• The effects of benzodiazepines include sedation, anxiolysis, muscle relaxation, and anticonvulsant activity, with different medications having varying onset times and durations of action 1.
• Common benzodiazepines include diazepam, alprazolam, lorazepam, and clonazepam, with dosages varying based on the specific medication and indication.
• Benzodiazepines can cause physical dependence with prolonged use, typically after 2-4 weeks of regular use, and should generally be prescribed for short-term treatment, with tapering recommended when stopping these medications to avoid withdrawal symptoms 1.

Clinical Considerations

• The use of benzodiazepines should be carefully considered, taking into account the potential benefits and risks, including the risk of dependence and withdrawal symptoms.
• Patients should be closely monitored for signs of dependence or withdrawal, and alternative treatments should be considered when possible.
• The co-administration of benzodiazepines with other central nervous system depressants, such as opioids, should be avoided due to the increased risk of respiratory depression and other adverse effects 1.

From the FDA Drug Label

CLINICAL PHARMACOLOGY Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system

CLINICAL PHARMACOLOGY Pharmacodynamics CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system.

The mechanism of action of benzodiazepines (BZDs) is thought to result from a facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system, by binding at stereo specific receptors at several sites within the central nervous system 2 3. Key points about the mechanism of action of BZDs include:

• GABA facilitation: BZDs facilitate the action of GABA, leading to anxiolytic, sedative, muscle-relaxant, anticonvulsant, and amnestic effects.
• Binding to stereo specific receptors: BZDs bind to specific receptors in the central nervous system, which is thought to be the primary mechanism of action.

From the Research

Mechanism of Action of Benzodiazepines

• Benzodiazepines act through allosteric modulation of the GABAA receptor to enhance the activity of GABA, an inhibitory neurotransmitter, resulting in a slowing of neurotransmission and sedative and anxiolytic effects 4.
• They increase the conductance of chloride through ionic channels, promoting a state of central nervous system depression 5.
• The clinical properties of benzodiazepines are dependent upon the composition of the different subunits of the GABAA receptor, with each subunit having multiple subtypes that impart different clinical responses 5, 6.
• Benzodiazepines bind at the interface between an α and γ subunit of GABA(A)Rs, preferentially enhancing synaptic receptors largely composed of α(1-3,5), β3, and γ2 subunits 7.
• They can modulate the GABAA-receptor channel through two separable mechanisms, with distinct components in the nanomolar and micromolar concentration ranges 8.

Subtype-Specific Effects

• Alpha(1)-GABA(A) receptors mediate sedation, anterograde amnesia, and part of the seizure protection, whereas alpha(2)-GABA(A) receptors mediate anxiolysis 6.
• Treatment with benzodiazepines can decrease GABA(A)R surface levels and the efficacy of neuronal inhibition in hippocampal neurons, with a dramatic decrease in surface and total levels of α2 subunit-containing GABA(A)Rs 7.
• The GABA(A)R surface depletion can be reversed by treatment with the BZ antagonist Ro 15-1788, and treatment with leupeptin can restore flurazepam lowered receptor surface levels 7.