From the Guidelines
Benzodiazepines primarily 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, hyperpolarizing the neuron and producing anxiolytic, sedative, 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.
The primary mechanism of action of benzodiazepines involves the activation of GABA neuronal receptors in the brain, leading to anxiolytic, amnestic, sedating, hypnotic, and anticonvulsant effects, but no analgesic activity 1. The potency and duration of action of benzodiazepines vary among different agents, with lorazepam being more potent than midazolam, which is more potent than diazepam 1.
It's essential to consider the potential risks associated with benzodiazepine use, including physical dependence with prolonged use, and the potentiation of their effects by other central nervous system depressants like alcohol, which can lead to dangerous respiratory depression 1. The use of benzodiazepines should be carefully balanced against the risk of harms, particularly in populations that are more susceptible to their adverse effects, such as the elderly and those with underlying medical conditions 1.
In clinical practice, the selection of a benzodiazepine should be based on the individual patient's needs and circumstances, taking into account factors such as the desired duration of action, the presence of underlying medical conditions, and the potential for drug interactions 1. By understanding the primary mechanism of action of benzodiazepines and carefully considering their potential benefits and risks, healthcare providers can optimize their use and minimize the risk of adverse effects.
From the FDA Drug Label
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 primary mechanism of action of benzodiazepines (BZDs) is binding to stereospecific receptors at several sites within the central nervous system. However, their exact mechanism of action is unknown 2.
From the Research
Mechanism of Action of Benzodiazepines
The primary mechanism of action of benzodiazepines (BZDs) involves the potentiation of neural inhibition mediated by gamma-aminobutytic acid (GABA) 3. This is achieved through their actions on the ionotropic GABA(A) receptors in the central nervous system. Key aspects of this mechanism include:
- Benzodiazepines do not activate GABA(A) receptors directly but require GABA to exert their effects 3.
- They enhance the activity of GABA by increasing the apparent affinity of GABA for increasing chloride conductance without increasing its efficacy 4.
- On the single chloride channel level, benzodiazepines seem to increase the probability of channel opening events 4.
- The benzodiazepine receptor (BZR) is a site on the GABA receptor-chloride channel complex, through which the gain of the signal transducer function of the latter is allosterically modulated 4.
Effects on GABA(A) Receptors
Benzodiazepines have a specific interaction with GABA(A) receptors, which can be modulated by different classes of ligands, including:
- Agonists, which increase the gain of the GABA-R function 4.
- Competitive antagonists, which do not alter the gain of the GABA-R function 4.
- Inverse agonists, which reduce the gain of the GABA-R function 4.
- Partial agonists and partial inverse agonists, which can have interesting therapeutic applications 4.
Signaling Cascade Activation
Prolonged exposure to benzodiazepines, such as diazepam, can activate an L-type voltage-gated calcium channel/Ca2+/protein kinase A (PKA) signaling cascade, leading to the down-regulation of the GABAA receptor α1 subunit 5. This signaling cascade involves the activation of PKA and is accompanied by the activation of transcription factors, such as the cAMP-response element-binding protein (CREB) and the inducible cAMP early repressor (ICER) 5.