Mechanism of Action of Benzodiazepines
Primary Mechanism
Benzodiazepines bind to a specific allosteric site located at the interface between the α (alpha) and γ (gamma) subunits of the GABA-A receptor complex, where they act as positive allosteric modulators that enhance—but do not directly activate—the inhibitory effects of GABA. 1
Molecular Binding and Receptor Interaction
Benzodiazepines activate GABA-A receptors in the brain, enhancing the activity of the inhibitory neurotransmitter GABA, thereby reducing the excitability of the central nervous system. 1
GABA is the primary inhibitory neurotransmitter in the central nervous system, and its activation reduces neuronal excitability. 1
The benzodiazepine binding site is distinct from the GABA binding site itself, allowing benzodiazepines to modulate—rather than directly activate—the receptor. 2
Functional Effects at the Receptor Level
Benzodiazepines increase the apparent affinity of GABA for increasing chloride conductance without increasing its efficacy. 2
At the single chloride channel level, benzodiazepine binding results in an increased probability of channel opening events when GABA is present. 2
Specific structural changes occur after benzodiazepine binding: Lys104 in the α1 subunit forms an electrostatic bond with Asp75 of the γ2 subunit, which stabilizes the positively modified state of the receptor. 3
Receptor Subtype Specificity
Most benzodiazepines have non-selective affinity for GABA-A receptors, interacting with α1, α2, α3, and α5 subunits. 1
Benzodiazepines with high affinity for the α1 subunit (such as alprazolam) may cause more sedation and cognitive impairment. 1
The choice of benzodiazepine should consider its affinity for specific GABA-A receptor subunits, which influences clinical effects including sedation, anxiolysis, and cognitive impairment. 1
Reversal of Benzodiazepine Effects
Flumazenil is a competitive antagonist at the benzodiazepine binding site on the GABA-A receptor, reversing CNS and respiratory depression. 1
Flumazenil blocks benzodiazepine sites on GABA-A receptors and antagonizes benzodiazepine actions, used clinically as an antidote for benzodiazepine overdose. 1
Flumazenil has a short elimination half-life of 0.7–1.3 hours and provides antagonism for approximately 1 hour; consequently, re-sedation can occur when used to reverse longer-acting benzodiazepines. 1
Clinical Implications of the Mechanism
Tolerance develops with chronic use as GABA-A receptors undergo adaptive changes, leading to physical dependence and withdrawal risk upon discontinuation. 1
Cognitive impairment, falls, and respiratory depression are direct consequences of excessive GABA-A receptor potentiation, particularly in elderly patients with altered pharmacokinetics. 1
The synergistic respiratory depression that occurs when benzodiazepines are combined with opioids or alcohol results from additive enhancement of GABA-A receptor activity in respiratory control centers. 4