Benzodiazepines Mechanism of Action

Receptor Structure and Function

• GABA receptors are membrane-bound proteins divided into two major subtypes: GABAA and GABAB receptors
• GABAA receptors have a pentameric structure assembled from five subunits selected from multiple polypeptide classes (α, β, γ, δ, ε, ρ, etc) to form an integral chloride channel
• Two benzodiazepine receptor subtypes commonly found in the CNS have been designated as BZ1 and BZ2 receptors, depending on whether their composition includes the α1 subunit or the α2 subunit, respectively

Benzodiazepines Mechanism of Action

• Benzodiazepines increase the efficiency of GABAergic synaptic inhibition
• The enhancement in chloride ion conductance induced by the interaction of benzodiazepines with GABA takes the form of an increase in the frequency of channel-opening events
• No change in the conductance or mean open time
• Benzodiazepines do not affect receptors for other amino acids such as glycine and glutamate

GABA Receptors

• The GABAA-receptor (or recognition site), when coupled with GABA, induces a shift in membrane permeability, primarily to chloride ions, causing hyperpolarization of the neuron
• GABA receptor appears to be part of a macromolecule that contains, in addition to the GABAA-receptor, benzodiazepine and barbiturate binding sites and the chloride ionophore (chloride channel)

Benzodiazepine Binding Site Ligands

• Zolpidem, zaleplon, and eszopiclone bind more selectively because these drugs interact only with GABAA-receptor isoforms that contain α1 subunits
• In contrast to GABA itself, sedative-hypnotics have a low affinity for GABAB receptors (spasmolytic baclofen)

Pharmacokinetics

• The metabolism of several commonly used benzodiazepines is affected by inhibitors and inducers of hepatic P450 isozymes
• In very old patients and in patients with severe liver disease, the elimination half-lives of these drugs are often increased significantly
• In such cases, multiple normal doses of these sedative-hypnotics can result in excessive CNS effects

Organ Level Effects

• Anti-anxiety and Sedation: exert calming effects with concomitant reduction of anxiety at relatively low doses, accompanied by some depression on psychomotor and cognitive functions
• Hypnosis: by definition, all of the sedative-hypnotics induce sleep if high enough doses are given
• Anxiolytic effects are mediated by GABAA receptors containing the α2 subunit, while hypnosis and anticonvulsant occur through those with the α1 subunit
• Anesthesia: at higher doses, depress the CNS causing general anesthesia
• Anticonvulsant Effects: capable to inhibit the development and spread of electrical activity in the CNS

Non-Benzodiazepine- (Z Hypnotics)

• Agents: Zolpidem, zaleplon, & eszopiclone (used for insomnia)
• Structurally unrelated to benzodiazepines but share a similar mechanism of action
• Act on a subset of the benzodiazepine receptor family, BZ1
• Compared with the benzodiazepines, they have relatively weak anxiolytic, anticonvulsant, and skeletal muscle relaxant properties at therapeutic doses

Z-Hypnotic Agents

• They have efficacies similar to those of the hypnotic benzodiazepines in the management of sleep disorders, with few withdrawal effects and minimal rebound insomnia
• Little or no tolerance and dependence with prolonged use
• Pharmacokinetics: Zolpidem and Zaleplon are rapidly metabolized to inactive metabolites by hepatic CYP3A4, while Eszopiclone is metabolized by hepatic cytochromes to form the inactive derivative and weakly active desmethyleszopiclone (longer duration of action)
• Dosage should be reduced in patients with hepatic impairment and in elderly
• Inhibitors of CYP3A4 (eg, ketoconazole) may prolong t1/2, while inducers of CYP3A4 (eg, rifampin) increase the hepatic metabolism

Adverse Effects of Z-Hypnotic Agents

• Adverse effects: GIT upset and CNS (dizziness, drowsiness, nightmares, headache, agitation)
• Eszopiclone adverse effects: dry mouth, peripheral edema, and unpleasant taste