Benzodiazepines Mechanism of Action

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Questions and Answers

Which of the following benzodiazepines are short-acting compounds metabolized directly by glucuronidation?

Lorazepam and nordazepam

Estazolam and oxazepam

Diazepam and flurazepam

Alprazolam and triazolam (correct)

What is the main reason why benzodiazepines with long half-lives are more likely to cause cumulative effects with multiple doses?

Because they have a higher affinity for GABA receptors

Because they are metabolized more quickly

Because they accumulate in the body over time (correct)

Because they are more lipid-soluble

What is the main mechanism of action of benzodiazepines in producing anxiolytic effects?

Through activation of GABAA receptors containing the α2 subunit (correct)

Through activation of GABAA receptors containing the α1 subunit

Through activation of dopamine receptors

Through inhibition of glutamate receptors

What is the main effect of benzodiazepines on sleep?

They decrease the latency of sleep onset Signup and view all the answers

What is the main anticonvulsant effect of benzodiazepines?

Inhibition of electrical activity in the CNS Signup and view all the answers

What is the antidote for the depressant actions of benzodiazepines?

Flumazenil Signup and view all the answers

What is the mechanism of action of Z-hypnotics?

They act on a subset of the benzodiazepine receptor family, BZ1. Signup and view all the answers

What is a characteristic of Z-hypnotics compared to benzodiazepines?

They have weaker anxiolytic, anticonvulsant, and skeletal muscle relaxant properties at therapeutic doses. Signup and view all the answers

What is a potential interaction with Z-hypnotics?

Inhibitors of CYP3A4 may prolong the t1/2. Signup and view all the answers

What is a common adverse effect of Z-hypnotics?

GIT upset and CNS effects. Signup and view all the answers

What is a characteristic of Eszopiclone?

It is metabolized by hepatic cytochromes to form an inactive derivative and weakly active desmethyleszopiclone. Signup and view all the answers

Why should the dosage of Z-hypnotics be reduced in elderly patients?

Because they have a slower metabolism of the drug. Signup and view all the answers

What is the primary effect of benzodiazepines on GABAergic synaptic inhibition?

Increase the frequency of channel-opening events Signup and view all the answers

Which of the following subunits is NOT part of the major isoform of the GABAA receptor found in many regions of the brain?

δ Signup and view all the answers

What is the mechanism of action of GABA receptors on neurons?

Induction of hyperpolarization Signup and view all the answers

Which of the following benzodiazepines binds more selectively to GABAA-receptor isoforms that contain α1 subunits?

Zolpidem Signup and view all the answers

What is the effect of benzodiazepines on the affinity of GABA for GABAB receptors?

Have no effect on the affinity of GABA for GABAB receptors Signup and view all the answers

What is the composition of the benzodiazepine receptor subtype BZ1?

α1 and β2 subunits Signup and view all the answers

What is the primary function of the chloride ionophore in the GABA receptor complex?

To induce a shift in membrane permeability, primarily to chloride ions Signup and view all the answers

Study Notes

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

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Description

This quiz covers the mechanism of action of benzodiazepines, including their effect on GABAergic synaptic inhibition and chloride ion conductance. It also explores the interaction between benzodiazepines and GABA receptors.