Podcast
Questions and Answers
Which of the following benzodiazepines are short-acting compounds metabolized directly by glucuronidation?
Which of the following benzodiazepines are short-acting compounds metabolized directly by glucuronidation?
What is the main reason why benzodiazepines with long half-lives are more likely to cause cumulative effects with multiple doses?
What is the main reason why benzodiazepines with long half-lives are more likely to cause cumulative effects with multiple doses?
What is the main mechanism of action of benzodiazepines in producing anxiolytic effects?
What is the main mechanism of action of benzodiazepines in producing anxiolytic effects?
What is the main effect of benzodiazepines on sleep?
What is the main effect of benzodiazepines on sleep?
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What is the main anticonvulsant effect of benzodiazepines?
What is the main anticonvulsant effect of benzodiazepines?
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What is the antidote for the depressant actions of benzodiazepines?
What is the antidote for the depressant actions of benzodiazepines?
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What is the mechanism of action of Z-hypnotics?
What is the mechanism of action of Z-hypnotics?
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What is a characteristic of Z-hypnotics compared to benzodiazepines?
What is a characteristic of Z-hypnotics compared to benzodiazepines?
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What is a potential interaction with Z-hypnotics?
What is a potential interaction with Z-hypnotics?
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What is a common adverse effect of Z-hypnotics?
What is a common adverse effect of Z-hypnotics?
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What is a characteristic of Eszopiclone?
What is a characteristic of Eszopiclone?
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Why should the dosage of Z-hypnotics be reduced in elderly patients?
Why should the dosage of Z-hypnotics be reduced in elderly patients?
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What is the primary effect of benzodiazepines on GABAergic synaptic inhibition?
What is the primary effect of benzodiazepines on GABAergic synaptic inhibition?
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Which of the following subunits is NOT part of the major isoform of the GABAA receptor found in many regions of the brain?
Which of the following subunits is NOT part of the major isoform of the GABAA receptor found in many regions of the brain?
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What is the mechanism of action of GABA receptors on neurons?
What is the mechanism of action of GABA receptors on neurons?
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Which of the following benzodiazepines binds more selectively to GABAA-receptor isoforms that contain α1 subunits?
Which of the following benzodiazepines binds more selectively to GABAA-receptor isoforms that contain α1 subunits?
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What is the effect of benzodiazepines on the affinity of GABA for GABAB receptors?
What is the effect of benzodiazepines on the affinity of GABA for GABAB receptors?
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What is the composition of the benzodiazepine receptor subtype BZ1?
What is the composition of the benzodiazepine receptor subtype BZ1?
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What is the primary function of the chloride ionophore in the GABA receptor complex?
What is the primary function of the chloride ionophore in the GABA receptor complex?
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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.
