Pharmacodynamics of Benzodiazepines, Barbiturates, & Newer Hypnotics

Question 1

The benzodiazepines, the barbiturates, zolpidem, zaleplon, eszopiclone,
and many other drugs bind to molecular components of the
_____________ in neuronal membranes in the central nervous system.

This receptor, which functions as a chloride ion channel,
is activated by the inhibitory neurotransmitter GABA (see
Chapter 21 ).

Answer 1

GABA A receptor

Question 2

The GABA A receptor has a pentameric structure assembled
from five subunits (each with four membrane-spanning domains)
selected from multiple polypeptide classes (α, β, γ, δ, ε, π, ρ, etc).
Multiple subunits of several of these classes have been characterized,
among them six different α (eg, α1 through α6), four β, and
three γ. A model of the GABA A receptor-chloride ion channel
macromolecular complex is shown in Figure 22–6 .

Question 3

A major isoform of the GABA A receptor that is found in many
regions of the brain consists of two α1, two β2, and one γ2
subunits.

In this isoform, the two binding sites for GABA are
located between adjacent α1 and β2 subunits, and the binding
pocket for benzodiazepines (the BZ site of the GABA A receptor)
is between an α1 and the γ2 subunit.

Question 4

However, GABA A receptors
in different areas of the central nervous system consist of various
combinations of the essential subunits, and the_______________
bind to many of these, including receptor isoforms containing α2,
α3, and α5 subunits.

Answer 4

** benzodiazepines**

Question 5

• *_________** also bind to multiple isoforms of the GABA A receptor but at different sites from those with
• *which benzodiazepines interact**.

Answer 5

Barbiturates

Question 6

In contrast to__________ bind more selectively because
these drugs interact only with GABA A -receptor isoforms that
contain α1 subunits.

The heterogeneity of GABA A receptors may constitute the molecular basis for the varied pharmacologic actions
of benzodiazepines and related drugs (see Box: GABA Receptor
Heterogeneity & Pharmacologic Selectivity).

Answer 6

benzodiazepines,
zolpidem, zaleplon, and eszopiclone

Question 7

In contrast to GABA itself, benzodiazepines and other sedativehypnotics
have a low affinity for GABA B receptors, which are activated
by the ___________ (see Chapters 21 and 27).

Answer 7

spasmolytic drug baclofen

Question 8

GABA (γ-aminobutyric acid) is a major inhibitory neurotransmitter
in the central nervous system (see Chapter 21 ). Electrophysiologic studies have shown that benzodiazepines potentiate GABAergic inhibition at ______________

Answer 8

all levels of the neuraxis, including the spinal cord, hypothalamus,
hippocampus, substantia nigra, cerebellar cortex, and
cerebral cortex.

Question 9

Benzodiazepines appear to increase the efficiency of
GABAergic synaptic inhibition.

The benzodiazepines do not substitute
for GABAbutappear to enhance GABA’s effects allosterically
without directly activating GABA A receptors or opening the associated
chloride channels.

The enhancement in chloride ion conductance
induced by the interaction of benzodiazepines with GABA takesthe form of an increase in the frequency of channel-opening events

Question 10

Barbiturates also facilitate the actions of GABA at multiple
sites in the central nervous system, but—in contrast to
benzodiazepines—________________.

Answer 10

They appear to increase the duration of the
GABA-gated chloride channel openings

Question 11

. At high concentrations,
the barbiturates may also be ________, directly activating
chloride channels.

These effects involve a binding site or sites
distinct from the benzodiazepine binding sites.

Answer 11

GABA-mimetic

Question 12

• *Barbiturates** are
• *less selective** in their actions than benzodiazepines, because they_____________

Barbiturates also
exert nonsynaptic membrane effects in parallel with their effects on GABA and glutamate neurotransmission.

Answer 12

**also depress the actions of the excitatory neurotransmitter glutamic
acid via binding to the AMPA receptor. **

Question 13

This multiplicity of
sites of action of barbiturates may be the basis for their ability to
_________ (see Chapter 25 ) and for their
_____________(which result in their low margin of safety) compared with benzodiazepines and the
newer hypnotics.centrations.

Answer 13

induce full surgical anesthesia

**more pronounced central depressant effects **

Question 14

The barbiturates may also be** _____,** directly activating chloride channels.

These effects involve a binding site or sites
distinct from the benzodiazepine binding sites.

Answer 14

GABA-mimetic,

Question 15

Barbiturates are less selective in their actions than benzodiazepines, because they
______________.

Answer 15

also depress the actions of the excitatory neurotransmitter glutamic
acid via binding to the AMPA receptor

Question 16

Barbiturates also
exert nonsynaptic membrane effects in parallel with their effects
on GABA and glutamate neurotransmission. This multiplicity of
sites of action of barbiturates may be the _____________(see Chapter 25 ) and for their
______________(which result in their
low margin of safety) compared with benzodiazepines and the
newer hypnotics.

Answer 16

• basis for their ability to induce full surgical anesthesia
• more pronounced central depressant effects

Question 17

The components of the GABA A receptor-chloride ion channel macromolecule
that function as benzodiazepine binding sites exhibit
heterogeneity (see Box: The Versatility of the Chloride Channel
GABA Receptor Complex).

Three types of ligand-benzodiazepine
receptor interactions have been reported:

Answer 17

(1) Agonists facilitate GABA actions, and this occurs at multiple BZ binding sites in the case of the benzodiazepines.

(2) Antagonists are typified by the synthetic benzodiazepine derivative flumazenil

(3) Inverse agonists act as negative allosteric modulators
of GABA-receptor function (see Chapter 1 ).

Question 18

Agonists facilitate
GABA actions, and this occurs at multiple BZ binding sites in thecase of the____________.

Answer 18

benzodiazepines

Question 19

As noted above, the nonbenzodiazepines
__________, _____________ and ______are selective agonists at
the BZ sites that contain an α1 subunit.

Endogenous agonist
ligands for the BZ binding sites have been proposed, because
benzodiazepine-like chemicals have been isolated from brain tissue
of animals never exposed to these drugs. Nonbenzodiazepine
molecules that have affinity for BZ sites on the GABA A receptor
have also been detected in human brain.

Answer 19

zolpidem, zaleplon, and eszopiclone

Question 20

(2) Antagonists are typified
by the synthetic benzodiazepine derivative_______, which
blocks the actions of benzodiazepines, eszopiclone, zaleplon, and
zolpidembutdoes not antagonize the actions of barbiturates,meprobamate,
or ethanol.

Certain endogenous neuropeptides are also
capable of blocking the interaction of benzodiazepines with BZ binding sites.

Answer 20

flumazenil

Question 21

Inverse agonists act as negative allosteric modulators
of GABA-receptor function (see Chapter 1 ).

Their interaction
with BZ sites on the GABA A receptor can produce _______ and ______________,
an action that has been demonstrated for several compounds,
especially the β-carbolines, eg, n- butyl-β-carboline-3-carboxylate
(β-CCB). In addition to their direct actions, these molecules can
block the binding and the effects of benzodiazepines.

Answer 21

anxiety and seizures

Question 22

The** ___________** macromolecular complex is one
of the most versatile drug-responsive machines in the body. In addition to the benzodiazepines, barbiturates, and the newerhypnotics (eg, zolpidem), many other drugs with central nervous system effects can modify the function of this important ionotropic receptor.

These include alcohol and certain intravenous
anesthetics (etomidate, propofol)in addition tothiopental.

Answer 22

GABA A -chloride channel

Question 23

For example, etomidate and propofol (see Chapter 25 ) appear
to act selectively at GABA A receptors that contain β 2 and β 3
subunits, the latter suggested to be the most important with
respect to the___________ of these
anesthetic agents.

Answer 23

hypnotic and muscle-relaxing actions

Question 24

The anesthetic steroid ___________ is
thought to interact with GABA A receptors, and these receptors
may also be targets for some of the actions of volatile
anesthetics (eg, halothane).

Answer 24

alphaxalone

Question 25

Other
drugs used in the management of seizure disorders indirectly
influence the activity of the GABA A -chloride channel macromolecular complex by** _____________**

Answer 25

• inhibiting GABA metabolism (eg, **vigabatrin) **or
• reuptake of the transmitter (eg, tiagabine).

Question 26

Central nervous system excitatory agents that act on the chloride
channel include \_\_\_\_\_\_\_\_\_\_ These **convulsant
drugs block the channel directly (picrotoxin)**or**interfere with
GABA binding (bicuculline).**

Answer 26

picrotoxin and bicuculline.