in this lecture we're gonna cover the pharmacology of anxiolytic and
hypnotic drugs so let's get right into it the primary use of anxiolytic and
hypnotic drugs is to treat anxiety and insomnia anxiety is generally defined as
an emotional state characterized by excessive feelings of worry fear and
nervousness while insomnia is generally defined as the inability to initiate
maintain or achieve restful sleep now in order to gain better understanding of
how anxiolytic and hypnotic drugs work first we need to discuss the role of
GABA in the central nervous system so gamma-aminobutyric acid or GABA for
short is a major inhibitory neurotransmitter what that means is that
when GABA reaches and binds to specific receptor located on a neuron it reduces
the activity level of that neuron and makes it less likely to fire its action potential
now GABA is recognized by both ligand-gated and
G-protein linked GABA receptors in this lecture we are going
to focus on the ligand-gated GABA receptor called GABA-A as this is the
main target of many anxiolytic and hypnotic agents now the GABA-A receptor is made
up of five subunit proteins arranged to form a central pore these subunits have
been labeled with Greek letters such as alpha beta gamma and delta the subunit
composition of GABA-A receptors in the brain most frequently consists of two
alpha subunits two beta subunits and one gamma or delta subunit furthermore for
each subunit many other subtypes exist the function of each GABA-A receptor
depends on which subunit it contains for example GABA-A receptors containing
alpha-1 subunit appear to be involved in sleep while those that contain alpha-2
or alpha-3 appear to be involved in anxiety now when two GABA molecules bind
to the GABA-A receptor conformational change is induced which
results in opening of the central pore that allows negatively charged chloride
ions to rush into the cell this in turn increases the negative charge inside the
postsynaptic cell which makes more difficult for an excitatory
inputs to cause an action potential now GABA-A receptors are present in high
concentration in the limbic system one part of the limbic system is the
amygdala which contains many neurons that use the neurotransmitter GABA to
control feelings of fear and anxiety in times of stress excitatory neurons in the
amygdala fire rapidly sending excitatory signals to other areas of the brain it
is this type of firing that leads to feeling of panic or fear the inhibitory
interneurons in the amygdala regulate these emotions by releasing GABA the
release of GABA and its binding to postsynaptic receptors such as GABA-A
inhibits the excitatory signals that result in feelings of anxiety and fear
GABA thus has a calming tranquilizing effect on our emotions and prevents us from
becoming overwhelmed in stressful situations now in addition to a distinct
binding site for the neurotransmitter GABA the GABA-A receptor has also a site
at which anxiolytic and hypnotic drugs bind these drugs can be divided into
three groups that is benzodiazepines barbiturates and non-benzodiazepine hypnotics
let's now discuss these one by one in
detail starting with benzodiazepines so benzodiazepines get their name from
their chemical structure which includes a benzene ring fused to a diazepine ring
their binding site appears to be the region between the alpha and gamma
subunit on the GABA-A receptor it's important to remember that
benzodiazepines do not bind to the GABA recognition site located at the junction
of the alpha and beta subunits thereby they don't induce opening of the channel
as directly as GABA instead the binding of a benzodiazepine to its receptor site
increases the affinity of GABA for the GABA binding site this leads to
increased frequency of the channel opening and in turn increased influx of
chloride ions at the postsynaptic cell which ultimately makes it difficult for any
excitatory inputs to cause an action potential so when the excitatory
signals caused by fear or stress are inhibited in this way the result is
decreased anxiety and greater feeling of calm in addition to that benzodiazepines
can also produce mild muscle relaxation as a result of their action on GABA
receptors in the spinal cord cerebellum and brain stem the examples of
benzodiazepines are Alprazolam Chlordiazepoxide Clonazepam Diazepam
Lorazepam and Temazepam when it comes to side-effects of benzodiazepines the most
common ones are related to their sedating and muscle relaxing action they
include drowsiness dizziness decreased alertness and concentration as well as
impairment of motor coordination now let's move on to the next group that is
barbiturates so barbiturates bind to GABA-A receptor
at the alpha or beta subunit which is different from the GABA binding site and
also different from the benzodiazepine binding site now just like
benzodiazepines barbiturates enhance the effect of GABA at the GABA-A receptor
however instead of increasing the ion channel opening frequency they increase
the ion channel opening duration in other words unlike benzodiazepines
barbiturates hold the ion channel open continuously for long periods of time in
addition to that barbiturates can decrease the activity of excitatory
neurotransmitters such as acetylcholine and glutamate and at higher doses they can
also mimic GABA and directly activate GABA receptors thus leading to profound
central nervous system depression this is why barbiturates have a much lower
therapeutic index than benzodiazepines meaning the toxic dose is not much
higher than the therapeutic dose the examples of barbiturates include
Pentobarbital Phenobarbital and Secobarbital when it comes to side
effects barbiturates most often cause dizziness lightheadedness sedation
as well as memory and attention impairments furthermore because of their narrow
therapeutic index it's important to remember that even small barbiturate
overdose can result in coma or death due to respiratory depression now let's move
on to our last group of drugs that is non-benzodiazepine hypnotics as I
mentioned at the beginning of this lecture
GABA-A receptors in different areas of the central nervous system consist
of various combinations of the subunits the specific subunit that appears to
mediate sedation is the alpha-1 isoform so as their name suggests
non-benzodiazepine hypnotics are structurally different from the
benzodiazepines and as you may already guessed they selectively bind to the
alpha-1 subunit of the GABA-A receptor thus triggering chloride channel opening
with resulting membrane hyperpolarization because alpha-1
containing GABA-A receptors are highly expressed in wake promoting regions of
the brain the preferential binding of non-benzodiazepine hypnotics to these
receptors results in sleepiness but not anti-anxiety effect the examples of
non-benzodiazepine hypnotics are Zolpidem Zaleplon and Eszopiclone when
it comes to side-effects non-benzodiazepine hypnotics can cause
cognitive impairments including memory loss daytime sedation as well as impairment
of motor function and with that I wanted to thank you for watching I hope you
enjoyed this video and as always stay tuned for more