فهم الصيدلة: مزيلات القلق والأدوية المنومة

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