Hello friends, once again welcome to your favorite pharma channel Ram Pharma Academy. Myself Mr. Ram Rao Fad, Assistant Professor at Maharashtra College of Pharmacy, Nilanga. In this video, we are going to discuss about the mechanism of action of GABA, that is Gamma Amino Bacteric Acid, Barbiturates and Benzodiazepines with animation at the receptor site.
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GABA, barbiturates and benzodiazepines primarily shows the pharmacological activity by binding to various sites present on the GABA-A benzodiazepine receptor chloride channel complex. GABA receptors are of three types GABA A, GABA B and GABA C. Out of which GABA B is the GPCR that is G protein coupled receptor while the GABA A and GABA C are ligand gated chloride ion channels. Here we are going to focus only on the GABA A receptor.
GABA-A benzodiazepine receptor chloride channel complex is a pentameric transmembrane anion channel which is composed of 5 alpha, beta, gamma and in some cases the delta, epsilon, theta or pi subunits. The most commonly found isoform is composed of 2 alpha subunits, 2 beta subunits and 1 gamma subunit. Initially, this channel is closed which is shown with the black oval in the center of the channel complex.
The primary ligand or primary agonist to open this chloride channel is the GABA i.e. gamma-aminobutyric acid, which acts as a primary inhibitory neurotransmitter in the central nervous system. Only the alpha and beta subunits are required for GABA action, and most likely the binding site for GABA is located on the beta subunit, as shown here as GABA-A receptor. Then, the second site where drugs belonging to benzodiazepine class can act is the benzodiazepine receptor.
This benzodiazepine receptor is present at the interface of alpha and gamma subunit as shown here with white square. Then the third important site where drugs belonging to barbiturate class can act is the barbiturate receptor or barbiturate binding site. The barbiturate site appears to be located on alpha or beta subunit. Here I have shown it on the alpha subunit. Now the important thing that we required is the chloride ions.
Right now you can see these chloride ions cannot enter into the cell because the channel is closed. Which will get opened upon binding of these drugs that we are going to discuss today. So, one by one we are going to discuss about the mechanism of action of all the drugs like GABA, barbiturates and benzodiazepines.
Let's start with the GABA first. GABA is the primary agonist of GABA-A benzodiazepine receptor chloride channel complex. Here you can see chloride ions cannot enter into the cell as the channel is closed. But when GABA binds with the GABA-A receptor as shown here, this binding leads to the conformational changes in the subunits of channel complex and channel gets opened.
Upon opening of the channel now chloride ion can enter into the cell as shown with the animation which increases negative voltage membrane potential and leads to the hyperpolarization of cell membrane as the negative charge gets entry into the cell and This potential is known as inhibitory post synaptic potential. That is IPSP Formation of inhibitory post-synaptic potential inhibits the generation of action potential in the cell, which blocks the further impulse conduction and leads to the CNS depression. In this way, GABA acts as a inhibitory neurotransmitter and produces CNS depression. Now, before talking about the mechanism of action of barbiturates and benzodiazepines, remember that sequence of events after the entry of chloride into the cell are similar to GABA action. Only the difference is that how channel is opened with the barbiturates and benzodiazepines.
That we are going to learn now. Let's move on to the mechanism of action of barbiturate drugs. Barbiturate drugs like phenobarbitone, amobarbital, secobarbital, etc. binds with the barbiturate site present either on alpha or beta subunits of GABA-A benzodiazepine receptor chloride channel complex. Here, barbiturates produces GABA-facilitated reaction.
By which they help the binding of GABA with the GABA-A receptor and increases the duration of opening of chloride channel. By which more amount of chloride can enter into the cell which leads to the hyperpolarization of cell membrane and stop the impulse conduction and produces CNS depression. So here barbiturates produces GABA-facillatory reaction.
But at higher concentration of barbiturates they can open the chloride channel complex directly also and hence produces GABA mimetic action. So barbiturates have both actions GABA facilitatory action and GABA mimetic action. Along with actions on the GABA receptor, barbiturates can block the excitatory neurotransmitter glutamate by blocking the AMPA receptors for glutamate.
In the case of the benzodiazepine class of drugs, they cannot open the channel directly in the absence of GABA. That means, even at higher concentration, benzodiazepine cannot open the chloride ion channel directly. So, benzodiazepines only have the GABA-facilitary reaction that we are going to learn now. Benzodiazepine class of drugs like diazepam, oxazepam, nitrazepam etc. binds with the benzodiazepine receptor present at the interface of alpha and gamma subunit of GABA-A benzodiazepine receptor chloride channel complex.
Upon binding, benzodiazepines increases the frequency of opening of chloride channel. Here you can see channel is getting open again and again which allows the entry of chloride into the cell and leads to the hyperpolarization of the cell. cell.
So here benzodiazepines acts as a GABA facilitators and not the GABA mimetics. So only benzodiazepines helps the binding of GABA with the receptor again and again hence increases the frequency of opening of chloride channel. Now moving to the last part of the video that is differences between the mechanism of action of barbiturates and benzodiazepines. First difference is barbiturates have GABA facilitatory action by increasing duration of opening of chloride channel.
While in the case of benzodiazepines, benzodiazepines also have GABA facilitatory action but by increasing frequency of opening of chloride channel and not the duration of opening. So, in case of barbiturates, duration of opening of chloride channel is increased while in case of benzodiazepines, it increases the frequency of opening of chloride channel. In both cases, it allows the entry of chloride into the cell.
Then, second difference is, at higher concentration, barbiturates can open the channel directly, and hence, they have the GABA mimetic action too. While in case of benzodiazepines, even at higher concentration, they cannot open the channel directly, that is, in the absence of GABA, and hence, they only have the GABA facilitated reaction, and not the GABA mimetic action. Ok students, this is the end of the tutorial.
In this video we have learned about the mechanism of action of GABA, barbiturates and benzodiazepines with animation. If you want more videos like this, please like and share the video with all your friends and don't forget to subscribe to our channel. Thanks for watching. Goodbye. Take care.