Anxiolytic & Hypnotic Drugs

foreign what's up Ninja nerds in this video today we're going to be talking about anxiolytics and hypnotics before we get started really into the lecture if you guys do like this video it makes sense it helps you guys to really kind of overcome this challenging topic because it really can be please support us the best way that you can do this by hitting that like button commenting down in the comment section and also subscribing also if you guys do want some notes and some illustrations that are really great help you guys to truly understand the topic go down in the description box below we have a link to our website where we have some awesome notes and illustrations let's get into let's talk about anxiolytics and hypnotics so when we talk about this we really have to get down to the kind of basic pathophysiology and what I mean basic I really mean basic I don't want to get too crazy I just want you to understand what anxiety truly is right so it's this kind of sense of unpleasant sensation of fear or apprehension that can present with physical symptoms right and we'll talk about that oftentimes it's like tachycardia palpitations hypertension maybe a little bit of breathing fat some Tremors some diaphoresis those are common features of anxiety well anxiety really when it comes down to it is due to some type of limbic system dysfunction right you know there's so many nuclei involved in our limbic system we're not going to go through that aspect but what I do want you to know is that the limbic system is the one responsible for our emotional aspects of our body right so it's the emotional component of our brain it's also involved in memories as well but there's some degree of limbic system dysfunction here and that's really what it's coming down to in this particular disease now if we dig into it a little bit more right so the limbic system is obviously important for memory it's important for emotions and our behaviors so if there's some dysfunction of the limbic system it's not out of this world to think that it can precipitate anxiety which is a type of emotion unpleasant sensation of fear and apprehension so what causes the limbic system dysfunction is really the question right well there's some particular neurons that are involved in the limbic system that actually release very specific types of neurotransmitters you know what those neurotransmitters are the two neurotransmitters that are integral to the function of the limbic system is going to be Gaba so Gaba is a very important one here this is also referred to as gamma aminobutyric acid and the other one believe it or not to a degree is also called serotonin we also write this as five hydroxytryptamine these definitely have an influence on the limbic system and so whenever Gaba is present and whenever serotonin is present what this generally will do is this will help to be able to maintain a good control of the limbic system but what if for some reason there's decreasing Gaba activity or there's decreasing serotonin activity if there's decreasing gab activity or decreasing serotonin activity this really kind of causes a lot of dysfunction of the limbic system when the limbic system becomes dysfunctional there's an excessive excitation of the sympathetic nervous system so now the sympathetic nervous system becomes hyperactive because of these low transmitters so these neurotransmitters are really really low it causes the limbic system to now become dysfunctional that then hyper stimulates the sympathetic nervous system the sympathetic nervous system then has the ability to go and stimulate multiple different organ systems like the heart and here it increases your heart rate it increases your blood pressure it acts on the muscle spindles and causes Tremors it acts on your sweat glands and causes diaphoresis it also acts on your respiratory system and maybe it kind of increases your respiratory rate all of these things are physical symptoms or features of anxiety and that's really the kind of the Crux of this disease so anxiety is limbic system dysfunction categorized by low amounts of Gab activity and low amounts of Serotonin activity that leads to this function of the limbic system and then hyperactivates the sympathetic nervous system which leads to all of this type of fear and apprehension response now the basic thing that I want you to take away from this is that anxiety is classified by low levels of Gaba and low levels of Serotonin and that's really what it comes down to in this particular disease and to give you kind of an understanding of this we'll kind of have a basic diagram here here's going to be a neuron of the limbic system right here's the neuronal limbic system and what it'll do is it'll signal to your sympathetic nervous system we have neurons such as serotonin neurons and we have neurons called gabergic neurons and what happens is this one releases Gaba Gaba is an inhibitory neurotransmitter so it's supposed to inhibit inhibit this limbic system neuron which would inhibit it from actually causing a lot of sympathetic Cascade but if you have low levels of Gaba what's going to happen low levels of Gaba will no longer be able to inhibit this and so this inhibition factor is gone and then you increase the sympathetic nervous system the other one is your serotonin this is five hydroxytryptamine when there's low levels of Serotonin it no longer is able to stimulate these coppergic neurons so normally it should be able to stimulate these gabergic neurons and then Gaba would inhibit the actual limbic system from causing a sympathetic response but if you have low levels of Serotonin you're not going to be able to stimulate Gaba Gaba will no longer be able to inhibit the limbic system activity and the sympathetic Cascade will increase the that's the basic pathophys so this is the big things that I really want you to know for anxiety now let's now talk about insomnia because now we're going to talk about hypnotic agents so anxiety we're going to use drugs that are going to try to increase Gavin increase serotonin the anxiolytic effects they'll cut the anxiety or in this situation insomnia the inability to sleep we're going to talk about drugs that are going to be hypnotic agents but first we have to understand the pathophysiology of insomnia I'm a friend so insomnia is the inability to fall asleep or maintain sleep right and why is that well there's a couple different structures that are really involved in this and really to come down to the most simplistic aspect you have some structures like the pineal gland right so the pineal gland is a really really important one it releases a particular hormone called melatonin so that's one particular structure that's involved in sleep cycles the other one is your hypothalamus and there's many different nuclei of the hypothalamus okay many different nuclei of the hypothalamus and then the last structure here that's really really important is called your reticular formation and there are so many different nuclei that are involved in the reticular formation but there is some type of dysfunction between the communication and these particular structures so what's really going on is that there is some type of disconnection usually these structures should talk to one another but there is some type of abnormality here where they're not actually communicating properly with one another let's dig into that a little bit more so what I actually want to do is I want to take some of these structures of the pineal gland the hypothalamus in a particular formation zoom in on them and talk about some of the neurotransmitters that it's involved and how they interact between these different structures and what's the real pathophysiology or this disconnect if you will so the first component is the pineal gland normally when the pineal gland is activated usually when a patient's in exposed to dark lights they should produce melatonin that's the first particular neurotransmitter that I want you guys to know or hormone so this first one is going to be called Mela tonin now when a person is in dark light melatonin should be released and what melatonin should do is is it activates acts on what's called melatonin one and melatonin two receptors that are present on the structure called the suprachiasmatic nucleus this is a really important structure that regulates our circadian rhythm it's found in the hypothalamus what melatonin acts on the suprachiasmatic nucleus it should naturally work to inhibit the supracasmatic nucleus turn him off so when he's off that's really when we want to try to do what go to sleep so naturally what should happen is this should normally do what this should inhibit the supracasmatic nucleus when the suprachiasmatic nucleus is inhibited it no longer will cause this inactivation of this structure so this is one of the structures of the hypothalamus that's really really important it's called the ventrilateral pre-optic nucleus I'm going to abbreviate that the vlpo it's found in the hypothalamus when the supracasmatic nucleus is inhibited what it generally will do is is it'll activate the vlpo so it'll stimulate the vlpo it should stimulate it now the vlpo has two things that it does one is when it's active it should promote sleep it should promote sleep it wants to promote sleep but in order for it to promote sleep it has to suppress arousal or wakefulness so how does it do that so then what happens is the vlpo secretes very specific types of neurotransmitters that suppress all these different nuclei so you have What's called the tubular mammillary nucleus the lateral hypothalamic nucleus and so many nuclei of the hypothalamus I'm sorry the reticular formation so you have the reticular formation nuclei and the posterior hypothalamic nuclei what happens is the ventral lateral pre-optic nucleus releases something called gamma amino butyric acid and what gamma aminobutyric acid should do to I want you to think about your reticular formation and your posterior hypothalamus is it should inhibit them if it inhibits them it should then inhibit arousal and wakefulness so now the vlpo is activated because of melatonin right because melatonin inhibits the supracasmatic nucleus which activates the vlpo vlpo promotes sleep and then it suppresses arousal and wakefulness by releasing Gaba to inhibit the reticular formation in the posterior hypothalamus that's the really cool concept now at the same time at the same time whenever a person is having insomnia right what you see in this particular process is that you wouldn't want to promote sleep you wouldn't want to promote sleep you want to promote arousal wakefulness if they have insomnia so imagine now I drop my melatonin levels if I drop my melatonin levels will I be able to inhibit the supracasmatic nucleus no so I will no longer be able to inhibit this bad boy if I can't inhibit him will I be able to activate the vlpo no so I won't be able to activate the vlpo if the vlpo is activated will it be able to promote sleep no and if he can't promote sleep can he then suppress the reticular formation and the posterior hypothalamus no he can't suppress it and therefore he can't suppress arousal wakefulness that's one particular problem so one part of this disease process insomnia is that the patient may have low levels of what melatonin now let's think about the next aspect here what if we go to the the second part here so get rid of melatonin let's say that the vlpo now is in this state where it's supposed to be active when it's active it wants to promote sleep so it'll do that right but in order for it to do that it has to suppress the posterior hypothalamus in particular formation so releases Gaba what if we had low levels of Gaba because Gaba is essential for being able to suppress the reticular formation and suppress the poster hypothalamus if we have low Gaba levels we'll be able to suppress this anymore no so you can't suppress it you can't suppress arousal and you won't be able to suppress the arousal on wakefulness and you won't be able to promote sleep so there's another particular problem is low levels of Gaba so if you have low levels of Gaba and low levels of melatonin the reticular formation will then be hyperactive and the vlpo will be inactive there's another particular concept here the reticular formation releases chemicals that are supposed to naturally inactivate the vlpo and if you inactivate the vlpo it would inhibit sleep right it would inhibit sleep now what are these chemicals that the poster hypothalamus and the particular formation releases to suppress the vlpo those chemicals are called orexin and histamine histamine so these chemicals naturally are going to suppress the vlpo which would then suppress sleep if you inhibit this are you going to be able to promote sleep no if you inhibit this is the vlpo going to be able to inhibit the reticulate formation no so the reticular formation will be active and then trigger arousal wakefulness so these would be the bad boys if they're in higher levels they're going to suppress the vlpos suppress sleep and keep the reticular formation activated to promote arousal wakefulness that's terrible but that is another pathophysiological concept here is that you can have hyal rexins and high histamine levels so that's the other pathophysiological process here so when it comes down to it the big thing that I want you to take away from this is that whenever you have low melatonin levels and low Gaba this will cause insomnia hyorexin levels and high histamine levels this will also cause insomnia and the basic concept behind this is that if you cause if this is all basically happening what all of these things are doing is is they are inhibiting the vlpo which is going to inhibit sleep and these are all going to stimulate the reticular formation and that is going to stimulate arousal or wakefulness and again inhibit sleep and that is the concept here so if we come up with hypnotics the hypnotic should be able to increase melatonin increase Gaba decrease orexin and decrease histamines whereas with anxiolytics we need to come up with drugs that increase Gaba and increase serotonin so now let's talk about those drugs that actually act as an anxiolytic and the drugs that act as hypnotics and patients who have anxiety or insomnia are my friends so not anxiolytics we got to give the drugs now that are going to be able to help these patients who are having anxiety so when we think about this let's talk about two things one is the mechanism so really how are these drugs actually helping to increase Gaba or increase serotonin because that was the whole goal right and then what are some of those drugs what are some of the names of those drugs that we're actually going to talk about so first thing for anxiolysis with mechanism here is again we have two particular neurotransmitters here one is this neurotransmitter right here my friends so this is a neuron that's going to be releasing something called five hydroxytryptamine that's also known as serotonin so this is also referred to as serotonin now serotonin is low in anxiety but it's also low in another disorder called depression and depression and anxiety often sometimes are good cousins or friends of one another and so they often coexist whenever there's low levels of Serotonin which we said that was the process of anxiety is there's low levels of Serotonin what was the problem with that well serotonin is naturally supposed to bind onto this receptor here you see this receptor on this blue neuron this is called a five-hydroxytryptamine receptor a serotonin receptor when serotonin binds onto this receptor it's supposed to stimulate so it should cause like a cationic influx and stimulate this neuron this neuron releases a neurotransmitter called Gaba and Gaba is supposed to naturally do what inhibit this limbic system neuron so naturally what it's supposed to do is is it should work to bind onto this particular sector so this is Gaba Gaba should bind into that little pocket there this little receptor here you see this receptor this is a really important receptor this receptor here is called the Gaba a receptor very very important receptor when Gaba binds onto this little pocket here and we'll talk about that a little bit it opens up this channel to allow for chloride ions to flow in these are negative ions when negative ions flow into this particular neuron what it's supposed to do is is it causes the cell to become super negative you know we call that when the cell becomes super negative it causes hyper polarization hyper polarization basically makes the cell super negative and that should decrease the action potentials so then the limbic system neuron shouldn't be firing excessively and so because of that there should be a decreased sympathetic effect so decrease fear apprehension tachycardia hypertension respiratory rates aren't going up as much you aren't having Tremors or diaphoresis as much right and so that's really what the benefit of Gaba would be but if you're having low serotonin you're not going to tell these neurons to make Gaba and so because of that the Gaba would be hello the Gaba would be low Gaba wouldn't be able to work on this receptor it wouldn't be able to allow for chloride and influx to cause hyperpolarization to decrease Action potentials so that's really what it comes down to in this particular process so what if I came up with a drug that specifically worked one of these drugs I'm going to use a drug and what I'm going to do is I'm going to inhibit that particular receptor right there that little protein there you know what that protein is supposed to do when serotonin is done exerting its function it's supposed to go back in to the axon right it's supposed to go back into the axon but then that lowers the serotonin level in the synapse what if I came up with a drug that inhibited that serotonin reuptake protein so I'm going to inhibit this Sarah this re-uptake protein this re-uptake mechanism I'll inhibit that what does that do to the serotonin now in the synapse if I don't take it back into the axon it's going to stay here now so what happens to the serotonin levels they go up if serotonin levels go up now then I'm going to be able to increase the stimulation of these cabergic neurons then they're going to release a lot of Gaba if they release a lot of Gaba then Gaba will be able to inhibit these particular neurons by causing chloride and influx because it'll stimulate this Gaba a receptor it'll increase hyperpolarization and if you do that it'll really really decrease the action potentials and decrease the sympathetic response that's a really cool concept another thing is if I had a drug that actually had the ability to bind so let's say I have another drug and it directly binds to this receptor so it stimulates the receptor and that increases the positive ions increases Gaba increases The Binding of Gaba receptor increases hyperpolarization decreases action potential and decrease the sympathetic or anxiety response that'd be another benefit too what are these drugs that can increase serotonin by inhibiting reuptake or drugs that combine directly to the serotonin receptor these would include your ssris so your selective serotonin reuptake Inhibitors will inhibit the reuptake of Serotonin there's another group which actually and blocks the reuptake of Serotonin and norepinephrine but they again they block the reuptake of Serotonin so these are two drug categories that are going to do what inhibit reuptake so these two here these ones specifically here is going to inhibit re-uptake and this one here is going to re inhibit reuptake and that's how it'll increase the serotonin activity these drugs include which ones so ssris I want you to remember escitalopram escitalopram citrulline is another particular big one here paroxetine is another one as well so these are some of the drugs that I want you guys to remember the snris are going to be things like venlaflaxine so venlaflaxine and Duloxetine Duloxetine these are going to be some of the drugs that we can utilize in anxiety but more specifically we'll talk about later chronic anxiety because patients who have chronic anxiety likely have some degree of associated depression and these drugs have been shown to be more effective and less abuse potential than the next drug category that we'll talk about the ones that affect Gaba and the last one is Boost Brown and boost bronze have actually been shown too directly stimulate the 5 h t receptor and this is going to be the name of that drug booster and there is no specific category it's just boost Pro there is even some thought that it actually may affect some of the dopamine receptors as well but for right now keep it simple we're going to focus on serotonin okay so that's one set of drugs ssris snris both inhibit the re-uptake of Serotonin increase the serotonin the synapse or buspirone which binds onto the serotonin receptor that will increase the inhibition of the limbic system and inhibit the sympathetic response what if I avoid the serotonin now and I just focus on Gaba the problem with Gaba was low so Gaba wasn't actually being either released enough or wasn't acting on this receptor properly well what if I gave drugs that either increased some way shape or form the gab activity what if I gave a drug that specifically specifically hit right here it stimulated this particular receptor so it stimulated the Gaba a receptor it bound onto the Gaba a receptor and enhanced the activity of the gabri receptor so Gaba doesn't even have to be present this drug will bind onto that little that little socket there on the Gaba receptor open it up that'll increase chloridine influx that'll increase hyperpolarization that will decrease the action potentials of the limbic system and suppress the sympathetic anxiety and fear response that's a pretty cool concept so we need to give drugs that are going to increase gab activity we specifically call these ones just so you know these are actually called Gaba Agonist that's really what we should call them so they're not increasing the levels of Gaba but they're kind of acting like Gaba and so they have the same effect so that's really really important because when you think about this if we were to actually take this gab a receptor and zoom in on it a little bit here it is it's a pentameric type of protein and it's made up of different subunits so you have one of the subunits a gamma subunit you have a beta one subunit you have a beta 2 subunit you have a alpha one subunit and an alpha two subunit out of all of these the one that's actually been shown to be most specific to actually inhibiting the limbic system neurons is the alpha two very very important so the alpha two is the one specific subunit that these Gaba agonists actually bind to so when Gaba agonists actually helped to open up this Gaba a receptor which of the actual sites do they have to bind onto in order to activate this Channel and cause chloride ions to flow into the cell they have to bind onto the Alpha 2 subunit that's very very important so again I want to write it down so that you understand here it's going to bind onto the Alpha 2 subunit of the Gaba a receptor what are these drugs that have this Gaba a agonistic activity or the Gaba a gab activity that's agonistic like these are going to be barbiturates and benzodiazepines but here's the thing I don't even want to waste any time we don't even use barbiturates anymore for anxiolysis the reason why is there's just too much toxicity with this drug there's so many there's so much more risk than there is benefit to the treatment of anxiolysis we use barbiturates more specifically in other things so seizure activity uh anesthesia or maybe even inducing a coma to reduce ICP but it is not an effective agent for anxiolitis because of the adverse effects of it so what we may utilize instead because there's not as many adverse effects as severe as barbiturates is benzodiazepines benzodiazepines there's different types so we can use them based upon their Half-Life so if something acts very very quickly and it gets metabolized and gets removed from the body or excreted it's clear quickly it's Half-Life is very short so that would be good drugs that you maybe you don't want to have it last as long all right so short acting drugs that I want you guys to remember here is going to be a couple one is called midazolam midazolam is a very commonly utilized one triazolam triazolam is another one intermediate there's a bunch of these Lorazepam is one um oxazepam alprazolam a couple more just to mention is Temazepam then you have your long acting and there's a bunch for these one as well so diazepam is one uh Chlor diazepoxide chlorodiazepoxide there's a bunch of these different types of drugs right but with that being said oh then there's another one that's actually important to remember clonazepam clonazepam is another one clonazepam but out of all of these the ones that we've actually seen benefit to to actually treating anxiety having an anxiolytic effect is the one that I'm going to circle Lorazepam is one oxazepam is one Alprazolam is one diazepam is one in clonazepam is one the reason you would pick one over the other is dependent upon how long you'd like this to act so if you gave something like diazepam a clonazepam it's going to have a longer anxiolytic effect whereas if you give something like razopam oxazepam or Alprazolam they're going to be more intermediate acting okay so that's an important concept to remember but again to take away from this anxiolytic drugs or drugs that are going to increase serotonin activity they either inhibit the reuptake SRI snri or they activate the serotonin receptor buspirone or they increase similarity of the gab activity in other words they stimulate the Gaba a receptor they act as an Agonist and that will by binding to the Alpha 2 subunit of that receptor increase chloride influx and inhibit the limbic system dysfunction by doing that we can use two Agonist drugs one is barbiturates which we don't use as much because they're so toxic and benzodiazepines the reason why if we were to really add on to the barbiturates is barbiturates when they bind onto the Gaba a receptor they increase the duration of chloride Channel opening and that is a really scary thing because if these things say open you can really inhibit a lot of different neurons so that's a really really important concept they actually increase the duration benzodiazepines on the other hand increase the frequency so they increase the frequency of chloride Channel opening and that's a really important kind of like takeaway point for this particular process here for your Gaba a Agonist okay all right that covers our drugs that are going to be utilized for anxiolysis so again a quick recap ssris snris for those that are increasing the serotonin by inhibiting reuptake this includes escitalopram paroxetine citrulline or your s nrislexine Duloxetine or you can have buspirin which is a direct serotonin type of Agonist you can also act to increase the Gaba a activity or Gaba activity by binding to the Gaba a receptor acting as an Agonist the drugs that increase Gaba activity by acting as an Agonist is barbiturates don't use them because of the toxicity the toxicity is due to a high duration of chloro Channel opening benzodiazepines are more beneficial and not as many toxic effects because they only increase the frequency of chloride ion channels and this includes the short-acting triaz lamidazolem intermediate acting which would be Lorazepam oxazepam Temazepam as well as alprazolam and then the last one is the long-acting diazepam chlordiazepoxide and clonazole with those these are the more particularly utilized ones for anxiolysis all right now let's talk about the drugs for hypnosis in other words you want to treat insomnia all right guys so when we talk about hypnosis you're trying to induce sleep and maintain sleep right so the mechanism behind this is that the pineal gland right released melatonin and this disease process there's low melatonin so let me kind of come up with a way to increase melatonin so that's one particular mechanism is I want to give drugs that are going to specifically act on the Melatonin receptors you remember how there was the Melatonin one and the Melatonin two receptors what if I gave a drug that acts as a Agonist to melatonin and it stimulates this receptor that would enhance that would basically be as if melatonin was present because in this disease one of the problems is that we have low melatonin right so one of the problems is low melatonin if I work to increase the effect of melatonin wouldn't a melatonin Agonist be the same as kind of increasing melatonin yes because it's going to activate those receptors and that's going to inhibit the supracasmatic nucleus which stimulates the vlpo which stimulates sleep and then releases Gaba to inhibit the reticular formation the posterior hypothalamus which would then inhibit arousal and wakefulness we know that so that's one way and what are some of the drugs that help to be able to increase melatonin by acting as a melatonin Agonist this includes rameltion and tassimeltion so remeltion Ramel tion okay the next thing is let's come to the Gaba we said Gaba was another particular problem right that Gaba was low in this particular pathophysiology so Gaba was low and if Gaba was low what we knew is that Gaba if it was in the lower amounts it wasn't inhibiting the posterior hypothalamus it wasn't inhibiting the reticular formation and so if it wasn't inhibiting the reticular formation it wouldn't be able to inhibit arousal and wakefulness and on top of that if you could inhibit the reticular formation the reticular formation would keep suppressing the vlpo so that you don't sleep so what if I come up with a way to have some type of drug to bind onto the Gaba a receptor so what if I stimulate the Gaba a receptor I give a drug that acts as a Agonist as tagaba and it stimulates this particular receptor if it stimulates this receptor it's going to inhibit the reticular formation if you inhibit the reticular formation you'll inhibit arousal and wakefulness so now this patient won't be able to stay awake on top of that if you inhibit the particular formation it can't release those factors that are supposed to naturally it's supposed to inhibit the vlpo right because it releases things like orexin and it releases things like histamines but if you inhibit the reticular formation it can't release those chemicals to inhibit the vlpo so the vlpo stays active and promotes sleep that's drugs that are going to increase Gaba we already talked about these here's the difference though here's the big difference on this part here on this part here for where the Gaba a receptors bind to I'm going to put it in a little note here it's the alpha one subunit so I'm going to put this is the Alpha One something I'm just going to put alpha one here so it's Alpha 2 for anxiolysis which is in the limbic system Alpha One on the reticular formation that's going to induce hypnosis that's really important because now I can add a third drug to drugs that actually increase that Gaba activity before it was barbiturates right we don't use these right because of increased toxicity we do not use these for hypnosis okay and then we have benzodiazepines these will actually do what they'll bind to the Alpha One and help to be able to increase chloridine influx and cause the reticular formation to be suppressed so the reticular formation is suppressed you won't be able to stay awake you'll fall asleep and this includes two particular drugs in the benzodiazepine so there was short acting intermediate acting and long acting right out of those particularly Temazepam and flurazepam are the most specific ones that I want you to remember so Temazepam Temazepam and florazepam are the most commonly utilized benzodiazepines for actually helping to induce hypnosis by inhibiting the reticular formation that adds the last drug so barbiturates would also do the alpha one but we don't use these and then the Z drugs Z drugs also bind to the alpha-1 subunit but they don't bind onto the Alpha 2 subunit so they have so if I were to kind of put a thing here they have positive alpha 1 but they do not have Alpha 2 activity this one has alpha one and it has Alpha two activity this one has alpha one and it has Alpha two activity you see the difference there what are some of the Z drugs that only induce hypnosis but do not provide anxiolysis this includes Zolpidem the leplon and a zopaclone these are going to be your Z drugs and again they do this by binding onto the Gaba a receptor and promoting chloride ion influx which inhibits what cause hyperpolarization decrease the action potentials and decrease the activation of the reticular formation so the reticular formation will be suppressed you won't be able to stay awake you'll then promote sleep beautiful okay the next concept is that we had another problem here which was that when the reticular formation is active when the particular formation is active it's giving drugs like it's secreting things like orexin and it's secreting things like histamine and histamine and erection are supposed to naturally do what inhibit the vlpo right so they're naturally supposed to naturally what they would do is they would inhibit the vlpo and then you wouldn't be able to promote sleep right now if I give a drug that basically will block it'll act as an antagonist so I would give a antagonist to orexin or an antagonist to histamine then I'll no longer be able to offer these drugs to inhibit the vlpo so now the vlpo would no longer be inhibited instead it'll be stimulated it'll be released from inhibition and it'll be able to promote sleep if it can promote sleep it'll then be able to suppress the reticular formation and prevent the further release of more erections and histamines but I should give drugs that can act as antagonists to block or Rex and a histamine so it doesn't shut down the vlpo because I need him active to sleep so I need to give drugs that will decrease oraxin so naturally the problem in this pathophysiology is that there's too much orxin and there's too much histamine oops let's do this in the blue color so there's too much oraxin or there's too much histamine in the pathophysiology so what I need to do is I need to give drugs that are going to block that effect they're going to block this effect so now you're no longer able to inhibit the vlpo you keep the vlpo activated now what are the drugs that help to block oraxon and block histamines so the drugs that actually decrease orexin is going to be something called suvarexent and it's a newer drug we don't know a ton about this drug but it is a newer type of drug and the other ones are the drugs that decrease the histamine so they block the increase in histamine they block the histamine from binding to the vlpo there's so many different types some of you may have used this before but diphenhydramine right diphenhydramine is a very commonly utilized antihistamine it's Benadryl and Benadryl will actually be able to promote sedation if you're using it for like an allergic reaction you may have noticed that it also can produce some residual sedation because the histamine right when it hits the vlpo it keeps the vlpo inactive so you can't sleep right but if you give diphenhydramine it blocks the histamine from binding to the vlpo now the vlpo is actually active and it promotes sleep so this would be again something like diphenhydramine diphon hydramine and this is more of an adverse effect unfortunately of the drug and the same concept you have antidepressants and these antidepressants are interesting in the sense that they can increase serotonin activity but they can also decrease histamine activity and that's really cool and what are some of these drugs so there's a bunch of them one is called Doxepin and Doxepin is actually what's referred to as a tricyclic antidepressant but it has antihistamine properties another one is called Mirtazapine mirtazapine and another one is called Trazodone and these are these types of atypical antidepressants but these are drugs that also have the ability to block the histamine from binding to the vlpo and the vlpo doesn't have histamine bind to it it's then active it can promote sleep and suppress the reticular formation and that's the basic concept in these particular problems these things are all doing what they're inhibiting the vlpo so that you don't sleep and they're stimulating the reticular formation so that you stay awake if you give drugs that help to do the opposite increase melatonin increase Gaba decrease orexin decrease histamines this will now do what this will help to inhibit the reticular formation and stimulate the vlpo and that is the goal here is to keep the vlpo active and the reticular formation off and by doing that this will all promote sleep and that is the ultimate goal here all right my friends that covers all the mechanism of anxious and hypnotics and all the drugs that are included in that the next thing is I want to take a quick approach so when a patient has anxiety how do I know which drug to pick because there was a bunch and if they have insomnia how do I know which drug to pick because there's so much so we'll talk about that briefly all right my friend so now let's talk about quickly an approach this so if a patient has anxiety right acute anxiety generally benzodiazepines are going to be the best fit for that patient during that acute anxiety attack they work very very quickly and so they're really going to be the best particular drug option for a patient who has having acute anxiety right so when you have acute anxiety benzodiazepines are going to be the go-to okay and again just as a reminder what were some of those drugs this would be the Alprazolam Alprazolam is a great one very commonly utilized one another one is clonazepam another one is going to be diazepam another one is going to be lorazepam another one is going to be oxazepam all of these can be utilized in a patient who has acute anxiety now here's the downside these drugs have the ability to produce abuse potential they're Controlled Substances so they have addiction potential so one of the downsides to these drugs is that they can cause abuse so we don't want to keep patients on these for a super long period of time so the preferred action of these drugs is we prefer for these to be a PRN basis only use when you have a patient who has really really bad anxiety and very specific types of disorders and it's for that acute kind of breakthrough anxiety when you have a patient with chronic anxiety and this is really when it comes down to like diseases such as really generalized anxiety disorder social anxiety disorder panic attack disorder phobias Etc then these patients may require something a little bit more long-term and in those particular scenarios for the long-term basis benzodiazepines aren't going to be the best and so what we prefer is to give drugs that increased serotonin so this would be your SSRI or an snri right and then for the chronic anxiety you can do a PRN benzodiazepine and that's generally how we would go about this another thing is let's say that again you do the PRM benzodiazepine but you're still worried that the patient has a high risk of abuse potential take that into consideration in their history an alternative an alternative to a PRN that benzodiazepine is something like buspirone so buspirone may be a decent alternative with very little likelihood of abuse potential so this is generally how you would go about this acute anxiety you start off with benzodiazepines just for the Breakthrough okay buspirone will not be good for acute anxiety okay this is good for the Breakthrough the other thing is ssris and snris you know how long they take these puppies can take up to four to six weeks four to six weeks to really become therapeutic and produce anxiolytic effects so that's why we use the PRM benzodiazepine or the bus front until these become therapeutic so that's the concept there all right that's how I would approach that one for hypnosis I like to think about I'm treating a patient who has insomnia for different reasons is there insomnia because they're super stressed and anxious and then they just their mind keeps running that they can't help themselves to fall asleep in those particular scenarios one of the drugs that may be beneficial because it has very profound anxiolytic effects is going to be benzodiazepines benzodiazepines and in this particular situation there's two flurazepam flurazepam is going to be one and Temazepam and I've been uh very fond sometimes of Temazepam I think it's very effective but again one of the things that you have to realize here is that these have a high abuse potential the people can become dependent upon these and then if you discontinue these medications they can develop rebound insomnia so that's a really really important thing to think about all right what if a patient is mild to moderate insomnia but it's not Stress and Anxiety related in that particular scenario your Z drugs your Z drugs are going to be great in this particular scenario so the Z drugs would be the options I would consider and that would be the Zolpidem the isoplo Clone and there's a lepilon with a little caveat here that I prefer the zilepylon Zolpidem Ambien is going to be the most commonly utilized one but I like the laplon because one of the cool things about this drug is it has a short half-life so if you give this drug it'll really help to induce sleep and it won't last super long so there's a lot of residual side effects when you wake up in the morning and so that's really one of the Beauties behind this drug is that it decreases the residual drowsy kind of nature that you have in the morning with some of these other drugs such as Zolpidem and the zopaclum don't get it twisted though these things do have abuse potential just nowhere as much of the abuse potential as compared to benzodiazepines and so just do realize that it used to be thought that these do not cause abuse these do have a sense of abuse and dependence and if you stop taking these you can develop rebound insomnia all right next thing is sleep induction for Sleep induction so I don't really it's not really a hard time of maintaining sleep I just need to fall asleep and so this really is going to be one of the particular drugs that increases the activity of melatonin so melatonin-containing drugs so this is actually going to be my melatonin agonists my melatonin Agonist and you guys remember what this one is this is your rameltion ramelteon is the particular option here there's still uncertainty of the super accent which is the orex and antagonist but there may plus or minus we're going to put plus or minus the orxin erection antagonists antagonist we just don't know enough about this drug category yet okay all right so we got stress anxiety benzos mild to moderate insomnia with no stress or anxiety relationship Z drugs so lepplon probably one of the best ones without having a lot of residual drowsiness and cognitive dysfunction in the morning both of these have abuse potential this one High abuse potential this one just a little bit more abuse potential I mean a little less of these potential in comparison to benzos sleep induction melatonin Agonist is definite but erection antagonist not enough information on just yet the last one is the patients who have a lot of depression related anxiety depression anxiety but particularly more depression related insomnia and this particular situation I would go with the drugs that have antidepressant functions ones that really jack up the serotonin but also block the histamine action and so this is where I would use particular drugs such as Doxepin Doxepin would be one that's the tricyclic antidepressant I would also go with the Mirtazapine mirtazapine or Trazodone Trazodone and these all will do what help to increase serotonin but also block the actual histamine one of the Beauties Behind these particular drugs is that there really is no abuse potential so with these there is no true abuse that you should see with these and that's really what makes these preferable so if a patient maybe has depression or maybe even some degree of anxiety related insomnia and they have a history of abuse don't give them benzos don't give them Z drugs consider something like this which has the ability to not cause abuse but will have anxiety and depression related effects and treat the patient's insomnia via histamine blocking effect via melatonin Agonist erects an antagonist effect via Gaba increasing gab activity increasing gab activity which one do you notice that is not on here the barbiturate because it'll kill you okay don't use it that covers the approach let's now really quickly go through the adverse drug reactions all right guys so now when we talk about adverse effects of anxiolytics and hypnotics the big thing that I really want to focus on is the benzodiazepines in the barbiture it's not so much the Melatonin Agonist not so much the ssris and snris because we'll talk more about antidepressants when we get into that pharmacology lecture talking about all the different types of antidepressants but when we talk about melatonin agonists If there really was one big thing it's been shown to potentially increase prolactin so you may see some gynecomastian males some menstrual irregularities or lactation problems in females that's really about it for the Z drugs I think it's important to remember that they again have abuse potential they used to think that they did not but they do have abuse potential but if I were to tell you the degree of dependence or abuse potential compared it would go Z drugs is the least then benzos then barbiturates have the most abuse potential okay the other thing is we don't know a lot about the orex and antagonist there may be some type of suicidal ideation and cytochrome p450 Metabolism just not enough info on that and again we're not going to talk about a bunch about the antidepressant drugs because we'll talk about those when we get into the antidepressant section so that deserves a really heavy conversation on barbiturates and benzodiazepines the whole purpose of this adverse drug reaction is to really kind of show you some of the negative connotations of chronic benzodiazepines and then why we avoid barbiturates so when you look here this this graph here is really just giving us a degree of C and S depression that's really all it's telling us this is telling us the degree of CNS depression so with some people right you may just want to be able to reduce their anxiety put them to sleep make them kind of cognitively unaware of what's going on so kind of just depress their level of Consciousness their Sensations their movements some you actually can take away their ability to breathe and augment their heart rate and blood pressure or some you put them into a coma here's the big thing with benzodiazepines they have CNS depression right but if you compare to barbiturates which is here in blue look at the barbiturates the barbiturates have no ceiling effect there is no ceiling effect there is no ceiling for barbiturates and there is an eventual ceiling for benzodiazepines they usually kind of top out at not having much more than just mild medullary depression so with that being said if you were to think about this with benzodiazepines benzodiazepines can have CNS depression but we'll give it two arrows barbiturates these things have a massive amount of CNS depression and that's a really really important thing because that's another reason why we don't really use barbiturates for anxiolysis and hypnosis is because just a little bit of a higher dose you get an anistatic medullary depression and coma effect that's why barbiturates more commonly used for patients who have seizures right so we'll treat seizures so anti-convulsant type of activity or you can use it in anesthesia like thiopental or putting a patient into a coma because of seizures or high intracranial pressure and you want to kind of decrease their ICP otherwise we don't really utilize barbiturates because again you can see the toxicity from their CNS depression not as much so with the benzodiazepines the next thing that I want you guys to understand is dependence and tolerance so dependence again kind of is the basic that that when you have these patients who take benzodiazepines right so benzodiazepines who take barbiturates and the last one is the Z drugs so barbiturates uh benzodiazepines and then the last one is your Z drugs when we talk about these the basic concept of these is that barbiturates if you give these again they'll help to be able to act as a Gaba agonistic activity but with continual usage what may happen is they may develop a sense of Tolerance where the same dose may be not produce the same therapeutic effect and then what happens is you have to increase the dose and increase the dose and increase the dose to get that same effect and so with that we see the highest degree of tolerance or dependence with barbiturates then we see the second most dependence intolerance with benzodiazepines and then we see the least amount of dependence and tolerance with the Z drugs and that's a really really important concept to understand is that with giving these drugs if the cut if the drug dosage is having to increase to meet the same therapeutic effect that's a concept of Tolerance and if you were to remove these drugs so then if you were to discontinue any of these drugs the patient would develop a rebound effect in other words if you stop barbiturates for a patient who's having seizures you abruptly stop it they'll start having breakthrough seizures right if you stop benzodiazepines for hypnosis and anxiolysis then you're going to have them have problems with anxiety and break through insomnia if you're using this for insomnia and then you discontinue it again they will develop rebound insomnia so it's an important effect thing to understand the next thing is drug interactions all right so the phenobarbital all right and pentobarbital and all the barbiturates are very powerful uh cytochrome p450 inducers and I think that's again another reason as to why to avoid these drugs so they have the ability to bind onto the cytochrome p450 system and increase the activity of this enzyme if this basically increases the activity of the cytochrome p450 enzyme it takes a drug and breaks the drug down more and so you'll basically enhance this pathway you'll stimulate this pathway and put it into hyperdrive and what you'll do is you'll decrease the efficacy of other drugs and so that's one of the really nasty things about barbiturates is that they cause a lot of drug interactions and decrease the concentration and efficacy of other drugs makes them sub-therapeutic that's a really bad thing all right so again to really highlight the reason why we stay away from barbiturates is because they have massive CNS depression they have a high degree of dependence and tolerance and if you discontinue them abruptly they can develop a very profound rebound effect and they have very significant drug interactions by acting as a cytochrome p450 inducer and producing sub-therapeutic drug levels of other drugs what's the last thing that I want to talk about and that's really the overdose and withdrawal factors so the last thing that I want to talk about here is overdoses or withdrawal and really I want to spend some time talking about more specifically the benzodiazepines all right and the reason why is again we shouldn't be utilizing uh you know barbiturates for anxiolysis and hypnosis right we should we would use benzodiazepines though and this again tries to highlight that yes barbiturates are super toxic and we try to avoid them but you should also be very careful with benzodiazepines and this is the reason why we know that it has mild cedis depression a degree of dependence intolerance right so that's one particular thing has a potential for abuse and rebound effects but the other thing is that you can easily overdose on this so if a patient overdoses they take too much right so they become dependent or they become very tolerant to it they keep increasing their dose increase in their dose increase in their dose to get the same therapeutic effect and then what happens well then they start kind of shutting down their limbic system function they start shutting down their reticular formation these patients can literally start to have a very significant decline in their level of Consciousness right so they could actually have anywhere from a point of maybe anxiolysis to actually sleeping to actually kind of being in a anesthetic State almost being into a comatose state so that's a really big thing they can also depress their effect on the heart so they could even cause maybe a small degree of bradycardia a small degree of hypotension but here's the most profound one they cause a significant respiratory rate and depth depression so they significantly depress the respiratory system that's the big things here don't worry about this part in this part but when a patient overdoses and they take too much of a benzodiazepine one of the very scary features is significant CNS depression right so loss of consciousness as well as hypotension bradycardia and respiratory depression so they may become apnic if that's the case how do we treat those patients we want to reverse the effect of the Gaba Agonist so I want to give a drug that acts as a Gaba antagonist and the drug that I really want you guys to remember that is useful for the benzodiazepine overdose is called flumasinil flumazino okay now in the same concept if a patient is taking benzodiazepines for insomnia or taking it for anxiolysis right and or maybe even for seizures or for muscle relaxant activities all because there's so many different functions of the benzodiazepines right but if it's taking it for those reasons all of a sudden you abruptly discontinue taking the benzodiazepines they can potentially go through withdrawal because they develop a rebound effect so then it's opposing all of these actions you go back into the whole anxiety response so they can actually develop potentially anxiety rebound anxiety the worst case scenarios they can even develop seizures this is a scary fact right they can also develop an increase in their heart rate and increase in their blood pressure so they become tachycardic and hypertensive they also can increase their respiratory rate and depth they can also have diaphoresis diaphoresis and they can have tremors if all of these things are present in a patient who just discontinued their benzodiazepine guess what you probably should give them the benzodiazepine back and then start slowly tapering down the dose don't just abruptly discontinue it put them on a benzodiazepine and then slow slow taper of the benzodiazepine so that's where we would do a taper so we would taper the benzodiazepines such as Lorazepam or diazepam is the preferred drugs but those are the concepts that I really want you guys to understand with anxiolysis and hypnosis again going over the whole pathophysiology of it I think it's important to know the neurotransmitters that are problematic then using the mechanism to understand I just have to oppose the pathophysiological process so you do the opposite of the pathophysiology increase serotonin increase Gaba for anxiolysis right if for insomnia I have to increase Gaba increase melatonin decrease or accident and decrease histamine and then talking about the approach understanding in a patient who has acute anxiety versus chronic anxiety which drug is preferred and then a patient who has insomnia depending upon the type of insomnia and the type of treatment that you want you determine the type of drug and then again overarching theme Here is barbiturates are a No-No and this is the reason why benzos are also ones that have very significant abuse potential too and this is kind of again showing you guys how do I recognize that and again worst case scenarios if they overdose or they withdrawal how to be able to recognize that and treat that all right let's do some questions and put all this together all right my friends let's do some questions here to kind of recap everything we talked about with anxiolytics and hypnotics so which of the following statements is correct regarding benzodiazepines they directly open chloride ion channels so I would say that again they work via the Gaba a receptor right so they actually bind to the Gaba a receptor whenever they bind to the Gabe a receptor that actually will open up the chloride ion channels so I wouldn't say that they directly open the chloride ion channels they have to bind to Gaba change the shape of the actual Gaba protein to or to open up that channel so I wouldn't say directly benzodiazepines show analgesic actions no not necessarily at very very high doses as we talked about they can have a slight anesthetic function especially midazolam but it doesn't mean that they actually can remove pain so I would not say that they have a complete analgesic action clinical Improvement of anxiety requires two to four weeks of treatment with a benzodiazepine you can actually experience it immediately the anxiolytic effect depending upon the appropriate dose and all benzodiazepines have some sedative effects absolutely when you think about benzodiazepines they have the ability to kind of reduce your reticular activating system to reduce some of the cortical activity so they can really kind of activate a lot of Gaba kind of activity in multiple different kind of central nervous system structures which definitely can reduce the level of arousal and wakefulness and that's really really very common with all of these so I would say definitely are going to have some sedative effects to them which of the following is a short acting hypnotics when we talk about hypnotics we have drugs that increase Gaba right so do any of those increase Gaba absolutely phenobarbital does diazepam does chloride diazepoxide does and triazolam does so then it comes down to which ones are short acting so for the barbiturates it's Ultra short acting we said we don't even use these anymore but it's thiopental and then you have as you go a little bit further down towards like the kind of long acting you get to phenobarbital so in this particular situation I would say that phenobarbital is a super long-acting one so I can't use that diazepam and chlordia is a pox that are long-acting um benzodiazepine so that's not the answer and then triazolam and midazolam are the shortest acting types of benzodiazepines so I would say triazolam here which of the following statements is correct regarding the anxiolytic and hypnotic agents so diazepam and phenobarbital induced the cytogram p450 system um phenobarbital definitely is a cytochrome p450 inducer phenobarbital is useful in the treatment of acute intermittent porphyria um actually it's contraindicated in porphyria okay phenobarbital induces respiratory depression which is enhanced by the consumption of alcohol 100 so if you take phenobarbital which is a CNS depressant plus ethanol which is also seen as depressant you'll definitely cause respiratory depression and that's a really really nasty kind of effect there so absolutely and boost front has actions similar to those depends of azipines I would say not necessarily it can treat anxiety not acute anxiety more chronic anxiety and it works via the serotonin Agonist activity not a Gaba activity all right so female phenobarbital definitely with ethanol will cause massive respiratory depression 45 year old man injured in a car accident brought to the Ed blood alcohol level through the roof Hospital shows a prior hospitalization for alcohol-related seizures unfortunately his wife confirms that he has been drinking heavily for three weeks what treatment should be provided to the patient if he goes into a draw so this is alcohol withdrawal alcohol withdrawal seizures are treated the same way that you would treat kind of like uh in these particular patients um when you have a patient who has alcohol withdrawal seizures there's two particular options barbiturates and benzodiazepines those are going to be the anti-convulsants that we talked about in the anxiolytic hypnotics that only have anticonvulsant activity there's been studies that show that phenobarbital is way superior to the benzodiazepines but benzodiazepines are other options that you can consider Lorazepam diazepam those are particular options so in this particular scenario Lorazepam would be the best option all right 36 year old male patient refers to a difficulty falling asleep for the past two weeks but needs to be able to get up early in the morning 6 a.m and doesn't want any daytime sedation which medication is best to recommend for the treatment of insomnia so you want something that's going to be quick to induce sleep but it won't kind of like linger around in the morning so in other words it's it's Half-Life short so Temazepam is kind of like somewhere between kind of a intermediate acting so it'll last a decent amount of time flurazepam that one's also kind of on the longer side buspirone doesn't really have any type of hypnotic functions the leplon is definitely going to be the shorter acting one this is great for Sleep induction and then it won't linger around and cause a lot of you know daytime somnolence so the left line is definitely going to be the best option in this particular scenario so I would go with that one and that is again one of the Z drugs whereas these ones they're going to have a little bit more of a lingering effect in the morning especially Temazepam and flurazepam boostprone is not even a good option 45 year old woman reports daytime anxiety about work and family problems causing difficulty functioning and participating in normal daily activities which of the following agents has a rapid anxiolytic effect and it's best for the acute management of anxiety that's always bentos benzos and then for chronic it's ssris or snris right or potentially boost prone is the other option here so I would say in this particular scenario it's going to be a benzo first and then later you can start adding on something like this or this or this so Lorazepam would be the best option here okay which of the following sedative hypnotic agents utilizes melatonin receptor Agonist as the mechanism of action to induce sleep all right so we need a melatonin receptor Agonist this is usually remeltion or this other one called tassimultion they're the same thing but these would both be your melatonin receptor agonists that help to induce sleep so they're good for Sleep induction so Tassie meltion or romelton would be the best option here 50 year old male presents with insomnia not responsive to sleep hygiene interventions has a long history of alcohol opioid abuse so he has abuse potential he has been successfully sober for 10 years congratulations but is very concerned about future addiction Independence rightfully so which is appropriate to address insomnia minimize the risk for dependence in this patient stay away from benzos stay away from barbiturates those are going to be the particular options here and as I told you before they used to think that the Z drugs did not have as much dependence and tolerance and would you know withdrawal symptoms but they do they're nowhere near they're not as severe as benzodiazepines and nowhere near severe barbiturates but they're still there so I got to get rid of the benzo because that's that's not a good option for me um I got to get rid of this alepplon and the Zolpidem because those also are Z drugs they have addiction potential not as high as the benzos but they have addiction potential Doxepin is a tricyclic antidepressant with antihistamine activity so therefore this would actually be a drug that I can use for depression as well as treat the patient's insomnia so this would be a lot safer and there's not as much dependence and tolerance and withdrawal symptoms from this so I would go with Doxepin which is a tricyclic antidepressant again you could also consider other options like trazodone or Mirtazapine which is one of those atypical antidepressants as well all right so Doxepin would be the option here 60 year old female patient demonstrating signs and symptoms of insomnia especially difficulty falling asleep she's afraid of taking medication that can negatively affect her memory and concentration as she's still working as a bookkeeper she's been taking Temazepam okay for the past four days in his nose memory problem and would like to discontinue it rightfully so which medication is appropriate to treat the insomnia and minimize the risk of cognitive impairment stay away from benzos right that would be the particular best option and probably even stay away from some of the Z drugs too so I would stay away from Zolpidem I would stay away from Alprazolam because that's a benzo diphenhydramine this is not used for sleep it's the adverse effect unfortunately of the antihistamine that you can use for allergic reactions so this is not a preferable agent rameltion is a melatonin receptor Agonist that was very helpful for Sleep induction 30 minutes prior to going to sleep it doesn't have a lot of that residual type of uh you know cognitive impairment in the morning and dependence and problems like that nature so or meltion which is a melatonin receptor Agonist or tassimaltion are going to be good options here all right last question 18 year old woman admitted to the emergency room after an accidental overdose of Alprazolam she's unconscious not considered a regular user of any of medications or list of drugs which treatment would you use to reverse the effect of the Alprazolam overdose so a benzo overdose they'll have a depressed central nervous system to the point of maybe where they're lethargic to they're almost in a comatose state they also will have maybe hypotension bradycardia and respiratory depression so flumazinil is the respiratory I mean is the benzodiazepine antagonist in this particular scenario so I would give them flumazinil not diazepam that's just going to make it worse not rameltans are going to do nothing and naloxone is for opioids so flomazine would be the preferable agent here all right my friend so that covers all the questions related to anxiolytics as well as hypnotics I hope it makes sense I hope that you guys enjoyed it as always until next time [Music]

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Length: 68min 52sec (4132 seconds)

Published: Fri Dec 23 2022