Anxiolytics & Hypnotics: Pharmacology of Anxiety and Insomnia Drugs

What's up ninjas? 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

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below. We have a link to our website where we have some awesome notes and illustrations. Let's get into it. 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 when 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. Often times, it's like tachycardia,

palpitations, hypertension, maybe a little bit of breathing fast, 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 app emotion, an 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 is 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 GABA 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, if these neurotransmitters are really, really

low, it causes the limbic system to now become dysfunctional. That then hyperstimulates 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 GABA activity and low amounts of serotonin activity. That leads to

dysfunction 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 the neuron of the 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 GABAergic 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

GABAergic neurons. So, normally, it should be able to stimulate these GABAergic 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. That's the basic pathophys. So, these

are the big things that I really want you to know for anxiety. Now, let's now talk about insomnia cuz now we're going

to talk about hypnotic agents. So, anxiety, we're going to use drugs that are going to try to increase GABA and

increase serotonin. They'll 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. All right, my friends. 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 in 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, and

particular formation, zoom in on them, and talk about some of the neurotransmitters that it's involved in

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, um 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 acts of a 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

suprachiasmatic 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 suprachiasmatic

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 ventrolateral preoptic nucleus. I'm going to abbreviate that the VLPO. It's found in

the hypothalamus. When the suprachiasmatic 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 tuberomammillary nucleus, the lateral hypothalamic nucleus, and so many nuclei of the

hypothalamus. I'm sorry, the the reticular formation. So, you have the reticular formation nuclei and the

posterior hypothalamic nuclei. What happens is the ventrolateral preoptic nucleus releases something

called gamma-aminobutyric acid. And what gamma amino-butyric 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 suprachiasmatic 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 and 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 suprachiasmatic

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 and 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 and reticular formation. So it releases GABA.

What if we had low levels of GABA? Cuz GABA is essential for being able to suppress the

reticular formation and suppress the posterior hypothalamus. If we have low GABA levels, will we be able to suppress

this anymore? No. So you can't suppress it. You can't suppress arousal and uh you won't be able to suppress the

arousal and 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

posterior hypothalamus and reticular 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

reticular formation? No. So the reticular formation will be active and then trigger arousal and wakefulness.

So these would be the bad boys. If they're in higher levels, they're going to suppress the VLPO, suppress sleep and

keep the reticular formation activated to promote arousal and wakefulness. That's terrible. But that is another

pathophysiological concept here is that you can have high orexins 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 tell to take away from

this is that whenever you have low melatonin levels and low GABA, this will cause insomnia. High orexin 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 hypnotics 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 in patients who have anxiety or insomnia. All right, my friends. So

now anxiolytics, we got to get 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 cuz that was the whole goal, right? And then what are some of those

drugs? What are some of the names of those drugs that are we 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

5-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 5-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 receptor. So this is GABA.

GABA should bind into that little pocket there. This little receptor here. You see this

receptor here? 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 in 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 what we call that? When the cell becomes super negative, it causes

hyperpolarization. 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 uh 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

low. The GABA would be low. GABA wouldn't be able to work on this

receptor. It wouldn't be able to allow for chloride ion 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's 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 sero- this reuptake protein, this

reuptake mechanism. I'm going to 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 GABAergic 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 ion influx cuz 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 A receptor, increases hyperpolarization, decreases action potential and decrease

the sympathetic or anxiety response. That'll be another benefit, too. What are these drugs that can increase

serotonin by inhibiting reuptake or drugs that can bind directly to the serotonin receptor?

These would include your SSRIs. So, your selective serotonin reuptake

inhibitors, they'll inhibit the reuptake of serotonin. There's another group which actually in blocks the reuptake of

serotonin and norepinephrine, but they 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 reuptake. 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. Citaline 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 venlafaxine. So, venlafaxine. 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 buspirone. And buspirone has actually been shown to directly stimulate the 5-HT receptor.

And this is going to be the name of that drug, buspirone. There is no specific category, it's just buspirone. There's

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 reuptake

of serotonin, increase the serotonin in 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 GABA 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 GABA A receptor. So, GABA doesn't

even have to be present. This drug will bind onto that little that little socket there on the GABA A receptor, open it

up. That'll increase chloride ion influx. That'll increase hyperpolarization.

That'll 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 GABA 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 cuz when you think about this,

if we were to actually take this GABA 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 two 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 help 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 two

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 two subunit of the GABA A receptor.

What are these drugs that have this GABA A agonistic activity or the GABA A GABA 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 anxiolysis 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 and it's cleared quickly, its 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. Um 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 chlordiazepoxide, chlordiazepoxide. There's a bunch of these different types

of drugs, right? But with that being said, oh and then there's another one that's actually

important to remember, clonazepam. Clonazepam's 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 ones

that I'm going to circle. Lorazepam is one. Oxazepam is one.

Alprazolam is one. Diazepam is one. And 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 or clonazepam, it's going to have a longer anxiolytic effect. Whereas if you give something like lorazepam,

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 are drugs that are

going to increase serotonin activity. They either inhibit the reuptake, SSRI, SNRI, or they activate the serotonin

receptor, buspirone. Or they increase similarity of the GABA activity. In other words, they stimulate

the GABA A receptor. They act as an agonist. And that will, by binding to the alpha two 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 onto 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 cuz if these things stay open, you can really inhibit a lot of different neurons.

So, that's a really really important concept is they 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, they're increasing the serotonin by inhibiting reuptake. This includes escitalopram, paroxetine,

citaline. Or your SNRIs, venlafaxine, duloxetine. Or you can have buspirone, 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 uh chloride 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 triazolam, midazolam. Intermediate-acting, which would be lorazepam, oxazepam, temazepam,

as well as um alprazolam. And then the last one is the long-acting diazepam, chlordiazepoxide, and clonazepam. 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,

releases melatonin. In 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 receptor. So, you remember how there was the melatonin 1 and the melatonin 2

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. Cuz in this disease, one of the problems is

that we have low melatonin, right? So, one of the problems is low melatonin. If I were to increase the effect of

melatonin, wouldn't a melatonin agonist be the same as kind of increasing melatonin? Yes,

cuz it's going to activate those receptors and that's going to inhibit the suprachiasmatic nucleus, which

stimulates the VLPO, which stimulates sleep and then releases GABA to inhibit

the reticular formation in 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 ramelteon and tasimelteon. So, ramelteon.

Ramelteon. 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 couldn't 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? Hmm. So, what if I stimulate the GABA-A

receptor? I give a drug that acts as a agonist as to GABA 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 reticular formation, it

can't release those factors that are supposed to naturally it's supposed to inhibit the VLPO, right? Cuz 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-1 subunit.

So, I'm going to put this is the alpha-1 subunit. I'm just going to put alpha-1 here. So, it's alpha-2 for anxiolysis,

which is in the limbic system, alpha-1 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-1 and help to be able to increase chloride 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 benzodiazepines. So, there were

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 flurazepam 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-1, 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-1 and it has

alpha-2 activity. This one has alpha-1 and it has alpha-2 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, zaleplon, and eszopiclone.

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 will 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 reticular formation is active,

it's giving drugs like it's secreting things like orexin and it's secreting things like

histamine. And histamine and orexin 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 will give a antagonist to orexin

or an antagonist to histamine, then I'll no longer be able to allow for 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 orexins and histamines. But, I should give drugs that can act as antagonists

to block orexin and histamine so it doesn't shut down the VLPO cuz I need him active to sleep.

So, I need to give drugs that will decrease orexin. So, naturally the

problem in this pathophysiology is that there's too much orexin and there's too much

histamine. Oops. Let's do this in the blue color. So, there's too much orexin 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 orexin and block histamines? So, the

drugs that actually decrease orexin is going to be something called suvorexant and it's a newer drug. We don't know a

ton about this drug, but it is a newer type of drug. The other ones are the drugs that

decrease the histamines. 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.

Diphen- 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

if 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 anxiolytics 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 cuz 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 friends. 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 in

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 increase 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 PRN

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 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 4 to 6 weeks, 4 to 6 weeks to really become therapeutic and produce anxiolytic effects.

So, that's why we use the PRN benzodiazepine or the buspirone 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 their 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 has 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 eszopiclone,

and the zaleplon. With a little caveat here that I prefer the zaleplon.

Zolpidem, Ambien, is going to be the most commonly utilized one. But I like zaleplon 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 eszopiclone.

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 to 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 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 agonist. My melatonin agonist. Do you guys

remember what this one is? This is your ramelteon. Ramelteon is the particular option here.

There's still uncertainty of the suvorexant, which is the orexin antagonist, but there may, plus or

minus, we're going to put plus or minus the orexin orexin antagonists.

Antagonists. 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. Zaleplon, 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, little less abuse potential in comparison to benzos.

Sleep induction, melatonin agonist is definite, but orexin antagonist, not enough information on just yet.

The last one is a patient who have a lot of depression-related anxiety. Uh depression, anxiety, but particularly

more depression-related insomnia. In this particular uh 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-related effects and treat the patient's insomnia

via histamine blocking effect, via melatonin agonist, orexin antagonist effect, via GABA increasing GABA

activity, increasing GABA activity. Which one do you notice that's not is not on here? The barbiturate cuz 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 and the barbiturates. Not so much the melatonin

agonist, not so much the SSRIs and SNRIs cuz 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

agonist, if there really was one big thing, it's been shown to potentially increase prolactin, so you may see some

gynecomastia in 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 as the least, then benzos, then barbiturates have the most abuse potential. Okay?

The other thing is we don't know a a lot about the orexin 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 a a bunch about the

antidepressant drugs cuz 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 CNS 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 anesthetic

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 and tolerance 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 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

breakthrough insomnia. If you're using this for insomnia and then you discontinue it, again, they will develop

rebound insomnia. So, that's an important effect thing to understand. The next thing is drug interactions,

right? So, the phenobarbital, all right, and pentobarbital, and all the barbiturates are very powerful

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 subtherapeutic. 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 subtherapeutic 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 CNS depression, a degree of dependence and tolerance, right? So, that's one particular thing. Has a

potential for abuse and rebound and 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 uh very tolerant to it, they keep increasing their dose, increasing their dose, increasing 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 the reticular formation. These patients can literally psychotic 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 uh anesthetic state to 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 and 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 apneic. 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 a useful for the

benzodiazepine overdose is called flumazenil. Flumazenil, 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 the sudden you abruptly discontinue taking the benzodiazepines, they can potentially go through

withdrawal, cuz 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 scenario

is they can even develop seizures. This is a scary fact, right? They can also develop an increase in their heart rate,

an 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 have

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 orexin, 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 to uh recognize that. And again, worst case

scenarios, if they overdose or they withdraw, 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 GABA-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 order 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 2 to 4 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

they're 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, chlordiazepoxide 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 chlordiazepoxide are

long-acting benzodiazepines, 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 induce the cytochrome P450

system. Um phenobarbital definitely is a cytochrome P450 inducer. Um

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 a CNS depressant, you'll

definitely cause respiratory depression. And that's a really, really nasty kind of effect there. So, absolutely. And

buspirone has actions similar to those of benzodiazepines. 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, phenobarbital definitely with ethanol will cause some 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 3 weeks. What treatment should be provided to the patient if he if he goes into

withdrawal? So, this is alcohol withdrawal. Alcohol withdrawal seizures are treated the same way that you would

treat kind of like in these particular patients. Um

When you have a patient who has alcohol withdrawal seizures, there's two particular options, uh barbiturates and

benzodiazepines. Those are going to be the anticonvulsants that we talked about in the anxiolytic hypnotics that only

have anticonvulsant activity. There's been studies that showed 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 reports to difficulty falling asleep for the past 2 weeks, but needs to be able to get up

early in the morning, 6:00 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. Um zaleplon 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, zaleplon

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. Buspirone 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

is best for the acute management of her anxiety? That's always benzos. Benzos, and then for chronic, it's SSRIs or

SNRIs, right? Or potentially buspirone 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 ramelteon or this other one called tasimelteon. They're the same thing, but these would both be your

melatonin receptor agonist that helps to induce sleep. So, they're good for sleep induction.

So, tasimelteon or ramelteon will be the best option here. 50-year-old male

presents with insomnia, not responsive to sleep hygiene interventions, has long history of alcohol and opioid abuse, so

he has abuse potential. He's been successfully sober for 10 years, congratulations, but is very concerned

about future addiction and dependence, rightfully so. Which is appropriate to address insomnia and 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 as severe as barbiturates, but they're still there.

So, I got to get rid of the benzo, cuz that's that's not a good option for me. Um I got to get rid of the zaleplon 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 is

demonstrating signs and symptoms of insomnia, especially difficulty falling asleep. Um 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 4 days, and has noticed 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, cuz 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 aller- allergic reactions. So, this is not a preferable agent. Ramelteon 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 cog- you know, cognitive impairment in the morning and dependence and problems

of that nature. So, ramelteon, which is a melatonin receptor agonist, or tasimelteon, are going to be good

options here. All right. Last question. 80-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 illicit drugs. Which treatment would be used 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 their

almost in a comatose state. Um they also will have maybe hypotension, bradycardia, and respiratory depression.

So, flumazenil is the respiratory I mean, is the benzodiazepine antagonist in this particular scenario. So, I would

give them flumazenil. Not diazepam, that's just going to make it worse. Not ramelteon, that's going to do nothing.

And naloxone is for opioids. So, flumazenil would be the preferable agent here.

All right, my friends. So, that covers all the questions related to anxiolytics as well as hypnotics. I hope it made

sense. I hope that you guys enjoyed it. And as always, until next time.