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Anxiolytic & Hypnotic Drugs — Transcript

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0:07What's up ninjas? In this video today,
0:08we're going to be talking about
0:09anxiolytics and hypnotics. Before we get
0:11started really into the lecture, if you
0:13guys do like this video, it makes sense,
0:15it helps you guys to really kind of
0:16overcome this challenging topic because
0:19it really can be. Please support us. The
0:21best way that you can do is by hitting
0:22that like button, commenting down the
0:24comment section, and also subscribing.
0:26Also, if you guys do want some notes and
0:27some illustrations that are really
0:29great, help you guys to truly understand
0:30the topic, go down the description box
0:32below. We have a link to our website
0:33where we have some awesome notes and
0:35illustrations. Let's get into it. Let's
0:36talk about anxiolytics and hypnotics.
0:38So, when we talk about this, we really
0:39have to get down to the kind of basic
0:41pathophysiology. And when I mean basic,
0:43I really mean basic. I don't want to get
0:44too crazy. I just want you to understand
0:47what anxiety truly is, right? So, it's
0:49this kind of sense of unpleasant
0:52sensation of fear or apprehension that
0:54can present with physical symptoms,
0:56right? And we'll talk about that. Often
0:58times, it's like tachycardia,
1:00palpitations, hypertension, maybe a
1:03little bit of breathing fast, some
1:05tremors, some diaphoresis. Those are
1:07common features of anxiety.
1:10Well, anxiety, really when it comes down
1:12to it, is due to some type of limbic
1:14system dysfunction, right? You know,
1:15there's so many nuclei involved in our
1:17limbic system. We're not going to go
1:19through that aspect, but what I do want
1:21you to know is that the limbic system is
1:23the one responsible for our emotional
1:25aspects of our body, right? So, it's the
1:27emotional component of our brain.
1:29It's also involved in memories as well.
1:31But, there's some degree of limbic
1:33system dysfunction here.
1:36And that's really what it's coming down
1:37to in this particular disease. Now,
1:40if we dig into it a little bit more,
1:42right? So, the limbic system is
1:43obviously important for memory. It's
1:45important for emotions and our
1:46behaviors. So, if there's some
1:48dysfunction of the limbic system, it's
1:50not out of this world to think that it
1:51can precipitate anxiety, which is a type
1:54of app emotion, an unpleasant sensation
1:56of fear and apprehension.
1:58So,
1:59what causes the limbic system
2:01dysfunction is really the question,
2:03right?
2:04Well, there's some particular neurons
2:05that are involved in the limbic system
2:07that actually release very specific
2:09types of neurotransmitters. You know
2:10what those neurotransmitters are? The
2:12two neurotransmitters that are integral
2:14to the function of the limbic system is
2:16going to be GABA.
2:19So, GABA is a very important one here.
2:20This is also referred to as
2:21gamma-aminobutyric acid. And the other
2:24one, believe it or not to a degree, is
2:26also called serotonin. We also write
2:28this as five-hydroxytryptamine.
2:31These definitely have an influence on
2:34the limbic system.
2:37And so, whenever GABA is present and
2:39whenever serotonin is present, what this
2:41generally will do is this is will help
2:43to be able to maintain a good control of
2:46the limbic system. But,
2:48what if for some reason
2:51there's decreasing GABA activity
2:54or there's decreasing serotonin
2:56activity? If there's decreasing GABA
2:59activity or decreasing serotonin
3:01activity, this really kind of causes a
3:03lot of dysfunction
3:06of the limbic system.
3:08When the limbic system becomes
3:10dysfunctional, there's an excessive
3:11excitation of the sympathetic nervous
3:14system. So, now the sympathetic nervous
3:16system becomes hyperactive because of
3:19these low transmitters. So, if these
3:21neurotransmitters are really, really
3:22low, it causes the limbic system to now
3:24become dysfunctional. That then
3:27hyperstimulates the sympathetic nervous
3:28system. The sympathetic nervous system
3:30then has the ability to go and stimulate
3:32multiple different organ systems like
3:34the heart. And here, it increases your
3:37heart rate. It increases your blood
3:39pressure. It acts on the muscle spindles
3:41and causes tremors. It acts on your
3:44sweat glands and causes diaphoresis.
3:48It also acts on your respiratory system
3:50and maybe it kind of increases your
3:51respiratory rate. All of these things
3:53are physical symptoms or features of
3:55anxiety.
3:56And that's really the kind of the crux
3:58of this disease. So, anxiety is limbic
3:59system dysfunction categorized by low
4:02amounts of GABA activity and low amounts
4:04of serotonin activity. That leads to
4:06dysfunction of the limbic system and
4:08then hyperactivates the sympathetic
4:09nervous system, which leads to all of
4:11this type of fear and apprehension
4:13response.
4:14Now,
4:16the basic thing that I want you to take
4:18away from this is that anxiety is
4:19classified by
4:21low levels of
4:24GABA and low levels of serotonin. And
4:28that's really what it comes down to in
4:30this particular disease. And to give you
4:33kind of an understanding of this, we'll
4:34kind of have a basic diagram here.
4:36Here's going to be a neuron of the
4:38limbic system, right? Here's the the
4:39neuron of the limbic system. And what
4:41it'll do is it'll signal to your
4:43sympathetic nervous system.
4:45We have neurons such as serotonin
4:47neurons.
4:49And we have neurons called
4:51GABAergic neurons.
4:53And what happens is this one releases
4:56GABA. GABA is an inhibitory
4:58neurotransmitter. So, it's supposed to
5:00inhibit inhibit this limbic system
5:02neuron, which would inhibit it from
5:04actually causing a lot of sympathetic
5:06cascade.
5:07But,
5:08if you have low levels of GABA, what's
5:11going to happen? Low levels of GABA will
5:13no longer be able to inhibit this. And
5:15so, this inhibition factor is gone.
5:19And then you increase the sympathetic
5:21nervous system.
5:22The other one is your serotonin. This is
5:25five-hydroxytryptamine.
5:26When there's low levels of serotonin, it
5:29no longer is able to stimulate these
5:31GABAergic neurons. So, normally, it
5:33should be able to stimulate these
5:34GABAergic neurons and then GABA would
5:36inhibit the actual limbic system from
5:39causing a sympathetic response.
5:41But,
5:42if you have low levels of serotonin,
5:44you're not going to be able to stimulate
5:45GABA. GABA will no longer be able to
5:47inhibit the limbic system activity and
5:50the sympathetic cascade will increase.
5:52That's the basic pathophys. So, these
5:54are the big things that I really want
5:55you to know for anxiety. Now, let's now
5:58talk about insomnia cuz now we're going
6:00to talk about hypnotic agents. So,
6:02anxiety, we're going to use drugs that
6:03are going to try to increase GABA and
6:05increase serotonin. They'll anxiolytic
6:07effects, they'll cut the anxiety.
6:10Or, in this situation, insomnia, the
6:12inability to sleep, we're going to talk
6:14about drugs that are going to be
6:16hypnotic agents. But, first we have to
6:18understand the pathophysiology of
6:19insomnia. All right, my friends. So,
6:21insomnia is the inability to fall asleep
6:23or maintain sleep, right? And why is
6:25that? Well, there's a couple different
6:27structures that are really involved in
6:28this. And really, to come down to the
6:30most simplistic aspect, you have some
6:33structures like the pineal gland, right?
6:35So, the pineal gland is a really, really
6:36important one. It releases a particular
6:39hormone called melatonin. So, that's one
6:41particular structure that's involved in
6:44sleep cycles. The other one is your
6:47hypothalamus. And there's many different
6:49nuclei of the hypothalamus.
6:51Okay, many different nuclei of the
6:52hypothalamus.
6:54And then the last structure here that's
6:56really, really important is called your
6:57reticular formation. And there are so
6:59many different nuclei that are involved
7:03in the reticular formation.
7:05But, there is some type of dysfunction
7:07between the communication in these
7:09particular structures. So, what's really
7:11going on is that there is some type of
7:14disconnection. Usually, these structures
7:16should talk to one another. But, there
7:18is some type of abnormality here where
7:20they're not actually communicating
7:22properly with one another.
7:23Let's dig into that a little bit more.
7:25So, what I actually want to do is I want
7:27to take some of these structures of the
7:28pineal gland, the hypothalamus, and
7:29particular formation, zoom in on them,
7:32and talk about some of the
7:32neurotransmitters that it's involved in
7:34and how they interact between these
7:35different structures. And what's the
7:37real pathophysiology or this disconnect,
7:40if you will.
7:41So, the first component is the pineal
7:43gland. Normally, when the pineal gland
7:45is activated, usually when a patient's
7:47in exposed to dark lights, um they
7:50should produce melatonin. That's the
7:52first particular neurotransmitter that I
7:54want you guys to know or hormone. So,
7:56this first one is going to be called
7:57mela-
7:59tonin.
8:00Now, when a person is in dark light,
8:03melatonin should be released. And what
8:05melatonin should do is is it acts of a
8:08acts on what's called melatonin one and
8:10melatonin two receptors that are present
8:14on the structure called the
8:15suprachiasmatic nucleus. This is a
8:17really important structure that
8:18regulates our circadian rhythm. It's
8:20found in the hypothalamus.
8:22What melatonin acts on the
8:23suprachiasmatic nucleus, it should
8:26naturally work to inhibit the
8:28suprachiasmatic nucleus, turn him off.
8:31So, when he's off, that's really when we
8:33want to try to do what? Go to sleep.
8:36So, naturally, what should happen is
8:38this should normally do what? This
8:40should inhibit the suprachiasmatic
8:42nucleus.
8:43When the suprachiasmatic nucleus is
8:45inhibited, it no longer will cause this
8:48inactivation of this structure.
8:51So, this is one of the structures of the
8:52hypothalamus that's really, really
8:53important. It's called the ventrolateral
8:55preoptic nucleus. I'm going to
8:56abbreviate that the VLPO. It's found in
8:58the hypothalamus.
9:00When the suprachiasmatic nucleus is
9:02inhibited,
9:03what it generally will do is is it'll
9:05activate the VLPO.
9:08So, it'll stimulate the VLPO. It should
9:11stimulate it. Now, the VLPO has two
9:13things that it does. One is when it's
9:15active, it should promote sleep. It
9:19should promote sleep. It wants to
9:20promote sleep.
9:22But, in order for it to promote sleep,
9:23it has to suppress arousal or
9:26wakefulness. So, how does it do that?
9:28So, then what happens is the VLPO
9:31secretes very specific types of
9:33neurotransmitters that suppress all
9:36these different nuclei. So, you have
9:37what's called the tuberomammillary
9:39nucleus, the lateral hypothalamic
9:41nucleus, and so many nuclei of the
9:43hypothalamus. I'm sorry, the the
9:45reticular formation. So, you have the
9:46reticular formation nuclei and the
9:48posterior hypothalamic nuclei.
9:50What happens is the ventrolateral
9:52preoptic nucleus releases something
9:54called
9:55gamma-aminobutyric
9:57acid. And what gamma amino-butyric acid
10:00should do to I want you to think about
10:02your reticular formation and your
10:04posterior hypothalamus is it should
10:06inhibit them.
10:08If it inhibits them, it should then
10:10inhibit arousal and wakefulness. So now
10:14the VLPO is activated because of
10:16melatonin, right? Because melatonin
10:19inhibits the suprachiasmatic nucleus,
10:20which activates the VLPO. VLPO promotes
10:23sleep and then it suppresses arousal and
10:26wakefulness by releasing GABA to inhibit
10:28the reticular formation in the posterior
10:29hypothalamus.
10:31That's the really cool concept. Now,
10:34at the same time at the same time,
10:38whenever a person is having insomnia,
10:41right?
10:42What you see in this particular process
10:45is that you wouldn't want to promote
10:46sleep. You wouldn't want to promote
10:48sleep. You want to promote arousal and
10:49wakefulness if they have insomnia.
10:51So imagine now,
10:53I drop my melatonin levels.
10:56If I drop my melatonin levels, will I be
10:58able to inhibit the suprachiasmatic
11:00nucleus? No. So I will no longer be able
11:03to inhibit this bad boy. If I can't
11:05inhibit him, will I be able to activate
11:07the VLPO? No, so I won't be able to
11:10activate the VLPO. If the VLPO is
11:13activated, will it be able to promote
11:14sleep? No.
11:16And if he can't promote sleep, can he
11:18then suppress the reticular formation
11:21and the posterior hypothalamus? No, he
11:24can't suppress it. And therefore he
11:26can't suppress arousal and wakefulness.
11:28That's one particular problem. So one
11:30part of this disease process insomnia is
11:33that the patient may have low levels of
11:35what? Melatonin.
11:38Now, let's think about the next aspect
11:41here.
11:42What if we go to the the second part
11:44here? So get rid of melatonin. Let's say
11:46that the VLPO now is in this state where
11:49it's supposed to be active. When it's
11:51active, it wants to promote sleep. So
11:53it'll do that, right? But in order for
11:55it to do that it has to suppress the
11:57posterior hypothalamus and reticular
11:58formation. So it releases GABA.
12:01What if we had
12:02low levels of GABA? Cuz GABA is
12:04essential for being able to suppress the
12:06reticular formation and suppress the
12:08posterior hypothalamus. If we have low
12:10GABA levels, will we be able to suppress
12:12this anymore? No. So you can't suppress
12:14it. You can't suppress arousal and uh
12:17you won't be able to suppress the
12:18arousal and wakefulness and you won't be
12:20able to promote sleep. So there's
12:21another particular problem is low levels
12:23of
12:24GABA.
12:26So if you have low levels of GABA and
12:27low levels of melatonin,
12:29the reticular formation will then be
12:31hyperactive and the VLPO will be
12:34inactive.
12:35There's another particular concept here.
12:38The reticular formation releases
12:40chemicals that are supposed to naturally
12:43inactivate
12:45the VLPO. And if you inactivate the
12:47VLPO, it would inhibit sleep, right? It
12:51would inhibit sleep.
12:52Now, what are these chemicals that the
12:55posterior hypothalamus and reticular
12:56formation releases to suppress the VLPO?
13:00Those chemicals are called
13:02orexin
13:05and histamine.
13:07Histamine.
13:09So these chemicals naturally are going
13:11to suppress the VLPO, which would then
13:14suppress sleep. If you inhibit this, are
13:17you going to be able to promote sleep?
13:18No. If you inhibit this, is the VLPO
13:21going to be able to inhibit the
13:22reticular formation? No. So the
13:23reticular formation will be active and
13:25then trigger arousal and wakefulness.
13:27So these would be the bad boys. If
13:29they're in higher levels, they're going
13:30to suppress the VLPO, suppress sleep and
13:33keep the reticular formation activated
13:35to promote arousal and wakefulness.
13:36That's terrible. But that is another
13:39pathophysiological concept here is that
13:42you can have high orexins and high
13:44histamine levels. So that's the other
13:46pathophysiological process here. So when
13:49it comes down to it, the big thing that
13:51I want you to tell to take away from
13:53this is that whenever you have low
13:54melatonin levels and low GABA, this will
13:57cause insomnia. High orexin levels and
14:00high histamine levels, this will also
14:02cause insomnia. And the basic concept
14:06behind this is that if you cause if this
14:08is all basically happening, what all of
14:11these things are doing is is they are
14:12inhibiting the VLPO, which is going to
14:15inhibit sleep
14:18and these are all going to stimulate the
14:20reticular formation
14:22and that is going to
14:24stimulate arousal
14:27or wakefulness and again inhibit sleep.
14:32And that is the concept here. So if we
14:35come up with hypnotics,
14:37the hypnotics should be able to increase
14:39melatonin, increase GABA, decrease
14:41orexin and decrease histamines. Whereas
14:43with anxiolytics, we need to come up
14:45with drugs that increase GABA and
14:47increase serotonin. So now let's talk
14:49about those drugs that actually act as
14:52an anxiolytic and the drugs that act as
14:54hypnotics in patients who have anxiety
14:56or insomnia. All right, my friends. So
14:57now anxiolytics, we got to get the drugs
14:59now that are going to be able to help
15:00these patients who are having anxiety.
15:02So when we think about this, let's talk
15:04about two things. One is the mechanism.
15:05So really how are these drugs actually
15:07helping to increase GABA or increase
15:09serotonin cuz that was the whole goal,
15:11right? And then what are some of those
15:13drugs? What are some of the names of
15:15those drugs that are we actually going
15:16to talk about? So first thing for
15:18anxiolysis with mechanism here is again,
15:20we have two particular neurotransmitters
15:23here.
15:24One is this neurotransmitter right here,
15:26my friends. So this is a neuron that's
15:28going to be releasing something called
15:305-hydroxytryptamine.
15:31That's also known as serotonin. So this
15:34is also referred to as serotonin.
15:37Now, serotonin is low in anxiety, but
15:40it's also low in another disorder called
15:43depression. And depression and anxiety
15:45often sometimes are good cousins or
15:47friends of one another and so they often
15:49coexist.
15:50Whenever there's low levels of
15:52serotonin, which we said that was the
15:54process of anxiety, is there's low
15:56levels of serotonin, what was the
15:58problem with that? Well, serotonin is
16:00naturally supposed to bind onto this
16:02receptor here. You see this receptor on
16:04this blue neuron? This is called a
16:065-hydroxytryptamine
16:08receptor, a serotonin receptor.
16:10When serotonin binds onto this receptor,
16:13it's supposed to stimulate. So it should
16:15cause like a cationic influx and
16:18stimulate this neuron.
16:20This neuron releases a neurotransmitter
16:23called GABA.
16:25And GABA is supposed to naturally do
16:27what? Inhibit this limbic system neuron.
16:31So naturally what it's supposed to do is
16:33is it should work to bind onto this
16:36particular receptor. So this is GABA.
16:38GABA should bind into that little pocket
16:39there.
16:40This little receptor here. You see this
16:42receptor here? This is a really
16:43important receptor. This receptor here
16:45is called the GABA
16:48A receptor. Very, very important
16:50receptor.
16:51When GABA binds onto this little pocket
16:54here, and we'll talk about that in a
16:55little bit, it opens up this channel to
16:57allow for chloride ions to flow in.
17:00These are negative ions. When negative
17:03ions flow into this particular neuron,
17:05what it's supposed to do is is it causes
17:07the cell to become super negative. You
17:09know what we call that? When the cell
17:10becomes super negative, it causes
17:12hyperpolarization.
17:14Hyper-
17:16polarization. Basically makes the cell
17:18super negative and that should decrease
17:21the action potentials. So then the
17:23limbic system neuron shouldn't be firing
17:25excessively. And so because of that,
17:27there should be a decreased sympathetic
17:30effect. So decrease fear, apprehension,
17:32tachycardia, hypertension, respiratory
17:35rates aren't going up as much. You
17:36aren't having tremors or uh diaphoresis
17:39as much, right? And so that's really
17:41what the benefit of GABA would be. But
17:43if you're having low serotonin, you're
17:44not going to tell these neurons to make
17:46GABA. And so because of that, the GABA
17:48would be
17:49low.
17:51The GABA would be low.
17:52GABA wouldn't be able to work on this
17:55receptor.
17:56It wouldn't be able to allow for
17:57chloride ion influx to cause
17:59hyperpolarization to decrease action
18:00potentials.
18:01So that's really what it comes down to
18:03in this particular process. So what if I
18:05came up with a drug that specifically
18:08worked, one of these drugs. I'm going to
18:10use a drug and what I'm going to do is
18:12I'm going to inhibit
18:14that particular receptor right there,
18:15that little protein there. You know what
18:17that protein's supposed to do?
18:19When serotonin is done exerting its
18:21function,
18:23it's supposed to go back in
18:26to the axon, right? It's supposed to go
18:27back into the axon. But then that lowers
18:30the serotonin level in the synapse.
18:32What if I came up with a drug that
18:34inhibited that serotonin reuptake
18:37protein? So I'm going to inhibit this
18:40sero- this reuptake protein, this
18:43reuptake
18:44mechanism. I'm going to inhibit that.
18:46What does that do to the serotonin now
18:48in the synapse? If I don't take it back
18:49into the axon, it's going to stay here
18:50now. So what happens to the serotonin
18:52levels?
18:53They go up.
18:56If serotonin levels go up now,
18:59then I'm going to be able to increase
19:02the stimulation of these
19:04GABAergic neurons.
19:05Then they're going to release a lot of
19:07GABA.
19:08If they release a lot of GABA,
19:11then GABA will be able to inhibit these
19:15particular neurons by causing chloride
19:16ion influx cuz it'll stimulate this GABA
19:19A receptor. It'll increase
19:21hyperpolarization.
19:22And if you do that, it'll really, really
19:25decrease the action potentials and
19:27decrease the sympathetic response.
19:29That's a really cool concept.
19:31Another thing is if I had a drug that
19:33actually had the ability to bind, so
19:36let's say I have another drug and it
19:37directly binds to this receptor. So it
19:41stimulates the receptor and that
19:43increases the positive ions, increases
19:45GABA, increases the binding of GABA A
19:47receptor, increases hyperpolarization,
19:49decreases action potential and decrease
19:50the sympathetic or anxiety response.
19:53That'll be another benefit, too.
19:55What are these drugs that can increase
19:57serotonin by inhibiting reuptake or
20:00drugs that can bind directly to the
20:01serotonin receptor?
20:03These would include
20:05your SSRIs.
20:06So, your selective serotonin reuptake
20:08inhibitors, they'll inhibit the reuptake
20:09of serotonin. There's another group
20:11which actually in blocks the reuptake of
20:13serotonin and norepinephrine, but they
20:16they again, they block the reuptake of
20:18serotonin. So, these are two drug
20:19categories that are going to do what?
20:22Inhibit reuptake. So, these two here,
20:24these ones specifically here is going to
20:26inhibit reuptake.
20:29And this one here is going to re-
20:30inhibit reuptake. And that's how it'll
20:33increase the serotonin activity. These
20:35drugs include which ones?
20:37So, SSRIs, I want you to remember
20:39escitalopram, escitalopram.
20:44Citaline is another particular big one
20:46here.
20:48Paroxetine is another one as well.
20:51So, these are some of the drugs that I
20:52want you guys to remember.
20:54The SNRIs are going to be things like
20:57venlafaxine. So, venlafaxine.
21:01And duloxetine.
21:03Duloxetine.
21:06These are going to be some of the drugs
21:07that we can utilize in anxiety, but more
21:09specifically we'll talk about later,
21:10chronic anxiety.
21:12Because patients who have chronic
21:14anxiety likely have some degree of
21:15associated depression, and these drugs
21:17have been shown to be more effective and
21:19less abuse potential than the next drug
21:21category that we'll talk about, the ones
21:22that affect GABA.
21:24And the last one is buspirone. And
21:25buspirone has actually been shown to
21:27directly stimulate the 5-HT receptor.
21:32And this is going to be the name of that
21:33drug, buspirone. There is no specific
21:34category, it's just buspirone. There's
21:36even some thought that it actually may
21:37affect some of the dopamine receptors as
21:39well, but for right now keep it simple,
21:40we're going to focus on serotonin.
21:43Okay. So, that's one set of drugs.
21:44SSRIs, SNRIs, both inhibit the reuptake
21:48of serotonin, increase the serotonin in
21:50the synapse, or buspirone which binds
21:52onto the serotonin receptor. That will
21:54increase the inhibition of the limbic
21:56system and inhibit the sympathetic
21:57response.
21:58What if I avoid the serotonin now and I
22:00just focus on GABA? The problem with
22:02GABA was low. So, GABA wasn't actually
22:05being either released enough or wasn't
22:06acting on this receptor properly.
22:08Well, what if I gave drugs that either
22:10increased, some way, shape, or form, the
22:11GABA activity?
22:13What if I gave a drug
22:15that specifically specifically hit right
22:18here? It stimulated this particular
22:20receptor. So, it stimulated the GABA A
22:24receptor. It bound onto the GABA A
22:26receptor and enhanced the activity of
22:28the GABA A receptor. So, GABA doesn't
22:30even have to be present. This drug will
22:32bind onto that little that little socket
22:34there on the GABA A receptor, open it
22:36up. That'll increase chloride ion
22:38influx.
22:39That'll increase hyperpolarization.
22:42That'll decrease the action potentials
22:43of the limbic system and suppress the
22:45sympathetic anxiety and fear response.
22:47That's a pretty cool concept. So, we
22:49need to give drugs that are going to
22:50increase GABA activity. We specifically
22:53call these ones, just so you know, these
22:55are actually called GABA
22:59agonist. That's really what we should
23:01call them. So, they're not increasing
23:03the levels of GABA, but they're kind of
23:05acting like GABA. And so, they have the
23:07same effect.
23:09So, that's really really important cuz
23:10when you think about this,
23:12if we were to actually take this GABA A
23:13receptor and zoom in on it a little bit.
23:16Here it is. It's a pentameric type of
23:18protein.
23:19And it's made up of different subunits.
23:20So, you have one of the subunits, a
23:22gamma subunit. You have a beta one
23:24subunit. You have a beta two subunit.
23:29You have a alpha one subunit and an
23:31alpha two subunit.
23:34Out of all of these, the one that's
23:36actually been shown to be most specific
23:39to actually inhibiting the limbic system
23:41neurons is the alpha two. Very very
23:44important. So, the alpha two is the one
23:47specific subunit that these GABA
23:49agonists actually bind to. So, when GABA
23:52agonists actually help to open up this
23:54GABA A receptor, which of the actual
23:57sites do they have to bind onto in order
24:00to activate this channel and cause
24:03chloride ions
24:05to flow into the cell?
24:07They have to bind onto the alpha two
24:09subunit. That's very very important. So,
24:11again, I want to write it down so that
24:13you understand here. It's going to bind
24:14onto the alpha two subunit
24:19of the GABA
24:22A receptor.
24:24What are these drugs that have this GABA
24:27A agonistic activity or the GABA A GABA
24:29activity that's agonistic like?
24:31These are going to be barbiturates and
24:33benzodiazepines, but here's the thing. I
24:34don't even want to waste any time.
24:36We don't even use barbiturates anymore
24:38for anxiolysis. The reason why is
24:40there's just too much toxicity with this
24:43drug. There's so many there's so much
24:45more risk than there is benefit to the
24:46treatment of anxiolysis. We use
24:48barbiturates more specifically in other
24:50things. So, seizure activity, uh
24:52anesthesia, or maybe even inducing a
24:54coma to reduce ICP. But it is not an
24:57effective agent for anxiolysis because
24:59of the adverse effects of it.
25:01So, what we may utilize instead, because
25:03there's not as many adverse effects as
25:05severe as barbiturates, is
25:07benzodiazepines.
25:08Benzodiazepines,
25:10there's different types. So, we can use
25:13them based upon their half-life. So, if
25:15something acts very very quickly and it
25:17gets metabolized and gets removed from
25:19the body or excreted and it's cleared
25:20quickly, its half-life is very short.
25:22So, that would be good drugs that you
25:23maybe you don't want to have it last as
25:25long. All right? So, short-acting drugs
25:28that I want you guys to remember here is
25:29going to be a couple. One is called
25:31midazolam.
25:33Midazolam is a very commonly utilized
25:35one. Triazolam.
25:38Triazolam is another one.
25:40Intermediate, there's a bunch of these.
25:43Lorazepam
25:44is one.
25:46Um oxazepam.
25:49Alprazolam.
25:52Um a couple more just to mention is
25:55temazepam.
25:58Then you have your long-acting.
26:00And there's a bunch for these one as
26:01well. So, diazepam is one.
26:05Uh chlordiazepoxide,
26:07chlordiazepoxide.
26:11There's a bunch of these different types
26:12of drugs, right?
26:14But with that being said, oh and then
26:16there's another one that's actually
26:17important to remember, clonazepam.
26:18Clonazepam's another one. Clonazepam.
26:22But out of all of these,
26:24the ones that we've actually seen
26:25benefit to to actually treating anxiety,
26:28having an anxiolytic effect, is the ones
26:31that I'm going to circle.
26:32Lorazepam is one.
26:36Oxazepam is one.
26:38Alprazolam is one.
26:41Diazepam is one.
26:43And clonazepam is one. The reason you
26:46would pick one over the other is
26:49dependent upon how long you'd like this
26:51to act. So, if you gave something like
26:52diazepam or clonazepam, it's going to
26:54have a longer anxiolytic effect. Whereas
26:56if you give something like lorazepam,
26:57oxazepam, or alprazolam, they're going
26:59to be more intermediate-acting. Okay?
27:01So, that's an important concept to
27:03remember. But again, to take away from
27:05this,
27:06anxiolytic drugs are drugs that are
27:08going to increase serotonin activity.
27:10They either inhibit the reuptake, SSRI,
27:11SNRI, or they activate the serotonin
27:14receptor, buspirone.
27:16Or they increase similarity of the GABA
27:19activity. In other words, they stimulate
27:21the GABA A receptor. They act as an
27:22agonist. And that will, by binding to
27:25the alpha two subunit of that receptor,
27:27increase chloride influx and inhibit the
27:28limbic system dysfunction.
27:30By doing that, we can use two agonist
27:33drugs. One is barbiturates, which we
27:36don't use as much because they're so
27:37toxic, and benzodiazepines.
27:40The reason why, if we were to really add
27:42onto the barbiturates, is barbiturates,
27:44when they bind onto the GABA A receptor,
27:46they increase the duration
27:50of chloride channel
27:53opening.
27:55And that is a really scary thing cuz if
27:57these things stay open, you can really
27:59inhibit a lot of different neurons.
28:01So, that's a really really important
28:03concept is they they actually increase
28:04the duration.
28:05Benzodiazepines, on the other hand,
28:07increase the frequency.
28:10So, they increase the frequency
28:13of chloride channel
28:15opening.
28:17And that's a really important kind of
28:18like takeaway point for this particular
28:21process here, for your GABA A agonist.
28:23Okay?
28:24All right. That covers our drugs that
28:26are going to be utilized for anxiolysis.
28:28So, again, a quick recap. SSRIs, SNRIs.
28:31For those, they're increasing the
28:32serotonin by inhibiting reuptake. This
28:33includes escitalopram, paroxetine,
28:36citaline. Or your SNRIs, venlafaxine,
28:39duloxetine. Or you can have buspirone,
28:42which is a direct serotonin type of
28:44agonist. You can also act to increase
28:47the GABA A activity or GABA activity by
28:49binding to the GABA A receptor, acting
28:51as an agonist. The drugs that increase
28:54GABA activity by acting as an agonist is
28:56barbiturates. Don't use them because of
28:58the toxicity. The toxicity is due to a
29:00high duration of uh chloride channel
29:02opening. Benzodiazepines are more
29:05beneficial and not as many toxic effects
29:07because they only increase the frequency
29:09of chloride ion channels. And this
29:10includes the short-acting triazolam,
29:12midazolam. Intermediate-acting, which
29:14would be lorazepam, oxazepam, temazepam,
29:17as well as um alprazolam. And then the
29:21last one is the long-acting diazepam,
29:22chlordiazepoxide, and clonazepam. With
29:25those, these are the more particularly
29:27utilized ones for anxiolysis.
29:29All right. Now, let's talk about the
29:31drugs for hypnosis. In other words, you
29:33want to treat insomnia. All right, guys.
29:35So, when we talk about hypnosis, you're
29:37trying to induce sleep and maintain
29:39sleep, right? So, the mechanism behind
29:40this is that the pineal gland, right,
29:42releases melatonin.
29:44In this disease process, there's low
29:46melatonin. So, let me kind of come up
29:48with a way to increase melatonin. So,
29:51that's one particular mechanism is I
29:52want to give drugs that are going to
29:54specifically act on the melatonin
29:57receptor. So, you remember how there was
29:58the melatonin 1 and the melatonin 2
30:02receptors? What if I gave a drug that
30:04acts as a agonist to melatonin and it
30:08stimulates this receptor?
30:10That would enhance that would basically
30:11be as if melatonin was present. Cuz in
30:13this disease, one of the problems is
30:15that we have low melatonin, right? So,
30:17one of the problems is low melatonin. If
30:19I were to increase the effect of
30:22melatonin,
30:24wouldn't a melatonin agonist be the same
30:27as kind of increasing melatonin? Yes,
30:29cuz it's going to activate those
30:30receptors and that's going to inhibit
30:32the suprachiasmatic nucleus, which
30:34stimulates the VLPO, which stimulates
30:36sleep and then releases GABA
30:40to inhibit
30:41the reticular formation in the posterior
30:43hypothalamus, which would then inhibit
30:46arousal and wakefulness. We know that.
30:48So, that's one way. And what are some of
30:50the drugs that help to be able to
30:51increase melatonin by acting as a
30:53melatonin agonist? This includes
30:55ramelteon and tasimelteon. So,
30:57ramelteon.
31:00Ramelteon.
31:03Okay.
31:05The next thing is, let's come to the
31:06GABA. We said GABA was another
31:08particular problem, right? That GABA was
31:10low in this particular pathophysiology.
31:12So, GABA was low and if GABA was low,
31:16what we knew is that GABA,
31:19if it was in the lower amounts, it
31:21wasn't inhibiting the posterior
31:23hypothalamus, it wasn't inhibiting the
31:25reticular formation. And so, if it
31:27wasn't inhibiting the reticular
31:28formation, it wouldn't be able to
31:30inhibit arousal and wakefulness. And on
31:33top of that, if you couldn't inhibit the
31:34reticular formation, the reticular
31:36formation would keep suppressing the
31:37VLPO so that you don't sleep.
31:40So, what if I come up with a way to have
31:44some type of drug to bind onto the
31:47GABA-A receptor?
31:49Hmm.
31:49So, what if I stimulate the GABA-A
31:53receptor?
31:55I give a drug that acts as a agonist
31:58as to GABA and it stimulates this
32:00particular receptor.
32:01If it stimulates this receptor, it's
32:03going to inhibit the reticular
32:05formation. If you inhibit the reticular
32:07formation, you'll inhibit arousal and
32:10wakefulness.
32:11So, now this patient won't be able to
32:13stay awake. On top of that, if you
32:14inhibit the reticular formation, it
32:16can't release those factors that are
32:17supposed to naturally it's supposed to
32:20inhibit the VLPO, right? Cuz it releases
32:22things like orexin and it releases
32:24things like histamines. But, if you
32:27inhibit the reticular formation, it
32:28can't release those chemicals to inhibit
32:30the VLPO. So, the VLPO stays active and
32:33promotes sleep. That's drugs that are
32:36going to increase GABA. We already
32:37talked about these.
32:39Here's the difference though. Here's the
32:40big difference.
32:42On this part here, on this part here,
32:45for where the GABA-A receptors bind to,
32:46I'm going to put it in a little note
32:47here. It's the alpha-1
32:51subunit.
32:52So, I'm going to put this is the alpha-1
32:54subunit. I'm just going to put alpha-1
32:55here. So, it's alpha-2 for anxiolysis,
32:59which is in the limbic system, alpha-1
33:02on the reticular formation that's going
33:04to induce hypnosis. That's really
33:06important.
33:07Because now I can add a third drug to
33:10drugs that actually increase that GABA
33:12activity. Before it was barbiturates,
33:15right? We don't use these, right?
33:17Because of increased toxicity. We do not
33:20use these for hypnosis.
33:22Okay?
33:23And then we have benzodiazepines. These
33:26will actually do what? They'll bind to
33:28the alpha-1 and help to be able to
33:30increase chloride influx and cause the
33:33reticular formation to be suppressed.
33:36So, the reticular formation is
33:36suppressed, you won't be able to stay
33:38awake, you'll fall asleep. And this
33:40includes two particular drugs in the
33:41benzodiazepines. So, there were
33:42short-acting, intermediate-acting, and
33:44long-acting, right? Out of those,
33:46particularly temazepam
33:48and flurazepam are the most specific
33:51ones that I want you to remember. So,
33:52temazepam,
33:54temazepam,
33:56and flurazepam are the most commonly
33:59utilized benzodiazepines for actually
34:01helping to induce hypnosis by inhibiting
34:03the reticular formation.
34:06That adds the last drug. So,
34:07barbiturates would also do the alpha-1,
34:09but we don't use these. And then the Z
34:11drugs. Z drugs also bind to the alpha-1
34:13subunit, but they don't bind onto the
34:15alpha-2 subunit. So, they have So, if I
34:17were to kind of put a thing here, they
34:19have positive alpha-1, but they do not
34:22have alpha-2 activity. This one has
34:25alpha-1 and it has
34:27alpha-2 activity. This one has alpha-1
34:30and it has alpha-2 activity. You see the
34:33difference there?
34:35What are some of the Z drugs that only
34:36induce hypnosis, but do not provide
34:38anxiolysis?
34:40This includes zolpidem,
34:44zaleplon,
34:47and eszopiclone.
34:50These are going to be your Z drugs. And
34:53again, they do this by binding onto the
34:55GABA-A receptor and promoting chloride
34:57ion influx, which inhibits will cause
34:59hyperpolarization, decrease the action
35:01potentials, and decrease the
35:04activation of the reticular formation.
35:06So, the reticular formation will be
35:07suppressed, you won't be able to stay
35:08awake, you'll then promote sleep.
35:11Beautiful. Okay.
35:13The next concept is that we had another
35:15problem here, which was that when the
35:17reticular formation is active,
35:19when the reticular formation is active,
35:21it's giving drugs like it's secreting
35:23things like orexin
35:26and it's secreting things like
35:27histamine.
35:28And histamine and orexin are supposed to
35:30naturally do what? Inhibit the VLPO,
35:33right? So, they're naturally supposed to
35:35naturally what they would do is they
35:36would inhibit the VLPO and then you
35:39wouldn't be able to promote sleep,
35:41right?
35:43Now, if I give a drug that basically
35:47will block it'll act as an antagonist.
35:50So, I will give a antagonist
35:53to orexin
35:55or an antagonist to histamine,
35:58then I'll no longer be able to allow for
36:00these drugs to inhibit the VLPO. So, now
36:02the VLPO would no longer be inhibited,
36:04instead it'll be stimulated, it'll be
36:06released from inhibition, and it'll be
36:08able to promote sleep. If it can promote
36:11sleep, it'll then be able to suppress
36:13the reticular formation and prevent the
36:15further release of more orexins and
36:17histamines. But, I should give drugs
36:19that can act as antagonists
36:21to block orexin and histamine so it
36:23doesn't shut down the VLPO cuz I need
36:25him active to sleep.
36:27So,
36:28I need to give drugs that will
36:30decrease orexin. So, naturally the
36:32problem in this pathophysiology
36:35is that there's too much
36:37orexin and there's too much
36:39histamine. Oops. Let's do this in the
36:41blue color. So, there's too much orexin
36:44or there's too much histamine in the
36:45pathophysiology.
36:47So, what I need to do is
36:50I need to give drugs that are going to
36:52block that effect. They're going to
36:54block this effect. So, now you're no
36:56longer able to inhibit the VLPO. You
36:59keep the VLPO activated now.
37:01What are the drugs that help to block
37:04orexin and block histamines? So, the
37:06drugs that actually decrease orexin is
37:08going to be something called suvorexant
37:11and it's a newer drug. We don't know a
37:13ton about this drug, but it is a newer
37:15type of drug.
37:18The other ones are the drugs that
37:20decrease the histamines. So, they block
37:22the increase in histamine. They block
37:24the histamine from binding to the VLPO.
37:26There's so many different types. Some of
37:28you may have used this before, but
37:30diphenhydramine, right? Diphenhydramine
37:32is a very commonly utilized
37:34antihistamine. It's Benadryl. And
37:36Benadryl will actually be able to
37:37promote sedation. If you're using it for
37:38like an allergic reaction, you may have
37:40noticed that it also can produce some
37:41residual sedation. Because the
37:43histamine, right? When it hits the VLPO,
37:46it keeps the VLPO inactive so you can't
37:48sleep, right? But, if you give
37:50diphenhydramine, it blocks the histamine
37:52from binding to the VLPO. Now, the VLPO
37:53is actually active and it promotes
37:55sleep. So, this would be again something
37:58like diphenhydramine.
38:00Diphen-
38:02hydramine. And this is more of an
38:03adverse effect, unfortunately, of the
38:05drug.
38:07And the same concept, you have
38:08antidepressants.
38:10And these antidepressants are
38:11interesting in the sense that they can
38:12increase serotonin activity, but they
38:15can also decrease histamine activity.
38:18And that's really cool.
38:20And what are some of these drugs? So,
38:22there's a bunch of them. One is called
38:25doxepin. And doxepin is actually what's
38:27referred to as a tricyclic
38:28antidepressant, but it has antihistamine
38:31properties.
38:33Another one is called mirtazapine.
38:35Mirtazapine.
38:37And another one is called trazodone. And
38:39these are these types of atypical
38:41antidepressants. But, these are drugs
38:43that also have the ability to block the
38:45histamine from binding to the VLPO. And
38:48if the VLPO doesn't have histamine bind
38:49to it, it's then active, it can promote
38:51sleep, and suppress the reticular
38:53formation. And that's the basic concept.
38:56In these particular problems, these
38:58things are all doing what?
39:00They're inhibiting the
39:02VLPO so that you don't sleep. And
39:04they're stimulating the reticular
39:06formation so that you stay awake. If you
39:09give drugs that
39:11help to do the opposite,
39:13increase melatonin, increase GABA,
39:15decrease orexin, decrease histamines,
39:18this will now do what? This will help to
39:21inhibit the reticular formation and
39:23stimulate the VLPO.
39:25And that is the goal here is to keep the
39:27VLPO active and the reticular formation
39:31off. And by doing that, this will all
39:33promote
39:35sleep.
39:36And that is the ultimate goal here.
39:38All right, my friends. That covers all
39:39the mechanism of anxiolytics and
39:41hypnotics and all the drugs that are
39:43included in that. The next thing is I
39:45want to take a quick approach. So, when
39:46a patient has anxiety, how do I know
39:48which drug to pick cuz there was a
39:50bunch? And if they have insomnia, how do
39:52I know which drug to pick because
39:53there's so much? So, we'll talk about
39:56that briefly. All right, my friends. So,
39:57now let's talk about quickly an approach
39:59this. So, if a patient has anxiety,
40:00right, acute anxiety,
40:02generally benzodiazepines are going to
40:03be the best fit for that patient during
40:05that acute anxiety attack. They work
40:07very, very quickly. And so, they're
40:09really going to be the best particular
40:10drug option for a patient who has having
40:12acute anxiety, right? So, when you have
40:15acute anxiety, benzodiazepines
40:18are going to be the go-to. Okay? And
40:20again, just as a reminder, what were
40:22some of those drugs? This would be the
40:24alprazolam. Alprazolam is a great one,
40:28very commonly utilized one. Another one
40:30is clonazepam.
40:33Another one is going to be diazepam.
40:38Another one is going to be lorazepam.
40:42Another one is going to be oxazepam. All
40:44of these can be utilized in a patient
40:46who has acute anxiety. Now, here's the
40:48downside.
40:50These drugs have the ability to produce
40:52abuse potential. They're controlled
40:54substances, so they have addiction
40:55potential. So, one of the downsides to
40:58these drugs is that they can cause
41:00abuse.
41:02So, we don't want to keep patients on
41:04these for a super long period of time.
41:07So, the preferred action of these drugs
41:09is we prefer for these to be a PRN
41:12basis. Only use when you have a patient
41:15who has really, really bad anxiety in
41:18very specific types of disorders, and
41:20it's for that acute kind of breakthrough
41:22anxiety.
41:24When you have a patient with chronic
41:26anxiety, and this is really when it
41:28comes down to like diseases such as
41:31really generalized anxiety disorder,
41:33social anxiety disorder, panic attack
41:36disorder, phobias, etc.,
41:38then these patients may require
41:41something a little bit more long-term.
41:43And in those particular scenarios for
41:45the long-term basis, benzodiazepines
41:48aren't going to be the best.
41:50And so, what we prefer is to give drugs
41:52that increase serotonin. So, this would
41:54be your SSRI or an SNRI,
41:59right? And then for the chronic anxiety,
42:02you can do a PRN
42:04benzodiazepine.
42:06And that's generally how we would go
42:08about this.
42:09Another thing is
42:11let's say that again, you do the PRN
42:13benzodiazepine, but you're still worried
42:14that the patient has a high risk of
42:15abuse potential. Take that into
42:17consideration in their history. An
42:19alternative
42:20An alternative to a PRN benzodiazepine
42:24is something like buspirone.
42:27So, buspirone may be a decent
42:29alternative with very little likelihood
42:31of abuse potential. So, this is
42:34generally how you would go about this.
42:36Acute anxiety, you start off with
42:38benzodiazepines just for the
42:40breakthrough, okay? Buspirone will not
42:43be good for acute anxiety, okay? This is
42:45good for the breakthrough. The other
42:47thing is SSRIs and SNRIs, you know how
42:49long they take? These puppies can take
42:51up to 4 to 6 weeks, 4 to 6 weeks to
42:54really become therapeutic and produce
42:56anxiolytic effects.
42:58So, that's why we use the PRN
42:59benzodiazepine or the buspirone until
43:01these become therapeutic.
43:03So, that's the concept there.
43:05All right, that's how I would approach
43:06that one. For hypnosis, I like to think
43:08about I'm treating a patient who has
43:10insomnia for different reasons. Is their
43:12insomnia because they're super stressed
43:14and anxious, and then they just their
43:16mind keeps running that they can't help
43:17themselves to fall asleep?
43:19In those particular scenarios, one of
43:21the drugs that may be beneficial
43:24because it has very profound anxiolytic
43:26effects is going to be benzodiazepines.
43:30Benzodiazepines.
43:33And in this particular situation,
43:34there's two. Flurazepam. Flurazepam is
43:39going to be one.
43:40And temazepam. And I've been uh very
43:42fond sometimes of temazepam. I think
43:44it's very effective.
43:46But again, one of the things that you
43:48have to realize here is that these have
43:50a high
43:52abuse potential. The people can become
43:54dependent upon these. And then if you
43:57discontinue these medications, they can
43:59develop rebound insomnia. So, that's a
44:01really, really important thing to think
44:02about.
44:03All right, what if a patient has mild to
44:05moderate insomnia, but it's not stress
44:06and anxiety related? In that particular
44:09scenario, your Z drugs. Your Z drugs are
44:11going to be great in this particular
44:13scenario.
44:15So, the Z drugs would be the options I
44:16would consider. And that would be the
44:18zolpidem,
44:20the eszopiclone,
44:25and the zaleplon.
44:27With a little caveat here
44:30that I prefer the zaleplon.
44:33Zolpidem, Ambien, is going to be the
44:34most commonly utilized one. But I like
44:37zaleplon because one of the cool things
44:39about this drug is it has a short
44:40half-life. So, if you give this drug,
44:42it'll really help to induce sleep,
44:45and it won't last super long, so there's
44:47a lot of residual side effects when you
44:49wake up in the morning. And so, that's
44:51really one of the beauties behind this
44:52drug is that it decreases the residual
44:56drowsy
44:58kind of nature that you have in the
44:59morning with some of these other drugs
45:01such as zolpidem and eszopiclone.
45:03Don't get it twisted though, these
45:04things do have abuse potential, just
45:07nowhere as much of the abuse potential
45:09as compared to benzodiazepines. And so,
45:12just to do realize that it used to be
45:13thought that these do not cause abuse.
45:15These do have a sense of abuse and
45:18dependence, and if you stop taking
45:19these, you can develop rebound insomnia.
45:23All right, next thing is sleep
45:24induction.
45:25For sleep induction, so I don't really
45:27it's not really hard time of maintaining
45:29sleep. I just need to fall asleep. And
45:31so, this really is going to be one of
45:32the particular drugs that increases the
45:35activity of melatonin.
45:36So, melatonin-containing drugs. So, this
45:38is actually going to be my melatonin
45:42agonist.
45:43My melatonin agonist. Do you guys
45:45remember what this one is? This is your
45:46ramelteon.
45:48Ramelteon is the particular option here.
45:51There's still uncertainty of the
45:52suvorexant, which is the orexin
45:53antagonist, but there may, plus or
45:55minus, we're going to put plus or minus
45:57the orexin
45:59orexin antagonists.
46:02Antagonists. We just don't know enough
46:04about this drug category yet. Okay?
46:07All right. So, we got stress anxiety,
46:10benzos. Mild to moderate insomnia with
46:11no stress or anxiety relationship, Z
46:13drugs. Zaleplon, probably one of the
46:15best ones without having a lot of
46:16residual drowsiness and cognitive
46:18dysfunction in the morning.
46:19Both of these have abuse potential. This
46:21one,
46:23high abuse potential. This one, just a
46:26little bit more abuse potential. I mean,
46:27little less abuse potential in
46:29comparison to benzos.
46:30Sleep induction, melatonin agonist is
46:32definite, but orexin antagonist, not
46:34enough information on just yet.
46:36The last one is a patient who have a lot
46:38of depression-related anxiety. Uh
46:40depression, anxiety, but particularly
46:42more depression-related insomnia.
46:44In this particular uh situation, I would
46:47go with the drugs that have
46:48antidepressant functions. Ones that
46:49really jack up the serotonin, but also
46:52block the histamine action. And so, this
46:55is where I would use particular drugs
46:56such as
46:58doxepin.
47:00Doxepin would be one. That's the
47:01tricyclic antidepressant.
47:04I would also go with the mirtazapine.
47:07Mirtazapine.
47:10Or trazodone.
47:12Trazodone.
47:14And these all will do what? Help to
47:16increase serotonin, but also block the
47:19actual histamine. One of the beauties
47:21behind these particular drugs is that
47:24there really is no abuse potential. So,
47:26with these, there is no true
47:30abuse
47:31that you should see with these. And
47:32that's really what makes these
47:33preferable. So, if a patient maybe has
47:35depression or maybe even some degree of
47:38anxiety-related insomnia, and they have
47:39a history of abuse, don't give them
47:42benzos. Don't give them Z drugs.
47:44Consider something like this,
47:47which has the ability to not cause
47:48abuse, but will have anxiety-related
47:52effects and treat the patient's insomnia
47:54via histamine blocking effect, via
47:58melatonin agonist, orexin antagonist
48:00effect, via GABA increasing GABA
48:03activity, increasing GABA activity.
48:05Which one do you notice that's not is
48:06not on here? The barbiturate cuz it'll
48:08kill you, okay? Don't use it. That
48:10covers the approach. Let's now really
48:12quickly go through the adverse drug
48:14reactions. All right, guys. So, now when
48:15we talk about adverse effects of
48:17anxiolytics and hypnotics,
48:19the big thing that I really want to
48:20focus on is the benzodiazepines and the
48:21barbiturates. Not so much the melatonin
48:25agonist, not so much the SSRIs and SNRIs
48:27cuz we'll talk more about
48:29antidepressants when we get into that
48:31pharmacology lecture talking about all
48:32the different types of antidepressants.
48:35But when we talk about melatonin
48:36agonist, if there really was one big
48:38thing, it's been shown to potentially
48:39increase prolactin, so you may see some
48:41gynecomastia in males, some menstrual
48:43irregularities or lactation problems in
48:45females. That's really about it.
48:48For the Z drugs, I think it's important
48:50to remember that they again have abuse
48:51potential. They used to think that they
48:53did not, but they do have abuse
48:54potential. But if I were to tell you the
48:56degree of dependence or abuse potential
48:58compared, it would go Z drugs as the
49:00least, then benzos, then barbiturates
49:02have the most abuse potential. Okay?
49:05The other thing is we don't know a a lot
49:07about the orexin antagonist. There may
49:09be some type of suicidal ideation and
49:11cytochrome P450 metabolism. Just not
49:13enough info on that. And again, we're
49:15not going to talk a a bunch about the
49:17antidepressant drugs cuz we'll talk
49:19about those when we get into the
49:19antidepressant section.
49:21So, that deserves a really heavy
49:23conversation on barbiturates and
49:25benzodiazepines. The whole purpose of
49:27this adverse drug reaction is to really
49:29kind of show you some of the negative
49:30connotations of chronic benzodiazepines
49:33and then why we avoid barbiturates.
49:35So, when you look here, this this graph
49:37here is really just giving us a degree
49:38of CNS depression. That's really all
49:40it's telling us. This is telling us the
49:41degree of CNS depression. So, with some
49:46people, right, you may just want to be
49:47able to reduce their anxiety, put them
49:49to sleep, make them kind of cognitively
49:51unaware of what's going on. So, kind of
49:53just depress their level of
49:54consciousness, their sensations, their
49:56movements. Some you actually can take
49:58away their ability to breathe and
50:00augment their heart rate and blood
50:01pressure, or some you put them into a
50:03coma.
50:04Here's the big thing.
50:06With benzodiazepines,
50:08they have CNS depression, right? But, if
50:10you compare to barbiturates, which is
50:12here in blue, look at the barbiturates.
50:14The barbiturates have no ceiling effect.
50:16There is no ceiling effect. There is no
50:19ceiling for barbiturates.
50:23And there is an eventual ceiling for
50:25benzodiazepines. They usually kind of
50:27top out at not having much more than
50:30just mild medullary depression.
50:32So, with that being said,
50:34if you were to think about this with
50:35benzodiazepines, benzodiazepines can
50:38have CNS depression, but we'll give it
50:40two arrows.
50:41Barbiturates,
50:43these things have a massive amount of
50:45CNS depression. And that's a really,
50:47really important thing, because that's
50:49another reason why we don't really use
50:50barbiturates for anxiolysis and
50:52hypnosis, is because just a little bit
50:55of a higher dose, you get an anesthetic
50:57medullary depression and coma effect.
50:59That's why barbiturates more commonly
51:00used for patients who have seizures,
51:02right? So, we'll treat seizures, so
51:04anti-convulsant type of activity, or you
51:07can use it in anesthesia, like
51:08thiopental,
51:10or putting a patient into a coma because
51:12of seizures or high intracranial
51:14pressure and you want to kind of
51:15decrease their ICP. Otherwise, we don't
51:17really utilize barbiturates, because
51:19again, you can see the toxicity from
51:21their CNS depression. Not as much so
51:23with the benzodiazepines.
51:26The next thing that I want you guys to
51:27understand is dependence and tolerance.
51:29So, dependence again kind of is the
51:31basic that that when you have these
51:34patients who take benzodiazepines,
51:36right? So, benzodiazepines who take
51:38barbiturates, and the last one is the Z
51:39drugs. So, barbiturates,
51:44uh benzodiazepines,
51:49and then the last one is your Z drugs.
51:52When we talk about these, the basic
51:53concept of these is that
51:56barbiturates, if you give these, again,
51:58they'll help to be able to act as a GABA
52:00agonistic activity.
52:02But, with continual usage, what may
52:03happen is they may develop a sense of
52:05tolerance, where the same dose may be
52:07not produce the same therapeutic effect.
52:09And then what happens is you have to
52:10increase the dose, and increase the
52:11dose, and increase the dose to get that
52:13same effect. And so, with that, we see
52:15the highest degree of tolerance or
52:17dependence with barbiturates. Then we
52:20see the second most dependence and
52:22tolerance with benzodiazepines, and then
52:24we see the least amount of dependence
52:25and tolerance with the Z drugs. And
52:27that's a really, really important
52:29concept to understand, is that with
52:31giving these drugs,
52:32if the if the drug dosage is having to
52:35increase to meet the same therapeutic
52:37effect, that's a concept of tolerance.
52:40And if you were to remove these drugs,
52:42so then if you were to discontinue
52:45any of these drugs,
52:47the patient would develop a rebound
52:50effect.
52:52In other words,
52:54if you stop barbiturates for a patient
52:56who's having seizures, you abruptly stop
52:58it, they'll start having breakthrough
52:59seizures, right? If you stop
53:01benzodiazepines for hypnosis and
53:02anxiolysis, then you're going to have
53:04them have problems with anxiety and
53:06breakthrough insomnia. If you're using
53:08this for insomnia and then you
53:09discontinue it, again, they will develop
53:11rebound insomnia. So, that's an
53:12important effect thing to understand.
53:15The next thing is drug interactions,
53:17right? So, the phenobarbital, all right,
53:21and pentobarbital, and all the
53:22barbiturates are very powerful
53:26cytochrome P450 inducers. And I think
53:29that's again another reason as to why to
53:31avoid these drugs. So, they have the
53:33ability to bind onto the cytochrome P450
53:35system and increase the activity of this
53:38enzyme.
53:39If this basically increases the activity
53:42of the cytochrome P450 enzyme, it takes
53:45a drug and breaks the drug down more.
53:48And so, you'll basically enhance this
53:50pathway. You'll stimulate this pathway
53:52and put it into hyperdrive. And what
53:54you'll do is you'll decrease the
53:55efficacy of other drugs. And so, that's
53:58one of the really nasty things about
53:59barbiturates is that they cause a lot of
54:01drug interactions and decrease the
54:03concentration and efficacy of other
54:06drugs. Makes them subtherapeutic. That's
54:08a really bad thing.
54:10All right? So, again, to really
54:12highlight the reason why we stay away
54:14from barbiturates is because they have
54:16massive CNS depression,
54:18they have a high degree of dependence
54:20and tolerance, and if you discontinue
54:21them abruptly, they can develop a very
54:22profound rebound effect, and they have
54:26very significant drug interactions by
54:28acting as a cytochrome P450 inducer and
54:30producing subtherapeutic drug levels of
54:32other drugs.
54:34What's the last thing that I want to
54:35talk about? And that's really the
54:36overdose and withdrawal factors. So, the
54:38last thing that I want to talk about
54:39here
54:41is overdoses or withdrawal.
54:43And really, I want to spend some time
54:45talking about more specifically the
54:47benzodiazepines.
54:49All right? And the reason why is again,
54:51we shouldn't be utilizing
54:53uh you know, barbiturates for anxiolysis
54:55and hypnosis, right? We should we would
54:57use benzodiazepines though. And this
54:59again tries to highlight that yes,
55:01barbiturates are super toxic and we try
55:02to avoid them, but you should also be
55:04very careful with benzodiazepines, and
55:05this is the reason why. We know that it
55:07has mild CNS depression, a degree of
55:09dependence and tolerance, right? So,
55:11that's one particular thing. Has a
55:12potential for abuse and rebound and
55:14effects.
55:15But, the other thing is that you can
55:16easily overdose on this. So, if a
55:17patient overdoses, they take too much,
55:19right? So, they become dependent or they
55:20become uh very tolerant to it, they keep
55:22increasing their dose, increasing their
55:23dose, increasing their dose to get the
55:25same therapeutic effect, and then what
55:27happens? Well, then they start kind of
55:29shutting down their limbic system
55:30function. They start shutting down the
55:32reticular formation. These patients can
55:34literally psychotic have a very
55:35significant decline in their level of
55:38consciousness, right? So, they could
55:40actually have anywhere from a point of
55:42maybe anxiolysis to actually sleeping to
55:44actually kind of being in a uh
55:46anesthetic state to almost being into a
55:48comatose state. So, that's a really big
55:50thing. They can also depress their
55:54effect on the heart. So, they could even
55:56cause maybe a small degree of
55:58bradycardia, a small degree of
56:00hypotension. But, here's the most
56:02profound one. They cause a significant
56:04respiratory rate and depth depression.
56:07So, they significantly depress the
56:08respiratory system. That's the big
56:10things here. Don't worry about this part
56:12and this part.
56:13But, when a patient overdoses and they
56:15take too much of a benzodiazepine, one
56:17of the very scary features is
56:19significant CNS depression, right? So,
56:21loss of consciousness, as well as
56:23hypotension, bradycardia, and
56:25respiratory depression. So, they may
56:27become apneic.
56:28If that's the case, how do we treat
56:30those patients? We want to reverse the
56:33effect of the GABA agonist. So, I want
56:35to give a drug that acts as a GABA
56:37antagonist.
56:38And the drug that I really want you guys
56:40to remember that is a useful for the
56:41benzodiazepine overdose is called
56:44flumazenil.
56:46Flumazenil, okay?
56:49Now, in the same concept,
56:52if a patient is taking benzodiazepines
56:55for insomnia or taking it for
56:57anxiolysis, right?
56:59And or maybe even for seizures or for
57:01muscle relaxant activities, all because
57:03there's so many different functions of
57:05the benzodiazepines, right?
57:06But, if it's taking it for those
57:07reasons, all of the sudden you abruptly
57:09discontinue taking the benzodiazepines,
57:11they can potentially go through
57:13withdrawal, cuz they develop a rebound
57:15effect. So, then it's opposing all of
57:17these actions. You go back into the
57:18whole anxiety response. So, they can
57:21actually develop potentially anxiety,
57:23rebound anxiety. The worst case scenario
57:27is they can even develop seizures. This
57:29is a scary fact, right? They can also
57:31develop an increase in their heart rate,
57:33an increase in their blood pressure, so
57:35they become tachycardic and
57:36hypertensive. They also can increase
57:38their respiratory rate and depth.
57:41They can also have diaphoresis.
57:46Diaphoresis, and they can have tremors.
57:49If all of these things are present in a
57:51patient who just discontinued their
57:53benzodiazepine, guess what? You have
57:55probably should give them the
57:56benzodiazepine back, and then start
57:58slowly tapering down the dose. Don't
58:01just abruptly discontinue it. Put them
58:04on a benzodiazepine, and then slow, slow
58:07taper of the benzodiazepine. So, that's
58:09where we would do
58:11a taper. So, we would taper
58:14the benzodiazepines, such as lorazepam
58:17or diazepam, is the preferred drugs.
58:21But, those are the concepts that I
58:22really want you guys to understand with
58:23anxiolysis and hypnosis. Again, going
58:26over the whole pathophysiology of it, I
58:29think it's important to know the
58:30neurotransmitters that are problematic.
58:32Then using the mechanism to understand I
58:34just have to oppose the
58:35pathophysiological process. So, you do
58:38the opposite of the pathophysiology,
58:39increase serotonin, increase GABA for
58:42anxiolysis, right? If for insomnia, I
58:44have to increase GABA, increase
58:46melatonin, decrease orexin, and decrease
58:48histamine. And then talking about the
58:50approach, understanding in a patient who
58:52has acute anxiety versus chronic
58:53anxiety, which drug is preferred? And
58:55then a patient who has insomnia,
58:56depending upon the type of insomnia and
58:58the type of treatment that you want, you
59:00determine the type of drug. And then
59:01again, overarching theme here is
59:04barbiturates are a no-no, and this is
59:06the reason why. Benzos are also ones
59:09that have very significant abuse
59:10potential, too. And this is kind of
59:12again showing you guys how to uh
59:13recognize that. And again, worst case
59:16scenarios, if they overdose or they
59:17withdraw, how to be able to recognize
59:19that and treat that.
59:21All right, let's do some questions and
59:22put all this together. All right, my
59:23friends, let's do some questions here to
59:24kind of recap everything we talked about
59:26with anxiolytics and hypnotics.
59:28So, which of the following statements is
59:29correct regarding benzodiazepines? They
59:31directly open chloride ion channels.
59:33So, I would say that again they work via
59:36the GABA-A receptor, right? So, they
59:38actually bind to the GABA-A receptor.
59:40Whenever they bind to the GABA-A
59:41receptor, that actually will open up the
59:43chloride ion channels. So, I wouldn't
59:45say that they directly open the chloride
59:47ion channels. They have to bind to GABA,
59:49change the shape of the actual GABA
59:51protein to order open up that channel.
59:53So, I wouldn't say directly.
59:56Benzodiazepines
59:57show analgesic actions. No, not
1:00:00necessarily.
1:00:02At very, very high doses, as we talked
1:00:04about, they can have a slight anesthetic
1:00:06function, especially midazolam, but it
1:00:09doesn't mean that they actually can
1:00:11remove pain. So, I would not say that
1:00:13they have a complete analgesic action.
1:00:16Clinical improvement of anxiety requires
1:00:172 to 4 weeks of treatment with a
1:00:18benzodiazepine. You can actually
1:00:19experience it immediately, the
1:00:21anxiolytic effect, depending upon the
1:00:22appropriate dose.
1:00:24And all benzodiazepines have some
1:00:26sedative effects, absolutely.
1:00:28When you think about benzodiazepines,
1:00:29they have the ability to kind of reduce
1:00:31your reticular activating system, to
1:00:34reduce some of the cortical activity.
1:00:35So, they can really kind of activate a
1:00:36lot of GABA kind of activity
1:00:40in multiple different kind of central
1:00:41nervous system structures, which
1:00:42definitely can reduce the level of
1:00:44arousal and wakefulness. And
1:00:46that's really, really very common with
1:00:48all of these. So, I would say definitely
1:00:49they're going to have some sedative
1:00:50effects to them.
1:00:52Which of the following is a short-acting
1:00:53hypnotics? When we talk about hypnotics,
1:00:55we have drugs that increase GABA, right?
1:00:58So, do any of those increase GABA?
1:01:00Absolutely. Phenobarbital does, diazepam
1:01:02does, chlordiazepoxide does, and
1:01:04triazolam does. So, then it comes down
1:01:06to which ones are short-acting. So, for
1:01:08the barbiturates, it's ultra
1:01:09short-acting. We said we don't even use
1:01:11these anymore, but it's thiopental.
1:01:13And then you have, as you go a little
1:01:14bit further down towards like the kind
1:01:16of long-acting, you get to
1:01:17phenobarbital.
1:01:19So, in this particular situation, I
1:01:20would say that phenobarbital is a super
1:01:22long-acting one, so I can't use that.
1:01:24Diazepam and chlordiazepoxide are
1:01:26long-acting benzodiazepines, so that's
1:01:29not the answer. And then triazolam and
1:01:31midazolam are the shortest-acting types
1:01:33of benzodiazepines, so I would say
1:01:35triazolam here.
1:01:38Which of the following statements is
1:01:39correct regarding the anxiolytic and
1:01:41hypnotic agents? So, diazepam and
1:01:43phenobarbital induce the cytochrome P450
1:01:45system.
1:01:46Um phenobarbital definitely is a
1:01:49cytochrome P450 inducer. Um
1:01:51phenobarbital is useful in the treatment
1:01:53of acute intermittent porphyria. Um
1:01:56actually, it's contraindicated in
1:01:57porphyria, okay? Phenobarbital induces
1:02:00respiratory depression, which is
1:02:01enhanced by the consumption of alcohol,
1:02:03100%. So, if you take phenobarbital,
1:02:05which is a CNS depressant, plus ethanol,
1:02:07which is also a CNS depressant, you'll
1:02:09definitely cause respiratory depression.
1:02:11And that's a really, really nasty kind
1:02:12of effect there. So, absolutely. And
1:02:14buspirone has actions similar to those
1:02:16of benzodiazepines. I would say not
1:02:18necessarily. It can treat anxiety, not
1:02:20acute anxiety, more chronic anxiety, and
1:02:22it works via the serotonin agonist
1:02:24activity, not a GABA activity.
1:02:27All right. So, phenobarbital definitely
1:02:29with ethanol will cause some massive
1:02:30respiratory depression.
1:02:3145-year-old man injured in a car
1:02:33accident, brought to the ED. Blood
1:02:35alcohol level through the roof.
1:02:37Hospital shows a prior hospitalization
1:02:39for alcohol-related seizures,
1:02:40unfortunately. His wife confirms that he
1:02:42has been drinking heavily for 3 weeks.
1:02:44What treatment should be provided to the
1:02:45patient if he if he goes into
1:02:47withdrawal? So, this is alcohol
1:02:49withdrawal. Alcohol withdrawal seizures
1:02:51are treated the same way that you would
1:02:53treat kind of like in these particular
1:02:55patients.
1:02:56Um
1:02:57When you have a patient who has alcohol
1:02:59withdrawal seizures, there's two
1:03:00particular options, uh barbiturates and
1:03:02benzodiazepines. Those are going to be
1:03:03the anticonvulsants that we talked about
1:03:05in the anxiolytic hypnotics that only
1:03:07have anticonvulsant activity. There's
1:03:09been studies that showed that
1:03:10phenobarbital is way superior to the
1:03:11benzodiazepines, but benzodiazepines are
1:03:14other options that you can consider.
1:03:15Lorazepam, diazepam, those are
1:03:17particular options. So, in this
1:03:18particular scenario, lorazepam would be
1:03:20the best option. All right.
1:03:2336-year-old male patient reports to
1:03:25difficulty falling asleep for the past 2
1:03:27weeks, but needs to be able to get up
1:03:28early in the morning, 6:00 a.m., and
1:03:30doesn't want any daytime sedation. Which
1:03:32medication is best to recommend for the
1:03:34treatment of insomnia? So, you want
1:03:35something that's going to be quick to
1:03:37induce sleep, but it won't kind of like
1:03:39linger around in the morning. So, in
1:03:40other words, it's it's half-life short.
1:03:43So,
1:03:44temazepam is kind of like somewhere
1:03:47between kind of a intermediate-acting,
1:03:49so it'll last a decent amount of time.
1:03:52Flurazepam,
1:03:53that one's also kind of on the longer
1:03:55side. Buspirone doesn't really have any
1:03:58type of hypnotic functions.
1:04:00Um zaleplon is definitely going to be
1:04:03the shorter-acting one. This is great
1:04:04for sleep induction, and then it won't
1:04:07linger around and cause a lot of, you
1:04:09know, daytime somnolence. So, zaleplon
1:04:11is definitely going to be the best
1:04:13option in this particular scenario. So,
1:04:15I would go with that one. And that is
1:04:16again one of the Z drugs. Whereas these
1:04:18ones, they're going to have a little bit
1:04:19more of a lingering effect in the
1:04:21morning, especially temazepam and
1:04:22flurazepam. Buspirone is not even a good
1:04:24option.
1:04:2645-year-old woman reports daytime
1:04:29anxiety about work and family problems
1:04:31causing difficulty functioning and
1:04:32participating in normal daily
1:04:33activities. Which of the following
1:04:35agents has a rapid anxiolytic effect and
1:04:36is best for the acute management of her
1:04:38anxiety? That's always benzos. Benzos,
1:04:40and then for chronic, it's SSRIs or
1:04:42SNRIs, right? Or potentially buspirone
1:04:45is the other option here. So, I would
1:04:46say in this particular scenario, it's
1:04:48going to be a benzo first, and then
1:04:50later you can start adding on something
1:04:51like this or this or this. So, lorazepam
1:04:54would be the best option here. Okay?
1:04:57Which of the following sedative-hypnotic
1:04:58agents utilizes melatonin receptor
1:05:00agonist as the mechanism of action to
1:05:02induce sleep? All right. So, we need a
1:05:04melatonin receptor agonist. This is
1:05:05usually ramelteon or this other one
1:05:07called tasimelteon. They're the same
1:05:09thing, but these would both be your
1:05:11melatonin receptor agonist that helps to
1:05:13induce sleep. So, they're good for sleep
1:05:15induction.
1:05:16So, tasimelteon or ramelteon will be the
1:05:18best option here.
1:05:2050-year-old male
1:05:21presents with insomnia, not responsive
1:05:23to sleep hygiene interventions, has long
1:05:25history of alcohol and opioid abuse, so
1:05:27he has abuse potential. He's been
1:05:28successfully sober for 10 years,
1:05:30congratulations, but is very concerned
1:05:31about future addiction and dependence,
1:05:33rightfully so. Which is appropriate to
1:05:34address insomnia and minimize the risk
1:05:36for dependence in this patient? Stay
1:05:37away from benzos, stay away from
1:05:39barbiturates. Those are going to be the
1:05:40particular options here. And as I told
1:05:43you before, they used to think that the
1:05:44Z drugs did not have as much dependence
1:05:47and tolerance and would, you know,
1:05:48withdrawal symptoms, but they do.
1:05:50They're nowhere near They're not as
1:05:52severe as benzodiazepines, and nowhere
1:05:54near as severe as barbiturates, but
1:05:55they're still there.
1:05:57So, I got to get rid of the benzo, cuz
1:05:59that's that's not a good option for me.
1:06:01Um I got to get rid of the zaleplon and
1:06:03the zolpidem, because those also are Z
1:06:05drugs. They have addiction potential.
1:06:07Not as high as the benzos, but they have
1:06:09addiction potential.
1:06:11Doxepin is a tricyclic antidepressant
1:06:14with antihistamine activity. So,
1:06:16therefore, this would actually be a drug
1:06:19that I can use for depression, as well
1:06:22as treat the patient's insomnia. So,
1:06:24this would be a lot safer, and there's
1:06:26not as much dependence and tolerance and
1:06:28withdrawal symptoms from this. So, I
1:06:30would go with doxepin, which is a
1:06:31tricyclic antidepressant. Again, you
1:06:33could also consider other options like
1:06:34trazodone or mirtazapine, which is one
1:06:37of those atypical antidepressants as
1:06:38well.
1:06:39All right. So, doxepin would be the
1:06:40option here.
1:06:4260-year-old female patient is
1:06:43demonstrating signs and symptoms of
1:06:44insomnia, especially difficulty falling
1:06:46asleep. Um she's afraid of taking
1:06:48medication that can negatively affect
1:06:50her memory and concentration, as she's
1:06:51still working as a bookkeeper. She's
1:06:53been taking temazepam, okay, for the
1:06:55past 4 days, and has noticed memory
1:06:56problem and would like to discontinue
1:06:58it, rightfully so. Which medication is
1:07:00appropriate to treat the insomnia and
1:07:01minimize the risk of cognitive
1:07:02impairment? Stay away from benzos,
1:07:04right? That would be the particular best
1:07:06option, and probably even stay away from
1:07:08some of the Z drugs, too. So, I would
1:07:10stay away from zolpidem. I would stay
1:07:12away from alprazolam, cuz that's a
1:07:13benzo. Diphenhydramine, this is not used
1:07:16for sleep. It's the adverse effect,
1:07:18unfortunately, of the antihistamine that
1:07:19you can use for aller- allergic
1:07:21reactions. So, this is not a preferable
1:07:23agent. Ramelteon is a melatonin receptor
1:07:26agonist that was very helpful for sleep
1:07:28induction, 30 minutes prior to going to
1:07:30sleep. It doesn't have a lot of that
1:07:31residual type of
1:07:33cog- you know, cognitive impairment in
1:07:35the morning and dependence and problems
1:07:37of that nature. So, ramelteon, which is
1:07:39a melatonin receptor agonist, or
1:07:40tasimelteon, are going to be good
1:07:41options here.
1:07:44All right. Last question. 80-year-old
1:07:45woman admitted to the emergency room
1:07:46after an accidental overdose of
1:07:47alprazolam. She's unconscious, not
1:07:49considered a regular user of any of
1:07:50medications or illicit drugs. Which
1:07:52treatment would be used to reverse the
1:07:54effect of the alprazolam overdose? So, a
1:07:56benzo overdose, they'll have a depressed
1:07:58central nervous system to the point of
1:08:00maybe where they're lethargic to their
1:08:01almost in a comatose state. Um they also
1:08:04will have maybe hypotension,
1:08:06bradycardia, and respiratory depression.
1:08:08So, flumazenil is the respiratory I
1:08:10mean, is the benzodiazepine antagonist
1:08:13in this particular scenario. So, I would
1:08:14give them flumazenil. Not diazepam,
1:08:17that's just going to make it worse. Not
1:08:18ramelteon, that's going to do nothing.
1:08:19And naloxone is for opioids. So,
1:08:21flumazenil would be the preferable agent
1:08:23here.
1:08:24All right, my friends. So, that covers
1:08:25all the questions related to anxiolytics
1:08:27as well as hypnotics. I hope it made
1:08:28sense. I hope that you guys enjoyed it.
1:08:30And as always, until next time.

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