2nd Generation Antipsychotics (Psychiatry) (Pharmacology) - USMLE Step 1

Welcome back to Mad Medicine.

In this lecture, we're gonna be discussing the second generation antipsychotics.

If you guys don't know, we have already covered the first gen antipsychotics in our

previous lecture, so you can go to our YouTube channel, youtube.com/madmedicine,

where you can find playlist for the USMLE Step One, both psychiatry and pharmacology.

And in those playlists, we have discussed the first generation or the typical antipsychotic.

So I highly recommend you check that out.

And don't forget to like, comment, and subscribe to our channel because

we're gonna be posting brand new videos for step one regularly.

So let's talk about these second gen antipsychotics,

AKA the atypical antipsychotics.

There are several that you need to know, but luckily, there is a very easy way of remembering

these drugs. Okay. So the first drug that you need to know is called aripiprazole.

And this one really isn't gonna conform to any

suffix pattern, but you just need to memorize aripiprazole.

And now the rest of the drugs are gonna
fall into one of two patterns. Right?

So the first pattern is gonna have a suffix of

a p I n e, the apines, which is

these drugs right here, which are these drugs, like clozapine, olanzapine, quetopine, and acinepine.

So these are gonna be your apine antipsychotics.

And then the last one are gonna be the i d o n e, idone antipsychotics

like illoperidone, paliperidone, risperidone,

lurasidone, and zeprazodone.

So these are gonna be all of your antipsychotics. So I highly recommend, for second

gen, you memorize the apine, the idone suffixes,

and then just memorize aripiprazole and you'll be able to spot any of these drugs very easily.

Now, when it comes to SGAs, these are gonna be able to treat

everything in FGA, the first gen antipsychotics treat

with the exception of schizophrenia.

First gen antipsychotics only treated- let's just write this down. First gen antipsychotics

only treated the positive symptoms of schizophrenia.

Okay? Schizophrenia.

Let's write this. Alright. When it comes to second gen antipsychotics, you're gonna treat both

the positive and the negative symptoms. So therefore, in theory, this is a much better

drug to use for treating treatment of schizophrenia, not just for this

reason, but for also the other side effect reasons that we're

gonna talk about in a second. And you can also use this for OCD.

So that's one main difference between first gen and second gen. It's gonna be the positive and

negative symptom treatment for schizophrenia. You can also use these for bipolar disorder, delirium,

Tourette's and Huntington's and psychosis, kinda like the

same as the first gen. Now one defining feature, and this is

very important, the defining feature between first generation and second generation antipsychotics

is gonna be decreased, EPS or the neurologic symptoms

that occur with the high potency first gen antipsychotics.

Okay? This is very high yield. High yield is fuck in my opinion because you

can be tested on what the defining feature between these two drug classes is and

it's the fact that you have less neurologic symptoms occurring with the second gen.

Now, when it comes to mechanism of action, we do not know exactly

what's happening with second generation antipsychotics. What we do know is that you have the

blockade of the postsynaptic d two receptors that also occurs

in, first generation antipsychotics.

Okay, also have this. So it's the same mechanism.

So just to review, if you guys have missed in the previous video,

we have two main dopamine receptors you need to know about. D one receptors activate

adenylyl cyclase and re increase and lead to an increase in camp cyclic AMP, and

the d two receptors deactivate this, endolyticic

and lead to decrease in cyclic AMP. Now when you inhibit the d two dopamine receptors

like you do with second generation antipsychotics, what's gonna end up happening

is you're gonna have decreased D two act binding,

right, because you're inhibiting it, which is gonna lead to

an increased D one receptor binding. And eventually

oh, bing. Binding. There we go.

And that's gonna lead to increase in cyclic AMP.

So, therefore, these drugs inhibit d two and act like a d one agonist in

a sense. Now, one thing to understand is because you have increased in cyclic AMP,

this increase is gonna have a negative feedback on our brain and then it's gonna

lead to actually decreasing our dopamine levels.

Okay? Overall, you're gonna have a decrease in dopamine.

That's very important. Now when it comes to,

what's actually happening with first gen antipsychotics,

it's the fact that these first gen antipsychotics is are increasing cyclic AMP

in our brain. That's what's happened. That's the actual effect. It's not decreasing dopamine levels,

it's increasing cyclic AMP by by having, an increase in d one receptor binding.

Now, these drugs also tend to block, the serotonin

two a receptors as well. And that's very important because often

these receptors, the serotonin two a receptors, are hyperstimulated

in schizophrenic patients, and hyperstimulation of this receptor

leads to increased hallucinations. Right? So you wanna reduce that. And in schizophrenia, that's one

of the hallmark signs of schizophrenia is hallucinations, especially auditory hallucinations.

So one way you can do it is by giving the second gen antipsychotics

And by blocking the HT two A receptor, the serotonin two

A receptor, you're gonna decrease the hallucinations

that are occurring in the schizophrenic patients. Okay? That's what's gonna end up happening.

You're gonna decrease hallucinations. So these are the two main,

mechanisms of action. Keep in mind, this really does not occur in first gen antipsychotics.

This does. This is definitely what, the d two receptor d two dopamine receptor blockade

is what occurs in the first gen. So this is also another, defining feature.

Now, ((Lou)), we're gonna talk about all of the adverse side effects of the second gen.

There are several adverse side effects and most likely for step one, you're gonna

be tested on these side effects. So, the first side effect we're gonna talk about

is the metabolic syndrome. Okay.

Now, this can happen with any antipsychotic class, but it often happens

with the second gen antipsychotics. Okay. This is very important.

The second gen antipsychotics are more likely associated with metabolic syndrome. So, what you're

gonna see is in these patients, they're gonna present out with weight gain, hyperglycemia,

hyperlipidemia and you're gonna see they're getting a little bit fatter since they've been taking

their medication. So the way I used to remember this is, by thinking about a

fat pine. Right? A pine, because these are the second gen antipsychotics, specifically like

clozapine and olanzapine.

These are the ones that are gonna cause, increase in the metabolic

syndrome. And I just put fat, so that's how I remembered

it because these patients have symptoms of just becoming fat. So that's the memory tool

I use. That's one side effect, metabolic syndrome.

There's a specific drug that you need to know out of all of the second

gen antipsychotics and it's not because of what it, what the mechanism is, but it's

because of the side effects, the negative side effects of this drug.

That drug is clozapine. Clozapine is a very,

very strong drug that's used for for schizophrenia,

but it has a lot of side effects. And because of these side effects, it's

usually not the first line or second line drug.

It's gonna be used for treatment resistant schizophrenia

and that's how they're gonna phrase it in step one. Okay?

So, look out for a patient who's on like a fourth or fifth line drug or a third line

drug who's been treated with others anti psychotic

drugs, but it hasn't been successful. So now, they've put on this other drug.

What ends up happening in these patients who are taking clozapine

is that they might present with bone marrow toxicity.

So neutropenia and, agranulocytosis

can occur in one to two percent of these patients. And that's very important because

that is something you will be tested on if you get a question about clozapine.

What are the side effects? What can happen? So this is very, very, very important.

Clozapine is associated with neutropenia and agranulocytosis.

Now, because of this, you need to monitor the neutrophil count weekly.

And these patients are also gonna become very susceptible to infection, so you need to

make sure if they're running a fever, you gotta make sure nothing's wrong.

They're not really getting sick. Now, you also need to monitor their white blood count overall and

this is all reversible once the drug is stopped. So that's the first thing.

Clozapine, you need to know, it can cause agranulocytosis

and they'll present this by asking you what laboratory

exam should be done with clozapine.

And that's gonna be either a monitor

the neutrophil count or white blood count overall.

Okay? You're looking for neutropenia and agranulocytosis.

Now, you can also have seizures, which are more common compared to bone marrow toxicity,

which occur- these seizures are gonna occur two to five percent

of the patients and myocarditis or cardiomyopathy.

This is also high yield, but in my opinion, if you're gonna try to remember

one of these two things, remember this right here, the side

effect of the neutropenia and, the a granulocytosis.

Myocarditis, cardiomyopathy, and seizures are also something

that can happen with clozapine. Just don't forget it.

Okay. So that is clozapine.

Now there are still more adverse side effects that you need to know about when

it comes to the second generation antipsychotics. And the

second the main one is gonna be endocrine issues, the next main

one. Right? So these, endocrine issues occur because,

usually, these drugs are gonna affect the tubulo infundibular,

pathway or tubulo infundibular system. And this is one of the main four dopamine pathways

in the brain because, normally, dopamine is released by the hypothalamus to to inhibit prolactin.

So when you have dopamine, right, so you have dopamine, you're gonna have a decreased

prolactin levels. That is normal. Now, what ends up happening is because you have decreased

dopamine levels due to blocking the d two

receptor, d two dopamine receptor, you're gonna lead to hyperprolactinemia.

Why is that? Because you are blocking the d two receptor, you're gonna have more

positive d one stimulation, which is gonna lead to increase in cyclic AMP.

This increase in cyclic AMP is gonna lead to a decrease in dopamine.

And because you are decreasing dopamine, this is all going to lead to hyper prolactin levels.

Right? So that is the mechanism that's happening

in patients who are taking second gen and first gen antipsychotics. Right? This also happens

in first gen. So this is kind of a review from the last lecture. Now when it comes to

hyperprolactinemia, in females, you're gonna see, glactorrhea. They're gonna have lactation.

In males, you will see gynecomastia

occurring. And in both males and females, you'll see you'll have inhibition of GnRH, which

leads to oligomenorrhea in females as well as loss of libido and impotence in males.

And this is more common in the first gen antipsychotics, but you can see it with the our

a, our apines and idones, second generation antipsychotics.

Just a little bit of a reminder of the suffixes.

Okay. So that is the endo the endocrine issues.

Now, there are still some more adverse effects

of the second generation antipsychotics that you need to know, and

these are gonna be very simple. Okay? These are going to be your anti

ham, h a m symptoms.

Now these symptoms are gonna be the first one is gonna be the antimuscarinic effects.

Okay? The antimuscarinic effects occur because you're blocking

the central and peripheral acetylcholine muscarinic receptors.

And these antimuscarinic effects are gonna,

present with someone having dry mouth, constipation, blurred vision, or just urinary

retention. Something that's very common with antimuscarinic

or acetylcholine muscarinic receptor blockers. That is something that happens

with these drugs. The other thing you could have is orthostatic hypotension, which is all

due to blockade, again, of central and peripheral alpha one adrenergic receptors.

This can also be accompanied with tachycardia,

but this is gonna be more common during initiation

and increasing the dose. Once you have initiated and once someone's

well along on their treatment with these drugs, it's gonna be perfectly fine. This will

go away. Orthostatic hypotension will usually go away.

And, the final the final effect is gonna be antihistamine

effect, which is gonna be blockade of the central

and peripheral histamine receptors and this can lead to sedation.

So, like I said, the acronym we use or the memory tool is anti ham.

Right? The h stands for the antihistamine, activity.

The a stands for the adrenergic antimuscarinic

effects. Right? Which Oh, sorry. The alpha one adrenergic effects, which are going to block

the which are going to lead to orthostatic hypotension.

Okay. So the alpha one blockade. Right. Let's just put that here. And then finally,

the m is going to stand for the muscarinic or the acetylcholine muscarinic receptor blockade.

Okay. So that's what happens. So the anti ham. This can also happen

in first generation antipsychotics.

Okay? More so in the low potency first generation antipsychotics.

This is very similar to those. Now, I wish we were done, but unfortunately,

we still have one more very important adverse side effect that you need to be

aware of. And we've already discussed this, so we're not gonna go too deep into it.

If you guys wanna watch our previous episode about the the first generation antipsychotics,

I highly recommend you do so to get a more detailed understanding of this.

But, the last or the second to last

adverse side effect that can that can occur is gonna be the neuroleptic

malignant syndrome, NMS. Now you may be saying, why am I bringing this up here?

It usually occurs in first gen antipsychotics. You're right. It usually does occur in the

first gen antipsychotics, specifically the high potency first gen antipsychotics,

but you definitely still need to know that it can happen in the second generation antipsychotics.

It's less common, but it can happen. And this is still gonna be caused by

blocking any, dopamine receptor. So anything that blocks dopamine

receptors that has dopamine blocking agents in them,

along with a genetic predisposition,

it can lead to NMS, the neuroleptic

malignant syndrome. So just a reminder, this syndrome can happen at any time and the

timeline does not matter. Unlike the extrapyramidal

symptoms like, you know, acute dystonia, which happens hours to days after starting the drug

and, you know, the, the akathisia, the parkinsonism,

and atardive dyskinesia, it's gonna happen a little bit later.

NMS doesn't usually follow any timeline, so it can happen at any point. So this

is a neurologic emergency and the symptoms are

gonna include myoglobin myoglobinuria, rhabdomyolysis,

and elevated enzymes. The vitals are gonna be very unstable,

okay, because they're going through a lot of stuff at this moment. They're also gonna

have fever and encephalopathy contributing to the unstable vitals.

And also, they're gonna have muscle rigidity, the lead pipe rigidity. And this is a

hallmark indication that someone is going through a neuroleptic malignant

syndrome. So I'm gonna write hallmark next to it as well as high yield as

fuck for you guys so you don't forget this is very important. Now this muscle

rigidity, this lead pipe rigidity, this is a very important phrase because this is gonna

be a giveaway for step one, is also gonna lead to all of these issues.

The myoglobin urea, the rhabdomyolysis, and the elevated

c k levels are all gonna be due to the lead pipe

rigidity in the muscles because the the the muscle cells are gonna end up bursting

due to that rigidity. Okay? Now that is one of the stuff one of the

things that can happen. And the last adverse effect that you need to be aware

of for second gen antipsychotics is gonna be QT prolongation.

Now, this can lead to Tresard du Plants and cardiac

death. So you can see right here, we have a little image of these undulating,

QRS complexes that aren't normal. Not QRS. Sorry. The, cardiac

arrhythmias right here. They're not normal. It's kinda in this wave like waveform.

So these are called Tresades de Pointes and, eventually, this will lead to cardiac death

if it's not taken care of and these patients aren't stabilized.

Okay. So this is definitely all the adverse effects you need to know. This is

very high yield. And, again, just like the first gen antipsychotics,

second gen antipsychotics are also pretty dense. Not as dense, but they're still pretty dense.

So I highly recommend you guys, you know, go over this lecture, go over this

content a couple times so you know this stuff inside and out and you have

a good understanding of what's happening. Now, when it comes to the second gen antipsychotics,

there's some fast facts you definitely need to know. Okay. So I would personally take

a screenshot of this this slide or just take a photo of it, keep it

in your phone so you can constantly look at it and remind yourself what's happening.

Olanzapine and clozapine

are more likely to cause weight gain and metabolic syndrome than any of these other

drugs. Okay. That's very, very important. And on the opposite end, aripiprazole

and ziprazodone are least likely to cause weight gain. So if you have a patient who's underweight

and schizophrenic, you might wanna give these patients olanzapine

and clozapine. Right? And remember, with clozapine,

you need to watch out for their,

neutrophil count. You have to make sure it's very, very strong.

And if you have someone who's overweight or, you know, a little bit on the heavier side

with schizophrenia, you might wanna give them aripiprazole and zaprazodone.

The next drug, risperidone, is most likely to cause the hyperprolactinemia

and the endocrine issues. So, with risperidone, you wanna watch out for a decreased libido

in males and impotence. You wanna wanna watch out for gynecomastia

as well as in males. And in females, you wanna watch out for oligomenorrhea

and, you know, lactation, galactorrhea.

Aripiprazole is gonna be the least sedating, but you have the highest risk for akathisia in

this drug because this is also a partial agonist

of the D2 receptor. So akathisia can occur,

in these drugs. This has a higher risk. And then quetapine

is the most sedating drug. The way

I always remembered it is that people are quiet with quietepine. I know it's like,

you know, misspelled. The e and the I are flipped, but that's how I remembered

quietepine as being the most sedating. The olanzapine,

this o, I always thought of someone with a really fat stomach.

Right, so that looked like o for me. So that was olanzapine.

So I I always remembered someone with a really fat circular or o like stomach,

who takes olanzapine, they'll become really fat. Now,

when it comes to the last drug,

Clozapine. Clozapine has the strongest anti muscarinic effects as well. So keep that in mind.

Clozapine is very, very, anti muscarinic. So you're gonna have the anti ham effects like

the sedation, the ortho psych hypertension. But when it comes to anti muscarinic effects, you'll see

dry mouth, constipation and blurred vision.

Specifically, these effects can occur with clozapine.

Now, clozapine also don't forget the agranulocytosis.

I didn't write that, but I was just gonna write here.

Agranulocytosis and they can you can also have

seizures plus

you can have cardiomyopathies.

There we go. So don't forget all

of the side effects for clozapine.

In my opinion, that's probably the most confusing one to remember. Now, with that being

said, we are done with the second gen antipsychotics.

Thank you so much for listening and

watching to this lecture and, I hope this was very helpful. Now, if you guys

don't know, don't forget to like, comment, and subscribe. And if you wanna watch these

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