The Adrenergic Receptors

The Adrenergic Receptors

August 28, 2019 100 By Bertrand Dibbert


Hey guys, this is doctor Joel. Thanks for
tuning in to this lecture on the adrenergic receptors. Below is a list or an overview
of what I’m going to be talking about in this lecture, you can click on any one of these
links to skip instantly to that part. This is a high yield topic, and at the end I do
provide you some practice questions just to help prepare your minds for the boards. Okay?!
Let’s get started! Alright, the adrenergic receptors, also known
as adrenoceptors are a group of G protein-coupled receptors in the sympathetic nervous system.
Now it’s important to know about G protein-coupled receptors and how each one of them works,
however, I’m not covering that in this lecture, so you’ll have to look for that lecture specifically. The sympathetic nervous system, however, is
also a good thing to keep in mind when you are first learning about the adrenergic receptors.
The reason is that if you think about what a target organ does during the “fight or flight”
response or the sympathetic response, you can work through what these receptors do.
So, if I were to say that one of these receptors was found in the heart and it was stimulated,
well, you can think through and logically reason that the sympathetic response, or the
“fight or flight” response in the heart, is for the heart to beat harder and faster. That
applies for most target organs. So, basically, just think to yourself: what does a target
organ do when I’m being chased by a lion.. and you’ve got it, OK. The picture on the right is a crude representation
of the sympathetic nervous system. The top nerve, the green nerve, is the preganglionic
nerve, the middle nerve is the postganglionic nerve, and the larger blue area on the bottom
is the target organ, or the organ that the sympathetic nervous system is trying to stimulate.
The preganglionic nerve, or the nerve on top in this picture, originates from the spinal
cord. The synapse in the middle represents one of the paravertebral ganglia, theses synapses
use cholinergic receptors which is, again, outside of the scope of this lecture. (So
you’ll have to look for that lecture specifically.) What we’re interested in, for this lecture,
is where the postganglionic nerve contacts the target organ. This is where the magic
happens, this is where the adrenergic receptors are. The normal physiology for a nerve impulse
is that it travels down this pre-synaptic nerve until it gets to the end here. And,
through a series of cellular processes (which I will cover in a different lecture), it causes
these vesicles filled with neurotransmitters to fuse with the membrane and spill out their
contents. In this example, the neurotransmitter I’ve chosen is norepinephrine, which is a
catecholamine, but other catecholamines work on these receptors as well, and other drugs.
And that’s why this lecture is important, we’re going to talk about those so that we
understand it. You can see from this picture here as well
that there are two main categories that I am going to speak on. The Alphas and the Betas.
And then I’m going to break those down into Alpha 1 and Alpha 2, Beta 1 and Beta 2. Now,
there are more adrenoceptors than these four, but these, I feel are the most important.
So if you can nail these down early on, it’s easy to add-on extras as we go. Let’s move on. Now, just as an overview for these four important
receptors. This is how I remembered these receptors early
on. Now, you have to remember that each receptor does more than just one thing, but when you
are first learning it helps.. It helped me anyway to clump them together.
Starting with the Alpha receptors. For the Alpha 1, I think of it as a constrictor,
or a vasoconstrictor. I remembered that in my mind pictorially by thinking of the one
as a vessel and the alpha symbol as a surgeon’s tie. So, you can see that as the surgeon pulls
on the two sides of the tie, it constricts down on the vessel. For the Alpha 2s, remember that the Alpha
2 receptor was pre-synaptic, meaning that it was on the same side that the signal originated
from. It deals with feedback, it’s a feedback mechanism. It keeps the presynaptic nerve
from running away with the reaction and it helps contain the reaction. So, I think of
the 2 as kind of an arrow, doubling back on the pre-synaptic side. Now, on to the Beta receptors. Beta 1 receptors and Beta 2 receptors do many
things, but I clump them together, so it helped me early on. I added more and more as I learned
more and more. Beta 1: One heart. Beta 2: Two lungs. Why did I do that? There are a
lot of Beta 1 receptors in the heart and a lot of important medicines that you learn,
at least in the beginning, that are usually beta-blockers, they decrease sympathetic tone
of the heart. So, they decrease the speed and the strength with which the heart beats.
Beta 2 receptors, the famous one that you learn right away, or that everyone kind of
knows, even before school is asthmatics. When their bronchioles close down, they take a
Beta 2 inhaler in the form of Albuterol, to open up the bronchioles so that they can breathe. So, Beta 1: One heart. Beta 2: Two lungs.
And we’ll add more on to it as we go. Now for a little more detail on the Alpha
1 receptor. The Alpha 1 receptor is post-synaptic. It is most sensitive to norepinephrine, and
then epinephrine and much less so to isoproterenol. And that makes sense because isoproterenol
is actually a beta agonist. Now, why is this bullet point important at all?
It’s important because when you start working through the physiology of what drugs do and
how things react in the body, you have to know what a receptor is most sensitive to
and then you also have to think through where are the receptors located. Also, historically,
these catecholemines: Norepinephrine, epinephrine and isoproterenol, are important because when
the adrenergic receptors were first classified by a pharmacologist, these are some of the
drugs he used to help differentiate between the different receptors. Next, Alpha 1 receptors have a high affinity
for phenylephrine. What is phenylephrine? It’s an Alpha 1 agonist. So, what might that
do on the body? I currently, as I am recording this, I have a stuffy nose. How could phenylephrine
help me? It would help by constricting the vessels in my nasal mucosa. And that would
decrease the edema and the congestion, and also decrease the production of mucous, or
rhinorrhea. So, just understanding the receptors, you understand how to treat and what things
do. Alpha 1 receptors are Gq protein-coupled receptors.
What does that mean? I’m going to cover those receptors in more detail in a separate lecture,
but let me give you an overview. Basically, what’s happening, is when the G-protein is
activated, it activates phospholipase c. Phospholipase C cleaves phospholipids that are around in
the area, many of them from the membrane itself. This creates PIP2: phosphatidylinositol 4,5-bisphosphate.
Most people just call it “pip two” or “PIP 2.” That is further cut or cleaved into inositol
triphosphate and diacylglycerol. Then, the IP 3 goes through the cell and acts on calcium
channels and releases calcium into the cell which we know calcium ions are often used
intracellular processes. So, that’s how that receptor works. What do you think of when you think of the
action of Alpha 1? I’ve mentioned it already in the previous slide, but basically, I want
you to think vasoconstriction, or just constriction of smooth muscle. So, what happens if we constrict
the peripheral vessels? Well, that would increase the peripheral vascular resistance and thus
increase the blood pressure. What about the smooth muscles in the eye, the iris dilator
muscle? It would dilate the eye. It would cause mydriasis and also some urinary retention
if the receptors in the urinary tract are stimulated. Now, on to Alpha 2 receptors. These are the
presynaptic receptors, and you can see why in this animation. Basically, as I mentioned
two slides ago, it acts as a negative feedback mechanism to keep the process regulated. Alpha
2 receptors are very sensitive to epinephrine and norepinephrine and, again, more so than
to the beta-agonist isoproterenol. The Alpha 2 receptors have a high affinity for clonidine.
Clonidine is what’s call a central-acting Alpha 2 agonist. What do you think it does?
Well, I’ve used this drug a couple of times. It works great, actually, for people who have
very high blood pressure and they come in maybe in a hypertensive emergency. Clonidine
will lower their blood pressure pretty quickly. It works by “tricking” the sympathetic nervous
system into thinking that it’s getting a lot of feedback, so it decreases the tone of the
sympathetic nervous system by just decreasing the release of norepinephrine in the presynaptic
side of all those nerves. It is a Gi protein-coupled receptor. So, basically, when the Gi protein
is activated, it inhibits adenylate cyclase, which decreases the production of cyclic AMP
from ATP, and thereby decreasing the activity of cyclic AMP dependant protein kinase. So,
what does it do on the body? You won’t be far off if you just remember “inhibition,”
or “feedback.” So, it inhibits the release of norepinephrine by this negative feedback
system that we can see on the right. It also inhibits the release of insulin from pancreatic
beta cell where there is actually a higher population of these Alpha 2 receptors. And
it also inhibits the release of acetylcholine in the parasympathetic nervous system. Let’s move on. For our review on the Alpha Receptors, first
off is Alpha 1. Remember it is Post-synaptic. There is only one pre-synaptic that we’ve
talked about and that’s Alpha 2. Alpha 1s are very sensitive to Norepinephrine. Compare
that to Alpha 2 where Epinephrine is greater than or at least equal to norepinephrine in
its ability to stimulate Alpha 2s. And, both are not very sensitive to beta agonists such
as isoproterenol. Alpha 1s: High affinity for phenylephrine. They are Gq coupled. Alpha 2s: High affinity for clonidine and
they are Gi coupled. Now, these few bullet points are pretty high-yield,
so try and remember these. Alright, let’s move into the Betas. First
off, Beta 1. Beta 1 receptors are post synaptic. They are very sensitive to Isoproterenol,
(the underdog has now become the champion) more so to isoproterenol than epinephrine
and norepinephrine. Beta 1 receptors are Gs protein coupled and remember this is opposite
of Gi. So it increases the activity of adenylate cyclase, thus increasing the production of
cyclic AMP and increasing the activation of cyclic AMP dependant protein kinase. What
are the effects? Well, remember, “One Heart,” Beta 1. And then other things as well, so
first off, we increase the chronotropy, inotropy and dromotropy of the heart. What does that
mean? Chronotropy is the speed with which the heart beats. Inotrophy is the force with
which the heart beats. Dromotropy is the speed of conduction through the heart. Beta 1 receptors
also increase renin release and lipolysis. And you can see how all three of those points
make sense in a sympathetic response. Beta 2 receptors are also post synaptic. They
are again very sensitive to isoproterenol and less so to the other catecholamines listed
there. They are also Gs coupled, so that’s easy.. Right? Both beta receptors that we’ve
talked about are Gs coupled. So what are the effects? So, bronchodilation is the first
one that I remembered, so that’s why I clumped it with lungs, because the asthmatic that
comes in is having a difficult time breathing, turning blue, they take a puff of albuterol
and they’re better. What else does Beta 2 do? Well, Beta 2 receptors
are vasodilators. They dilate vessels in the heart and in the skeletal muscle, which helps
us when we are running from a lion. They thereby decrease the peripheral vascular resistance
and there are even some of these receptors in the uterus, so they can relax the uterus. Now on to the review. So, Beta 1: post synaptic.
Beta 2: post synaptic. They are both very sensitive to the non-selective beta agonist,
isoproterenol. And they are both Gs coupled. So, what are the effects? Beta 1 increases
the speed and strength of the heart, increases renin release. Beta 2 dilates things such
as vessels and the bronchi and also relaxes smooth muscle. OK? Good! Well that was a fast lecture. We’re on to
the knowledge challenge already. We’ll walk you through real slow, don’t worry, you’ll
do fine. This is the first case: A 59 year old male
presents to your clinic. He’s complaining of having a difficult time initiating his
urine stream. He just can’t pee, the poor guy. When he is finally able to start his
urine stream, he only dribbles into the toilet. You recognize this as a case of benign prostatic
hyperplasia, which is relatively common in older gentlemen, and you offer him a prescription
of, What? How about Tamsulosin? Why? Why would you give
him an alpha 1 receptor antagonist, or blocker? What you’re trying to do is to relax the urinary
tract and this guy has a problem with that because he has a hyperplasia going on in that
area. So, if you can relax that area as much as possible, you could help the urine move
though. Now Tamsulosin isn’t just an Alpha 1 receptor antagonist, it’s actually a little
bit more specific. It’s an Alpha 1a receptor antagonist. I told you, there was more than
just those four. There’s actually a beta 3, there’s multiple subgroups of the Alphas,
but just for this basic lecture, it’s enough to know that an alpha 1 receptor is going
to help this gentleman pee. What if you gave him Clonidine? What would
happen? Well, he would have a decrease in his blood pressure and probably still wouldn’t
be able to pee. He wouldn’t be happy with you, he’d start looking for another provider
at this point. What about Epinephrine? What would Epinephrine
do? That would actually make it harder for him to pee. You don’t often pee when you’re
running from a lion. It would stimulate the Alpha 1 receptor and thus tighten everything
down in that area. He wouldn’t be happy with you at all, he would get sweaty and his heart
would start racing and he’d feel fidgety and agitated. He would definitely go and find
another practitioner at that point. What about Albuterol? Albuterol usually delivered
via inhalation or aerosol. That wouldn’t help him. It would maybe dilate his bronchioles
a little bit but he wouldn’t be able to pee any better. So, if you picked Tamsulosin, Good Job. Okay, next up is a 48 year old male. He presents
to the ER with rigors, hypotension, malaise and confusion. All around, he’s just not feeling
good at all. He is found to be septic on his labs and he is admitted to the ICU. Soon after
arriving in his room, you notice that his blood pressure is falling rapidly and his
mental status is getting worse. He’s crashing on you! Which of the following drugs could
be used to treat his condition in the short term out of the choices below? So, how about Norepinephrine? Why? Well, norepinephrine
would do a great job at increasing this person’s blood pressure because it is a non-selective
Alpha and a Beta 1 selective agonist, it stimulates all three of those receptors, so it’s going
to clamp down on the peripheral vasculature through Alpha 1 mechanism. What about the
Alpha 2? Well, Alpha 2 seems to be contradictory, doesn’t it? And, technically, it is, but it’s
overpowered by the Alpha 1 and the Beta 1 because, what’s Beta 1 going to do? Beta 1
is going to increase the chronotropy, inotrophy and dromotropy of the heart. So the heart’s
going to beat harder and you’re going to have the peripheral vasculature clamp down. So,
all-in-all, you’re going to get a presser effect out of norepinephrine. What about Tamsulosin? Well, Tamsulosin is
the wrong thing to do because it’s an Alpha 1 antagonist, it’s going to try and release
things or dilate things and that’s what you’re trying to get away from. Clonidine is again going to decrease the blood
pressure. Lastly, Albuterol, Not really going to help
someone who is crashing with hypotension from sepsis. So if you picked Norepinephrine, good job. Alright, the last question: You are managing
a 49 year old male patient who is recovering from an appendectomy on the general medicine
wards of your community hospital. Your medical assistant comes to you and reports that this
patient’s blood pressure is 180 over 110. You decide, correctly (this is what you are
supposed to do!), you decide to examine this person for yourself, just to make sure. And,
other than a little post-surgical pain, he feels fine. He’s eating he’s drinking, watching
TV. You repeat the blood pressure and find that it is a correct number, it still is about
180 over 110. And your assistant turns to you and says, “Hey, what medicine should we
give him? What should we do?” What do you choose? Well, Clonidine, if it was there, would be
a good choice, but there’s another correct answer there. How about Metoprolol? Metoprolol
is a Beta 1 antagonist or blocker and remember Beta 1: One Heart. So, it’s going to decrease
the sympathetic tone in the heart, the heart is going to beat slower and with less force.
That will decrease the blood pressure. What if you gave him Epinephrine? His blood
pressure would go through the roof. It would probably be well into the 200s. Albuterol? Well, again, albuterol is not really
the right delivery method. Usually that’s an inhalation or an aerosol and while it would
open up his bronchioles and maybe have a little bit of a side effect tachycardia, really that’s
not going to touch his blood pressure at all. It would probably still stay about the same. Lastly, what about Phenylephrine? Phenylephrine:
One of the uses of phenylephrine is actually as a presser so that would, again, increase
his blood pressure by clamping down on the peripheral vasculature and that would be the
wrong choice. If you chose D. Metoprolol, Awesome, Good
Job. Hey guys, thanks for watching this video.
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