What's up, Ninge Nerds? In this video today, we're going to be talking about adrenergic agonists, and these are going to be some really cool drugs that I want to talk to you guys about. But before we start talking about these drugs, what we use them in, I think it really makes most sense if we take a deep dive into talking about the adrenergic neurons, how norepinephrine is actually released, how it's made, talking about the receptors that it acts on, and then the effect that it has on those target organs. One of the things I tell you guys before we get started, though.
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But let's get started talking about the adrenergic neuron and talking about the effect that the actual norepinephrine, epinephrine, as well as these different drugs have on the adrenergic receptors. All right, so first things first. We take a zoomed in look at one of these actual neurons that are releasing norepinephrine.
Now, when norepinephrine gets released, it works on particular receptors that will exert its effect depending upon the target organ that we find it in. But I want to briefly go through how norepinephrine is actually synthesized, how it's released, how it's actually recycled or broken down, because there is certain drugs that don't directly work on the receptors that norepinephrine binds to. They work in other ways to increase the amount of norepinephrine in the synapses. And then there's some drugs that do a little bit of both.
So let's talk about this first. So whenever norepinephrine is actually synthesized, it's actually synthesized via a particular amino acid that we get from our diet called tyrosine. And that tyrosine will get taken up into these adrenergic neurons in combination via a co-transporter with sodium. So either way, both of these will help to be able to get tyrosine into this neuron. Once tyrosine gets into the neuron via these co-transporters, then what happens is through a series of reactions, it'll get converted into norepinephrine.
So what happens is tyrosine actually gets converted into something called L-DOPA, and then DOPA will actually be worked on by another molecule to convert it into dopamine. And then what happens is dopamine will actually get taken up into this vesicle here. And once it gets taken into this vesicle via specific types of transporters, Then in this vesicle, it actually gets converted via specific enzymes into what we're going to abbreviate neuroepinephrine.
So this is the basic pathway of how we synthesize norepinephrine. So it depended upon tyrosine. Now, once norepinephrine is in these vesicles, the question that you ask is, how do we get it to this point to where it actually fuses with the cell membrane and then via the process of exocytosis, we release the norepinephrine into the synapses? Well, this is a neuron.
A neuron releases particular neurotransmitters based upon action potentials moving down the axon, activating or stimulating these channels here. What are these cool little red channels called? These are voltage-gated calcium channels.
We're gonna abbreviate that as CAV. This is a voltage-gated calcium channel. We're gonna stimulate this puppy and once it opens we're gonna get calcium to rush in to this actual neuron.
When it rushes into the neuron the calcium has the ability to stimulate this fusion process. of the vesicle which contains all this norepinephrine inside of it, right, and maybe even a little bit of dopamine sometimes too, we have the ability to release that norepinephrine now into the synapses. That's the process.
Now, once norepinephrine is released into the synapses, so here's all this norepinephrine, it's then going to diffuse across the synaptic cleft and bind onto these different types of receptors depending upon what the target organism is. We'll talk about those below. But there's many different types of receptors. I'm going to take you through some of them.
You guys might remember them. If you did forget them, I want you to go to our playlist in the neuro playlist and look at the video on adrenergic receptors. We have an entire, like, intense video on that. So go check that out. Now, once norepinephrine gets released in the synapses, it has to diffuse across the synaptic cleft.
Once it diffuses across the synaptic cleft, it's going to then bind onto particular receptors. And depending upon what target organ or what type of, like, tissue this receptor is at will determine the type of overall function. But really it's the receptor because it has a particular effect that it has on these cells that will really cause this particular target organ effect, which is really cool. When norepinephrine gets released, it's going to bind onto different types of receptors, right?
We already know how it gets made and how it gets released. It's going to bind onto all these different types of receptors and depending upon what target organ it is and what kind of effect that receptor has, it'll determine the overall effect, the overall function or physiology. So for example, we have different types of receptors.
We have alpha receptors, type 1. And we have alpha-2 receptors. And we have three beta receptors. We have beta-1 receptors, beta-2 receptors, and a modified beta-2, which is actually...
called a beta-3 receptors. So we have all these different types of receptors that norepinephrine has the ability to bind to. Now once it binds to these particular receptors on these tissues, what is the overall kind of intracellular mechanism, and then what's the overall target organ effect? Well for right now, I just want to take a second to say what it does to the receptor intracellularly, that's the next thing. So once norepinephrine binds onto alpha-1 adrenergic receptors, I want you to remember it works through what's called the phospholipase C pathway.
And if you guys remember, phospholipase C really worked to increase two particular second messengers. One is it increased a molecule called IP3, inosityl triphosphate, if you guys remember that one. And the other one is called diacylglycerol.
And basically what IP3 did is it really helped to increase calcium levels in particular smooth muscle cells. And really when that calcium increased in the smooth muscle cells, it induced a contraction. So, primarily, the overall effect of these receptors is to stimulate contraction of particular smooth muscle cells.
And we'll talk about what that looks like on the target organs whenever they contract a little bit later. But that's the big thing I want you to know. For alpha-2 receptors, it actually works via what's called the adenylate cyclase pathway. And it actually works through what's called the G-inhibitory protein.
So this one, it works through what's called the GQ protein, which works through the phospholipase C pathway. alpha-2 it works through the G inhibitory protein and what that does is that reduces your cyclic AMP levels and if you reduce cyclic AMP levels you're actually going to inhibit this particular cells from releasing a very specific neurotransmitter or releasing a particular hormone so this inhibits secretion or release of a particular hormone or molecule from the target organ that we're going to actually work on The beta-1 receptor works through a G-stimulatory pathway. And in fact, all the beta receptors, beta-1, beta-2, beta-3, all work through the same one.
They all work through the G-stimulatory pathway. And because of that, they're all going to work through the adenylate cyclase pathway. With this one, it decreased cyclic AMP.
Guess what it does to all of these? Which may seem a little odd, right? It's going to increase cyclic AMP.
It's going to increase cyclic AMP. And it's going to... increase cyclic AMP. Now generally for beta-1 receptors it's a little odd and we'll talk about really the effect that this has on the target organs because it's mainly the heart and the kidneys but in this one it really wants to stimulate contraction and beta-2 it increases cyclic AMP but in particular smooth muscles that it actually causes smooth muscle relaxation and then beta-3 it works on smooth muscle and causes smooth muscle relaxation So for this one, I do want you to remember contraction, but it's a very specific one, and this is going to be cardiac muscle. But for both beta 2 and beta 3, these are actually going to cause relaxation of smooth muscle.
And I think that's the biggest thing to be able to remember here. Cyclic AMP from beta 1 is going to cause contraction of cardiac muscle, whereas those smooth muscle cells where they have beta 2 and beta 3, are going to undergo relaxation from the cyclic AMP pathway. All right, so that's the basic concept that I want you guys to understand.
So norepinephrine is released. It has the ability to then go and bind on to all of these different types of receptors and exert its effect. After norepinephrine has exerted its effect, then it needs to either be broken down or re-uptaken to be recycled.
So then here's our norepinephrine, our cute little norepinephrine. It's going through the synaptic cleft. And then it runs into this cute little enzyme here called catechol-O-methyltransferase.
And what this enzyme does is, is it works to be able to degrade, so it works to specifically stimulate this process of the pathway. So generally it could go this way, norepinephrine could move this way, or it could be metabolized via the second pathway via the catechol-O-methyltransferase. And then it gets broken down into a metabolite.
And this is an inactive metabolite. Can't do anything. Usually just gets peed out.
That's one thing that can happen. Now the norepinephrine that doesn't get metabolized, it's still active, can then get taken back up into this neuron via this norepinephrine reuptake transporter. And then once the norepinephrine gets taken back in, then what can happen is it might have the ability to go right into the, boom, right into this actual synaptic vesicle, get recycled and then get reutilized to pump more norepinephrine out.
The other thing though is that there's another pathway that this actual norepinephrine could go. Instead of going into the vesicle, we could have this thing get metabolized and again, excreted as an inactive metabolite via... Special enzyme found in the mitochondria.
You know these mitochondrial enzymes are called? These mitochondrial enzymes that can work at this particular step here to stimulate this particular pathway is called monoamine oxidases. So monoamine oxidases.
Monoamine oxidase enzymes. They work to stimulate this pathway. So either way we can inactivate these via these enzymes or the monoamine oxidases and we can take it back up into the actual vesicle.
via these transporters. So we have an idea now of how norepinephrine is made, we have an idea of how it's released, we have an idea of the receptors that it can work on and the overall intracellular pathway that that will have whenever the norepinephrine binds onto those receptors. We'll talk about the target organs later, and then we'll be able to make sense of how this one causes contraction, inhibits secretion, contraction, relaxation, et cetera.
We also know that when norepinephrine's done exerting its effects, It can get metabolized via this enzyme, catecholamethotransferase. It can also be taken back up into the vesicle to be recycled via this transport protein, reuptake protein. And it can also further be metabolized into inactive metabolites via monoamine oxidases. Now there's two more things I gotta talk about. Norepinephrine is not the only type of adrenergic neurotransmitter that can exert these effects.
on the alpha and beta receptors. You know there's another neurotransmitter that can also exert its effects on these? You know that is? Epinephrine. So norepinephrine is one of the molecules that's released by our sympathetic or adrenergic system, but you know epinephrine is as well?
So we have neurons right here in our sympathetic chain, right, and they're gonna go and supply the adrenal medulla. And whenever they get to the adrenal medulla, the adrenal medulla can release two particular types of neurotransmitters. One is it mainly releases norepinephrine, about 80% of its norepinephrine. And then the remaining 20% of it is actually epinephrine.
But epinephrine is very similar in structure to norepinephrine. They're very similar in structure. When you, they both have what's called the catechol ring. It's just they have a difference in their actual, one of the groups coming off of them.
If you really want to know what I'm talking about here, when you look at norepinephrine, you have this ring here, it's called the catechol ring. They both have them, but really they only differ in one particular point. So they have these hydroxyl groups coming off here. They both have this, but what happens is this one has this group here where we have what's called this amine group and it has like this CH3 group coming off here and then here you have this one which just has this NH2 group coming off here. But really they just differ by this group here on the end and that's really the big difference between norepinephrine and epinephrine.
Now epinephrine can exert the exact same effects as this, it's just the question is how does the epinephrine exert its effects on all these different types of receptors. When it's released from the adrenal medulla, this puppy can get into the bloodstream. Both of these puppies can get into the bloodstream.
When they get into the bloodstream, they then can circulate through the blood to different types of target organs. These are the target organs we're going to talk about. Bind onto these receptors and exert their effects in the same way norepinephrine did it by these neurotransmitter release from this neuron.
So it's important to be able to remember that. I just want to talk about that quick. It's not just epinephrine that exerts these effects, but also norepinephrine.
Now, you're probably wondering, Zach, I thought we were going to talk about like drugs working against the system. Yes, we are, but we have to build our foundation to understand these. Because guess what?
Drugs can work in a couple different ways. So we have the different types of agonists. I actually want to kind of talk about that real quickly before we get into those. So I want to talk about the types of agonists, these adrenergic agonists, if you will. Now, There's a couple different types.
One is there's direct acting antagonists. And these are the ones that we're going to spend most of our time talking about. Direct agonists means that they are the ones that bind directly to the receptor and act like norepinephrine or epinephrine.
That's really all it is. So when we talk about these, there's what's called direct agonists. And really the ways that I want you to think about these is that these directly act and stimulate a particular type of, I'm going to put adrenergic receptor. In other words, let's say I have a drug, norepinephrine, epinephrine bind to the beta-1 receptor and then work to cause contraction of cardiac muscle.
If I give another drug, I'm gonna bring it here, I'm gonna draw in red, this gets into the circulation and it binds onto this receptor and it produces the exact same effect as if norepinephrine, epinephrine bind onto it, that's an agonist, but it's a very specific type of agonist. If it binds directly to the receptor, that's a direct agonist, okay? Another type of agonist, and you know what's also really interesting?
Sometimes these agonists aren't, they're like, you know, a little bit interesting. They're like, I'm not really committed to one receptor. Some of them, I can bind onto them. Multiple receptors and we'll talk about that a little later. You can have what's specifically called selective agonists called alpha 1 beta 1 agonist Or you can have some agonists that bind on to Multiple alpha and beta and we'll talk about those a little bit later.
The next category here is called indirect And really what I want you to think about these indirect agonists is that they really work to, let's say, increase norepinephrine accumulation. They want to keep the norepinephrine in the synapses higher. They don't directly bind to the receptor, but if they increase norepinephrine, they can amplify the effect that it may have on those receptors.
And really, there's one, booger sugar, cocaine, which is going to be one of these. And then other ones, amphetamines. Okay, so amphetamines.
These are two types of indirect agonists. But you're probably asking, how do they increase norepinephrine? I know you are. So the way that they do that is they work, I didn't mention this for no reason, right? These drugs, which I'm going to kind of denote in red here, are going to work to try to do whatever they can.
to get more norepinephrine to be released, recycled, or not be broken down. So these drugs would work to inhibit, maybe this enzyme, because if I don't do this pathway, what am I gonna have more of that doesn't get broken down? I'm gonna have more norepinephrine, right? I'm going to work to maybe inhibit this transporter, because now I'm not gonna recycle it, I'm gonna keep the norepinephrine out here in the synapses.
It's not getting broken down. and I'm not letting it get recycled, I'm going to keep it in the synapse there. That's pretty cool, right? And they also can work to inhibit the monoamine oxidase inhibitor.
I mean, monoamine oxidases. If you inhibit that, do you break it down into a metabolite? No. So you just allow for us to be able to increase norepinephrine in the vesicles.
Increase norepinephrine in the synapses or prevent it from being metabolized. That's the whole concept. And if I do that, I'm going to have more norepinephrine to bind on to more of the alpha or beta receptors and exert its effects.
Okay? We don't commonly utilize cocaine for any types of particular medical things. It used to be one.
You could use it like intraoperatively or you could use it for like epistaxis and things of that nature. We don't often do that. Amphetamines, they can be utilized. We're not going to talk too much about these. We'll talk about them in another section of pharmacology, but we can utilize these things in like ADHD, we can use it in narcolepsy, a lot of other conditions as well.
But we're not going to go too much down that rabbit hole. We'll have another section when we get to these specific drugs later. The last one is mixed. So mixed agonists. And these mixed agonists, they just do both.
In other words, they stimulate the adrenergic receptor and they help to increase the norepinephrine in the synapses. or the amount that's being recycled or preventing them from getting metabolized. Really the only two that I want you to remember, one we don't really use anymore, ephedrine. The other one we do commonly utilize a lot is a decongestant, is pseudoephedrine. So there is one particular drug that I would actually take into consideration here, which is pseudoephedrine.
And this one is utilized as a nasal decongestant because The basic concept is that when you cause, it binds primarily onto what's called alpha receptors or increases norepinephrine to bind onto alpha 1 receptors. So it vasoconstricts the blood vessels and the nasal cavities. So we don't make as much mucus. We don't have as much blood flow to the area and causing a lot of secretion.
So it just helps to decongest a lot of that sinus congestion stuff. So that's really the only kind of utilization of that drug. But this category, this my friends, is the big one that we have to spend most of our time talking about.
And we'll talk about it in a couple different ways. I organized it in a way that we talked about the agonists that bind onto alpha-1 receptors and produce that effect, the ones that bind onto alpha-2, the ones that bind onto beta-1, the ones that actually have a little bit of equal beta-1 and beta-2, then beta-3, and then we'll cover the ones that are just polyamorous and they bind onto all of them. They can bind a little bit of alpha, a little bit of beta, they can do a bunch of different stuff. Before we do that, though, what I want to have a good foundation to develop here is whenever norepinephrine... epinephrine or these direct agonists bind onto a alpha-beta receptor, what is the overall effect that it's going to have?
Then we'll talk about once we build that foundation, what are actually some reasons why we would give this to people to augment these functions? Let's talk about that now. So whenever norepinephrine or epinephrine or these agonists bind onto a particular receptor, let's talk about that effect. If it binds onto an alpha-1 receptor, we know that'll increase the inositol's triphosphate and diacylglycerol increasing calcium levels to cause contraction.
But contraction of what? Smooth muscle. And really the big one is the smooth muscle on blood vessels.
So if I really constrict the heck out of this vessel, I squeeze it. So I'm going to squeeze this vessel. What I'm going to do is, I'm going to increase systemic vascular resistance. And that's going to do two things that can potentially decrease blood flow beyond that area.
So if I'm having blood running through this area and I'm clamping down right here, it can potentially reduce the blood flow out of this area. That's not hard to imagine. The other thing is, is it can really increase blood pressure.
Imagine blood running through that narrow area. Whenever the diameter is really, really tiny, the pressure running through that area is super high. So you can really increase your blood pressure.
And that's an important concept as well. So we're going to really increase blood pressure in this situation here. So that's one particular thing. The other thing is that we have alpha-1 receptors on the sphincters around the rectum or anal area, as well as around the sphincter around the urethra. And these are designed that if we stimulate these, They'll squeeze the heck out of that muscle and squeeze them and prevent urine from being evacuated from the bladder or toots toots being evacuated from the rectum.
And so this will lead to inhibition of, you know, in this situation, defecation and urination. So it'll inhibit defecation and it'll inhibit urination. Now you might be saying, why in the heck would that be useful? This is more of the actual adverse effect of it.
I mean, in general, in your sympathetic nervous system. When you're running away from a bear, you don't want to be pooping or peeing yourself. So it's a general sympathetic function, but this might actually be more of a side effect of these drugs that are alpha-1 agonists rather than an actual true desired effect.
Think about that. The other thing is that we have an alpha-1 receptor present on the actual pupil muscle. And this muscle is called the dilator pupillae. So the way that the muscles actually work, they're kind of like little radial spokes.
And whenever they contract, they actually pull the iris outwards, so they increase the pupil hole. So because of that, this actually will induce what's called pupil dilation. So it'll induce pupil dilation.
So the overall effect of these drugs, or norepinephrine, epinephrine, binding to the alpha-1 is to constrict blood vessels, increasing pressure, or reducing blood flow to a particular area beyond that compression, inhibiting defecation and urination, and causing pupillary dilation. All right, we'll talk about how that's actually important later. The next thing that I want you guys to understand here is that We have what's called alpha-2 receptors.
Now, if epinephrine and norepinephrine bind onto the alpha-2 receptors, and they work on that, what are they potentially doing? They're inhibiting secretion. Secretion of what?
Well, alpha-2 receptors are actually present on these presynaptic neurons. So you have these different types of presynaptic neurons on the terminal, on the presynaptic nerve terminal. So let's actually write that down. So on this presynaptic nerve terminal, and these are really scattered throughout the central nervous system. So presynaptic nerve.
terminal. Now the reason why this is important is let's say norepinephrine is released from these vesicles that we talked about above. When norepinephrine is released, it's going to try to work on different types of neurons or target receptors, whatever it may be, and try to exert its effect. Once it's done, sometimes we already talked about how it can actually be recycled via the transporters or metabolized, etc. But one of the other things that we didn't talk about is that norepinephrine can actually inhibit its further release.
Because it can bind onto these alpha-2 receptors on the nerve terminal, and what happens is that decreases cyclic AMP, and that actually hyperpolarizes the neuron and inhibits it from releasing more norepinephrine. So the overall effect here is that you'll actually reduce norepinephrine release from these presynaptic nerve terminals. And we'll talk about why that's important, but that's the basic effect. The other thing is that you have all these different types of cells called pancreatic beta cells in your pancreatic area. And these pancreatic beta cells do have lots of alpha-2 receptors on them.
And whenever norepinephrine or epinephrine or these drugs bind onto them, what it does is it actually inhibits the secretion of insulin. And because you inhibit the secretion of insulin, you don't put glucose into your cells. And so that can potentially increase your blood glucose levels, which is an important thing to remember. More of a side effect of this drug potentially than anything.
All right, the next one. we have beta-1 receptors. Now there is beta-1 receptors on two parts of the heart. So if epinephrine, norepinephrine, or these agonists bind onto this, you know you have your SA node, you also have your AV node, you have your bundle of his, your right bundle branch, your left bundle branch. Well those nodal cells do have beta-1 receptors on them.
And if epinephrine, norepinephrine, or these agonists bind onto those beta-1 receptors, what do you think they're going to do? They're going to increase the conduction from the SA node, increase the conduction through the AV node, increase the conduction through the bundle system. And because of that, they will Increase your heart rate. You also have beta 1 receptors on the contractile portion.
Alright, the contractile portion of the cardiac muscle. Remember what I told you? Beta 1 receptors increase cyclic AMP and increase contraction.
That's one of the things. Things I wanted you to remember. They also can increase heart rate or the conduction.
But here's the other thing. They really squeeze the heck out of the muscle there, the heart muscle. And so they increase what's called contractility. And if I increase contractility, what am I going to do? I'm going to increase stroke volume and then therefore increase cardiac output.
Well, what do you do if you increase heart rate? You also increase cardiac output. So all of this really increases cardiac stimulation to increase cardiac output. That's a really cool concept there. The other thing is that you have beta-1 receptors on these cells in the kidney called your juxtaglomerular cells.
So there is nice beta-1 receptors. So there's beta-1 receptors in the heart, but there's also beta-1 receptors on these JG cells. And whenever they're stimulated, they increase the release of what's called renin.
And then renin activates angiotensin 1 and then eventually angiotensin 2, that whole jazz, and then increases your renin-angiotensin-aldosterone system. And we know that whenever this is super activated, angiotensin squeezes the heck out of the vessels. Increased aldosterone, ADH, which pulls in more water and sodium, which increases your blood pressure. The overall effect of this is to increase your blood pressure.
So that might be another thing is you may actually cause an increase in the blood pressure because of this stimulation. So cardiac stimulation as well as renin-angiotensin-aldosterone system activity is increased. The next thing is if you have a drug that binds onto beta-2 receptors, it increases cyclic AMP within particular muscles like smooth muscles and then relaxes them. What kind of smooth muscles would we want to relax in a sympathetic response? Well, I actually would want to kind of potentially think about this.
I have beta-2 receptors that are on blood vessels, but these are going to be, I want you to really, really think about these guys. Blood vessels. But these blood vessels are supplying two things. They're supplying the heart, and they're supplying our skeletal muscles. So we need these muscles to have good, good blood flow to be able to really have a lot of contraction strength and get a lot of oxygen going to that muscle, a lot of nutrients going to the muscle in the heart, so that way we can contract them and then utilize them to run away from the bear.
So when you think about that, if I vasodilate them, yes, I'll increase the blood flow to these actual muscles. So you're gonna get a two prime effect. You're gonna decrease the systemic vascular resistance in these vessels that'll increase the blood flow to the muscles like the cardiac muscle and the skeletal muscle but it will reduce the blood pressure because you're increase in the diameter and there's less of that effect now for blood to run through. So it's not going to have a high pressure system as much.
On the bronchials there's smooth muscle within these bronchials. You guys know that right? That whenever we actually took like a cross-section of this bronchial here, I take a cross-section here and I zoom in on it.
Here's the lumen but what's surrounding that lumen is the bronchial smooth muscle. So if I give drugs that will act on that smooth muscle there it's going to relax it. What will that do?
Bronchodilate right? Not this, bronchodilate right? So it'll induce what's called bronchodilation. Now, whenever I cause bronchodilation, why is that important? Because it's going to help me to be able to get more airflow in and out of the lungs, which is important so that I can oxygenate my blood, so I can run away from that barrier the best I can, right?
But that's a cool concept there. The next thing is, so we have beta-2 receptors on this puppy here, beta-2 receptors on this one. Now, here's another one. You have another type of cell.
So this was beta cells. This one's going to be alpha cells. And then you have beta-2 receptors present on the liver. So we have these beta-2 receptors. receptors that whenever you hit the liver, think about this, think about sympathetic surge, right?
Whenever sympathetic gets activated, you want a lot of glucose nutrients to be in the blood so that you can supply those muscles. And so because of that, I want the liver to just jack up my glucose levels. And it does that via two mechanisms. I'm not going to write them down.
Gluconeogenesis, making glucose from non-carbohydrate molecules, and glycogenolysis, breaking down glycogen into glucose. Alpha cells is actually going to stimulate an increase in glucagon. glucagon, and glucagon actually works to increase blood glucose levels as well, so that we can run away from a bear and we have plenty of nutrients to be able to do that.
The last thing is that you have beta-2 receptors that are also present on the uterus. In all reality, there's alpha-1 and beta-2, but if we have beta-2, there's a particular reason for it. We do this because it's actually going to relax the smooth muscle, and it's going to inhibit uterine contractions. This is an important concept because this may be important whenever a...
A mother is maybe not close to the time period that we want to deliver the baby. Maybe they're preterm or trying to delay them for about 48, 72 hours. So we can give them a drug to actually inhibit those uterine contractions to allow for the mother to have more time if she's in preterm or premature labor.
All right, that's the beta-2 receptor effect. The last one is the beta-3 receptor. And the beta-3 receptor is actually two target organs. One is the fat tissue, the adipose tissue, which actually what's called lipolysis, but it's not clinically relevant. The other one that is clinically relevant is the beta-3 receptor.
the beta-3 receptors present on the detrusor muscle. And whenever this is on the detrusor muscle, this actually will work to inhibit, remember, it's relaxation, my friends. So relaxing smooth muscle, relaxing smooth muscle, relaxing smooth muscle, inhibiting secretion. But in here, we're relaxing the smooth muscle of the detrusor. Puppy ain't gonna contract.
You don't wanna be peeing on yourself when you're running away from the bear, so it's going to inhibit the urination process. So you get the point here of how these receptors, depending upon the target organ that they're found on, exert their particular effect. And all these drugs that we're giving, are doing, is increasing the effect that norepinephrine or epinephrine has via being indirect, or binding onto the receptors just like they would in increasing the effect. or mixing themselves up and doing a little bit of both.
Let's focus now on those direct agonists and go over them one by one. Alright, so now, alpha-1 agonists, whenever we have a particular direct agonist, this is a drug that's gonna bind onto the alpha-1 receptor. When they bind onto the alpha-1 receptor, then what are they gonna do?
They're gonna cause contraction of smooth muscle. So we already talked about that effect that it would have on the blood vessels. We talked about on the, potentially the pupil.
We'll talk about another effect, which is the blood vessels that are supplying like the nasal cavity area as well. But, The basic concept here is that you're going to have alpha-1 receptors that are present on blood vessels, but I think this is oftentimes forgotten. There's alpha-1 receptors that are present on the arteries and on the veins, and I think that this is a really important concept to understand here.
If we think about this, we'll write this in red here. If we have alpha-1 receptors on the blood vessels, the artery component of it, what's that going to do? What's the overall effect?
It's going to squeeze the heck out of the vessel and increase resistance and increase your blood pressure, right? That's one thing, is that we know that the Alpha-1 receptors will increase your systemic vascular resistance when stimulated, when you stimulate these puppies, and that's going to increase your blood pressure. There's another concept though, which is the Alpha-1 receptors on the veins. If you squeeze the heck out of these veins, what you're doing is you're really pushing a lot of blood into the right heart, so you're increasing your venous return. If we increase venous return, that increases preload.
If you increase preload, you increase cardiac output. If you increase cardiac output, you can potentially increase blood pressure. So in the same way here, we're also going to stimulate alpha-1 receptors that are present on the blood vessel, and that is going to increase your venous return, which is going to increase your stroke volume, increase your cardiac output, and again, increase your blood pressure.
So overall effect here is we can get a two-way increase in blood pressure, whether it be squeezing the heck out of the arteries or squeezing the heck out of the veins. So the overall effect here is hypotension. You could be potentially reversing that.
So in diseases where you need to increase blood pressure would be hypotension. So this would be beneficial in what? Hypotension. Now, there is one particular drug that I think is great at treating hypotension. One of these drugs here that we can actually utilize here, there's two particular drugs that I actually like to utilize in this scenario here.
One is called phenylephrine. So phenylephrine is a great drug to treat hypotension. And this oftentimes can be used in situations like shock.
Maybe it's whenever they're undergoing a procedure, so they're periprocedural or peri-surgical, around that time, perioperative. They get a little bit of blood pressure that's dropping from propofol or whatever the sedation is. You can give them a little bit of this drug to kind of just squeeze the vessels a little bit and up their pressure.
So I find that to be a pretty good drug is phenylephrine. The other one, and you can even use this in like septic shock as well, the other drug here is a little bit different, and this one is called Midodrine. So Midodrine is a really cool one, but I think one of the benefits and why I wanted to mention here the effect that Alpha-1 receptors have on the veins is because Midodrine, so we've got to actually write this one out here, Midodrine, is going to be a really cool one because what Midodrine does is it really works on squeezing these veins really, really well.
And because it squeezes the veins really, really well, it really helps to improve the venous return to the right heart. Why is that important in elderly individuals? Whenever they maybe go from a seated position or a laying down position to standing, they have these abrupt postural changes and their venous return drops and their blood pressure drops.
It's called orthostatic hypotension. Midodrine happens to be very, very good in a specific subtype of hypotension. So phenyloferrin is good generally, especially in like, you know, perioperatively, very commonly utilized, but also in shock states. We can use this in septic shock.
Midodrine is good in a very specific type of hypotension called orthostatic hypotension. So orthostatic hypotension, because when the patient stands up their venous return drops. They don't have a good systemic venal constriction. So you give them this drug, it'll squeeze the heck out of those veins and push the blood back up so you don't drop your pressure during these postural changes.
Why this is actually really important to understand. All right, so that's the two effects there. The next one is that we do have a little bit of an effect on this pupil muscle, right? I told you that it can cause this pupil to kind of contract, and then when it contracts, if we have an effect on the alpha-1 receptors here on the pupil, it's going to cause pupil.
Dilation. The only reason I'd really want to dilate my pupil is I'm either trying to take a look back here at the retina and I need this thing to be bigger so I can take a look back here or I'm trying to do some type of procedure here. So really the main indication for this is some type of optho procedure of some type, whether you're trying to dilate the pupil to get a good look at the retina, whatever it may be. This could be a drug to utilize and the primary one that's utilized in this scenario here is phenylephrine.
So I would actually remember that phenylephrine could be utilized in this particular scenario. Alright, the last one here is the blood flow. Coming back to this, remember if I were to actually kind of zoom in on this a little bit, let's say here I have a blood vessel, I'm going to kind of just plump it up a little bit. Now phenylephrine, as well as other drugs, can squeeze the heck out of these vessels, right?
So if they squeeze down here, they're going to potentially reduce the blood flow down here. So they're going to really squeeze the vessels and then what happens is what if there's actually a lot of bleeding here? What if somebody has a lot of bleeding or secretions because if we supply a lot of blood flow to the glands here You can have a lot of secretion so it can cause a lot of congestion in the nasal cavity So if you have increased blood flow and naturally it's going to increase secretions So you're gonna have lots of blood flow there to increase a lot of secretions in the nasal cavity as well as increase the epistaxis Right. So if I give a drug What if I squeeze these vessels, so I increase the systemic, I actually squeeze on the vessels, and when I squeeze on these vessels, what I'm going to do is, if I squeeze down on them, I'm going to increase the systemic vascular resistance. And therefore, I'll actually inhibit this process.
What I'll do is, is I'll actually inhibit the increase in blood flow. And that might reduce the secretions, and it might reduce the further bleeding. So there's two drugs that we can utilize in epistaxis and where there's lots of secretions. You know rhinitis, whenever somebody has like a really bad rhinitis, whether it be an allergic rhinitis or maybe even like a viral rhinitis, they have lots of secretions.
We can utilize two drugs to reduce the secretions, reduce the congestion there, and that would be things like phenylephrine or oxymetazoline. So two drugs that are actually pretty good in this situation here is phenylephrine as well as oxymetazoline. Sometimes we use oxymetazoline more commonly in the secretion effect, whereas phenylephrine might be more commonly utilized in the epistaxis effect. Just watch out because one of the big things to think about with these drugs is that they really squeeze the heck out of these vessels.
And if you take them away, you potentially can cause a rebound effect. And so what I really want you to remember, especially with oxymetazoline, is watch out for a potential complication or adverse effect from this one. And that is that if you are utilizing this because you have a lot of congestion and you keep spraying Afrin like it's going out of style or oxymetazoline in for a couple days and all of a sudden you just stop it, you can actually have a rebound congestion where then all of a sudden you stop squeezing the vessels, they open up and then the secretions actually continue.
So just watch out for potential complication with oxymetazoline and that is like this rebound congestion as well. One more thing that I want to talk about that is a potential adverse effect with these drugs is really specifically phenylephrine. Whenever somebody squeezes the heck out of their vessels, what can it do?
If you increase the blood pressure, your natural reflex, if you guys remember, I'm not going to draw the whole diagram, but I want you guys to remember that we have those baroreceptors around the aorta and the carotids, and they pick up whenever there's a big rise in blood pressure. And if you remember, when they send that signal, they send it to the actual central nervous system. So it'll go to the CNS, right, to the brainstem.
And the brainstem will say, hey, hey, hey, blood pressure's too high. We've got to drop the rate down a little bit. And so what it'll do is it'll activate the vagus nerve, and the vagus nerve will come here and release acetylcholine onto the SA node and AV node. And what does that do? It drops the heart rate down a little bit.
And so because of that, you want to be careful, especially with phenylephrine. One of the kind of potential effects out of this one is because of that super high resistance and blood pressure, it can cause what's called a reflex bradycardia, which can actually sometimes be used to your advantage in patients who are really critically ill and are tachycardic. You can actually use this as a pressure to squeeze their vessels, increase their pressure, and also maybe help with their heart rate a little bit.
But that's the big thing to watch out for. So watch out for rebound congestion with these when used for a lot of like decongestion effect. And then watch out for reflex bradycardia when utilizing phenylephrine for hypotension-related problems.
All right, cool. Let's come down and talk about the alpha-2 agonists. All right, so the next one is the alpha-2 agonists. Now, in reality, when you think about this, adrenergic agonists, right, you would want them to be what's called sympathomimetic. In other words, you want them to try to act like a sympathetic thing, have a sympathetic effect, if you will.
In other words, they increase the heart rate, they increase the blood pressure, they're producing all of those effects. With these drugs, they're actually Actually, technically, sympatholytics, which is weird, because we put them in an agonistic category. But if you remember, the overall effect, if you remember that little diagram that I told you here, where we have, here's a neuron, and it's releasing a particular norepinephrine onto it. And when it releases the norepinephrine, binds onto this, produces its particular response, and then there's a little alpha-2 receptor here where it can bind onto, and the overall effect is to inhibit further norepinephrine release. Well, that norepinephrine release is being inhibited in multiple places.
One is you're depleting the norepinephrine release within the central nervous system. And that can actually change a patient's overall level of, you know, I'd say function. So think about this. Norepinephrine, sympathetic drive, what is it? overall effect that it should have on your overall level of alertness and cognition.
It should make you like ready. You know you can see the stitch on every baseball if it's getting thrown at you. You're able to really really hone in. If you really drop that down, you make the patient maybe more lethargic, more sedated, more kind of calm. And so I think that's one of the things that you can see here is you can make that you can see a little bit of a sedation effect with these drugs.
You can see that the patient may be a little bit more lethargic. watch out for that with these potential drugs. This is sometimes one of the potential side effects or adverse effects of this drug that it has on the central nervous system.
So if we're looking at the norepinephrine release, this kind of pathway is occurring a lot within the brain. brain stem. It's occurring a lot within the actual cortex as well.
So the other thing here that I think is important to remember is that these neurons that are releasing norepinephrine, they affect a lot of different areas of our body, not just the central nervous system, but they do have a profound effect on the nerves that supply the lungs, the nerves that supply the heart, the nerves that supply the blood vessels as well. So there's potentially less norepinephrine that are affecting these pathways. And really, it kind of originates from the effect that it has on like the brain stem.
And so you actually kind of get a reduced... potentially a slight decrease in the respiratory drive. So maybe some small degree of respiratory depression.
So it may actually just kind of slightly drop your respiratory rate and the depth, just a little bit. That might be a slight side effect. The other thing here is it also may actually kind of reduce the effect that it has on the heart.
So less norepinephrine being released on the heart also can do what? It can decrease the heart rate and it can potentially decrease the contractility. Either way, both of these things leads to a reduction in cardiac output.
The other concept here is that there's less norepinephrine to squeeze on the vessels. And if there's less norepinephrine to squeeze on the vessels, it's actually going to reduce the systemic vascular resistance. and drop the patient's blood pressure. And we know that blood pressure is not just dependent upon resistance, it's also dependent upon cardiac output. So you can drop the blood pressure.
So this is kind of the effect that happens because of inhibiting a lot of these neuroepinephrine-releasing neurons with kind of in the central nervous system. As you may get some kind of like sedation, lethargic effect, kind of chilling the patient out a little bit. You can have a slight decrease in the respiratory drive.
You can drop their heart rate, drop their contractility, and drop their squeeze on the blood vessels and drop their pressure. So I think it's important to remember that this could be utilized in a lot of particular ways. And the main drug that we actually utilize here is called clonidine.
So there's one drug called clonidine. There is another one that is actually relatively interesting as well as called alpha-methyl-DOPA. This also can kind of work via this pathway.
So because of that, I want us to primarily focus though on clonidine. When clonidine works, one of the big things is that you can think about here with the sedation and the lethargy, it can really kind of chill people out who are super hyperactive. and so what kind of diseases would a patient be so hyper that you actually want to relax them out a little bit ADHD so a particular indication for this drug is it could be utilized in situations like attention deficit hyperactivity disorder particularly with more hyperactive component here's the other thing it also can drop blood pressure right it can drop the blood pressure what kind of disease would you want to utilize this in if a patient has high blood pressure it could also be utilized in hypertension. So we can utilize clonidine in situations where a patient has maybe tension deficit hyperactivity disorder, we can use it to reduce the patient's blood pressure if they have underlying hypertension.
Here's the other concept that I wanted to get this diagram out of the way. When a patient utilizes particular drugs and maybe they abuse them and abuse them and abuse them. For example, they use things like alcohol, they use things like benzodiazepines, they use things like opioids and they just abuse this system right they abuse this system if you decide to withdraw in other words you stop taking opioids you stop drinking alcohol you stop utilizing benzos this system gets really affected okay so if a patient automatically goes through withdrawal of particular drugs for example opioids alcohol and benzos is a big one when the patient goes through withdrawal of this system goes haywire and it releases massive amounts of norepinephrine causing the patient's heart rate to go up causing their contractility to go up causing their blood pressure to go up causing the respiratory rate and depth to go up causing them become irritable causing them to become agitated and delirious.
This is the effects of opioid, benzo, or alcohol withdrawal. If we give them a drug like clonidine, what it'll do is it'll block that massive norepinephrine surge and help to keep them calm, sedate them, make them a little bit chill, help to drop the respiratory rate and depth down a little bit, help to be able to drop their heart rate down a little bit, help to drop their blood pressure down a little bit. So remember that this drug is also really good in withdrawal.
Symptoms to reduce withdrawal symptoms. And again, this is a really, really important thing to be able to remember. So let's just quickly recap the three particular indications here. One is ADHD, because if you have lots of norepinephrine really released in the synapses in the brain, it's gonna make the patient super hyperactive, very, very kind of like on edge. You give them a little bit of this drug, it drops the norepinephrine release there, kinda chills them out, especially in diseases like ADHD.
You also can have a lot of norepinephrine that could potentially be released here that causes the patient's heart rate to go up, contractility, blood pressure to go up. Hypertension would be one of these potential things where it would be important to treat. If they have hypertension, you can potentially drop the norepinephrine released by these neurons, having less effect on the heart, less effect on the blood vessels, and drop their blood pressure. So that could be used in hypertension.
The last thing is, when a patient is on opioids, ethanol, or benzos, they're taking them, and then they stop taking them. When they stop... taking them, the norepinephrine system goes haywire.
They release massive amounts of norepinephrine when you withdraw. It causes them to have the exact opposite effect, agitated, delirious, on edge, maybe aggressive. It causes them to have an increased respiratory rate and depth.
It causes them to have an increased heart rate, increased blood pressure. You can shut down that massive norepinephrine surge by giving them a drug to inhibit the withdrawal symptoms. You drop their norepinephrine, you chill them out. You drop their respiratory rate and depth.
You drop their heart rate, you drop their blood pressure. That's an important thing to think about there. All right, and so the last one here that you also could remember that is a part of this category here is alpha-methyl-DOPA.
I'm not going to go over it too much. Just remember that alpha-methyl-DOPA is the same kind of pathway here, but it really works in hypertension, especially in pregnancy because, again, that's one of the many drugs that can be utilized to treat hypertension in pregnancy along with hydralazine, libatalol, and nifedipine. All right, cool.
That covers the alpha-2 agonist. Now let's go over the betas. All right, engineers, now let's talk about beta-1 agonists. So whenever we talk about beta-1 agonists, remember, what was the overall effect that it had?
It worked particularly in two ways. It worked on the nodal system. So it worked on the SA node, AV node, bundle of his, the bundle branches, all those beautiful things to be able to do what?
Increase heart rate, right? So the overall effect that it would have on the bundle system is it really is going to be helpful in being able to increase the heart rate. So you stimulate these beta-1 receptors, and it's going to increase heart rate. The other situation here is it's also going to act on the contractile myocardial cells and increase contractility. And if you increase contractility, what do you do to the overall stroke volume?
You increase stroke volume, what do you do to the cardiac output? You increase cardiac output. So because of that, you're getting an increase in heart rate, you're getting an increase in the contractility of the heart to push more blood out of the heart. There's a really interesting drug that we can actually utilize here. This drug is called dobutamine.
So dobutamine is a primary beta-1 agonist. It's a primary beta-1 agonist. And the primary utilization of this drug would be to augment this, increase heart rate and increase contractility.
And what kind of situations would you want to increase the patient's heart rate? You'd wanna do that if they have bradycardia. So dobutamine is not a terrible drug to utilize as an indication in bradycardia. That could be a potential indication.
So that would be one utilization. Use it in bradycardia if it's going to increase heart rate. The other thing is it increases cardiac output to get blood out of the heart.
And what kind of diseases would this be beneficial whenever they're not having a great cardiac output? What if they're in cardiogenic shock? What if they're in some type of acute heart failure? So we can utilize this drug in acute heart failure, and we can also utilize this drug in maybe some degree of cardiogenic shock.
So I think that's a really, really cool thing to be able to remember with these particular drugs, is there is three particular indications that we could utilize dobutamine for. One is we can utilize this to treat bradycardia. We can use this to increase the inotropic action of the heart, cardiac output, and acute heart.
heart failure and cardiogenic shock. I think one of the big things to think about with this disease is what is the potential contraindications or adverse effects that you'd wanna watch out for. It's pretty straightforward. The contraindication or kind of maybe concerning feature here is if a patient has a very, very elevated heart rate, what can this potentially do? It can increase the heck out of the heart rate.
So one of the potential complications of this drug is tachyarrhythmia. So watch out for tachycardia. as a potential adverse effect. The other thing here is, it also squeezes the heck out of the heart.
And that's gonna utilize a lot of energy. And squeezing the heart time and time and time and time again is gonna increase its demand, right? So if you squeeze and squeeze and squeeze that heart, you're gonna increase its demand.
If a patient has underlying coronary artery disease, right, and they have very decreased oxygen supply, what do you think is gonna happen if you have an increased demand and less supply? you're gonna worsen their angina and so because of that a potential adverse effect here is it can increase angina how because it increases the demand on the heart you know that's why we utilize this drug in stress tests and patients who can't tolerate getting on a treadmill and working out and working and working working increasing their demand we give them dobutamine because it does it for them it causes their heart to contract more and then beat faster and that increases their demand and can put them into a state where if they don't have a good supply to their heart, so they have like a little plaque that can actually cause them to have some angina and some ST changes. So think about that as well as a potential thing to watch out for with this drug. All right, next, my friends, is the beta-1 and beta-2 agonists. Now, the reason why I wanted to mention this one is because this drug is really unique, and this drug is called isoproteranol, also known as isoprenoline.
So isoproteranol. This is a really cool drug, okay? And what I really want you to understand about this drug is that with like dobutamine, dobutamine has beta-1 primary effect.
Its beta-2 effect is so minimal. It's almost not there. So I don't even like to think about it like that. I like to think about it as a primary beta-1.
Isoproteranol is a little bit funky though because it has an equal amount of beta-1 and beta-2 love. It loves that beta-1 and beta-2 equally, all right? Whereas dobutamine, it just primarily loves beta-1 and almost has no love for beta-2. That's why I want you to just primarily think of it as a beta-1. Isoproteranol, though, it has an equal affinity for beta-1 and beta-2, so we can't call them in one of these special agonists.
So because of that, I want you to think what that would have the effect of. We know because it hits the beta-1, we already know that we can use it the same way. It increases the heck out of the heart rate. So it would be great in situations like bradycardia.
I had a cardiac ICU nurse once tell me that... Isopraterinol can get the heart rate out of the stone. Okay, so it's a really, really good drug to get you out of those rough situations when a patient has bradycardia.
We also know that it can increase your contractility. And if you increase contractility, what does that do? If you squeeze the heck out of the heart, it's going to increase the cardiac output.
So we already know that we can utilize this in situations like acute heart failure that we already talked about. And we can also use this potentially a little bit in cardiogenic shock. However, Here's the downside.
This is why you want to say you would think, so let's actually, I'm going to retract my statement here and say you would think that it would be good in acute heart failure and cardiogenic shock because it increases cardiac output. Here's the potential downside of that. With isoproteranol, it has beta-2 receptors.
Where's beta-2 receptors on? The blood vessels. That's why skeletal muscles and cardiac muscle and things of that nature, right? So because of that, there is beta-2 receptors here.
And when you hit those beta-2 receptors, so this one's all beta-1. These are all beta-1 receptor effect. This is beta-2 receptor effect.
If you do this one, what do you do to the blood vessels? You relax the heck out of them and because of that you can cause a decrease in their systemic vascular resistance and drop their blood pressure. So the reason why you would not use this in a cardiogenic shock state or an acute heart failure state is because it can really drop the patient's blood pressure and if they're already hypotensive you don't want to make them even worse.
You would think maybe it could be a drug that I could possibly add on to utilize an acute heart failure and utilize in cardiogenic shock if I add on something else to squeeze the vessel. But again, we oftentimes, if we need to, use something like dobutamine or milrinone. So the primary indication that we utilize isoproteranol for is just very severe bradycardia.
We often don't utilize this in acute heart failure and cardiogenic shock because, yes, it does increase contractility, but it dilates the vessels a little bit too much. and then drops the patient's blood pressure. So because it can drop their blood pressure, that wouldn't be a good situation to utilize in a patient who is in shock state. So I would just be aware that bradycardia, again, One of the potential adverse effects of isoproteranol is it increases the heart rate. So you want to watch out for this in patients who have an underlying tachycardia.
Now one more thing, which is actually cool and I didn't put the diagram in here, but we also know that isoproteranol has beta-2 receptors, my friends. So because it works on the beta-2 receptors, what else could it actually do? Relax the smooth muscle within the bronchioles. And so what other disease state could I do that would induce if I induce broncho?
dilation. I could use this in situations like asthma. However, it's not too common that we utilize this drug in asthma. So I just want you to realize the primary indication for isoproteranol is very severe bradycardia. Okay, you would think based upon an increase in contractility and increase in cardiac output to be great in acute heart failure cardiogenic shock but because it can drop the patient's blood pressure a little bit too much More than dobutamine would, we prefer to avoid this drug in that situation and primarily keep it on for bradycardia.
Because it does have beta-2 receptors, it may have a small effect in being able to bronchodilate and treat patients who may also have concomitant asthma. So these are things to be able to think about. So bradycardia and to a small degree, asthma.
Okay, let's come down and talk about the primary beta-2 agonists now. All right, so next thing is the beta-2 agonist. Now with beta-2 agonist, what's really important to remember here is that they work on the smooth muscle of the bronchioles.
And so because of that, they're going to be really, really good at being able to, if you have beta-2 receptors here, they're going to be great at bronchodilating. And that would be great in situations where patients already have a lot of bronchospasm and maybe a lot of like diseases that are causing like reactive airway diseases. So I really want you guys to remember what kind of diseases that may be and that's usually asthma and COPD.
And these will be very, very good indications, all right, for a beta-2 agonist. Now, the question is, is what kind of drugs are going to be utilized to treat COPD and asthma? Well, there's two different kind of categories you can think about here.
So one of the drugs here is called albuterol. Now, albuterol is a great drug because it definitely is a beta-2 agonist. But one of the big things to remember about this drug is that it is short-acting, okay?
So it's very short-acting, and it works very, very quickly. So remember that this is short. So we could utilize it in asthma and COPD as an acute treatment.
The other ones would be like the long acting. There's a lot of them. I'm just going to write down one like salmeterol, but there's formoterol, there's valant, there's so many different things. Lots and lots of these types of drugs.
The big thing to remember for these is that they're more for the long acting effect. So because they're long acting, this would be more for that chronic type of COPD or chronic type of asthma. So albuterol more for PRN type of situations, acute exacerbations. salmeterol, formotrol, those kinds of things. That's gonna be more for the long-acting chronic management of asthma and COPD.
The last drug that we can also utilize, we just don't commonly utilize it very often, is terbutaline. Terbutaline is another drug that we can utilize here, and it's also very short-acting, but it's great in very severe asthma. So it's very short-acting, and it's great, particularly in more of the asthma rather than COPD category.
All right, the next thing. we can utilize these particular drugs for is remember I told you that they actually relax the uterus so they inhibit the actual uterine contractions if we inhibit uterine contractions this would be important in a mother who does not want to have the baby too early so this would actually inhibit labor we call these tocolytics and the primary tocolytic that we would actually want to utilize to inhibit uterine contractions to inhibit labor is if a woman who's doing preterm labor and they need about 48 to 72 hours before they have their baby. And so in these situations, we use one primary drug, and that is terbutaline.
So terbutaline is really great in these situations to give the pre-term labor kind of a little bit of a delay. So this will actually give you about 48 hours of delay for the pre-term labor, okay? The next one here is we can also utilize these drugs, very specifically albuterol.
We can utilize this drug in patients who have hyperkalemia. Now you're like, Let me explain. When norepinephrine and epinephrine bind onto receptors, they can bind onto beta-2 receptors.
Now what happens is albuterol, when it binds onto beta-2 receptors on different cells, what it can do is it can increase or stimulate the activity of something called the sodium potassium ATPase. And what this pump does is it helps to be able to pump what? It helps to be able to pump potassium. In this situation, we pump lots of potassium into the cell, and we pump lots of sodium out of the cell. That's the primary job of this pump.
In this situation, what if I have a disease where I have lots and lots of sodium? Lots of potassium in the bloodstream and I want to get rid of that potassium. Well, if I have a patient who has hyperkalemia, I can utilize this beta-2 receptor to stimulate this and to shunt all this potassium out of the blood via the sodium potassium ATPase into the cell. So I shunt or shift potassium out of the blood into the cell. And so this would be a primary indication.
So in patients who have hyperkalemia, hyperkalemia. we can utilize this drug such as albuterol to be able to help shift some of the potassium into the actual cell and that would be a cool indication for this drug. Alright, so that's the beta-2 agonist.
Now, the last thing I want to talk about here is kind of like the adverse effect of this one. So, obviously, one of the adverse effects with this drug is that you have to be careful if you have a patient who has normal potassium. If they have normal potassium, what could it do? It could actually cause a drop in potassium.
So, just be careful in patients who have normal potassium levels. You might stimulate that pump a little bit too much and drop their potassium level. The other thing with beta-2 agonist is that you also have beta-2 agonist where? You'll see that in the next slide. You also have them on the liver, and you also have them on the pancreas.
And I told you the two effects of these is that one is you increase glucagon, and the other one is that you cause the liver to make lots of glucose. The overall end effect of both of these is they increase your blood glucose levels. So watch out for hyperglycemia as a potential adverse effect here.
And the last adverse effect that I did not talk about here, but if you guys remember from adrenergic receptors, on our skeletal muscle, muscles, we have these things called muscle spindles. And these muscle spindles have beta-2 receptors. And whenever they are tense, it increases a lot of the actual sensory and efferent pathways. So the efferent pathways to the muscle and causes it to tense up. When it tenses up, you can get a little bit of a tremor effect.
So because of that, I have lots of beta-2 receptors here on this muscle spindle. And that is going to increase the afferent-efferent signals to the muscle. And this can actually cause tremor. So I think the big things to watch out for for this is that patients may develop hyperglycemia, they may develop tremors, they may develop hypokalemia, and a very minor effect, it's very very minor, is that beta-2 agonists, they have a teensy, teensy little bit of beta-1 activity. So if they're really in high doses, they're getting it very very consistently, it can kind of increase the heart rate a little bit because it can bind up to some of the beta-1 receptors in the heart.
But very very minor effect. All right, that covers our beta-2 agonists. Now Now let's cover those actual drugs that can have a little bit of alpha and a little bit of beta and talk about those. All right, so with beta-3 agonists, before we get into the alpha and beta, I kind of gave you a little bit of a false hope, but we're going to talk about that in just a second. But with beta-3 agonists, what I want you to remember for this one is that they bind onto the beta-3 receptors on the actual smooth muscle of the bladder, the detrusor muscle, and they inhibit the contraction of the actual detrusor muscle, therefore inhibiting urination.
So if I have a drug that's going to inhibit detrusor activity, And then by inhibiting the trust or muscle activity, it's actually going to inhibit urination. This would be a great drug whenever a patient is having undesirable urination. They're having incontinence, or their bladder is contracting undesirably.
You know, a disease that this would be great in is something like overactive bladder, or maybe urinary. urgency or frequency. In these kinds of situations, this would be a great indication for one of these beta-3 agonists. So what is a drug that we can actually utilize to specifically act on those beta-3 receptors and when we hit those beta-3 receptors, Here's our beta-3 receptor. When we give this drug it's going to inhibit the uterine contractions, inhibit urination which is good in this situation of overactive bladder or urinary frequency and urgency.
This drug would be Myra Begron. So don't forget that one. Alright my friends, now we come to the big, big stuff here, which is the alpha and beta agonist.
So these are drugs that don't really fit into a category of being a pure alpha agonist or a pure beta agonist. They're a little bit of both. The first one that I want to talk about here is called norepinephrine. Now norepinephrine's a really interesting drug, and when we look at the alpha and beta activity, here's what I want you to take away.
Yes, it does have alpha one activity, alpha two activity, beta one activity. beta-2 activity. I don't want you to look too much into that. I want you to primarily think about alpha-1 and beta activity. So, and even more specifically, I want you to think it has more alpha activity than it does beta activity.
So, norepinephrine is primarily an alpha-1 agonist, if you really want to think about it, but at higher doses, it does have a beta activity. So, let's think about what that looks like. like cardiovascular wise for this patient.
So because we have an SA node, we have an AV node, we have the bundle of his, we have the bundle branches, all that stuff, we will have an effect on that bundle system. But it's primarily at high doses. At very low doses, you don't get a ton of beta-1 activity, but you do have it there.
So it's important to remember that you do have beta-1 receptor activity. And because you can stimulate these beta-1 receptors, even though I'm gonna put like a little, a little kind of side note here. It is important to remember this. You get more beta-1 effect with higher doses of norepinephrine.
Very low doses, you don't get much of that effect. But because you get a beta-1 receptor stimulation, you can see a very mild increase in the heart rate. Very important to be able to remember that, okay?
But we're going to come back because that's not the net effect according to the textbooks out there. In true clinical reality, I can honestly say that I've never really seen some of the stuff that we talk about in the textbooks, but it is something that you do need to know for your boards. But norepinephrine at high doses generally can have more of a beta-1 receptor effect, which can mildly increase the heart rate.
All right, let's come back to a couple other things later. It also can act on the beta-1 receptors of the contractile cardiac muscle. So because it can do that, it can have a mild increase in the contractility. And if it does increase the contractility, it will also help to be able to slightly increase that cardiac output. But not a ton.
But it does give you a little bit of inotropic action and a little bit of chronotropic action. So you do see a small increase in heart rate, small increase in the contractility, very mild though. But you see this effect better when it's at high doses, okay?
The next thing that I want you to understand though is that we have alpha-1 receptors. And this is where you get that bang for the buck with norepinephrine, okay? Because we have these alpha-1 receptors, they are present on blood vessels, my friends.
And you're going to get the same exact effect here as you had when we talked about it with phenylephrine. So here's what I want you to think about. We bind on to these puppies. and we squeeze the heck out of the arteries, what's the overall effect here if we squeeze the arteries? Let's do it here in red, just so that we understand this.
If you stimulate the alpha-1 receptors, you're going to, on the blood vessels, the arteries, it's going to increase the systemic vascular resistance, and I mean really, I wanna put a double layer there, it's gonna really squeeze those arteries and really help to be able to increase your blood pressure. And if you really wanna think about this, guys, I think it's important to remember it's mainly the systolic blood pressure that we're really jacking up, I'm sorry, diastolic blood pressure, when you squeeze the vessels. Okay?
Because remember, diastolic blood pressure is dependent upon a lot of resistance, but it's also dependent upon other factors such as like the volume of blood which is actually present within the vessels. So blood volume obviously plays a role in diastolic blood pressure, but so does resistance. So if you really squeeze the heck out of these vessels, you're going to increase the blood pressure, but the one that you'll really increase here is the diastolic blood pressure, just like phenylephrine. Here's the other concept. You squeeze the heck out of the arteries, and you squeeze the heck out of the veins.
So if I stimulate these alpha-1 receptors that are present on the veins, I'm going to squeeze more blood into the right heart and then therefore increase venous return. If I increase venous return, I increase preload, stroke volume, and cardiac output. If I increase cardiac output, I could theoretically increase my blood pressure. But the blood pressure that I'm really increasing when I increase cardiac output is systolic blood pressure. So because of that, I will see an increase in systolic and diastolic blood pressure.
overall I'm gonna see an increase in the actual blood pressure okay that's one of the great things about this drug so because it really is utilized to increase your blood pressure and really squeeze on those vessels it's really good at hypotension related things so this would be one of the reasons why I would say that this is a great drug to utilize in situations like hypotension and when I say this I mean shock states so it's really really good in shock and really any kind of shock at that. I think the most commonly utilized one and most accepted one is septic shock, but it is a drug that can be utilized in hypotension. Okay, and it's because it really squeezes the heck out of those blood vessels, both veins and arteries, which both help to increase your blood pressure.
Now here's one of the things to think about with phenylephrine. Remember I told you that whenever you squeeze the heck out of these blood vessels, it does what? It activates the bare receptors. And the bare receptors send that information to the central nervous system, then they tell the vagus nerve to go and actually release acetylcholine, which does what? Creates a reflex bradycardia.
So because you squeeze the heck out of these vessels, what's a potential adverse effect that you can see, I'm going to do this here in blue, of squeezing these vessels? I can see what's called a reflex bradycardia. And I'm talking a really intense increase in the reflex bradycardia. So because of that, when you look at it, The direct effect that the beta-1 receptors have on the heart rate is very mild and then the effect that they'll have on really kind of a reflex bradycardia is relatively significant and so because of that we kind of look at this as a combination of these two. So you really kind of see actually when you combine both of them a little bit of a drop in the heart rate whenever you're on these actual drugs and so you can see a reflex bradycardia an increase of effect of actually I should draw here a reflex bradycardia, but you see a really intense effect of that reflex bradycardia.
And so because you drop the heart rate and you have an increased effect on the heart rate directly, when you look at the two of them combined, the two of them, if I have an increased effect of the reflex bradycardia, it might drop the heart rate down overall. And we'll talk about that when we talk about these charts over here in a second. But direct effect on beta-1 has a slight increase in heart rate, slight increase in cardiac output. The actual interesting thing is that it squeezes the heck out of the arteries and the veins, increasing your systolic and diastolic blood pressure. When you increase blood pressure, it creates a reflex bradycardia that when combined with the direct effect on the heart rate that the norepinephrine has, actually kind of leads to a slight decrease in overall heart rate with this drug.
The next thing that we want to talk about here with this drug is not only is it utilized in hypotension, like septic shock. And again, thinking about the slight reflex bradycardia here, there's one other thing that I want you guys to think about here. When we say it increases cardiac output, the direct effect, yes.
But there's one more thing that I want you to think about. When you squeeze the heck out of these vessels, so I really squeeze these arteries, right? I increase systemic vascular resistance. What does that do to the afterload? What does it do to the afterload?
So if I have a lot of resistance, my left ventral is going to have to pump a lot of that blood against that high afterload. So increasing afterload does what to your actual cardiac output or your stroke volume? It drops your stroke volume, which does what to your cardiac output?
It drops your cardiac output. So when you look at this combination of the cardiac output here and the cardiac output here, they kind of level each other off and you get kind of a baseline normal or no change in cardiac output with norepinephrine. Again, in true clinical reality, I can't say that I've really ever seen reflex bradycardia with a patient on norepinephrine or a drop in their cardiac output but these are things to consider for your actual board exams. So to sum it all of this norepinephrine has a very minor effect on beta-1 receptors. At higher doses we'll see a little bit of an increase in the heart rate and contractility.
Okay it's primarily an alpha so it's gonna do the same thing as phenylephrine squeeze the arteries squeeze the veins both of them increase systolic and diastolic blood pressure. The other thing is that because it squeezes the arteries, it may increase the afterload and then slightly drop the cardiac output. And so because you have a slight increase in contractility from the direct effect and a slight decrease in cardiac output due to the alpha-1 effect, you then may have kind of a normal or no change in cardiac output with this drug.
All right, but it really will increase your blood pressure, which is great in hypotension or shock. All right, now that we've covered norepinephrine, let's come down and talk about its brother and sister, which is going to be dopamine and epinephrine. Epinephrine and dopamine are very similar within their actual kind of like activity.
So they do have alpha and beta, but it's the exact opposite of norepinephrine. That's why I'm combining them and I'll add a little caveat to one of these, particularly epinephrine has another effect. But epinephrine prefers the beta over the alpha and then dopamine, obviously there's not just dopamine, you know, it's not just the primarily because dopamine is dopamine. You will get what's called a dopamine type of receptor. Obviously, that's its preferred one, but we're not talking about dopamine receptors.
We're talking about beta and then alpha receptors. So the overall theme here, if you look at this, is that epinephrine will prefer the beta 1 and beta 2 over the alpha, and dopamine will prefer the beta over the alpha. So because of that, what's the overall effect that they'll have on the cardiovascular system is important. So again, it's the same concept here.
I feel like we're really kind of beating a dead horse here is that we have the effect on the conduction system. It's going to, if you have the beta-1 receptors that are being stimulated, what's the overall effect? Two. One is you increase the heart rate, right? The other is you increase contractility with both of these.
As you increase contractility and you increase heart rate, the overall effect is that you're going to increase cardiac output. You're going to increase your cardiac output. Here's one big thing though.
because I actually want to like really, really show some support to these beta ones because it has way more beta effect than it does from norepinephrine. These are really going to increase the heart rate and really increase the contractility, which will really increase your cardiac output here. So I really kind of want to put an emphasis on that with these two drugs. Epinephrine and dopamine. Okay.
One of the big things to think about here is that dopamine and like the lower doses has more of a beta effect. Same thing epinephrine on the lower doses has a little has more of a beta effect as you increase. the dosage of epinephrine and norepinephrine, you start getting more of the alpha effect.
Okay, so that's an important thing to remember. So we talked about the beta effect. Let's talk about the alpha effect.
Now, here's where it's a little bit interesting. Very, very interesting. Interesting my friends.
Okay, so we're not going to focus too much on the alpha receptors in the veins. But if you remember, epinephrine has beta love and alpha love. There's beta two receptors and alpha one receptors present on the arteries.
Okay, which one does it prefer more? Well, we know that at low doses, it's going to prefer the beta two receptors. So let's actually put down here that if we had epinephrine, or we have dopamine, we We know the overall effect here. We know the overall effect is a combo between these two. So the combo effect between these two is that if it hits the alpha-1 receptor, it would actually cause at higher doses, at high, high doses, you would get a slight what?
At high doses, you may get a little bit of that systemic vascular resistance. You may get the alpha-1 activity there. But because we're talking about the lower doses, you're going to get less of the alpha-1 activity. So you're going to get a decrease in alpha-1 activity. And so because of that, you're going to get less of an effect of the vasoconstriction.
And because of that, you're going to get a decrease in systemic vascular resistance, and you're going to decrease the blood pressure. For this one, for the beta-2, you're going to have an increase in the beta-2 receptor activity, and that's also going to decrease the systemic vascular resistance and decrease the blood pressure. So it can actually decrease the patient's blood pressure.
Now that's an important concept to be able to remember here. Now, the thing where it can change a little bit, though, is that if I increase the dosage, then I might get a little bit kind of a change in that effect. The overall concept here is that I will see a decrease in the systemic vascular resistance with both epinephrine and dopamine.
With the slight caveat here that if I were to do the opposite situation here where I said I increased the dosage of the epinephrine, then I would actually see an increase in alpha 1 receptor and increase the dose of the epinephrine. in the systemic vascular resistance and an increase in the blood pressure. So as you increase the dosage of the epinephrine and the dopamine you'll hit more alpha receptors.
If you hit more alpha receptors they'll be good to increase your blood pressure. So only at high doses of epinephrine and norepinephrine will they have an effect on blood pressure. And that's why these can be beneficial in situations such as what?
They can be beneficial in situations like hypotension, but they have to be utilized in higher doses. So we can use these in hypotension, like a shock state, right? Maybe septic shock, maybe cardiogenic shock, but we can use them in shock if they're on high dose.
doses. With respect to the heart rate and the cardiac output, that's a different situation here. This would be good in situations where you really need to kick the heart up. So this could be used in acute heart failure.
Okay. And this also could be used in cardio genic shock. But the big thing here is because we can use it in acute heart failure and cardiogenic shock, that's because of the beta receptor activity. The effect that when we can use it in situations like hypotension, like septic shock, is really whenever we increase the dosage of the dopamine or we increase the dosage of the...
epinephrine because then you're going to get an increase in their blood pressure because you're going to get more of the alpha effect, more of the resistance, and then bump their BP up. So that's an important thing to be able to remember. So it's good in hypotension at high doses of epi and dopamine.
Okay, so the other thing here is that because you can also use it to increase heart rate, what else could you use dopamine for? And epinephrine. I think that's another thing to add on here. So not only can you use this to be able to increase, to be utilized to increase contractility, so let's actually put this all right here. So I think this is an important thing to think about.
Because it increases the contractility of the heart and the cardiac output, that can be used in acute heart failure and cardiogenic shock. But because it also increases heart rate, what would that be utilized in? Bradycardia. So we can utilize this in bradycardia.
And especially epinephrine, we can utilize this in cardiac arrest. Because it can get some heart rates for you. Okay, so think about that. Epinephrine and dopamine, because they have a lot of beta receptor activity, will increase the heart rate and increase the contractility.
Both of them will increase cardiac output. The reason we can use epinephrine and dopamine is bradycardia and epinephrine specifically for cardiac arrest. So remember that bradycardia can be utilized in both of these.
Both of these can be utilized in that cardiac arrest, more specifically for epi. It also can increase contractility, so you get more inotropic action, squeezing blood out of the heart in, acute heart failure, and cardiogenic shock. And it can also be used in hypotension, such as shock, maybe a septic shock. If you have higher doses of epinephrine, and higher doses of dopamine. Why?
Because at low doses, they have more of the beta-2 receptor activity, less of the alpha-1 receptor activity, so they actually can drop the pressure. But if you increase the dosage, you get more of the alpha, and then you can increase your blood pressure. So it's important to remember that. Okay, the next thing is that epinephrine specifically can also be utilized, because it binds on very, very powerfully to the beta-2 receptors here. So it also can stimulate the beta-2 receptors in the bronchioles.
And that can actually cause bronchodilation. And because it can actually cause bronchodilation, this can be really utilized in situations like asthma, this can be utilized in situations like COPD, and it can be utilized in situations like anaphylaxis, especially anaphylactic shock. And because of that, it's because it can actually bind onto the beta-2 receptors very powerfully, because it loves its beta receptors. And this is more particularly for epinephrine. So remember it can be utilized in asthma, COPD, anaphylaxis because of the bronchodilation, particularly epi.
Epi can also increase your heart so it can be used in bradycardia and cardiac arrest. It can also increase your contractility which can push more blood out of the heart. So that can be good in patients who have acute systolic heart failure or cardiogenic shock due to like an MI. It can also, if you give it high doses, squeeze the vessels and so it can be used in situations like hypotension, maybe related to septic shock, dopamine.
can also increase your heart rate, can be utilized in acute heart failure and cardiogenic shock, can also be used in hypotension like septic shock, but at high doses because it has more alpha receptor activity. But dopamine cannot be utilized in asthma because it doesn't really have much beta-2 activity as compared to epinephrine. So you're not going to see more of that bronchodilation effect there. All right, my friends, that covers these.
The last thing that we have to talk about is there's always this question that may come up on your exams about being able to interpret a graph between... norepinephrine, epinephrine, and isoproteranol. So I want to show you guys that graph and really kind of give you an explanation behind it so that you can ace that when the exam questions come up.
Let's talk about particularly how you are going to have to probably compare the hemodynamic or cardiovascular effects of norepinephrine versus epinephrine, which you can also almost apply to dopamine, because remember, epinephrine and dopamine have pretty much similar types of effects on their cardiovascular system or hemodynamic effects. isoproteranol because this kind of question or graphical representation may come up on the exam. So what we're really trying to compare between these is heart rate, blood pressure, systemic vascular resistance, cardiac output, MAP, and pulse pressure, and how norepinephrine, epinephrine, and isoproteranol affect all of these parameters.
So first things first, let's really put to practice everything that we talked about with norepinephrine. That's why I spent so much time on this so you guys can understand this kind of aspect of the the graphical representation. So when we think about norepinephrine, when we look at the graphical representation of it, what did I tell you was the big thing? Norepinephrine has a little bit of beta activity, a little bit of beta activity.
So because it has a little bit of beta activity, it might have a slight increase in the heart rate. At higher doses, you may see that more. But because we also have a lot of alpha-1 activity, we squeeze the heck out of the vessels, and when you squeeze the vessels, it creates a reflex bradycardia. So if you were to actually look at the graphical representation here, what you would see is, you would see that whenever you have norepinephrine and you start it, you would see a slight drop in the heart rate. And that is due to what?
Again, I really want you guys to understand this. What's the primary receptor that's responsible for this, what's called reflex bradycardia? This is due to the alpha-1 receptor. You do have a little bit of beta-1, right?
And so if you increased your beta-1, increased your beta-1, increased your beta-1, you might start seeing less of this negative inflection point due to norepinephrine, okay? This is the thing in true reality I can't say that I've ever seen. This is theoretically something that you can see with phenylephrine, but it's the same concept. Because norepinephrine, it is primarily an alpha-1 agonist, you theoretically, because it is an alpha-1 agonist, may see more reflex bradycardia. In true clinical reality, maybe the reason I don't see it that often is because...
patients that I have are usually on very high doses of norepinephrine. So I usually see more of a neutral effect of anything, a slight tachycardia from higher doses. But nonetheless, there the next thing is what kind of effect it has on blood pressure, but that includes systolic and diastolic blood pressure. So what I want you to see with this part of the graph is that when you look at it, you're going to see that the systolic blood pressure Pressure jumps up pretty high for norepinephrine and you're also going to see the diastolic blood pressure jump up pretty high with this and that's a really cool concept and the reason why the systolic blood pressure goes up is what reason?
It's there's two reasons. One is because you have so this would be the systolic blood pressure and this would be the diastolic blood pressure. They're both going up, right?
And with heart rate you're seeing a slight decrease in the heart rate. With the systolic blood pressure going up, it's for two effects. Remember, there's alpha-1 receptors on arteries and veins, and I can't stress that enough.
So because there is alpha-1 receptors that are present on veins, that's going to increase venous return, increase preload, increase cardiac output, and increase systolic blood pressure, because systolic blood pressure is dependent upon cardiac output. The other thing is that there's beta-1 receptors. And so there's a little bit of beta-1 receptor effect here. And so if you get a little bit of beta-1 receptor, you can increase contractility and increase cardiac output. So you also have a beta-1 receptor stimulation.
The two combos is what increases your systolic blood pressure. Two things, alpha-1 constriction of the veins and beta-1 stimulation on the contractile portion of the heart. That's the thing I want you to remember for this diastolic blood pressure, I was at systolic blood pressure.
The diastolic blood pressure is primarily dependent upon two things, the resistance and the blood volume. If I squeeze the heck out of the vessels, what happens to the resistance? It goes up. And that's what increases the diastolic blood pressure. So alpha-1 receptors will be the reason that we have an increased diastolic blood pressure, and that systolic blood pressure will be increased.
Why? Because of the two-fold thing. One is because of the alpha-1 receptors squeezing the veins, increasing return. and beta-1 receptors increase in the contractility of the heart.
Both of those things will increase cardiac output, which will increase systolic blood pressure. Pretty cool, right? Then the other thing here is that if you look for the systemic vascular resistance, you're going to see that the systemic vascular resistance in this one is insane, right?
It's going to have a high systemic vascular resistance. And the reason why it has a high systemic vascular resistance is because of the alpha-1 receptors. So systemic vascular resistance will be increased and that's primarily because the alpha-1 receptors are stimulated like a son of a gun and they're squeezing the heck out of vessels.
So you can actually make a correlation here that whenever systemic vascular resistance goes up, what does it do to the diastolic blood pressure? It increases it. So there is a correlation between these two points.
Now cardiac output, this is where it's a little bit interesting. Cardiac output happens to be neutral and I already explained why but I'm going to quickly do it again. Remember I told you that there is a Beta-1 receptor effect.
That when you stimulate that one, it increases cardiac output. So there's one reason that we could increase cardiac output. But we also said there's an alpha-1 receptor effect.
And if we stimulate that one, it increases afterload. And if we increase afterload, we drop cardiac output. You see how both of them end up canceling each other out?
And so if they cancel each other out, you get a kind of a neutral effect on cardiac output, which is pretty cool. MAP. MAP is extremely dependent upon diastolic blood pressure. If you guys remember the formula for MAP, in this case MAP is going to really shoot up.
But the concept behind this is that MAP is dependent upon diastolic blood pressure. So if we look at MAP, we know that it's extremely dependent upon diastolic blood pressure. And diastolic blood pressure is extremely dependent upon systemic vascular resistance.
So because of that, if resistance goes up, diastolic blood pressure goes up, and mean arterial pressure goes up. The reason why MAP is dependent upon diastolics is the formula. So MAP is equal to the diastolic blood pressure plus one-third of the pulse pressure.
If you drop your diastolic blood pressure, you're going to significantly drop your MAP. Okay? So a very important concept there.
And the last one is pulse pressure. So it's just looking at the difference between the systolic and the diastolic blood pressure. It does increase that pulse pressure difference a little bit because, again, I'm increasing my systolic but I'm also increasing my diastolic. So I will see somewhat of a mild increase in the pulse pressure difference there.
Alright, so this is kind of the overall hemodynamic effects that norepinephrine has. Reflex bradycardia due to primarily the alpha-1 reflex effect. Increasing systolic due to alpha-1 venal constriction and beta-1 stimulation. Increased diastolic blood pressure due to alpha-1 arterial vasoconstriction and Increasing the systemic vascular resistance due to alpha-1 arterial vasoconstriction, neutral cardiac output, increase in MAP due to massive systemic vascular resistance, and a slight increase in pulse pressure.
Epinephrine is another one that I want to talk about now. So this is a really interesting concept. So I want you to again think about heart rate, blood pressure, systemic vascular resistance.
Now we know that because epinephrine works on the beta-1 receptors on the conduction system. It's going to increase heart rate. So what would we expect?
We would expect an increase there. It also doesn't really have any reflex kind of bradycardia because it doesn't really have much alpha-1 receptor activity. So because of that, we will see an increase in the heart rate. And what's the increase in the heart rate due to? It is due to the beta-1 receptor stimulation.
We also will see an increase in systolic blood pressure because it's going to squeeze the heck out of the heart, right? And because it has an intense contractility, it'll increase cardiac output and increase systolic blood pressure because systolic is dependent upon afterload, is dependent upon preload, and dependent upon contractility. So if I really increase the contractility, I'm going to push more blood out of the heart and increase my systolic.
So I will see a pretty generous increase in the systolic blood pressure. The other concept here is that because we do see an increase in systolic blood pressure, That is due to what? That's due to the beta-1 receptor stimulation.
Here's the other one, and it's a mild one, but it's a slight decrease in the diastolic blood pressure. Slight decrease in the diastolic blood pressure. Why is there a slight decrease in the diastolic blood pressure? I want you guys to think about this. Remember, what are the two receptors that are controlling resistance?
So if I were to look at the resistance here, it should kind of correlate that. If I look here, I may see a slight decrease in my systemic vascular resistance because these kind of correlate with one another. We already know that.
So there will be a slight drop in systemic vascular resistance. And the reason for this is the same. That if we were to kind of look at this, there is a beta-2 receptor that is going to be more preferred and being stimulated than comparison to the alpha-1 receptor. So because you're hitting more of the beta-2 receptors, you're vasodilating and you have less alpha-1 receptor activity.
So, because of that, you're not going to get as much vasoconstriction. And so, it just dilates the vessels a little bit. And if you reduce the actual systemic vascular resistance a little bit, you're going to reduce the diastolic blood pressure.
Pretty straightforward, right? Now, in the same concept here, we already talked about norepinephrine that the MAPs were really, really increased here, right? The difference between the actual systolic and diastolic.
And the same concept here, the MAPs for epinephrine will actually be just slightly increased as well. So, let's talk about these factors here. Now, Cardiac output is actually going to be significantly increased because it squeezes the heck out of the heart and then increases your heart rate. So it's going to increase cardiac output. The MAP is only mildly increased.
You get a way higher increase in MAP as you have more alpha-1 receptor activity. But the MAP goes up just a little bit and the reason why is we already talked about how diastolic blood pressure is the big factor here right between MAP. So you're probably thinking Zach you said diastolic blood pressure if it's low it will drop the MAP. Yes.
That's not the only factor though. It's also the pulse pressure that's also a big factor in this as well. So in patients who had on norepinephrine, they had high diastolics and they had an increase in their pulse pressure. Well, that's an important thing to understand here that MAP is not just diastolic.
It's mainly dependent upon diastolic, but MAP is equal to the diastolic blood pressure plus one third of the pulse pressure. And the pulse pressure is the difference between the systolic and the diastolic blood pressure. Well, the pulse pressure was a little bit increased between norepinephrine. But in this situation, it's also a little bit increased. So there is a kind of a decent difference between the systolic and the diastolic.
So because there is a slight decrease in the diastolic blood pressure, but there's an increase in the pulse pressure, it kind of evens out to just be slightly increased. So it's just a slight increase in the main arterial pressure because you have a higher pulse pressure and just a slight decrease in the diastolic blood pressure. Okay, so that's the big concept behind this.
Now... The last concept is the pulse pressure. We already talked about this, that the pulse pressure is a little bit increased. Why?
Because I have an increase in my systolic blood pressure because of the beta-1 activity and I have a slight decrease in my diastolic blood pressure because of the beta-2 being way more potent effecting, so causing more vasodilation, and then less alpha-1, so less vasoconstriction, and that's going to reduce my resistance and drop my diastolic. So the difference between these is increased, and that's one of the reasons why we have a slight increase in the mean arterial pressure. With a primary effect being an increase in cardiac output, an increase in heart rate, an increase in systolic, slight decrease in systolic due to a decrease in resistance, and again, an increased pulse pressure, slight increase in mean arterial pressure.
But guess what? That mean arterial pressure will shoot the heck up if you have the patient going on higher doses of epinephrine. Why? I just want to write that down as a little caveat here, that remember, at high doses of epinephrine, you get increased alpha-1 receptor activity, which increases your... diastolic blood pressure because it increases your resistance.
So you will get higher maps with higher doses of epinephrine. All right, let's come down and talk about isoproteranol. All right, isoproteranol. So we know that it has a direct effect on the beta receptors, beta 1 and beta 2 receptors, whereas epinephrine had beta 1, beta 2, alpha, all those. So Isoproterenol is pretty much, I just want you guys, don't forget this, it's a beta 1 and it loves beta 1 just as much as it loves beta 2. Whereas norepinephrine and epinephrine, again, when we talked about those, norepinephrine more alpha than beta.
Epinephrine loves beta way more than alpha and it hits both beta 1 and beta 2. This has no alpha, so don't forget that. So heart rate hits the beta 1 receptors. What are we going to see? Bump.
Baboosh. So we see an increase in the heart rate, right? That's obvious. And the reason why we would see an increase in the heart rate is what?
Because of the beta-1 receptors. BP, what does it do? Well, it increases the contractility.
If it increases the contractility, it It increases the cardiac output that increases your systolic blood pressure. So we should see an increase in the systolic blood pressure. So systolic blood pressure should go up. And why should systolic blood pressure go up?
Because of the increased contractility due to increased beta-1 receptor activity. All right. Diastolic.
Diastolic is dependent upon alpha-1 receptors and beta-2 receptors. Does it have any alpha-1? No.
It only has beta-2. And it loves beta-2 just as much as it loves the actual beta-1. Epinephrine loves beta-1 receptors, loves them.
It has a little bit of love for the alpha receptors. This one's got no love for the alpha receptors and loves the beta-2. So it's going to do what to your diastolic? It's going to tank it. So it will tank the diastolic blood pressure.
Why will it tank the diastolic blood pressure? Because it hits only beta-2. If, my friends, you're only hitting the beta-2 receptors, what are you going to do?
You're going to cause intense vasodilation. So it's going to do what? It's going to stimulate those beta-2 receptors which are going to vasodilate the vessels. That's going to drop the resistance and that's going to drop the diastolic.
Because remember, diastolic is dependent upon volume and also dependent upon resistance. So, stolic is dependent upon cardiac output. Last thing here, we already know that if the diastolic is tanking, it's because the resistance is tanking.
So, the systemic vascular resistance is also going to be low. Why? Because of the beta-2 receptor stimulation. No alpha to even counteract anything. So because of that cardiac output, cardiac output is again dependent upon heart rate and dependent upon contractility, dependent upon preload, dependent upon afterload, all those things.
So those are the two things. So because of that, we know that it's increasing contractility and we know that it's increasing heart rate. So what happens to the cardiac output? Goes up. So we can say that the cardiac output, yes, it will go up.
The MAPS, going in the dump, right? Why? Remember, what does it do to the diastolic blood pressure?
It tanks the diastolic blood pressure significantly. Remember I told you the diastolic blood pressure is the primary factor here. It is to some degree the pulse pressure, right? Because we said that the formula is MAP is equal to the diastolic blood pressure plus one third of the pulse pressure, but it's a third of the pulse pressure.
So you can see how diastolic is the way more important factor here. In epinephrine, it's slightly decreased the diastolic and just increased the pulse pressure. So it was enough to kind of counteract it to get it up just a little bit. In this situation, we take a dump on that diastolic blood pressure.
and we only have a little bit of an increase in the pulse pressure, but it is a significant dump in that diastolic. So you see if we dump that diastolic how it's going to really, really drop the mean arterial pressure. So diastolic is the primary factor that affects the mean arterial pressure. You dump your diastolic, you'll drop your MAP. If you have a little bit of a pulse pressure increase, yes, it will help the MAP, but it's only a third.
You see how diastolic has a way more profound effect on MAP than pulse pressure does. For epinephrine, it was able to increase the pulse pressure enough. to counteract the slight decrease in the diastolic.
And isoproteranol, it's going to have an increase in pulse pressure, but it's not going to be enough for that huge jump and drop in the diastolic blood pressure. So MAPS will drop. Pulse pressure, it's going to be big.
They're going to have a huge increase there, right? Why? Look at this thing.
Look at the huge difference between these two. So yes, you're going to see that the MAPS will drop in this situation. And it's because their pulse pressure, yes, it is a little bit increased, but their diastolics are super, super low. So my friends, this covers our... whole topic and lecture on adrenergic agonists.
I hope it made sense and I hope that you guys enjoyed it. Let's do some cases and finish this video off strong. All right, my friends, we're going to talk about some cases now with the adrenergic agonists. All right, so let's get to it.
First one here. We talk about these particular drugs, which of the following is correct regarding adrenergic neurotransmission? So norepinephrine is the major neurotransmitter released from synaptic nerve terminals.
That's definitely true, especially the postganglionic ones. Norepinephrine is mainly released from the adrenal glands. It is released from the adrenal glands, but it's also released from the synaptic nerve terminals. That's not necessarily true. Tricyclic antidepressants and cocaine prevent the release of norepinephrine from nerve terminals.
It's actually the exact opposite in this situation. Generally, cocaine would actually increase the release of norepinephrine from the nerve terminals. And then monoamine oxidase converts dopamine to norepinephrine in the nerve terminal. That's actually not true.
Monoamine oxidase actually... It helps to break down norepinephrine into inactive metabolites. So that's also not correct.
So the only one that's actually completely correct is A. Norepinephrine is the major neurotransmitter released from the synaptic nerve terminals, especially the postganglionic ones. All right, which of the following adrenergic drugs is used in the treatment of overactive bladder? Okay, well, again, you got to think about the bladder here for the adrenergic system. So we have the sphincter muscle, which is alpha-1 adrenergic receptors.
But we also have the detrusor muscle, which is going to be the beta-3 adrenergic receptor. So if we want to stimulate the beta-3 adrenergic receptors, that'll inhibit the urinary contraction, which is whenever patients have increased urinary spasm or contractions, frequency, urgency, that would be the best situation. That drug that is actually going to work at the beta-3 receptor to inhibit the detrusor muscle is going to be myribegron.
Because we already know that epinephrine is particularly beta-1, beta-2, alpha. Dobutamine is primarily beta and phenylephrine is primarily alpha. So none of these have a true beta-3 activity. Which of the following classes of adrenergic agents has utility in the management of hypertension? So alpha-1 agonists, that would actually increase your blood pressure, so we don't want that.
Alpha-2 agonists, that's actually interesting. Remember, we have clonidine and then the other one I talked about briefly on the whiteboard, alpha-methyl dopa, which is safe in pregnancy. These are actually good as hypertensive agents because, again, they help to be able to prevent the release of norepinephrine from the nerve terminals, the presynaptic nerve terminals, which, again, control the sympathetic tone to the heart, the blood. blood vessels.
And so because of that, you should get vasodilation, decrease heart rate, decrease contractility. And so yes, alpha-2 agonists, definitely. Beta-1 agonists, it's going to increase heart rate, increase contractility. That's not good.
And beta-3 has really no effect on their cardiovascular system. So it has to be alpha-2. Which of the following is correct regarding the responses mediated by adrenergic receptors?
So stimulation of alpha-1 increases blood pressure. That's definitely true because it squeezes the heck out of the vessels and increases the resistance, increases the BP. Definitely true.
Stimulation of sympathetic presynaptic alpha. alpha-2 receptors increases norepinephrine release. It's actually the opposite. When you hit the alpha-2 receptor, it inhibits the further norepinephrine release.
So that's not correct. Stimulation of beta-2 receptors increases heart rate. That's not true.
It's actually beta-1 receptors. And stimulation of beta-2 receptors causes bronchoconstriction. That's not correct.
It actually causes bronchodilation. So with that being said, A is the only correct answer. An asthma patient was given a non-selective beta agonist, meaning a binom to beta-1 and beta-2, to relieve bronchoconstriction. We which adverse effect would you expect in this patient? So if I give a patient a non-selective beta agonist, that means that they can bind on to the beta 1 receptors, increase the heart rate, increase the blood pressure.
They can also bind them to the beta 2 receptors, which helps to be able to cause bronchodilation, which is, again, the primary problem here is that we want to allow for them to have bronchodilation because they're obviously bronchoconstricted in this asthma situation. But because of that, we're also going to hit other beta 2 receptors. So we may see potentially an increase in their blood glucose levels.
We may see a little bit of vasodilation. dilatory effect that actually supplies the skeletal muscles, but that's mainly to increase blood flow to the skeletal muscles. We also may see other effects, particularly again on other organs.
But I think the big one here is you can obviously see based upon this question here is that it's looking at the beta one receptor effect. So if the beta two receptor effect is mainly to cause bronchodilation because they're bronchoconstricted, what's the beta one that's actually causing the problem here? So would it be bradycardia? Well, no, it would actually be tachycardia.
So tachycardia is definitely likely. Plus, if I hit the beta-1 receptors, I'm likely going to increase cardiac output. I'm going to increase the contractility of the heart rate because I'm increasing the heart rate.
I'm increasing the contractility. I'm going to increase cardiac output and increase the patient's systolic blood pressure. Now, remember, we do hit a little bit of the beta-2 receptors, so it may cause a little bit of small drop in the diastolic blood pressure, but the mean arterial pressure, the actual measurement of perfusion should be slightly increased.
diastolic only drops just a teensy bit, but their overall mean arterial pressure should be slightly increased. So because of that, I wouldn't say that hypotension is actually going to be the problem here. I would say that tachycardia would be, and it definitely wouldn't cause worsening bronchoconstriction because you're hitting the beta-2 receptors.
So it should bronchodilate. So I'd say the answer here is definitely tachycardia. All right, next one.
A 22-year-old male is brought to the emergency room with suspected cocaine overdose. Which of the following symptoms is most likely in this patient? Well, remember, cocaine is going to inhibit the normal...
norepinephrine from the presynaptic nerve terminals. It also has a little bit of an effect on the alpha receptors, but primarily, primarily the effect of cocaine is to be able to increase the release of norepinephrine from the presynaptic nerve terminals. So because of that, whenever that happens, one of the big, big effects here is that it increases the patient's heart rate. It increases the patient's contractility.
It actually can cause an intense vasoconstrictive response though. That's the big thing is it really constricts the heck out of those vessels because you're releasing lots of norepinephrine. So because of that, whenever you squeeze those vessels, you increase resistance, it increases the systolic blood pressure. And so these patients would be extremely hypertensive as well. So I'd say hypertension would be the primary big thing that you would see in these patients.
All right. So that covers these cases that we talked about with adrenergic agonists. I hope it made sense.
I hope that you guys liked this lecture and learned a lot. As always, until next time.