Understanding Adrenergic Agonists: Mechanisms, Effects, and Clinical Uses

what's up ninja 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 to really support us if

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section but most importantly subscribe also you want some awesome notes illustrations to follow along with me

during this video go down the description box below we'll have a link to our website where we have all these

amazing illustrations and notes there to check out 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 zoom in with like 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 drug 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 noro

so this is the basic pathway of how we synthesize norepinephrine so dependent 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 going to abbreviate that as c a v this is a voltage-gated calcium channel we're

going to stimulate this puppy and once it opens we're going to 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 neural epinephrine 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 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 into the synapses it has to

diffuse across the synaptic cleft once it diffuses across the synaptic left it's going to then bind onto

particular receptors and depending upon what target organ or what type of like tissue this receptor's 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 on to 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 3 beta receptors we have beta 1 receptors beta2 receptors and a modified beta2 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 on to alpha-1 adrenergic receptors i want you

to remember it workstar was 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

ionocytotriphosphate if you guys remember that one and the other one is called diacetylglycerol

and basically what ip3 did is it really helped to increase calcium levels in particular smooth muscle cells and

really when that calcium increase 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 pathway for the 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 a 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

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 is 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 methyl transferase 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 methyl transferase and then it gets broken down into a metabolite

and this is a 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 etc we also know that when norepinephrine's done exerting

its effects it can get metabolized via this enzyme catechol motor transferase 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've got to 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 going to 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 percent 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 cataclysm 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 a norepinephrine 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 released from this neuron so it's important to be able to remember that i

just want to talk about it 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 this system yes we

are but we have to build our foundation 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 agonist 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 going to breathe it here i'm going

to draw in red this gets into the circulation and it binds on to 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 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 multiple receptors and we'll talk about that a

little bit later you can have what specifically called selective agonists called alpha one beta one 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 there was 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 going to have

more of that doesn't get broken down i'm going to have more more norepinephrine right i'm going to

work to maybe inhibit this transporter because now i'm not going to recycle it i'm going to 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 it might mean mono-main 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 onto 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

but 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 sector 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 okay 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 pseudo

ephedrine and this one is utilized as a nasal decongestant because

the basic concept is that you when you cause it binds primarily onto what's called alpha receptors or increases

norepinephrine to bind onto alpha-1 receptors so a 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 two the ones that bind in the beta one the ones that actually have a little bit of equal beta

one and beta two then beta three and then we'll cover the ones that are just polyamorous and they bind to all of them

they can bind a little bit 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 on to an alpha one receptor

we know that it'll increase the inner cycles triphosphate and diacetyl glycerol 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 right 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 of the around the rectum anal area as well as around the sphincter on 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 two's 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 generally 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 and agonist

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 like spokes and whenever they contract

they actually pull the iris like outward 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 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 pre-synaptic

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 these are really scattered

throughout you know 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 et cetera

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 hyper polarizes the neuron and inhibits it from releasing more norepinephrine so the overall effect

here is that you'll actually reduce neuroepinephrine 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 your pancreatic area and these pancreatic

beta cells do have lots of alpha-2 receptors on them and whenever norepinephrine epinephrine or these

drugs bind onto them what it does it actually inhibits the secretion of insulin and because you inhibit the

secretion of insulin you don't put insulin into you 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 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

all right the contractile portion of the cardiac muscle remember what i told you beta 1

receptors increased cyclic amp and increase contraction that's one of the 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 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 juxta

glomerular 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 you know angiotensin wanda and then convert

eventually angiotensin to 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 ran an angiotensin aldosterone system activity is increased the next thing is if you have a drug

that binds onto beta2 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 effector 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 increasing 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 bronchioles there's smooth muscle

within these bronchials you guys know that right that whenever we actually took like a cross section of this

bronchiole 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'll 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 be able to

get more air flow in and out of the lungs which is important so 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 we have beta two receptors on this puppy here beta2 receptors on this one now there

here's another one you have another type of cells 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 that

whenever you hit the liver then everything you think about this thing about sympathetic surgery

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 in 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

and this is an important concept because this may be important whenever a mother is

maybe not close to the time period that we want to deliver the baby maybe they're pre-term 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 pre-term 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 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 receptors present

on the detruster muscle and whenever this is on the detruster 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 detruster this puppy ain't going to contract you don't

want to 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 all right so now alpha one agonist whenever

we have a particular direct agonist this is a drug that's going to bind on to that alpha one receptor when they bind

into the alpha one receptor that we're 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 uh 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 point

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 interceptors 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 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 uh whenever they're undergoing a procedure so they're peri procedural or parry kind

of like surgical around that time peripery operative they get a little bit of blood pressure that's dropping from

you know 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 metadrine so midadrene is a really cool one but i

think one of the benefits and why i wanted to mention here the effect that alpha one receptors have on the veins is

because midodrin so we've got to actually write this one out here metadrine

is going to be a really cool one because what mediatrine 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 redu

improve the venous return to the right heart why is that important in elderly individuals whenever they maybe go from

a seated position or 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 mediadrin happens to be very

very good in a specific subtype of hypotension so phenylephrine is good generally especially in like

you know perioperatively very commonly utilized but also in shock states we can use this in septic shock

midi drain 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 vinyl 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 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 pupils 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 it's you're trying to dilate the people 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 all right 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 going to 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 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 oxymetazoli 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 con a 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 then all of a sudden you just stop it you can actually have a rebound congestion where

then all of a sudden you stop squeezing them vessels they open up and then the secretions actually continue so just

watch out for a 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 bare receptors around the aortic and the carotids and

they pick up whenever there's a big rise in blood pressure and if you remember when they incr 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 blood pressure is 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 create 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 blood

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 agonist all right so the next one is the alpha 2 agonist 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 they have a sympathetic effect if you will in other words they increase the heart they

increase the blood pressure they're producing all of those effects with these drugs they're actually technically

sympatholytics which is weird but because we put them in an agonist 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 on to 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 what's the overall effect that it should have on your overall level of alertness and cognition it should make

you like like ready you know you can 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 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 so 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 this kind of pathway is

occurring a lot within the 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 right they affect a lot of different areas of our body okay 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 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 in the heart so less norepinephrine being released on the heart also can do what

it can decrease the heart rate and it could 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 in 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 quantity and there is another one that is actually relatively interesting as well is called

alpha methyl dopa this also can kind of work via this pathway so because of that i want us to

primarily focus on quantity 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 a 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 attention 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 kind of 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 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 to 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 their respiratory rate and depth

down a little bit helps 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 going to 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 kind of chills them out especially in diseases like adhd you also can have a lot of

norepinephrine that could potentially being 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'd be impo

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 can 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 withdrawal causes them to have the exact opposite effect agitated delirious

on edge maybe aggressive causes them to have an increased respiratory rate and depth causes them have an increased

heart rate increase 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

in 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 as a part of this category here is alpha methyl dopa

i'm not going to go over too much just remember the 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 hydrolyzing libado law and nevada pain

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 agonist so whenever we talk about beta one agonist remember what was the overall effect that it had

it worked particularly in two ways it worked on the nodal system so worked on the sa node av node bundle of hiss the

bundle branches all those beautiful things to be able to do what increased 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 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 want to 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 and 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 failure in 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 want to 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 going to utilize a lot of energy and squeezing the heart time

and time and time and time again is going to increase its demand right so if you squeeze and squeeze and squeeze that

hard you're going to increase its demand if a patient has underlying coronary artery disease right

and they have very decreased oxygen supply what do you think is going to happen if you have an increased demand

and less supply you're going to 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 agnes

now the reason why i wanted to mention this one is because this drug is really unique and this drug is called

isoproterenol also known as isopropanoly so isoproterenol 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 beta2 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's a primary beta 1. isoproterenol 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 the butamine it just

primarily loves beta 1 and almost has no love for beta 2. that's why i want you to just primarily think about it as a

beta 1. isoproterenol though it has an equal affinity for beta1 and beta2 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'd be great in situations like bradycardia i had a

cardiac icu nurse once telling me that isoproterenol can get the heart rate out of a stone okay so it's a really really