Transcript for:
Adrenergic Agonists: Synthesis, Effects, and Clinical Applications

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 you guys do like this video if it makes sense you enjoy it please hit that like button comment down in the comment 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 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 here's the downside this is why you'd 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 here's a potential downside of that with isoproterenol has beta2 receptors what's two 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 two receptors here and when you hit those beta two receptors so this one's all beta one these are all beta one receptor effect this is beta two 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 if they're already hypotensive you don't want to make them even worse okay you would think maybe it could be a drug that could possibly add on to utilizing acute heart failure and utilizing 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 isoproterenol 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 isoproterenol 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 in cool and i didn't put the diagram in here but we also know that isoproterenol 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 bronchials and so what other disease state could i do that would induce if i induce bronchodilation 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 isoproterenol 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 and 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 beta2 receptors it may have a small effect of 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 talk about the primary beta two agonists now all right so next thing is the beta two agonist now with beta2 agonists 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 gonna be really really good at being able to if you have beta2 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 would be very very good indications all right for a beta 2 agonist now the question 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 has a beta2 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 acting so we could utilize it in asthma and copd as an acute treatment the other ones would be like the long acting there's there's a lot of them i'm just going to write down one like cell meter all but there's formoterol there's vlan there's so many different things okay 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 all right so albuterol more for prn type of situations acute exacerbations salmeterol for motorol those kinds of things that's going to be more for the long-acting chronic management of asthma at 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 and 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 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 ter-butylene 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 and patients who have hyperkalemia now you're like what in the heck let me explain when norepinephrine and epinephrine bind onto receptors they can bind onto beta-2 receptors right now what happens is albuterol when it binds onto beta-2 receptors on different cells what it can do is 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 a 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 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 beta2 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 all right so that's the beta two agonists now the last thing i want to talk about here is the 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 with if it's 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 beta2 agonists is that you also have beta-2 agonists wear 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 increased 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 muscles we have these things called muscle spindles and these muscle spindles have beta2 receptors and whenever they are tense it increases a lot of the actual sensory efferent pathways so the afferent efferent pathways to the muscle and causes it to tense up when it tenses up you can get a little bit of a trimmer effect so because of that i have lots of beta2 receptors here on this muscle spindle and that is going to increase the afferent efferent signals to the muscle and this can actually cause tremors 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 is very very minor is that beta-2 agonists they have a teensy tainty 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 agonist 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 alphabet i kind of give you a little bit of a falsehood but we're going to talk about that in just a second but with beta 3 agonist what i want you to remember for this one is that they right onto the beta 3 receptors on the 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 the trusser 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 bagron so don't forget that one all right 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 is 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 two activity i don't want you to look too much into that i want you to primarily think about alpha one 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 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 going to 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 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 and 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 don't have 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 1 receptor effect which can mildly increase the heart rate all right let's come back to another a couple other things later it also can act on the beta 1 receptors of the contractile cardiomy 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 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 one 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 onto these puppies and we squeeze the heck out of the arteries what's the overall effect here if we squeeze the artery let's do it here in red just so 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 want to put a double layer though it's going to really squeeze those arteries and really help to be able to increase your blood pressure and if you really want to 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 going to 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 and increase the 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 kind of leads to a slight decrease in overall heart rate with this drug all right the next thing that we want to talk about here with this drug is not only is it utilizing 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 it does 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 ventricle 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 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 summate 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 going to 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 you because you have a slight increase in contractility from the direct effect and then a slight decrease in cardiac output do 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 normal epinephrine 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 the these particularly epinephrine has another effect but epinephrine prefers the beta over the alpha and then dopamine obviously there's not just dopamine rece 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 okay 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 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 at 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 my friends okay so we're not going to focus too much on the alpha receptors and the veins but if you remember epinephrine has beta love and alpha love there's beta 2 receptors and alpha 1 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 2 receptors so let's actually put down here that if we had epinephrine or we have dopamine 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 alpha one activity there but because we're talking about the lower doses you're gonna get less of the alpha one activity so you're gonna get a decrease in alpha one activity and so because that you're going to get less of an effect of the vasoconstriction and because that you're going to get a decrease in systemic vascular resistance and you're going to decrease the blood pressure right 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 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 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 cardiogenic shock but the big thing here is because we can use an 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 their blood pressure because you're going to get more of the alpha effect more of the resistance and then bump their bp up that's an important thing to be able to remember so it's good in hypotension at high doses and 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 an epinephrine i think that's another thing to add on here so not only can you use this to be able to increase uh to be utilized to increase contract contractility so let's actually put this all right here so i think it's an important thing to think about because it increases the contractility of the heart in 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 then bradycardia so we can utilize this in bradycardia and especially epinephrine we can utilize this in cardiac arrest because they 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 could 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 beta2 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 rate 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 may be 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 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 isoproterenol 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 and then isoproterenol 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 isoproterenol 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 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 bait 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 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 increase your beta 1 increase your beta 1 increase 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 antagonist you theoretically because it is an alpha and agonist may see more reflex bradycardia and 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 if anything has 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 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 one receptors on arteries and veins and i can't stress that enough so because there is alpha one 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 one constriction of the veins and beta one stimulation on the contractile portion of the heart that's the thing i want you to remember for this diastolic blood pressure it's a solid 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 one receptors will be the reason that we have an increased diastolic blood pressure and the 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 increasing 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 one 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 after load 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 all right 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 vino 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 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 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 the solid blood pressure because the stomach is dependent upon afterload it's dependent upon preload and depend 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 straight forward right now in the same concept here we're going to talk 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 wave higher increase in map as you have more alpha one 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 maps 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 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 mean 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 affecting 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 and increase in systolic slight grease decreases systolic due to a decrease in resistance and again an increased pulse pressure slight increase in mean arterial pressure but guess what that mean or tear 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 now 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 talk about isoproterenol all right isoproterenol so we know that it has a direct effect on the beta receptors beta 1 and beta2 receptors whereas epinephrine had beta 1 beta 2 alpha all those so isoproterenol is pretty much i just want you guys don't don't forget this it's a beta 1 and it loves beta 1 just as much as it loves beta 2. all right 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 what increases the contractility if it increases the contractility it increases the cardiac output that increases your systolic blood pressure so we should see a increase in the systolic blood 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 and it has a little bit of love for the alpha receptors this one's got no love for the alpha receptors and loves the beta2 so what'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 two if my friends you're only hitting the beta two receptors what are you gonna do you're gonna cause intense vasodilation so it's gonna 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 neurodiastole is dependent upon volume and also depend upon resistance systolic 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 beta2 receptor simulation no alpha do i even counteract anything so because of that cardiac output cardiac output is again dependent upon heart rate and depending 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 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 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 isoproterenol 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 look at that look at this thing look at a 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 increase 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 terminal so that's not necessarily true tricyclic antidepressants in 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 helps to break down norepinephrine into inactive metabolites so that's also not correct so the 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 receptors so if we want to stimulate the beta-3 adrenergic receptors that will 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 detrosor muscle is going to be myrabegron 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 one agonist um that would actually increase your blood pressure so we don't want that alpha two agonists that's actually interesting remember we have clonidine and then the other one i talked about briefly on the white board 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 vessels and so because of that you should get vasodilation decrease heart rate decrease contractility and so yes alpha 2 again is definitely beta 1 agonist it's going to increase ra 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 into the vessels and increases the resistance increases the bp definitely true stimulation of sympathetic pre-synaptic alpha-2 receptors increases norepinephrine at least it's actually the opposite when you hit the alpha-2 receptor it inhibits the further norepinephrine release so that's and that's not correct stimulation of beta-2 receptors increases sorry that's not true it's actually beta-1 receptors and stimulation of beta-2 receptors causes bronchial constriction 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 to beta 1 and beta2 to relieve bronchoconstriction 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 onto the beta-1 receptors increase the heart rate increase the blood pressure they can also bind 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 beta2 receptors so we may see potentially an increase in their blood glucose levels we may see a little bit of vasodilatory 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 1 receptor effect so if the beta 2 receptor effect is mainly to cause bronchodilation because they're bronchoconstricted what's the beta 1 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 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 okay the 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 proper constriction because you're hitting the beta2 receptors so 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 remember cocaine is going to inhibit the 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 terminal 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 agonist i hope it made sense hope that you guys liked this lecture and learned a lot as always until next time [Music] you