iein engineers in this video we're gonna talk about alpha blockers let's go and get started iein engineer so that's go ahead and talk about the mechanism of action of alpha blockers alpha blockers their mechanism of action is actually relatively simple and these kinds of drugs they don't have a large variety of indications it's pretty narrow their range of therapeutic action but we're gonna talk about them anyway because they are utilized in certain situations all right alpha blockers what do they do they block the alpha receptors there's two types of alpha receptors right alpha 1 and alpha 2 alpha 1 are primarily gonna be the ones that we talked about in this video but we will we will mention one of the alpha 2 receptors okay alright so the first thing we have to realize is the alpha 1 receptors that are present on the vascular smooth muscle right you know that you have alpha one receptors here right alpha one receptors that are present on your vascular smooth muscle now what happens is you guys know that epinephrine or norepinephrine isone or epi or epi can act on these alpha 1 receptors and when they act on the alpha 1 receptors they promote vaso constriction and whenever there's vasoconstriction what does that do that increases the total peripheral resistance and that does two things that increases after load which puts a lot of stress on that heart and it also increases the blood pressure leading to hypertension right and that can be a problem over a long period of time well if we give an alpha blocker what they're going to potentially do is is basically block epinephrine or norepinephrine from being able to bind onto these alpha 1 receptors if you block the alpha 1 receptors what happens well then there's no vasoconstriction what's the opposite of vasoconstriction vaso dilation so now there's going to be vaso dilation now whenever you vasodilate a vessel what happens well that does what it decreases the total peripheral resistance right so you decrease that total peripheral resistance and as a result that does two things that decreases the after load which is that stress on the heart as well as it decreases the blood pressure so this would be good and conditions like hypertension pretty simple stuff right all right that's one of the things I want you to realize the other thing is that there's alpha one receptors that are located on the prostatic smooth muscle and there's also alpha one receptors which are located here on the internal urethral sphincter so again what is this muscle right here called it's called the internal your wreath role sphincter and this is a smooth muscle structure and there's also some prostatic smooth muscle around here too that helps to squeeze some of the prostatic fluid into the prostatic urethra which is a part of semen right all right so what does it do it binds onto you know epinephrine and norepinephrine right what do they usually do well epinephrine and norepinephrine they can bind on to these alpha one receptors on the prostatic smooth muscle and they can induce prostatic muscle contraction and that prostatic muscle contraction can help to cause increase in prostatic fluid and that's a component of ejaculate so in ejaculatory mechanisms the sympathetic nervous system is actually important you could remember parasympathetic for erection point and sympathetic shoot so it's important for the ejaculatory response because prostatic fluid is a component of the ejaculate or the semen right it's the seminal fluid plus the sperm the other thing that the alpha 1 receptor whenever there's epinephrine and norepinephrine happens whenever it binds here is it actually causes this internal urethral sphincter to really squeeze really tight and when it causes that internal urethral sphincter to contract what does that do them if you squeeze the sphincter are you gonna be able to allow for urine which is in the bladder to exit out through the urethra no because it's squeezing it it's blocking it from exiting so because of that that can lead to urine retention and this should make sense with the urine retention aspect because in a fight or flight situation you're not going to be worried about making urine in that space situation now take the alpha blockers what do they do well the alpha blockers are gonna do what if we give an alpha blocker it's going to relax the internal urethral sphincter if you relax the internal urethral sphincter what happens then it's going to allow for urine flow so it's gonna help with urine flow and that's going to help to eliminate situations of urinary retention like in what situations you know there's people who have big old prostates the size of grapefruits right and because of that they really kind of obstruct the urinary outlet what you can do is you can actually kind of help by relaxing that internal urethral sphincter and allowing for some of the urine to pass in patients who have B pH so not only these drugs good and maybe second-line and hypertension to drop pressure but they can also be utilized in patients who also maybe have a concomitant benign prostatic hypertrophy or some type of urinary retention cause of some other type of situation and to help them to get some of that urine out particularly in things like B pH all right now the next thing we should know is these types of alpha 1 receptors right they're specific drugs that only selectively bind to them and inhibit that site those are called selective alpha blockers so we have what's called selective alpha one blockers and what are the names of these drugs one is called terrazzo syn the other one is called docks as Osen the other one is called prazosin and the last one is called tamsulosin and this one's probably one of the more common ones that have hurt I heard of right now these drugs only bind and inhibit the alpha one receptors that's important to remember they don't bind to the alpha 2 receptors now to look at their mechanism of action particularly on the smooth muscle and how they promote relaxation of the smooth muscle let's go ahead and zoom in on a smooth muscle cell how do these alpha blockers and we're gonna talk about non-selective alpha 1 and alpha 2 blockers in a second they both can perform this type of function but I want you guys to understand just in general with respect to primarily the Selective alpha blockers how do they relax that smooth muscle of like the internal urethral sphincter or how do they relax these smooth muscle within the vascular system alright so you guys know that within smooth muscle cells you have these channels these calcium ion channels and what happens is calcium can enter through these channels right and what happens is this calcium what will it'll do is it'll bind with a specific protein called Cao module in' which is a protein inside of this actual cytoplasm whenever calcium calmodulin combine they make this molecule called a cam kinase and then cam kinase will phosphorylate a molecule called myosin light-chain kinase if we put a phosphate on myosin light-chain kinase it activates this myosin light-chain kinase and then what he does is he comes over here and he puts phosphates on these myosin heads and whenever you phosphorylate the myosin heads it causes them to become active and buying into the actin site and because of that it induces muscle contraction now let's take it even a step further than that on top of that if you use drugs like well let's say be more specific you have epinephrine and norepinephrine and then you have these alpha one receptors that are present on them remember we said that they generally Douce smooth muscle contraction how do they do that you know when it binds on to these alpha one receptors it can bind onto a g-protein all right and there's g-protein what it might do is it might actually help to become active because what happens is when a g-proteins bound it takes and it binds gtp and it gets rid of GDP and it becomes active and it moves and it might stimulate some type of effector enzyme let's say in this case we say this effector enzyme is maybe adenylate cyclase or maybe its phospholipase alright see whatever it is we're going to activate this effect or enzyme and this effector enzyme it might either take ATP if it's a dental excite place and convert it into cyclic AMP E or it might activate another pathway you know in certain in certain situations if it's not a dentally cyclase and it's phospholipase C it might be taking pip2 and breaking that down into da g and i p3 either way the overall goal is the same sick game P is going to activate a protein kinase and this protein kinase will help to phosphorylate the myosin light-chain kinase or i p3 will bind on to or you know da g actually can help to make protein kinase or i p3 will increase calcium by causing what that's smooth endoplasmic reticulum in these cells to release calcium out either way the overall result is the same there's an increase in calcium or there's an increase in the activity of the myosin light-chain kinase and an increase in muscle contraction so we're gonna amplify the Rd normal effect if we give an alpha blocker what is it gonna do it is going to inhibit the action of epinephrine onto this which is either going to decrease the conversion of ATP into cyclic AMP II and decrease protein kinase production or decrease the degradation pip2 into daj which decreases protein kinase or decreases ip3 production which decreases calcium regardless if you decrease protein kinase activity you decrease the phosphorylation of myosin light-chain kinase and if you decrease the calcium you lead to decrease cam kinase and decrease activation of the myosin light-chain kinase that means less phosphorylation reactions and that means a decrease in muscle contraction if there's a decrease in muscle contraction what do we call that well now it's called smooth muscle relaxation it's going to relax and that is called if it's a smooth muscle right if it's gonna be for the actual vascular smooth muscle that might lead to vasodilation but either way the overall effect here is we're gonna say decrease muscle contraction will lead to smooth muscle relaxing okay now the other drugs that we have to focus on here are actually important because they're non selective alpha blockers so they can by they can block alpha 1 and alpha 2 before we talk about something here with this smooth muscle cell I want to mention them okay so again you have what's called non selective alpha blockers and these are specific to alpha 1 and alpha 2 these ones are very interesting and they're called one is called phenoxy Benza mean and this is interesting because this is actually we're gonna see i'm gonna explain the mechanism a little bit later this is called an allosteric inhibitor you guys are like whoa they're taking me back to biochemistry right now we are and that's important we'll talk about what that means in just a second okay the other type of non-selective alpha blocker is called phentolamine it's called phentolamine and phentolamine it does not lie on to the allosteric site it is an active site inhibitor okay and we're gonna explain what that means okay here we have a smooth muscle cell we've already talked about how the alpha one the more specific ones right which is the terraza send oxytocin processing tamsulosin how they inhibit that alpha 1 receptor we talked about that what we want to know now is what's the big difference why is zach stressing so much about how non-selective alpha blockers work through an allosteric and active site let me explain so here we're gonna have phenoxy ben's amine right here's our receptor we have two sites of the receptor here on this point here which I'm kind of highlighting that's the catalytic site or the active site that's where the substrates gonna bind which can either be epinephrine norepinephrine whatever right here is going to be another site called the allosteric site it's another part of the enzyme or receptor which is not the active site phenoxy bends I mean particularly binds right here into that allosteric site and it changes the shape when it changes the shape of this catalytic site guess what cannot happen now epinephrine and norepinephrine won't be able to bind here isn't that cool if I change the site of that active site now the epinephrine and norepinephrine no matter their concentration and high concentrations they're not going to be able to bind on to that site and induce their effect so this is what we call a irreversible inhibitor this is extremely important because I'm gonna explain why in a little bit phentolamine is an active site inhibitor what does that mean that means that this drug binds directly into the active site okay now epinephrine and norepinephrine technically can't bind there right but you guys remember back in biochemistry that there was what's called competitive competitive inhibitors and competitive inhibitors if you guys remember if we increase the substrate concentration what can it do to the competitive and it can knock it out of the active site so if someone has extremely high levels of epinephrine and norepinephrine what kind of what kind of disease is that called whenever somebody has high amounts of that be an orphan Fe that's called pheochromocytoma right and adrenal medulla tumor so in that kind of situation of that extremely high epinephrine open never levels what could it do it could knock the phentolamine out of this site so which one of these would be better to use in someone with pheochromocytoma phenoxy been Zameen because no matter the how the high concentrations are weapon and epinephrine or epinephrine it's not going to be able to knock that site it's not gonna be able to help to bind on to that site because when phenoxy bends I mean is bound to the allosteric site it changed the shape of that active site pretty cool but with that being said that means that if in Tolman can get knocked out of that site it is a reversible inhibitor alright cool so we've established all of this type of effect now let's go ahead after we talked about the overall mechanism of action the cellular level the two different types of alpha blockers let's go and get to the indications all right so we've already talked about some of the effects of these drugs when we talked about the mechanism of action as well as when we talked about the non selective alpha blockers right so you guys should already we should be able to blast through this part because we already know now the mechanism of action it's very simple right that these are drugs under they cause a vasodilation if they vasodilator CIL's they decrease total peripheral resistance and therefore they drop blood pressure now these drugs can be utilized for hypertension but here's the thing they do have some side effects that we'll have to talk about and they're not the best hypertensive medications so they're primarily prescribed maybe as a second line anti hypertensive and even more than that they might be more commonly prescribed if somebody has hypertension and an underlying benign prostatic hypertrophy because you can get that dual action of the drug okay so with that being said let's move on to the next type of indication in this situation we know what does it do if somebody has a big old prostate right big old prostate bagels I like the size of a grapefruit and that sucker is just kind of squeezing on that urethra it's gonna be very difficult for some of the urine to get out so if we can relax even if it's just a little bit relaxed that internal urethral sphincter if we relaxed that bad boy what's it gonna do it might help to increase the urine outflow and that might help to relieve urine retention secondary to BPH so this can be good for patients with BPH or we can say urine retention secondary to BPH so secondary to BPH all right so the next type of indication for these drugs particularly tamsulosin i want to mention that one Tamsui low sim this is the more common type of alpha one blocker that's used for this condition it's also can be used a lot more commonly in the BPH but tamsulosin nonetheless is used in patients who have calculi right which is kidney stones in their ureter here's the reason why it can act on smooth muscle and if it can act on this smooth muscle where this renal this actual calculi or this kidney stone is stuck then technically it can act on the smooth muscle and cause smooth muscle to relax if that relaxed what can it do to the lumen it can dilate the ureter lumen if we dilate this ureter lumen what's that going to do it might help for this big old sucker to pass through and help us to pass this without having to go in and do some type of sir surgical procedure like a Lithia trip see are going with the ureter o-scope and take that out or some type of percutaneous net for a lotta me all these different things that you want to try to avoid maybe give them fluids give them pain medications give them the damn solution or flomax is the brand of it and hope that it can dilate that urine or not that you can pass it okay so it can help in passing calculi that are actually in the ureter okay the next one we kind of talked about this one a little bit too if you guys know we've talked about phenoxy bends and mean and fin polo mean well remember when somebody has an adrenal medulla tumor right so they have what's called pheochromocytoma Sophia chromo saitama and that's basically a tumor that's developing within the adrenal medulla which is secreting out tons of epinephrine primarily and norepinephrine and these are basically acting on that those peripheral vessels right and increasing the actual blood pressure by that basal constrictive response if we give a drug like phenoxy Benz I mean it's gonna bind super tightly rate to that allosteric site prevent the norepinephrine epinephrine regardless of how high it is from binding and thereby as a result help to drop that blood pressure so that's one of the benefits and then again this is more specific with phenoxy bends I mean you could use the phentolamine but the phenoxy bends amine is going to be the best and again it's because we talked about it's an irreversible allosteric inhibitor alright so the last thing that I want to talk about here with the indications is when it comes to specific drugs okay when people use what's called mono amine oxidase inhibitors which are commonly used as much anymore they are like third-line for patients with resistant or refractive depression if you use these monoamine oxidase inhibitors and you combine it with certain foods that are rich in what's called pyrrha mean which is things like cheese these wine stuff like that what happens is this creates what's called a hypertensive crisis okay so this can lead to what's called a hyper tensive crisis so basically where their blood pressure is greater than 180 over 120 and if it's an emergency they have end organ damage if it's an urgency they don't have end organ damage but in this kind of situation one of the drugs that could be pre commonly prescribed it's been pole Amin okay so if phentolamine is another one that can be commonly utilized and last one that I'll mention very briefly is if someone's using cocaine sometimes with cocaine you don't want to give something like a beta blocker because remember if you guys remember very very quickly let's say here I have a blood vessel and here I have a receptor that's my beta receptor and over here I have another one and that's my alpha receptor okay let's just say that this is a beta 2 receptor whatever you give a beta blocker what does it do it blocks that receptor site right and now if I do that I increase I have epinephrine and norepinephrine right if they can't bind to the beta receptor where are they gonna now bind on to the alpha 1 receptor and that can lead to unopposed action on the Alpha receptor so in that kind of situation we might want to give a drug that can really bind tightly there and help whenever someone is using things like cocaine or methamphetamine in that kind of situation we might use either phentolamine or phenoxy Benz Amin okay to control their hypertension high blood pressure to reduce the risk of like an aortic dissection alright so that covers the indications alright so in this last part here we're gonna talk about the side effects the adverse drug reactions and potential contraindications are things that you should be very careful of when you use some of these drugs they're pretty self-explanatory there's one little funky one in there that you might see on your boards exams because they always like to ask the weird stuff but what are some of the side effects it's pretty simple we got to think about their mechanism of action remember that again these alpha blockers could potentially be blocking alpha one receptors and alpha two receptors there's alpha one receptors present on the vascular smooth muscle right normally epinephrine and norepinephrine want to bind onto these receptors but we're going to use an alpha blocker and prevent that right so we're going to inhibit that what does that promote that promotes vaso dilation now there's two things with this right one of the things here is that when you cause vasodilation there's a potential of causing low blood pressure right because what it does is it decreases the total peripheral resistance and therefore it decreases the blood pressure what the blood pressure drops too much in a patient maybe they get too much of the medication a little bit more sensitive it could potentially cause hypotension the other thing that you got to think about with these is that with vasodilation if it occurs near maybe like a skin surface so if it occurs near a skin surface there's the potential of this causing flushing in addition whenever you cause vasodilation what else can happen it could technically allow for some increased capillary permeability at the peripheral tissues and if there's increased capillary permeability there can be increased fluid leakage out of the capillaries and this fluid can leak into the interstitial spaces so let's say that it leaks into the interstitial fluid if you increase the interstitial fluid in that space that can lead to edema and this most commonly can occur in the periphery so peripheral edema lower extremity edema you know what else is interesting with vasodilation there's also the risk of decreased blood pressure right so decreased perfusion going to the kidney if there's decreased perfusion going to the kidney what can that well it could stimulate the j.g cells and the JG cells could release what renin and if we release renin what does that do that actually increases angiotensin ii so if there's increase angiotensin ii what's the overall effect here well one of the things is that it can actually stimulate aldosterone production if you stimulate aldosterone production what does that do that increases sodium and increases water reabsorption and that can lead to an increase in potentially blood volume if there's an increase in blood volume that can lead to increase fluid leaking and if there's increase interstitial fluid that can lead to edema so there can be that double edge sort of peripheral edema due to vasodilation but also whenever there's that drop in pressure that could also trigger this kind of reflex mechanism to potentially exacerbate the peripheral edema even more lastly is whenever you vasodilator you drop blood pressure what else can that cause remember it can activate the actual a reflex arc it can activate the carotid sinus and it can activate the aortic sinus and whenever you activate the aortic sinus and the carotid sinus what does that do it increases the sympathetic nervous system and that tries to respond to that drop in blood pressure by increasing heart rate what's that called they call that reflex tack ok reflex tachycardia so again what are some of the side effects one is going to be peripheral edema which can be caused by vasodilation as well as this reflex reaction due to the renin aldosterone system it could be flushing due to vasodilation near the skin surfaces and it could also be reflex tachycardia due to this actual response up from the drop in pressure and lastly it could also potentially be hypotension okay so those are some of the potential side effects the other thing is it can act on the alpha-1 receptors that are present on the iris right so are present on the iris that's that smooth ma I'm sorry that's that muscular structure which is present within the eye here and it actually helps to control either pupil area dilation or pupillary constriction well normally if epinephrine and norepinephrine bind onto these they cause pupillary dilation okay which is called madrassas what's the opposite of people area dilation if we're blocking it pupil constriction if we cause pupil constriction that's called meiosis right now here's what is actually really interesting about this if someone is getting a cataract surgery okay so let's say that they're getting a cataract surgery so what happens in a cataract surgery is you can make a little incision into the cornea if they're getting a cataract surgery and they are on some kind of drug particularly tamsulosin it can cause meiosis and it can lead to the iris prolapsing through the actual corneal surgical incision okay so the IRIScan prolapse through corneal incision and this is called intra operative this as a heck of a long name intra operative floppy iris syndrome this is a pretty interesting one again don't know how often you probably see this in real life but on the boards they're probably like to ask this kind of stuff so again this is a potential contraindication so you probably would not be giving somebody an alpha blocker like tamsulosin if they're going to get a cataract surgery because it can cause the pupil to constrict and potentially prolapse through that corneal incision site so that's something we have to watch out for all right what else let's think about this right remember what epinephrine and norepinephrine did on this site okay it act on the particularly let's focus on this internal urethral sphincter right epinephrine norepinephrine what do they love to do here they love to cause that internal urethral sphincter to constrict and hold really tight well what we're gonna do is we're going to block that so the opposite of that is constriction of the internal resource Pinker is relaxation if we cause relaxation of internal urethral sphincter that can cause two potential problems obviously the benefit is urinary outflow but if you give too much of it and you relax it so much people can potentially urinate without even wanting to so there is the potential risk of urinary frequency and maybe urine incontinence but urinary frequency is by far going to be the most common type of side effect because if you're relaxing that you're more likely to have to feel like you have to go to the bathroom right and if you guys remember that micturition reflex whenever this internally through sphincter relaxes okay that's more of an involuntary effect or in this case is due to an alpha blocker we still have that external urethral sphincter which we have voluntary control over but if you get to the point where you have so much urine accumulating proximal to that and continuously stretching that bladder there's a chance of urinary incontinence our urinary frequency is one of the side effects that you have to watch out for with the possibility of urinary incontinence here's another one that they could ask another thing is if you give these drugs okay you're relaxing this internal urethral sphincter okay if you relax the internal urethral sphincter you guys know that there's a little tube coming through the prostate gland right and basically what happens is you have the seminal vesicles and they have a small little ejaculatory duct and basically that combines with the vas deferens which makes the common ejaculatory duct and that runs through the prostate and empties into the prostatic urethra well if this muscle is relaxed normally normally this muscles held really tight so that way when sperm is released out through that common ejaculatory duct from the prostatic urethra only goes out through the urethra and through the external urethral orifice this internal urethral sphincter is held really tight to prevent it from refluxing into the bladder but if that muscle is really weak there's a potential for it to go to different areas so I could go down through the urethra and it could potentially go into the bladder what is that called whenever semen is going into the bladder it's called retrograde ejaculation okay so retrograde ejaculation this is also a pretty common side effect when someone gets like a prostatic surgery okay so again that's another potential side effect that you could see with these drugs go up here to the other effect there's alpha one receptors that are present on the vas deferens because again it helps with smooth muscle contraction epinephrine and norepinephrine right well if I block that smooth muscle contraction what am I gonna do I'm gonna cause smooth muscle relaxation and if I cause smooth muscle relaxation of the vas deferens that might cause decreased type of ejaculatory response so again I'm gonna cause the vas deferens it has smooth muscle and that's gonna relax it'll decrease the peristaltic activity moving it through the actual vas deferens and then combining with the small duct of the seminal vesicles forming the common ejaculatory duct running through the prostate gland and the empty net into the prostatic urethra so there's a potential of a decreased ejaculatory response and utilizing these drugs as well the last effect here is actually very interesting because now we're at a point where we're talking about the alpha 2 receptors so this is gonna be a little bit more specific to phenoxy Ben Zameen and phentolamine so this would be like phentolamine and phenoxy Ben's Amin okay because these are the only ones that really have that dual action where they combine on alpha 1 and alpha 2 now normally epinephrine or I'm sorry norepinephrine more particularly will act on this alpha 2 receptor okay what happens is let's say here you have a presynaptic neuron so here's my pre synaptic neuron okay and here this is my post synaptic neuron norepinephrine can be released from this presynaptic neuron and what happens is it can act on to these postsynaptic neurons and generate action potentials and if it generates these action potentials it can lead to norepinephrine release from this postsynaptic neuron which can act on particular target organs right but norepinephrine has this type of negative feedback mechanism where basically it can come back bind onto this alpha 2 receptor and that alpha 2 receptor will trigger signaling mechanisms that will inhibit norepinephrine release okay so if there's decreased norepinephrine release there's decreased action potentials and if there's decrease action potentials there's a decrease in norepinephrine or at least that's the normal negative feedback mechanism well phenoxy benz amina phentolamine unfortunately can block this if they block that receptor is norepinephrine gonna be able to trigger this negative feedback mechanism anymore no if it can't trigger the negative feedback mechanism its released from inhibition and health and harpin F release will continue that means that there will be a increase in action potentials down this postsynaptic neuron and increased norepinephrine release of the postsynaptic neuron guess where this norepinephrine is going to act on now it's gonna act on that SA node and it's gonna act on that AV node and guess what it's going to do now on those it's going to increase heart rate and it's going to increase AV conduction and as due by doing this what is this going to lead to this is going to lead to what's called a reflex tachycardia which might be a little bit more pronounced with these types of drugs okay so that is the potential side effects or a DRS all right so the contraindications are gonna be pretty simple now since we kind of went haywire on these side effects and a DRS so again tamsulosin is primarily one of these drugs that we want to be careful prescribing when someone is getting a cataract surgery so it's gone someone's getting a cataract surgery would you want to give them tamsulosin no why because there's the risk of that intra operative floppy iris syndrome and there's no stinking way I'm going to write all that back up there again so we're gonna put if' eye ass and you guys know what that means all right last but not least if we give a drug okay one of those alpha-1 blockers right they potentially have the the opportunity to cause relaxation of that internal urethral sphincter and that will lead to your an outflow which we said it could potentially cause urinary frequency if someone has urinary incontinence which means that they can't control their ability to not urinate or you're gonna want to give something that potentially could increase the urinary frequency absolutely not so because of that if you don't want to do that then like it's news pee and upside down this can be very contraindicated if you have someone with urinary incontinence this is not something that we would want to give to somebody because you can potentially worse than that and that's not something anybody wants okay Inez Djoser in this video we talked about alpha blockers if you guys stuck in this entire time can't say thank you enough you guys are awesome I ninja nurse if you guys like this video hit that like button comment down the comments section and please subscribe also if you guys get a chance please go down into the description box we have links to Instagram Facebook and patreon account you guys want to go check that out we truly appreciate it as always ninja nerds until next time [Music]