this is Dr busty and we're going to do a drug class review on the alpha blockers and we're going to break these down into their primary areas of uh mechanism although they all affect Alpha receptors some of them are specific and some are even very very specific but aren't even used for blood pressure management um and some distribute in other areas of the body like the blood brain barrier and have Central effects and so we'll start off first with a centrally acting um Alpha receptor um um Agonist and these are the specifically to the Alpha 2 receptors that are present there and so when we look at their location so obviously if they're in the brain then the drugs have to pass through the blood brain barrier to get into the central nervous system and they work on the pre synaptic terminals that's where the Alpha 2 receptor is located and when it activates this receptor it decreases and that's important um because we have drugs that do the opposite of this we have Alpha 2 receptor and antagonist uh they're used for the treatment of depression that's called moripe or Remeron and so when we activate the Alpha 2 receptor pre synaptically we actually decrease the release of norepinephrine from this those uh Terminals and so we have an overall reduction in the sympathetic um uh uh nervous system outflow from the central nervous system and that then affects all the different organ systems um that are inovated by the sympathetic uh nervous system and so we we see we'll see side effects as a result of that um that occur because of that mechanism but also then make sense why we have some side effects that occur when we stop these medications specifically clonidine so we have clonidine guanosine and then methyl DOA methyldopa typically has to get metabolized to a metabolite that then works as an alpha 2 uh receptor Agonist but um it's important to recognize it's an older agent we don't use it as much anymore but historically it was one of the drugs of choice in pregnancy related hypertension and so when we look at the sort of mechanism once it gets into the central nervous system and it reduces over that sympathetic tone what does that then do uh to the to the organ systems that are innovated so it's not just you know the heart but it's also the blood vessels as well um and um different glands and different structures um even can cause sexual dysfunction as a result of the re the reduction in sympathetic tone and so to zoom in a little bit this is described on how it works um a little more detail so those slides are there for you if you need the extra details but here is the pre synaptic terminal as the impulse is traveling down the um axon of that nerve it gets to the pr synaptic terminal where that houses these vesicles and the vesicles contain the hormones that it's going to be releasing whether that's serotonin norrine dopamine whatever the neurons purpose is and in this case what we're concerned about is the adrenergic system or the sympathetic tone so that's going to be norepinephrine and so these vesicles that contain norepinephrine when we activate the receptor this process gets inhibited and so what ends up happening is the norepinephrine then gets normally released in the synaptic terminal to then stimulate the next nerve okay which can then distribute to some organ system or tissue in the body uh is not then activated or innervated and so we see a overall reduction in the sympathetic tone coming out of the central nervous system or you can almost think of it as a little bit of a CNS depressant so to speak uh without causing respiratory depression it just will make you feel tired and that makes sense it can also then contribute to depression and so that makes sense why these patients experience some of these these side effects so it binds the presynaptic Alpha 2 receptor it decreases the release of norepinephrine um and as a result of that that impacts blood vessels the heart and so we see a reduction in the pulse we see a reduction in the in the force of contraction so it has negative inotropic effects we see vasodilatory effects on the blood vessels so that's going to reduce our afterload and cause U and reduce our systemic vascular resistance to lower the blood pressure and so that's where we start to see some of this this effect and why we use them in patients with um hypertension to so to summarize this this slide um you know compiles all those mechanisms together so we see a reduction in cardic output uh mainly because we're not stimulating the heart rate and we're not increasing the force of contraction that would cause an increase in stroke volume so our cardiac output drops okay as we decrease cardiac output we will have a reduction in blood pressure for that reason alone second is that we're going to decrease total peripheral resistance and that has to do with the Vaso vasodilatory properties of the blood vessels in the periphery and so we reduce systemic vascular resistance or afterload that reduces our total peripheral resistance that's going to lower our blood pressure and then lastly and less commonly discussed is a reduction in the release of renin so there are a number of things that stimulate renin from the juular glomular cells in the renal aper and arterial one is low perfusion so if it's not getting adequate blood flow it will release it to try to increase plasma volume and the second is the sympathetic nervous system it can augment the release of it and so if we're reducing the sympathetic outflow we are therefore not going to release the renin so therefore the renin Angiotensin aldosterone system won't be uh activated as efficiently or effectively and so therefore we will won't see an increase in plasma volume um as a result of that which can then feed back and actually contribute to the reductions in cardiac output and so when we look at all the things as it relates to blood pressure management there are obviously a number of contributing components to this we're going to be focusing our attention predominantly on the reduction in the sympathetic tone on the heart in particular and the blood vessels which I just summarized and so when you think about all the different organ systems that are affected specifically within the cardiovascular system we can receive reduction in the heart rate so negative chronotropic effect we reduce the conduction velocity which gives that negative chronotropic effect and the reduction of the pulse negative inotropy and then we vasod dilate these blood vessels okay and these are the different uh receptors that are augmented by the sympathetic nervous system so we're not antagonizing the receptor we're reducing the tone from the central nervous system feeding onto those receptors that then exert these effects okay all right so when you summarize this in the formula if some of you probably seen the mean arterial blood pressure or blood pressure equals cardiac output times systemic vascular resistance and uh when you look at what makes up cardiac output that is made up of the heart rate times the stroke volume and the way that this this formula works is that if you affect one variable in there if something else doesn't compensate to create the balance there'll be a net reduction or a net increase in the blood pressure as a result of that well in this case we see that we're reducing the pulse we're reducing preload because of the vasodilatory effects we're reducing as afterload because of the vasodilatory effects again that feeds up and reduces our systemic vascular resistance but we're also reducing the inotropy which has a pretty profound impact on stroke volume so we see this really nice reduction in cardiac output we see a reduction in systemic vascular resistance and that can cause um reductions in blood pressure but at the same time we can also see that how this could also cause dizziness lightheadedness orthostatic symptoms especially if patients are on uh medicines that would cause also things like reductions in preload like diuretic okay and so these are why you see some of the side effects that some of these patients H have now when you look at the Alpha 2 receptor Agonist um let's look at them side by side a little bit to see how they are similar and how they're different um what's important to recognize with clonidine and guanosine in particular is that they are um also used for other indications and you'll see that we use them not just for hypertension but we also use them for nicotine an opiate benzo dipene um alcohol withdrawal to reduce that overall sympathetic response that's happening as a result of withdrawing the other thing that you'll see that we use it for is ADHD and they do have specific dosage formulations for those indications so for example clonidine extended release formulation is known as cve catve is the specific dosage formulation approved for patients with ADHD um and so it's just important to to recognize that um as well we do have an epidural solution option duracon which is used for patients with um cancer and where their pain management issues warrant some additional um treatment the so you see that the we have the drug uh generic name and then the parenthesis related to the dosage formulation to help you as you kind of wrap your mind around these drugs the indications dosing and you can see with clonidine especially if you're using the tablet formulation you may have to administer multiple times throughout the day because it doesn't work for very long uh period And so you you can't use it as a single dose once a day anti-hypertensive medication but that's one of the reasons why they develop the transdermal patch which is cpress TTS um which is the transdermal um system that you put the patch on once every seven days and the whole point of that is to re improve the compliance and adherence but also provide uh more stability in the blood pressure because one of the number one problems when you're non-compliant or you miss a dose is that patients can have some of this rebound tacac cardan hypertension that can be actually pretty pretty significant um so if you're on a transdermal patch system and you're going to switch to tabs then you need to really consider a taper um so so that you know there's no withdrawal from from the medicine guanabenz was an older agent is no longer on the market so the DSC stands for discontinued but it was just put there for historical uh reasons guanfacine again is similar to clonidine in that it is being it is used for other indications including ADHD and the formulation is in tun and that is also an extended release option now when you look at guanfacine compared to clonidine one of the big differences is the halflife and because guanfacine has a longer halflife than clonidine it can be administered once a day and um provide uh continuous anti-hypertensive lowering uh benefits for that reason now it only does come in a tablet formulation extend release or immediate release um but uh it doesn't have a trans dermal but it doesn't need one given the fact that it has a longer Half-Life and then as I mentioned earlier methyl Doopa which methyldopa uh historically was one of the drugs of choice in impr pregnancy related hypertension this drug has to get metabolized to an active metabolite to then exert the Alpha 2 Agonist activity um for lowering the blood pressure unfortunately it's got some side effects which we'll mention here in a minute and is uh has to be dosed more frequently throughout the day so there are issues with compliance and adherence okay let's CL let's integrate some of this information clinically and ask some questions that many times we get asked and come up in clinical practice so which Alpha 2 uh Agonist can be used to wean patients off of the mechanical ventilation if they're in the ICU so so we just were talking about medications that we would use as an outpatient management of hypertension but there's actually an alpha 2 Agonist that is used in the ICU and that's dexamine or precedex uh it is used for ICU sedation so going back to the mechanism if I reduce sympathetic outflow from the central nervous system I'm in a sense suppressing That central nervous system so it can create a little bit of a drowsy sensation without affecting their drive for respiration so if you're trying to wean them off the mechanical ventilation to ex uh to exate them from the breathing tube then you need to strengthen those muscles and you don't want to have any medicines on board that are going to suppress the respiratory drive because you're trying to get them off of the breathing machine and on their own again and sometimes that that can take a that period of time and so we can use it for up to 24 hours most commonly in the ICU unfortunately one of the side effects in is is hypotension just because of the mechanism which is already at high risk um in patients in the ICU because they're in the ICU for other reasons that can sometimes cause hypotension like sepsis or heart failure other things so uh but high doses and Rapid infusions can stimulate the alpha 2B receptors and cause actually some Vaso constriction and Hyper hypertension which seems counterintuitive but it has to do with the receptor sub subtype that it gets activated so infusing a little bit faster at higher doses that sometimes we see in um the ICU you may not um experience that as bad now Alpha 2 Agonist that can be used to treat clausine or clauser which is an antic psychotic induced silara so these are patients on on um clopine they start to have like this drooling um and so clonidine is known to cause dry mucous membranes and dry out the mouth and so it is used off label which means it doesn't have an FDA proven indication to treat this but it has been shown to be useful in that patient population uh who may have to be on that medication and it that can be a bothersome side effect for them so why is a history of medication non-compliance a concern for patients taking clonidine and I would say specifically clonidine uh tablets and I've already kind of mentioned this that cpress tablets are immediate release formulations that offer a short halflife which means you have to continue to administer it throughout the day you know two to three times a day in order to maintain that blood pressure control without lay bile effects well any you know human is going to obviously make er make mistakes and it's not going to be perfect in everything that they do and so one of the complications with this use of this tablet formulation is that if there are is any bit of non-compliance they can develop rebound hypertension in tacac cardia that is actually pretty significant and again as I mentioned that was the purpose of developing the transdermal therapeutic or transdermal system um that was that that you apply once every seven days and so that actually offers some benefit all right so how do alpha 2 agonists worsen depression and erectile dysfunction well again in order for them to be centrally acting they have to penetrate the bloodb brain barrier which means they're getting into the brain to decrease sympathetic tone so if we're reducing the sympathetic tone coming out of the central nervous system we're going to feel more tired we're going to feel more fatigued going back in the ICU that causes sedation right without reducing the drive to breathe and so we can see that in patients with depression that's not going to help them along right that's going to make them also feel worse that's the same effect that we see with lipophilic beta blockers they're going to penetrate the bloodb brain barrier the same reason um we can also see erectile dysfunction and the reason we see erectile dysfunction is that erection and ejaculation are influenced and regulated by the autonomic nervous system so the um erection uh component is a parasympathetic response ejaculation is a sympathetic mediate response so if I'm reducing the sympathetic tone remember it's affecting all organs in the body not just the heart and blood vessels um but remember it works on the kidneys and it can work on the blood vessels and the tissues in the uh genital area so this reduces um some of the or causes sexual dysfunction and in part may affect um ejaculation which abnormal lad test has been associated with the use of one of the Alpha 2 Agonist well methyl Doopa unfortunately this is one of its limitations is that it can induce a hemolytic anemia so that's not good especially if you are pregnant this one of the reasons why it's fallen out of favor even though historically it was used and is taught to be the drug of choice in pregnancy related hypertension is not recommended as the first line treatment by AOG which is the you know American College of obstetrics and gynecology uh but it the the test that the the lab test that becomes positive is the kums test and again that's reflective of the of a hemolytic uh reaction and this may have to do with what we call molecular mimicry uh what that means is that when the drug is present uh on it may bind to the surface of the red blood cells and that that binding to you know there's proteins on their surface of the of any cell but on the red blood cell that may stimulate the immune system that see it as abnormal and as a result of seeing it abnormal it attacks it and it destroys it and obviously releases the intracellular components which then induces you know hyper abil rmia fatigue shortness of breath can lead to jaundice those kind of things which anti-depressant Works opposite to the Alpha 2 Agonist and that is marzipan or Remeron uh like I said we use that for depression especially in patients who tend to be a little bit more anxious because one of the side effects of this drug is sedation they also tend to to have more weight gain so in skinnier patients who need it and have trouble with sleeping this is a good option um for them and so this is where side effects can work in your favor and you might use a particular agent like this drug for that purpose but keep in mind that merapen orron is the only Alpha 2 antagonist remember all the drugs we've been talking about clonidine guanosine methyldopa are alpha 2 receptor Agonist and they work on the pre I aptic terminal in the central nervous system predominantly all right so those are the alpha 2 receptors let's move on to the alpha 1 receptors and then we have sort of the mix both alpha 1 and Alpha 2 so when we talk about alpha 1 blockers especially in the context of hypertension management we are not talking about uh Flomax or or oxetol okay those agents are used for patients with benign prostetic hyperplasia or BP symptoms because they're focused on an alpha 1 receptor that's very specific and predominantly found in the det muscles around the prostate gland and facilitate emptying of the bladder so we are focused on Alpha 1 receptors outside of that area although they can work in the bladder as well um they're just not as specific as TS Flomax or roit trol so these work on the Alo receptors and they stimulate a g- couple protein that affects basically the intracellular concentration of calcium and that becomes very important important for actin Amin so in order for a muscle cell whether it's smooth muscle or skeletal muscle in order for actinomycin to interact it needs that calcium to be present in the cytoplasm in order for that actinomycin interact and increase the force of contraction so if I take away the calcium then actin and mein are not going to interact it relaxes you can get then Vaso dilation and this is just descriptively in the words of what I just described for you and as far as its mechanism but let's look at the picture again I know it's kind of small but you don't need to have this image memorized it just drives home the point that we have Alpha receptors which are g-coupled protein receptors on the surface of the smooth muscle in the vasculature because we're talking about heart hypertension when that that receptor get gets antagonized it stimulates phos phospholipase C which then does the pip2 reaction where dag and ip3 are formed ip3 would normally then stimulate the sarcoplasmic reticulum which is is found inside the cell and the sarcoplasmic reticulum houses in part a lot of calcium and so if it doesn't get stimulated then the calcium does not come out into the cytoplasm so that actin and mein monofilaments can then interact so remember actinomyosin can only interact and increase contraction when calcium is present in higher concentrations if you take away calcium then actinomyosin do not interact and the whole cell relaxes and so we get the vasodilation properties of the blood vessels because we're reducing cytool calcium which decreases actin Amin interaction and causes a vasod dilation now this functional vasodilation term that's presented here on this slide is referring to the fact that if we dilate all these vessels we are going to in a sense hypo profuse certain organs that expect better blood flow one of those organs is the um uh kidneys and so the renal aarant arterial okay uh senses this profusion okay or actually reduction in the profusion and the JG cells say look I need better profusion here I'm going to release renin and activate Ras because I know when I activate Ras I increase phasal constriction Medi by Angiotensin 2 and on top of that I increase plasma volume because I'm going to cause aldosterone to be released which increases sodium water reabsorption well when you use alpha 1 blockers in isolation as monotherapy for the management of hypertension you can induce the RAS system which then creates a feedback loop to overcompensate and override the effects of the alpha blocking properties on top of that it can then create fluid volume overload because of that sodium water reabsorption and so the allh Hat trial which was a really big uh multi-arm clinical trial uh that was done many years ago the arm that included the alpha 1 blockers was stopped early because those patients were doing worse so when we have Alpha blocking properties what we are doing is we're reducing predominantly the afterload but we will also relax the uh cause dilation of the of the veins the veins do have some smooth muscle it's just not as much as a arterial that reduces our overall stroke volume and because of that effect we can see a compensator increase in the heart rate so it's a reflex tacac cardia to compensate remember these equations want to stay the same so if cardiac output is going to be the same then then the heart rate right times stroke volume if stroke volume is reduced heart rate better go up if there's to be no change in the cardiac output and so this is where patients if they're on drugs that reduce the heart rate like beta blockers DTI and Verapamil amoon selol then we can't get the compensatory increase then what ends up happening is there heart rate is already low from another drug and now their stroke volume is reduced significantly and these patients can see profound drops in their cardiac output which can make them very orthostatic and that's the one of the number one complaints with these drugs especially when they're used in the older patient population as a replacement for uh Flomax uroxatral for bp8 many times patients have to fail one of these drugs by developing orthostasis well the problem with that is you get orthostasis what if you fall and hit your head you know a lot of older patients unfortunately are antiplatelet anti-coagulants if you fall and break a hip well we know that breaking a hip at an older age you just circle the toilet right your your risk for um mortality and death goes way up so this is a table that summarizes the different Alpha 1 blockers you can see here at the bottom these are the specific Alpha 1A a receptor blockers that we would use for BPH those are not in the context of hypertension when you look at doxazosin prisin tasin you see that trosin and doxazosin can also be used for BPH but you unfortunately get more of the peripheral effects versus the onea receptor antagonism is localized in the bladder around that DET truser muscle won't cause the hypotension as see with tasin um and doxazosin um you might also see some of these used um for other conditions like nightmares and things like that but um that's typically off label uh many of these drugs can be given uh twice a day U because of their shorter half-lies um and so you have to be careful like specifically like prisin for that situation okay uh so there's this first dose Phenomenon with these drugs and what that is is basically the orthostatic symptoms because of that reduction in stroke volume this is going to be exacerbated or worsened or let's say more pronounced if patients are on diuretics because they're going to reduce their plasma volume or volume depleted patients so they're dehydrated for whatever reason for that's diuretic induced or they're just not ingesting a lot of fluid those patients are going to be even more risk of orthostasis the beta blockers and non Diop pering chal channel blockers dealt in rile because of their negative chronotropic effects that reduce the pulse remember if I cause a functional vasil dilation I'm going to get a reflex Taco cardia in order to try to maintain that cardiac output but if I'm on drugs like these that prevent The Reflex Taco cardia then I got a reduction in stroke volume plus I have already a known reduction in the pulse so I can't compensate these patients get real light-headed and dizzy and can sometimes fall uh if they're not on these two drugs then they can develop the reflex tach cardia which can be problematic if the patient has underlying angena because if you increase the pole you're increasing the oxygen demands increasing oxygen demand is especially in the presence of of es schic heart disease is only going to increase your risk for a cardiovascular event and then as I mentioned specifically as in the context of the all hat trial when you develop a functional Vaso dilation you can rev up that renin Angiotensin renin anot tensin aldosterone system uh which then increases plasma volume raises blood pressure and has remodeling effects all of those things are not good in patients at high risk r or who already have known heart failure now to finish up this discussion on Alpha uh blockers or Alpha receptor antagonist uh we have the non selective agents and this is our phentolamine and phenoxybenzamine which we predominantly or you know more commonly teach that we use it predominantly for foch chromosoma uh and the other more common indication is extravasation of catacol amines so foch chromosoma is basically a tumor of the adrenal gland that makes too much norepinephrine and epinephrine predominant norepinephrine so these patients have very high uncontrolled blood pressures that are difficult to manage um and many times the treatment obviously is surgery but in order to go to surgery you have to have you know stabilized blood pressure so sometimes we have to start these drugs in order to um you know to manage that now phoxy benzamine uh benefit is that it's a oral option whereas phentolamine is only parentally administered so now you get fentam IM IV whereas phoxy benzamine is oral or IV again if you're trying to treat patients as an outpatient before they um go on to need um surgery uh one of the benefits to phoxy benzamine is that oral Administration now with extravasation of catac colomines let's say you have somebody who's getting norepinephrine or epinephrine in a peripheral IV or a poorly placed IV and that IV infiltrates into the tissue well that's going to cause vasal constriction of all those blood vessels in that tissue and reduce the profusion to that tissue that can cause basically an infarction and death of that tissue so one of the things you want to do in that scenario is obviously turn the the infusion Off remove the IV cathet you tried to extract some of the fluid out the quickest and easiest thing is just to get some nitr paste ointment and and apply it all over the tissue but the next option is to draw up some of these drugs and inject it literally in the tissue all around the area that was infiltrated so that it vasodilates those blood vessels so that it peruses the tissue again so it doesn't die um and the sooner that you do that the better the chance of that tissue surviving and so these are these are common uses uh for these particular two agents and has a very specific indication so you know there's a there's a lot going on with the alpha blockers remember there's the Alpha One or Alpha 2 acting agents that work in the central nervous system and they activate the receptor to reduced release of norepinephrine we have the alpha 1 receptor antagonist that work predominantly in the blood vessels of the vasculature to causes vasod dilation and then we have the mix both alpha 1 and Alpha 2 or non- selective alpha blockers where we predominantly are using those in patients with FOC foch chromosoma or in patients who have extravasation of catac colomines into the tissue so hopefully found that to be useful but also made sense don't forget about dexamine uh or precedex that's used in the ICU because it's also an alpha 2 Agonist and it has a unique mechanism unique indication um and a role in therapy in that particular scenario