this is Dr busty and we're going to do a drug class review focused on uh the beta blocker specifically um you'll see that beta blockers are broken down into those that are selective agents and that doesn't mean that it's only beta 1 receptors but it's selective to beta 1 uh then there's the non- selective uh beta blockers that are blocking both beta 1 and beta 2 and then we have our mixed which have some Alpha One blocking properties that's specifically Carval all and la betal la um we'll come back to this list again and we'll go through the specific drugs and and their differences and um but then also their similarities um here in a minute but that's just an overview of the different agents that we're going to be discussing but let's start off going into what do beta blockers do to the cardiovascular hemodynamics we traditionally think of beta blockers as anti- rhythmic medications because if you look at them they have um anti- rythmic properties that um and that's one of the reasons why Von Williams classification Class 2 um anti- rythmics because they have negative chronotropic which we'll talk about negative dromotropic and lucot Tropic uh properties um that affect as it relates to cardiac induction um it obviously has other effects like negative inotropic effects it does influence the blood vessel diameters because beta 2 receptors are found in the blood vess vasculature and when they are stimulated or activated they cause vasodilation so if you have a beta blocker and it's and it does inhibit the beta 2 receptors at any level it will block that vasom dilation and cause Vaso constriction so beta 2 receptors in the blood vessels when they're activated cause vasod dilation therefore if we block them they will get Vaso constriction there's also effects on the renin angio aldosterone R renin Angiotensin aldosterone system Ras and then there's also effects on remodeling which is one of the main contributors to its benefits in heart failure which is different from other drugs like non dihydropterin calcium channel blockers DM and Verapamil so as I mentioned these are Class 2 Von Williams anti- arhythmic medications and we're going to break down the mechanisms into the organ systems that it affects because you'll see that it affects the central nervous system it affects the heart it does affect the kidneys blood vessels the uh endocrine system specifically the RS and so it's important to make sure that you understand beta blockers um not only in its entirety but also the fact that you'll be able to look at it from different angles because it explains sometimes why we see certain side effects and complications with the medications in their use so let's focus in on the central nervous system first well some of our beta blockers not all but some of our beta blockers are more lipophilic that means they can pass through the blood brain barrier getting into the central nervous system can be a good thing but also a bad thing from a from the potential good thing well if I get in the b in in into the central nervous system and I reduce the sympathetic tone coming out of the central nervous system then every organ system that's being interated by the sympathetic nervous system is going to be blunted it's going to be slowed down well that might be helpful in patients who are getting too much stimulation of let's say the heart and they go into sudden cardiac death from a dysrhythmia all right so there's theoretical uh benefits in and patients against sudden cardiac death with our lipophilic agents there's really no hard evidence that proves that but it is a theoretical unfortunately drugs sitting in the central nervous system can have side effects and if we decrease sympathetic tone coming out obviously you're not going to feel as excited and energetic um you're going to feel a little tired and weak and fatigued and this is one of the number one complaints of this medication class sometimes um not only does it reduce the pulse and stuff like that that makes you feel a little tired but if it gets into the brain then you're even going to feel worse and that can be relevant the so what who cares in patients who struggle with pretty sign moderate to severe depression uh because beta blockers can worsen it for that reason now as it relates to the heart I've already introduced the concept that it is an anti-ar rythmic and it does a lot of different things and I'm going to break that down for you a little bit more specifically here in a minute um where we dig into what is actually happening to the action potentials in nodal cells so SA node avv node well we know that these drugs have negative chronotropic negative dromotropic and negative lucot Tropic effects um and and then and so if you think about well gosh what's going on there well that has to do with what's going on in the nodal cells of the heart okay specifically in phase four now unfortunately uh nodal cells have a different type of action potential than when we see in ventricular myosite and so if you need a good review or you're not sure about anti- rythmics make sure that you uh look in into that topic um because that's one that will where I cover the details of what happens in the various nodal uh action potentials between noal Cells versus ventricular M sites but I'll introduce you some of that here as well now the part of reducing the pulse reducing the force of contraction that has benefits too while it can hurt you in some respects if you need good for squeeze it it also reduces the oxygen demands that are on the heart and this is one of the reasons why beta blockers are used for Anga so chest pain patients chronic stable angena this can be helpful if you have unfortunately systolic dysfunction and you don't have good squeeze a negative inotropic drug is not going to be very helpful to you and then the other thing that in the context of the heart is that it does affect Remodeling and this is probably one of the benefits that helps to offset the risk of sudden cardiac death that we see in heart failure patients and why uh you know we push these medications s because they do have abil some not all of them but many of them have data that support their use in red uh red reducing mortality associated with in heart failure patients however we don't see that same effect with DM and Verapamil which also have negative inotropic negative chronotropic and dromotropic effects so they have a lot of similar effects on the heart but it lacks the remodeling benefits and so therefore we don't see the same outcomes when using DTA and Verapamil in these patients so let's zoom in a little bit more and talk about what is happening to the noal cell where is this negative dromotropic and and and chronotropic activity happening well again this is a nodal cell this is much different than the action potential in a ventricular myosite um nodal cells are pacemaker cells and as a result you don't see any kind of flat lines in this AC it's always preparing itself for the next fire fire fire otherwise you'd be dead um so if you look over here the inside of the cell has a resting membrane potential of NE a net negative Z around -70 or so um and during phase four we have sodium coming in and as sodium comes in it's positively charged being positively charged cation it's going to make the inside of the cell less negative and more positive and so we become more and more more and more positive until we hit this threshold and once it hits that threshold then we have this w rapid influx okay because the slope is very steep rapid influx during phase zero of a divalent cation okay two charges calcium okay was coming in rapidly and as more positives come in obviously the inside of the cell becomes more positive until we actually exceed that of the zero and we go from being negative to now positive well now the cell's got to turn itself around and get back to square one in order for it to generate another pulse otherwise you won't have a pulse um and so we've got to get those positives out of the cell and so during phase three we have potassium which is a cation so positives leaving okay and so they as you take away the potassium inside the cell and move it outside the cell the cell becomes more and more and more negative bringing it back down to start the process all over again the speed at which and the slope of these lines influence the rate of the contractions now when you look at agents that work in this on these Pathways Class 2 beta blockers specifically are targeting phase 4 okay and that was described on the previous slide but they also have some dromotropic properties over here as well okay so this is predominant your chronotropic these are your dromotropic effects over here um and this is affecting phase zero influx of calcium okay now now you can see that the positive signs are greater over on phase 4 than on phase zero splitting here is a little bit here now you also see down here plus or minus class three agents um don't forget that some of the other anti rythmics like amone and soal also have beta blocking properties and function like a beta blocker and so that's why they have negative chronotropic and dromotropic properties associated with them as well looking at where our class four anti- arhythmic agents that's your delm and Verapamil not all calcium channel blockers but only the non- dihydropyrene they work primarily on phase zero so beta blockers predominant work on phase four uh beta blockers predominantly work on phase zero um and so they have slight differences in addition to their ability to remodel so let's what look what happens under the influence of a beta blocker so the dotted line represents before starting the beta blocker um and then you can imagine if we're targeting phase 4 and we're going to reduce the sodium inward movement then it's going to take longer to get to the threshold so you see that the slope has now changed and the time to get to because time is going this way right the time to get to that threshold is taking longer and so it starts to stretch out the pulse okay you start to see that it's starting to get further and further apart and and that is the negative chronotropic effect but don't forget it also has a negative dromotropic properties and then so the solid line represents the influence of the heart under the by the influence of the beta blocker itself so again we should see a reduction in the pulse and that reduction in the pulse is being um caused because we're slowing that movement of sodium during phase four that reach as that threshold okay now in addition to affecting the cardiac conduction it also affects the cardiac contraction and that has to do with the contribution of calcium inside the cytoplasm and so when we block these uh receptors we also affect the G couple protein receptors that facilitate REM um the dispensing of calcium into the cytoplasm that becomes very relevant because if calcium is not present in the cytool of the ventricular Mite then actin and mein cannot interact and that's what's demonstrated on this somewhat detailed image that I know may be hard to fully appreciate but this is all you have to get out of this is that this is the inside of the cell and this is the outside of the cell okay so this is the cell membrane obviously okay and so inside the cell we have our actin and mein monofilaments so here's your actin and then this is your myosin I'm sorry myosin is right here and so you see that they need to interact and as they interact they they require the presence of calcium which can come from outside of the cell in okay but it also comes from the sarcoplasmic reticulum and is dumped in and that's what is influenced in part by the beta receptors and so if we reduce cytosolic calcium then we do not allow actinomyosin to interact that reduces the force of contraction you have a negative inotropic effect when you do that and so when you look at the context of that effect on the heart um trying to start to pull this together and you think about our the impact on mean arterial pressure or blood pressure okay then you see that cardiac output times stroke volume is the formula and that stroke our cardiac output is influenced by the heart rate times the stroke volume and so we're going to reduce the pulse we're also going to reduce the Vol stroke volume because we have a negative inotropic effect and you can see that the medications that affect inotropy and decrease it one of those is the beta blocker so any drug that modulates the sympathetic tone or sympathetic activity on the heart can in part do that okay and so beta blockers are a big um contribut it's not the full list of beta blockers but you can see the main ones that are there okay and we obviously have drugs that increase the force and contraction if we need that but that's a separate discussion all right so when we do this we reduce the pulse we reduce the force of contraction right we're causing a negative dromotropic effect what all that does is it facilitates again Remodeling and reduced um uh myocardial oxygen consumption okay and so we see improvements in areas of blood flow that can also shift because you're relaxing the heart and so there is a distribution because uh well I'm sorry actually if you expand and you you slow the pulse down too much then you cause increased distension that can cause redistribution of the blood vessels because of compression um in a tight space and so in some patients okay this is very rare but if you slow down the pulse and you reduce the inotropy and you get increased indolic pressures that pushes and squeezes on the blood vessels and again can reduce the profusion and on rare occasions cause angen itself so most of the time we think of beta blockers is reducing engin and that is true and that is its primary overall mechanism and benefit when you think about it in the context of Eng but there are rare situations when it can sometimes also induce angena because of compression on the blood vessels so they can't peruse so looking at the chronotropic effects right we have drugs that are going to decrease um chronotropy and again we have our beta blockers here um specifically we have drugs that can increase it okay um as well and so so what ends up happening is it's important to uh I'm sorry so it's important that when you look at these and why we put these charts together is to recognize that if you have more than one drug on board that has a negative chronotropic or negative inotropic effect you start to see Synergy or additive effects and that can cause more side effects and so when you're doing a medication use evaluation or starting another medication it's really important to look at other medications to make sure some of these other drugs aren't necessarily being on on board um because you might see worsening um side effects that we'll talk about here so to summarize and to pull all the hemodynamics together a little bit here you can see that mean arterial uh pressure or me uh blood pressure is influenced by the cardiac output times the stroke volume and cardiac output is the heart rate times the stroke the systemic vascular resistance I'm sorry up here uh heart rate is uh or sorry critic output is heart rate times the stroke volume and so then the components that make up stroke volume are the preload uh afterload and inotropic properties well beta blockers are going to reduce the pulse they're going to reduce stroke volume because of a negative inotropic effect and that has a reduction a net reduction in cardiac output now you would think that just looking at the equation if I reduce cardiac output then I'm going to reduce the blood pressure unfortunately member B beta blockers also block the beta 2 mediated vasodilation happening in the blood vessel so you can cause a vasoconstrictive effect on this blood vessel and that makes the systemic vascular resistance or in part the afterload to increase and so you've got one part of the equation decreasing the other part of the equation increasing and so when you look at the overall net effect on blood pressure one is increasing it one is decreasing it the overall net effect seems to be a slight reduction in blood pressure but when you think about them this is one of the reasons why these drugs are not good at reducing blood pressure so when you look at some of the guideline recommendations and what is recommended first line as initial monotherapy for patients with chronic um high blood pressure when you look at the different a you know ethnicities and and risk factor groups it doesn't matter which one you do not see okay there are no beta blockers listed here okay now it doesn't mean that you don't ever add on a beta blocker later on or that you can't use them especially if you have another comorbidity that benefits from that beta blocker but realizing going back to that mechanism and considering the full effect of the drug on not only the heart but also the blood vessels helps you to understand why they're not very good blood pressure lowering medications and so and part of that is I just spelled it out here right so the beta 2 mediated vasod dilation is being uh blocked and so we get that Vaso constrictive effect at the same time the lipophilic beta blockers which are able to penetrate the central nervous system are um able to reduce the sympathetic tone also being mediated even on the alpha receptors so Alpha 1 receptors are causing constriction beta 2 receptors when they're activated cause dilation if we antagonize the beta 2 receptors we're going to get constriction but if we antagonize the alpha stimulation we're going to get dilation you see that and you got to kind of somewhat keep it straight in your head because if you don't understand the physiology and you start modulating the activity of the physiology then then you're not going to make sense of all these effects so now other effects that can sometimes happen that also influence the blood pressure is that of renin so if you look here um um if you reduce stroke volume and I reduce my cardiac output which I just showed you then I'm not going to get as much profusion to the kidney well what's the kidney going to sense the jux Glo cells are going to say look I'm not getting profused so I'm going to release um renin and as a result Ras gets activated um now when you give a beta blocker though so yes you do get this but you also get beta 1 mediated blockade of renin release so you know the hope the hope is that there's a net no effect on renin but it doesn't mean that it can't still happen now the exceptions to the rules that I'm talking about in in these mechanisms here apply to carve all beta all because of their alpha 1 mediated inhibition they're the mixed beta blockers and so they are effective or more effective at lowering the blood pressure compared to selective agents and non-selective agents that we'll go over here in a minute so the question then is do beta blockers actually have a diuretic effect um and that comes from what I was just saying a second ago when you look at blood flow coming into okay this is your nefron this is your glomerulus when you look at the blood flow coming in through the renal aarant arterial there are cells located in that area like right here okay that are um the JG cells okay now if we zoom in a little bit in that area so here's our nefron and the glomerulus and if you want to think about it but there are JG cells that surround this area of the renal aeren arterial and they sense profusion pressure and when they're not getting profused like they were supposed to they release renin and when you release renin okay then you start to facilitate the conversion of angiotensinogen to Angiotensin one and angot tensin one then gets converted to Angiotensin 2 and we know that Angiotensin 2 does a lot of things okay now um Angiotensin 2 is known to be a potent um Agonist to the very obviously the Angiotensin 2 receptors and there's a a number of different subtypes of receptors but when it binds to the Angiotensin 2 subtype one receptor it is known to cause a lot of Vaso constriction it is also known to increase the release of aldosterone and aldosterone then is going to uh have an effects on plasma volume so if you look here so the adreno gland will release aldosterone and which goes to the the distal convoluted tubal here and causes sodium and water reabsorption well that's going to increase our plasma volume which will in turn increase perfusion back to that kidney okay that was responding now again the J the release of that renin is beta 1 mediated so in part we will reduce the uh Ren and release that causes this so in in some respects we are blocking this and having a Smite diuretic effect but no one would ever call beta blocker a diuretic okay uh and this is splitting a little bit of hairs here but it does encompass the entirety of its um of its mechanism now as I mentioned it does affect the blood vessels because remember uh Angiotensin 2 is causing basoc constriction and so but if we never stimulate Angiotensin 2 production we don't need to worry about that and so beta blockers red re reduce the release of renin which will reduce the Angiotensin 2 production and hopefully also reduce this but right the big butt here again is that unfortunately beta blockers blunt that beta tube mediated vasal dilation and so the the net result one is the diuretic effect that's there is minuscule and clinically almost irrelevant uh however it does take place physiologically beta receptors are present in the JG cells and beta blockers will affect them the the effect on blood pressure hopefully that you can see or the lack thereof has to do with what's happening in the vasculature the exception okay to summarize is carbol and labetalol because of their alpha 1 blocking Properties or Baya blockers that get into the central nervous system because they're more lipophilic and are able to uh reduce the sympathetic tone okay and that's on all receptors in the sympath on tissue alpha 1 and beta 1 and beta 2 receptors all right so now that we kind of have you know Torn to Pieces the mechan ISM of action probably more than you wanted um but my goal and I don't mean to you know make it sound ridiculously detailed my goal is that you learn things in their proper context and I think that's what's missing a lot in medical education the other thing that I want you to do is be able to look at a drug and look at it from different angles and understand what's happening in various aspects of the physiology because it starts to put things together why in certain patients in certain clinical scenarios we get different types of side effects or clinical effects that we desire and sometimes that we don't desire and you can't do that confidently in my personal and professional opinion unless you understand the totality of how a drug works and influences or has the ability to influence uh the different organ systems and tissues in our body so let's move on to the drug class review and go through the individual agents what I've tried to do is create these charts that do cross comparison so that you sort of see them you'll see that the columns are broken up into a specific indicator that or characteristic that I want you to be aware of and so the First Column here represents the generic and brand or marketed products and if it is available combined with something so for example a tenolol you'll see the little plus sign here it's combined with chlorthalidone and that's uh tenoretic you can see that other agents um are combined with um HCT um and and so you can again have duel because many of these patients who are getting treated for hypertension uh need more than one agent okay uh so brand names generic names the indication and you can see that across the board most of these are are used for hypertension because early on in the in the um development of these drugs they there weren't a lot of agents available and so it was the the best thing that we had U but now newer agents are more effective at lowering blood pressure than these medications and that's one of the reason reasons why they have fallen out of being recommended as initial monotherapy for strictly hypertension unless there's some other reason that you're using them um to to manage that patient um from a dosing standpoint you can get away with once a day for the most part there are a few options that have to be given twice a day here okay again some of these drugs we don't use as much anymore um because of their half-lies and their overall uh compliance and issues um and then sort of what is their ability to control blood pressure uh which is the trough to Peak ratio and the trough to Peak ratio is reflective of the ability of if I give a drug once a day do I maintain adequate blood pressure lowering for the full 24-hour period as a single dose Administration in once a day if it can't maintain at least 50% of the lowering okay I.E at trop to Peak ratio greater than 5050 then many of times it it has to be given twice a day in order to control blood pressure all right now I do want to make note of a couple things that are important to recognize on here one is AOL has uh intrinsic sympathomimetic activity that means it can hover over the ba The receptors and the beta receptors and actually stimulate them instead of antagonize them and so generally the reason probably many of you have never even heard of asol or even never seen it in clinical practice is due to the fact that that's that one effect is not really found to be helpful and could be harmful and is proven to be no benefit so we just don't use it anymore um we have a tenolol which is one of more of our hydrophilic okay hydrophilic uh beta blockers u b so rol uh does not have an FDA proved indication for heart failure but has data to support it use in heart failure um esmolol has a very short halflife okay making it very um only useful in the acute setting and it must be given by an IV infusion and Via a pump you don't want to just do the roller clamp um because this drug it spills into the body too quickly it can cause obviously significant hemodynamic compromise and so it has to be given by an IV Administration via pump um and titrated to the response that you want but the nice thing is if I get the response that I don't want I can just turn it off or adjust the rate okay and that it'll go away pretty quickly there are two forms of mopol there's mopol tartrate versus succinate it is important to recognize they are not the same or um at all um from the standpoint of uh mopol succinate has an FDA proved indication for heart failure whereas U mopol tartrate does not mopol tartrate is also has to be given twice a day whereas succinate is an extended release product that can be administered once a day and that's tool XL u in fact it's a score tablet and you can break it in half you can't crush it but you can break it in half all right moving on to our beta our non- selective beta blockers that's your nyol pindolol and propanolol and just like with acebutolol no one really uses pindolol because of its Isa activity so it's kind of fallen out of favor very pretty much non-existent so really it's natal and propanolol now these two drugs are also used other in addition to hypertension they're also used for other conditions as well one of them that you see up here listed is verical esophageal veral bleed prophylaxis to prevent those esophagal vares in the context of patients with curosis um you will see sometimes these being used and part of that has to do with the fact that they're being non selective beta blockers that means that they're going to antagonize both beta 1 and beta 2 more readily and if I block the beta 2 receptor s in blood vessels okay specifically the esophagal veres I'm going to cause more vasal constriction because remember beta 2 receptors that are stimulated or activated cause dilation so if I antagonize them or inhibit them right I'm going to cause Vaso constriction that's going to redistribute the blood out of the splenic circulation and around the ESOP esophagus and push it into Central circulation um and reduce the pressure on those in the context of esophagal varices in patients who have curosis now we will also see uh some of these drugs used for anxiety or Panic uh you know sort of social phobias where patients get real anxious uh stage fright um so some of these patients will take these before they give a lecture and that'll reduce don't only your pulse and Tremors but also you know kind of help them feel more calm uh propanolol is more Hydro I'm sorry more lipophilic natol is more hydrophilic and is renally eliminated and so you have to be careful on renal impairment this drug can accumulate because it has a pretty long halflife compared to propanolol now propanolol is more uh eliminated by the liver and you can see that it's a substrate of multiple isoenzymes of the cytochrome p450 system so there is small risk for drug interactions but it is lipophilic now being a lipophilic beta non-selective beta blocker it is used for also you know like I was mentioned anxiety and stuff but it's also used for for migraine prophylaxis and if you think about this migraine being in the brain I've got to get if I want a drug to do something to the central nervous system I've got to pass through that bloodb brain barrier the only way I'm going to pass through the blood brain barrier is to be lipophilic and pass through that um so be more lipid friendly and loving um that's good and it's bad okay obviously uh lipophilic beta blockers as I mentioned earlier that get in the central nervous system can also make you feel real tired and can worse depression right and it can cause uh you to feel fatigue but it also causes constriction of those blood vessels because it's blocking the beta 2 receptors and that can be helpful in patients suffering from migraine so we don't see natalo being used for migraine prophylaxis because it doesn't get into the central nervous system but we also don't see as much depression and fatigue with nla because of that reason so there's pros cons and that's where pharmacotherapy comes in a place where you pick the right drug for the right clinical scenario and right situation and you you use it when you utilize some of those side effects into your favor or you avoid certain drugs to prevent that side effect from happening in a patient where there are higher risk for that side effect to be manifested even more so and then the last drugs listed here are the mixed beta blockers so they they can and block beta 1 and beta 2 but also Alpha 1 and remember even though that the beta 2 receptors are being antagonized sometimes in the blood vessels and that causes constriction you're also blocking the Alpha One receptors which which when they're activated cause Vaso constriction so if I block Alpha One if I block them then I'm going to cause vasod dilation and so you get some effect of Vaso constriction but you also get some vasod dilation the net effect of these drugs on the blood vessels is a net vasodilation and that's why carvol and Le alol tend to be better anti-hypertensive medications for lowering blood pressures compared to the other agents selective and non-elective now carvol um and LOLOL um a couple things well carvol has very specific use in heart failure um whereas we don't see that with leol and within the context of heart failure you have to start out at a very very small dose and titrate very slow because of this effect on the alpha receptors the patients can feel really bad for that first two weeks of starting to use the medication and you really need to titrate it slowly um in that context so every two weeks titrate up until you get to Target doses now Leal La is also used a lot in uh females who are suffering from preeclampsia um during pregnancy so it can it can help manage blood pressure pretty efficiently and so a the American College of obstretrics and Gynecology list uh le la is one of the recommended agents so which beta blockers are known to reduce heart failure this is a core knowledge point and integrates into the clinical practice environment so we have carvol that has a FDA proved indication we have Metropol succinate okay specifically Toprol XL not the tar trait they both have mortality reducing data um and to support and I listed those clinical trials and references here for you unfortunately uh Zaba or bopol has no uh has data to support its use but no FDA approved indication and so if you want to be technical um and legalistic about that you you use these two now someone may say well which one is better carvol or mopol succinate and unfortunately there have been no head-to-head trials with those two formulations to prove or answer that question all right which beta blocker must be started low dose and titrated slowly again this goes back to our Carval La so as I mentioned that and I'm driving home this point through repetition because it's important clinically and failing to consider this can worsen your patient and make them feel so bad that they end up having to be admitted and two that you need to communicate to your patient so that they're aware that this is going to happen and they'll push through it because when they feel bad for that first 10 to 14 days okay when they come out of that that window they're going to feel better and if they don't realize that that's only a temporary feeling then they're going to give up and they're not going to be probably be very trust uh happy or trust you if you don't communicate so talk to your patients and counsel them about this and make sure that you start the right Doses and titrate appropriately so we start out at low doses twice a day unless you're using the long acting agent you titrate every two weeks so remember that's going to get them they're every time they every time you titrate they're going to go through a little slump and you got to counsel them again okay you're going to go through another little slump just stick with it pull through you know call us if you need anything but stick through it right till we get you to these Target doses Target doses are somewhere around 25 to 50 milligrams twice a day and so that becomes uh that becomes important for them to realize that where they're trying to go and they will make it if they stick through it and they and they work with you and you titrate it appropriately so that is why um if we do it too fast then it's going to cause a heart failure exacerbation basically they're going to have that negative inotropic properties they're going to have a reduction in their blood pressure they're going to feel terrible and they're going to become more short of breath and that leads to nothing but non-compliance and then they won't trust you and so then you're taking away a drug that is known to reduce mortality and you know again don't do that okay all right so why is IV B metoprol okay and this is mol tartrate 5 milligram every 5 minutes time three no longer really used an N stemi but still is used in stemi so this is a unique spe specific clinical scenario within the context of acute myocardial inunction or ACS where there's actual heart damage so historically people used to do this um where we would give IV beta blockers and then convert them to oral agents in the acute setting so in the emergency department we would initiate beta blocker IV and um the data you know in the some of the trials had showed that there was any mortality benefit um however okay while it didn't reduce mortality it did reduce the rate of reinfarction and the onset of vfib you like well that's pretty significant yes it is but unfortunately it's offset by an increased risk of cardiogenic shock now and and who are those patients who go into cardiogenic shock okay U these are older patients over the age of 70 whose systolic blood pressures are usually lower and they're usually already B bra cartic and so in a select group of people you do want to be careful with the use of IV beta blockers in them and that is one of the reasons why the recommendation is that we start beta blockers orally within the first 24 hours of the uh of admission from the onset of these um symptoms that caused the heart failure um sorry M Mi assuming there's no contraindications which we'll cover in a little bit okay all right so uh how can beta blockers reduce the risk of sudden cardiac death and viib in heart failure and the reason I pose this question and it becomes relevant is in the early 1990s beta blockers were considered contraindicated in these patients because of their negative inotropic FS it made no sense whatsoever to give a a disease state that has poor contraction and low inotropy a drug that causes even worsening inotropic effect and worsens cardiac output um so why on Earth you know what was the shift in the Paradigm so back in the early 1990s it was contraindicated and now we we really push them and use them in heart failure and so it's the answer is three-fold one is is that it reduces the remodeling that increases noal Cell Activation and what I mean by activation it precipitates some of these you know PR rhythmic kind of effects that makes you more irritable um as a heart tissue and so you can have a chronotropic um effect where we a we affect the rate of rise and if you achieve the threshold faster and you're running your heart is beating faster then you're more likely to increase oxygen demand and then precipitate a cardiac drimia um and so that that scar tissue that forms um precipitates that risk of a re also a a um not only does it affect the noal cell but it also affects the ventricular myosite um and the ventricular myosite then then can go into vac when it develops these the scar tissue so remember beta blockers reduce remodeling well that comes into the context of vac and V FIB where we have can runs of Beats or we can have you know depending on the length of the number of of Beats of vac that you have um influences what we call it but if you have loss of consciousness now you have you are typically pulseless uh vtac V fig that's Cardiac Arrest uh and that can happen that's what sudden cardiac death traditionally is is it's a sudden onset of vtac or V FIB that cannot profuse your organs and so you lose Consciousness um at first and that has to do with the fact that over time as you you develop uncontrolled hypertension or you've had a heart attack and you start to have remodeling the remodeling areas create problems for conduction of electricity through the ventricular myosite and what up ends up happening is you create a circuit that has a delay of profusion but if the if the if the the reperfusion of that of that ax potential back up into certain tissue occurs at a specific time then you can flip into this sort of circuit that creates the right that affect and that's what causes the vac and that doesn't allow for a ventricular filling and it starts to reduce the cardiac output which is why people end up passing out so if delm and Verapamil also have negative chronotropic and inotropic effects like beta blockers why are they not recommended in heart failure and that goes back to the fact that they do not inhibit remodeling process that that facilitates both noal cell conduction and that causes that um that risk of reentrant um tachus rmas which beta blocker must be given by an IV infusion pump well we've already said that that's esmolol or breva block it has a short halflife of 9 minutes um and so where do we most commonly see it used in practice okay so what cardiovascular emergency is asmol most commonly used firstline therapy upfront started as soon as possible aortic dissection hands down remember the aorta is the largest artery in your body and it houses a very large amount of blood and if you're having blood hypertension and taco cardia and the the wall of that artery is dissecting out and separating then that wall is going to become weak and if it we gets weakened too much and ruptures that patient dies okay unless you can somehow clamp that off and surgically repair it quickly which in most cases is very hard to do in the acute rupture and that's why when patients come in and they have evidence or concern for a aortic dissection you need to lower that patient's pulse down to around 50 to 60 as fast as you can and then you need to reduce that blood pressure usually using sodium nitroprusside get that systolic blood pressure close to 100 90 to 100 and get them and a stat consult to thoracic surgery that patient needs a surgical um intervention the antihypertensive agents that we're using are only a temporary um part of the solution now we also use esmolol or well let me say we don't use it there is investigations and there is discussions about using esmolol in even cardiac arrest and you might be like I don't make any sense why would I want to slow down the heart rate and reduce inotropy during the midst of a pulses cardiac event well part of the problem is remember they get too much sympathetic stimulation they may be precipitated into this vtac V fib and so there is a group out of Harvard that looked at um what happens if you give beta blockers in the midst of a code and basically what they found is they got some some improvement in Ros now it was a retrospective analysis so it's you know not a good study design it's prone to bias um it was a you know select group of of cases very very small sample size so it's nothing that you're going to change practice on but it it definitely raised the interest of are we in Cardiac Arrest giving somebody especially when we give Epi are we potentially worsening the scenario uh they gave a beta blocker to blunt some of the sympathetic stimulation of the heart to maybe give it a little bit of a rest and it and some of these patients bounc back and these this was given and if you look at this paper these were given towards the end of the code where many people would have called it or started calling it and and be done with it some of these patients did have improved Ros and were admitted and some a few patients actually survived to discharge now again I would not Advocate or say that we need to start everybody on esmolol during a cardiac arrest what I'm saying is cardiac arrest where there's a lot of sympathetic tone in stimulation May warrant the discussion of Are We given too many sympath athetic drugs okay and we're worsening the condition and there are studies going on right now looking at that um so this is our uh what what was I going to say here oh this is just showing the esmolol in our in our diagram I'm sorry about that 9 minutes right and so we only use it typically intraoperatively or in aortic dissection or when we have uncontrolled tus rhythmia and we want to get it under control and we want to be able to you know um slow the pulse down quickly now to summarize a lot of these effects this chart here is just showing you the different drug you know drugs that bind to different receptors and we can see here that the mixed agents Carval betalol effect our Alpha receptors you can see that even beta 1 selective agents at certain doses will start to antagonize beta 2 receptors and then of course we have non- selective agents natalo and propanolol um here that inhibit both now then as I mentioned we have hydrophilic um beta blockers and then we have our lipophilic ones that get into the central nervous system that can cause some side effects that we'll we'll also mention here in a minute propanolol being another one which is why we use it for migraine prophylaxis probably use more commonly for panic and Stage fight kind of disorders uh because of that reason and so the question of which beta blockers are useful in migraines again those that are going to be lipophilic and okay so they get in the central nervous system but also then um block the beta 2 receptors okay specifically because remember vaa 2 receptors when they're activated vasodilate blood vessels so if we antagonize them with beta blockers that and the right location then we will get Vaso constriction that reduces the perivascular edema around those blood vessels that increases that decreases the pressure and response okay now it says here another Clin clinical integration Pearl here which medication should you not give concominant with propanolol especially in migraines and the answer to that is DHE um because it's a sort of a non-specific monomin oxidase uh is just a strong vasoconstrictor and when it does that it um when you give that on top of a drug that's already facilitating Vaso constriction you get a synergistic or addtive vasoconstrictive effect and so you don't want to co-administer these two medications in the context of acute migraine uh for that reason which long acting beta uh blocker can be broken um in half and that's tool XL which is the succinate formulation not the tartrate the succinate formulation it is a scored tablet and scored being that you see this little um line in the in the indention in the tablet that allows you to break it now if you break it in half right here and they swallow it still whole you still get the extended release kind of effects if so that doesn't mean you can't crush it you can't grind it up um and do that you'll lose the um extended release effects and make it more immediate release are beta blockers contra indicated in patients with heart block well it depends on the type or degree of heart block that you have so first deegree heart block it is a relative contraindication whereas second and third degree or six sinus syndrome it's an absolute contraindication uh you better use uh or not use them in those patients can beta one selective agents worsen asthma well the answer is yes and if you think about that remember Bronco dilation of just like in the blood vessel Bronco dilation is dilation of the uh mediated by the beta two receptors so if I block the beta 2 receptors okay then I'm going to get uh some Bronco constrictive effects now remember beta 1 selective agents are selective okay but they're not beta 1 only so even with beta 1 selective agents you can see increases in Broncos spasm um because as you push the dose you lose the selectivity of that and so you have to be very careful and patients with hyperactive airway disease especially when it's not really well managed all right which beta blocker should be dosed adjusted in renal impairment okay kind of mentioned this a little bit earlier um with natalo but it's important to do that with also other hydrophilic hydrophilic beta blockers and that is a tenolol and don't forget about your class three anti- rythmic sodol which is uh remember it has dual purposes or du dual properties amiodarone is more lipophilic and which is why it's not listed here but sodol natol Atenolol classic make sure you readly dose adjust those drugs why do beta uh diabetics um um still sweat okay when they're T when they're having uh hypoglycemia while taking a beta blocker and this uh image comes from uh with use from ebm consult and you're welcome to use that site and and and see this article in full length with some of the information and data um but uh what happens here is if you look at um the effects on um so this is the adrenal glands and down here is the sweat glands okay so this is cardiac and smooth muscle so the sympathetic nervous system mediates a lot of things by norepinephrine as the transmitter the exception to that rule in the post klonic sympathetic nerve fiber is acetycholine at the level of the sweat gland it's the only component of the sympathetic nervous um sympathetic nervous system that uses acetycholine to inate an organ system whereas the other ones are typically norepinephrine um and so therefore because of that we are not able to block this and so therefore they're still able to sweat but we don't get the tacac cardia and we don't see the increase in pulse and blood pressure that occurs when we in the in the um Tremors that occurs uh during a hypoglycemic episode remember the body is having a stressful response into having a low sugar how do beta blockers worse in depression and also cause erectile dysfunction again those agents that are like lipophilic that penetrates through the blood brain barrier are going to reduce sympathetic tone sympathetic tone is going to cause you to feel tired fatigued right hopefully some of you are not asleep right now right but that so people feel terrible so they have uncontrolled depression and um they you might make it worse and this is very important to consider I've seen this numerous times um where patients just cannot tolerate it they get too depressed now in the context of erectile dysfunction the process of erection and ejaculation is automated and controlled by the autonomic nervous system so uh erection is mediated by the sympathetic nervous system and ejaculation is a mediated by the parasympathetic no I'm sorry got that completely backwards the erection is mediated by the parasympathetic nervous system and ejaculation is mediated by the sympathetic nervous system there's this there's this uh if you want to remember it point and shoot point P parasympathetic that's the erection shoot ejaculation sympathetic so if it helps you to uh remember it um so you don't get confused like I did that's a way to do that but unfortunately it can cause erectile dysfunction and on top of that depression also can worsen and cause erectile dysfunction as well so patients may not admit to these things they may not even be aware of it and think something else is going on and and so clinicians who are not aware of this may not even recognize it or even bother to counsel or ask the patient if they're experiencing this so let's summarize some of the side effects well obviously we have a negative chronotropic effect so we can see bra cardia so do not start a patient on a beta blocker who's already bra cardic all right I've seen that before think who should you not give a beta blocker for on a test if you give given a question ask yourself who should I not say this is the right answer to right do I have do I have braic cardia do they have second or third degree or six sinus uh third degree heart block or six sinus syndrome uh remember first degree heart block relative Contra indication second and third degree tend to be more absolute uh if they have uncontrolled hyperactive airway disease okay remember you're blocking beta 2 receptors and beta 2 receptors in the Airways cause Bronco dilation so if I block those beta 2 receptors I'm going to get Bronco constriction I mean think about albuterol it is a beta 2 Agonist it's stimulating the beta 2 receptor to dilate it so if I'm given a beta 2 antagonist or inhibitor then I'm going to cause Bronco constriction or Bronco spasm and so you have to be very careful in these patients including COPD patients because some COPD patients have a hyperactive component to their disease that's called acos asthma COPD overlap syndrome um uh it can mask the symptoms of hypog glycemia so they won't get the Tremors they won't get the shakes they won't get the taco cardia increase in blood pressure but they will still sweat um it can worsen and aggravate uh peripheral vascular disease so it can cause more claudication and the reason that it can do that is because you're getting the beta 2 mediated antagonism that so you get vasal constriction so if you've got blood vessels that are clogged up with atic plaque and you take a uh you know I mean just think about this blood vessel here and you got this big old plaque here and you cause Vaso constriction well now your diameter or your radius of that of that of that blood vessel has now been further reduced if I cause a spasm um and reduce blood flow so it can worsen claudication and PVD uh we talked about fatigue we talked about depression we talked about sexual dysfunction and just be careful you can see some rebound effects with acute withdrawal especially with our shorter acting agents so to pull it all together and summarize couple Core Concepts and fast facts One beta blockers are Class 2 Von Williams anti- arhythmic medications because of their negative chronotropic dromotropic and lucat Tropic effects uh they have also don't forget negative inotropic effects which reduce cardiac output that's not always a good thing right especially in our heart failure patients so they can feel bad but remember they benefit patients in heart failure because of their remodeling benefits okay um they are are not very useful as monotherapy okay as add-on therapy fine but not as monotherapy for hypertension only and selective are not only okay so when you if you have a beta 1 selective agent that doesn't mean that it doesn't antagonize beta 2 especially as you get the higher doses only two FDA approved beta blockers for heart failure that is carvol and Metropol sux andate or tool XL remember is z beta or bopol has data but doesn't have an FDA prud IND our lipophilic beta blockers and are more commonly used AR mopol and propanolol but you could also add on here carvol and LOLOL as well remember if you're starting somebody out in carvol for heart failure start low Doses and titrate slow every two weeks all right and don't forget to counsel your patient um and then bradicardia fatigue depression bronchospasm those are classic side effects that occur fast facts don't forget tool XL is split um or has that scored and so you can break it in half but not crush it and still contain maintain the extended release it's the only extended release product that I know of that you can actually break uh Bop r as I mentioned has data in heart failure but no indication and back in the 90s beta blockers were contraindicated okay but now they are the treatment one of the drugs of choice in addition to ACE inhibitors and arbs for the management of heart failure for reducing such sudden cardiac death