Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode, 131 I'm your co host, Dr. Kane, Speaker 1 00:35 and I'm Dr. Patel. And before we announce the exciting title of our episode, I do want to remind our awesome audience that there is a quick 15 second survey on vaccine hesitancy. It's right on our HelixTalk website, and we want to know more about what you have encountered as far as hesitancy is considered from covid 19 vaccine from friends, family, colleagues, patients, etc. We want to record more of an informed episode coming from the audience. So you're going to be on the front line contributing towards the content of this episode, and we really appreciate your time. So if you can finish that survey for us, that'll be greatly appreciated. Dr. Sean Kane 01:19 And while you're there, we might as well. Mentioned that we do have a mailing list now. So if you want an email whenever new episodes come out, you can go to HelixTalk.com click on the mailing list, subscribe, and then you'll get a nice email every three weeks on Tuesdays, whenever we release those new episodes. Speaker 1 01:33 So that being said, drum rolls for our HelixTalk episode 131 titled come one come all know everything about beta blockers. Dr. Kane, I believe this was one of our listeners suggested topic to dive more into different type of beta blockers available. So we are going to just do that, learn about the basic pharmacology. What are some of the pkpd differences? What's their evidence based use, efficacy and safety parameters? Exactly. Dr. Sean Kane 02:00 So. Dr. Patel, I think it sounds logical that we should start where probably most pharmacy students start, which is the anatomy and physiology of the adrenergic system, specifically those alpha and beta receptors, right? Speaker 1 02:13 And there's a category adrenergic receptor, you know, it includes more types, but let's focus it on alpha and beta, because that's relevant to our topic today. So mainly we have beta one receptor and beta two receptor, and when it comes to Alpha receptor, we have alpha one and alpha two. Beta one receptor mainly located in the heart. When I was in pharmacy school, I learned you have one heart. So remember, beta one it's located in the heart, but it's also in kidneys and fat cells. But when we talk about the effect of beta blockers, it really is coming from the effect on the beta one receptor located in the heart. And then we have beta two receptors. Again, these are mainly located in the bronchial smooth muscles of your lungs. You have two lungs, so beta two. Remember, two. And there are other tissues where beta two receptors are located in the periphery, for example, a vascular endothelium. You know, other other areas, such as uterine muscles, etc, but mainly in those bronchial smooth muscles of your lungs. Dr. Sean Kane 03:14 Then we've got the Alpha receptor. So alpha one, this is mostly in your smooth muscle, like in your vasculature, and then alpha two, it matters if it's on the pre synaptic side or the postsynaptic side. So if it's on the pre synaptic side, it's actually a negative feedback loop for your sympathetic tone. So if you activate the pre synaptic alpha two, it will shut down or decrease the amount of sympathetic tone that you have. And if it's on the postsynaptic side, this has an effect on vascular smooth muscle again and also platelets Speaker 1 03:44 once again. There there's two different types of adrenergic receptor antagonists available, the alpha antagonist and the beta antagonist. And really the job of these substances or products or drugs you want to call it, they basically inhibit the action of adrenergic neurotransmitters. These are your epinephrine and norepinephrine on the respective receptor sites. So understanding this anatomy and physiology is important, because now we're going to dive into the pharmacology of these agents. Dr. Sean Kane 04:12 So if you go back to, you know, alpha one as an example, we said that alpha one is mostly in your vasculature, smooth muscle. So if you're blocking that, you're blocking the effects of epinephrine and norepinephrine on your vasculature, which means that it's going to cause vasodilation, and that is going to decrease your peripheral vascular resistance and drop your blood pressure. So an alpha one blocker is going to decrease your blood pressure because it's blocking the sympathetic tone on that vascular smooth muscle. Speaker 1 04:40 And alpha two, we kind of have to think about the pre synaptic and the postsynaptic, like you discussed earlier, Dr. Kane. So talk about it. Action in the periphery, the activation of alpha two leads to decreased sympathetic output from, you know, sympathetic nerve ending. So we have this nitric oxide released vasodilation occurring in the blood vessels. We talk about an action on the central nervous system. Basically, it decreases that negative feedback you mentioned, decreases the sympathetic output, again, decreases the output of the epinephrine and the norepinephrine. Dr. Sean Kane 05:16 And then, of course, we also have non selective alpha blockers as well, so they work on both alpha one and alpha two, yep. Speaker 1 05:23 And moving on to the beta receptors. We do have quite a few different generation depending on kind of what source you look at, but mainly they're non selective beta blockers and beta one selective beta blockers. So beta one, as I said, you know, it's sounds like it, it's more selective for the beta one receptor, the non selective effect both the beta one and beta two receptors. And let's not go into the generations, because they're just kind of who came first. And yeah, we have the newer ones and the older ones. But collectively, let's look at what kind of effect we would exert by using beta receptor antagonist in different areas of the body. So when we talk about cardiovascular effect of it, we know that beta blockers have negative ionotropic, meaning how how hard the heart is contracting in negative chronotopic, meaning how fast the heart is beating, activity in the myocardium. And overall, by doing this, it reduces the cardiac output. And if you remember the you know the equation for blood pressure, it's cardiac output times peripheral resistance. If you reduce one, you're going to reduce the overall blood pressure. Dr. Sean Kane 06:35 We also have, you know, an anti hypertensive quality for our beta blockers. So these do decrease renin activity, which can decrease your blood pressure as part of the renin angiotensin aldosterone system, but also they're going to decrease the peripheral vascular resistance. So they're going to cause vasodilation in your vascular beds, that will drop your blood pressure as well. Speaker 1 06:53 And as we said, there are beta two receptors located in your branch or smooth muscles, which are located in the lung. So blocking that in the pulmonary system, it's going to actually cause bronchospasms. And you know, in patients who don't have airway diseases like asthma and COPD, this is not much of an issue, but when they do have respiratory illnesses such as COPD or asthma, blocking the beta two receptors in the lung can actually cause more breathing issues and more aggravation of those conditions. Dr. Sean Kane 07:24 Kind of interesting. You know, most of the time when we think about sympathetic tone, we're thinking about heart rate and blood pressure. But we can also have metabolic effects of beta blockade. So blocking beta receptors can decrease gluconeogenesis from the liver, so you decrease the amount of glycogen to glucose from the liver. It also can mask hypoglycemia so patients won't feel some of the symptoms, especially like shakiness when they get hypoglycemic. Because of the beta blocker, it can increase your LDL and triglycerides, which is not a good thing, can decrease your HDL, which is not a good thing. And then we do have some of our vasodilating beta blockers like Carvedilol, that can also increase insulin sensitivity, which typically is a good thing. So it's kind of a mixed bag. But when it comes to diabetic patients, the main thing that comes to my mind Dr. Patel is that they need to be aware as they initiate a beta blocker that it can change how they feel when they get a low blood sugar. Speaker 1 08:18 Yeah, absolutely. And that's gonna, you know, we're gonna revisit that again, and we talk about safety concerns from, you know, beta blockers. And then going back to its effect on the lipid levels. You know, majority of the profile is with the HDL, and its impact on the HDL and impact on the triglycerides, it does either increase LDL by a little bit or has no impact. So it's kind of looped that it increases LDL and triglycerides, but not to the same degree as it increases triglyceride by itself. So Dr. Kane, you know, we kind of talked about the Alpha receptor, beta receptors and their subtypes. There are actually more subtypes of beta blockers. So let's dive right into it. We have a total of four categories. And depending on what literature you're looking at, based on the PKP properties, they might be divided into more subtypes, but we normally based on their receptor activities, we have four of them. So we have non selective which impact both beta one and beta two receptors, or cause antagonism there, and as we discussed earlier, it's going to result into more vasoconstriction, bronchoconstriction, like you discussed about insulin sensitivity, Dr. Kane, it may delay recovery from hypoglycemia and type one patient, because of that, glycogen to glucose conversion doesn't happen Very quickly, and also it impairs exercise performance in some patients too, and these are, you know, commonly, your nadolol, propranolol, and timolol. That's going to be your non selective types. Dr. Sean Kane 09:50 Then we have our beta one selective, or sometimes called cardio selective, beta blockers. These are generally preferred in patients that have reactive airway disease like asthma and COPD, because. We lack that beta two blockade that is predominant on the lung. Some of these beta blockers, many of them at higher doses, they kind of lose some of that selectivity. So Metoprolol is a great example. Once you exceed about, like 100 milligrams a day, you do lose some of that beta selectivity, and you basically end up with a beta one and a beta two blocker. But the main ones for this cardio selective beta one blockade are going to be Atenolol, which from our previous episode, we actually gave atenolol an award for being one of the worst antihypertensives on the market. But better would be Metoprolol tartrate, or succinate, betaxolol, bisoprolol, nebivolol is interesting because it has some other effects, specifically related to nitric oxide that can cause additional vasodilation, which is where its brand name of bistolic comes from, like decreasing your systolic pressure in two different ways, the beta one, selective blockade, and also the nitric oxide pathway that it works on. Speaker 1 10:54 Dr. Kane, I did not put the brand name for nebivolol together like that. That definitely helps to remember it better. And then we have beta blockers that have something called intrinsic sympathomimetic activity. And basically these agents, they do have reduction in heart rate and do have that negative inotropic activity, but it's less than the other beta blockers. And there's only two agents in this category that the acebutolol and pindolol and Dr. Sean Kane 11:23 I'm going to be honest, I've never, ever, ever seen a patient on either of these agents. I know I learned about them in school, but I have yet to see one in the wild. Speaker 1 11:32 I 100% agree with you. I haven't seen them either. Dr. Sean Kane 11:36 So then our last category are beta blockers that also have alpha one blockade as well. So alpha one antagonist plus beta blockers. These are unique, because that alpha one blockade is going to give you more of an antihypertensive effect by causing more peripheral vasodilation. We have Carvedilol, which comes as immediate release and extended release, and also labetalol. And these are also non selective beta blockers. So they're blocking alpha one, beta one and beta two. And again, it's the non selected beta blocker, plus a little extra in terms of that peripheral vasodilation, by blocking alpha one as well. Speaker 1 12:11 And so now that we know the four subtypes, more general subtypes, let's learn about some of the important pkpd parameters. And again, like I said earlier, this might be one way to kind of subgroup them separately. And the biggest one that comes to mind is this lipophilicity, you know, component. And basically it determines how fast the drug would cross the blood brain barrier. In order to do that, your your drug needs to be more lipophilic. And in order for them to cross the blood brain barrier and exert any effect in the CNS, such as, you know, tremor reduction, or, you know, migraine prevention and things like that. So if we can kind of take all of them and we can assign the levels of lipophilicity, we have low, moderate and high. The low lipophilicity agents are your nadolol, pindolol, labetalol, bisoprolol, nebivolol and atenolol. All your moderate ones are your metoprolol, either tartrate or succinate, betaxolol and timolol. Timolol kind of falls between low and moderate. And then the high lipophilicity agents are your Carvedilol and propranolol. Dr. Sean Kane 13:16 And as part of that, for example, with tremor, propranolol is commonly used for that, but that's also a reason why some of these more, higher lipophilicity drugs are more associated with cognitive effects like depression, is that they're getting into the brain. They're causing, you know, CNS effects, which sometimes can be what we want them to be doing, but sometimes it's also a side effect associated with those meds as well. Speaker 1 13:40 Yep, it's a double edged sword for some of them. So Dr. Sean Kane 13:43 then the next way that we can distinguish our pkpd parameters between our beta blockers is how they're eliminated from the body. So renal elimination, where you have to be aware of renal adjustments, and if someone has acute kidney injury, they may need an adjustment. The one that always comes to my mind is atenolol. So Atenolol, again, we gave it an award for being one of the worst antihypertensives, my least favorite beta blocker. But there's others out there too, like nadolol and bisoprolol. Those are way less commonly used. Atenolol is in our like, top 50 drugs prescribed in America. But there's three beta blockers that do rely on kidney elimination, and we have to be aware of that? Speaker 1 14:21 Yeah, there is a couple other in this category, not so much excreted by renal tissues, but more, just requiring renal dose adjustment. And then there is quite a few more in the hepatic elimination category. So again, similar to renal, you know, dose adjustment, these also require dose adjustment, the patient has hepatic insufficiency and even not use it in, you know, severely compromised liver conditions. And these are going to be your labetalol, carvedilol, metoprolol, timolol, propranolol, etc. And when we talk about hepatic elimination, you know, these are most of your beta blockers. Others are metabolized by a CYP enzyme, mainly the 2D6, 1A2, 2C19. And there's one or two that are metabolized by two c9 as well. Dr. Sean Kane 15:11 And clearly, you know, both with hepatic dysfunction, but also from a drug interaction standpoint, that's relevant, there are drugs that are going to block some of those pathways that will make the beta blocker stay around in your blood longer because of that drug interaction. Speaker 1 15:23 Yes, absolutely good to consider those drug interactions in mind too, and we will discuss them in a bit quickly summarizing. And we're not going to sit here to, you know, go over there's 15 or 17 different beta blockers here to tell you what are their starting doses, and, you know, what are their max dose or optimal doses, but the concept we normally drive home is to always start low and go slow. And when you're starting a patient on beta blocker therapy, and they're naive to this, beta blocker therapy, let them know that they're going to feel worse before they start feeling better, especially in the in the case, when they're initiated for heart failure therapy, they're going to feel more fatigued, they're going to feel more tired, and they're going to eventually get better. So they have to kind of stick it out with the therapy. Dr. Sean Kane 16:09 Another key point with these is that patients should really try to avoid abruptly stopping these therapies. Basically all beta blockers have a boxed warning saying that you should not abruptly stop because it increases the risk of angina, especially if you have coronary artery disease. Basically, you're going to make the patient extra tachycardic because they're going to withdraw from their Beta Blocker, and if their heart can't handle the stress or strain of being tachycardic, they can have a heart attack. So all of these have box warnings, and patients should be aware that they really should avoid missing doses, and certainly should avoid abruptly stopping without some tapering approach or kind of talking to their prescriber about that the Speaker 1 16:46 antihypertensive effect of the beta blockers, you know, just like any other antihypertensive, it is dose dependent, but so are the safety issues we talked about how beta one receptor, you know, antagonist, the beta one specific beta blockers, when they, you Know, dose increases, they kind of start losing that selectivity to the beta one receptor, you know, start affecting the beta two as well. So that's one example. And when it comes to regimens, you know, CHF patients definitely have a guideline directed medication therapy to follow, meaning they have certain doses to start as an initial dose, and then, you know, they're aimed to titrate or reach a target doses thereafter. Dr. Sean Kane 17:27 So as we mentioned, you know, this isn't just cardiovascular indications, although that's mostly what we're looking at in terms of place in therapy. You know, different beta blockers are used for a variety of different things. So if we think about migraine prophylaxis as an example, propranolol definitely comes to my mind. You know, that was one of our very lipophilic beta blockers. You'll also see some data from metoprolol tartrate, timolol and atenolol, but definitely propranolol comes to my mind again. A lot of that is driven by that lipophilicity of the drug, Speaker 1 17:56 congestive heart failure. You know, these not all beta blockers, but there's three beta blockers that have shown in primary literature reduced mortality, and that's your carvedilol, metoprolol succinate, not tartrate, and bisoprolol. And again, as we said earlier, for these agents, there is a certain, certain dose, initial dose that you want to start with, and then you want to aim to titrate the goal to reach that target dose according to the guideline directed medication therapy. Dr. Sean Kane 18:24 AFib is another very common disease state and a common indication for beta blockers to control ventricular rate. And a variety of beta blockers are actually FDA approved. A couple of the big ones that come up for AFib include Atenolol, for better or for worse, sotalol, metoprolol tartrate, succinate, carvedilol, basically any beta blocker will do, but only a handful of them have technically been FDA approved for afib. Speaker 1 18:48 And then we know that patients who've had a heart attack a myocardial infarction. You know, there is evidence that for morbidity and mortality when beta blockers are used, minimum three years post the first event. And so you know, you're going to see patients on a lot of different agents again, but metoprolol and carvedilol is commonly used, especially when patients have left ventricular dysfunction. Carvedilol is preferred. Dr. Sean Kane 19:15 And then for as an antihypertensive, or even for angina, most beta blockers do carry an indication. There's not really a particular one that's better or worse for this, but a variety of them can be used. Speaker 1 19:26 And Dr. Okay. And, you know, talking about how many different types of beta blockers are out there, you know, some of the agents, like we mentioned one or two times earlier, they're just not used. You know, nadolol, timolol, we're not gonna see those agents being prescribed as commonly So, like if preparation for NCLEX, or what you kind of see more commonly in practice, think about those top 200 beta blockers you know definitely in mind. But one beta blocker that kind of stands out to me is labetalol, especially in pregnant patients. And I know we have recorded a use of labetalol as a special beta blocker or a special anti hypertensive in a different episode. But we want to keep that in mind. labetalol has a really good efficacy and safety outcomes in patients who are pregnant and need to be on antihypertensive therapy. Dr. Sean Kane 20:14 And I would say, Dr. Patel, it's not so much labetalol is particularly good in pregnancy. It's more that it's the main studied beta blocker, and we just have better data and know more about it in pregnancy. So it's not that any other beta blocker is bad, per se. It's just that labetalol tends to be the one that has been studied in pregnant women, right? And the beta Speaker 1 20:33 law comes with a wide range of doses, and so titration of the doses need to be occurred, you know, according to patient tolerance of side effects as well. So that's that's definitely to keep in mind. And then tremors is an indication. Again, any beta blocker that is lipophilic, highly lipophilic, it's going to cross that blood brain barrier. However, propranolol seems to have the most evidence and FDA indications for the control of tremors. Dr. Sean Kane 21:03 So that's kind of on the efficacy side in terms of FDA approvals or common uses for these beta blockers. Let's flip it a little bit. So what about the safety concerns? What are things that we need to look out for in terms of adverse effects or precautions with these beta blockers? Speaker 1 21:18 First and foremost, something that comes to mind is bradycardia. You know, we tell students always that, you know, you think about monitoring patients heart rate, mostly our patients who have other AV node conduction defect, or maybe they're receiving other medications that can block conduction at the AV node, such as, you know, digoxin or calcium channel blockers such as veropamal or delta are going to be at a higher risk for having bradycardia. Again, you're duplicating the effect on the AV node. Dr. Sean Kane 21:46 There one for me. Dr. Patel comes up a lot because it's really goofy as heart failure. So beta blockers cause heart failure or worsen heart failure, and yet we also use them to treat heart failure. It seems like a contradiction, but it's actually not so in patients who have an acute exacerbation of their heart failure, where they have acute decompensated heart failure, giving a beta blocker to that patient will make their heart failure worse. But once they've compensated, once they have kind of stable heart failure and they're euvolemic On physical exam, they're ready to go home and things like that, a beta blocker will actually prolong their survival over a long period of time. We literally used to think that beta blockers were contraindicated in heart failure, and now we recognize that they are one of the core treatment regimens for heart failure. So it's kind of odd and weird, but when the heart is really decompensated, we don't want to have a negative inotrope on board. But once it's more compensated and back to a stable baseline. This is going to prevent some of the neuro hormonal changes associated with especially systolic heart failure, and it can prolong survival in those patients. Speaker 1 22:51 And actually, based on that survival data, Dr. Kane, you know that it's actually included into the Medicare's reimbursement model. So you have a patient that's newly diagnosed with heart failure coming in, you can't give them beta blocker, but you got to stabilize them. And as they leave the door, they have to be on beta blocker. So that's something that you know Medicare payment guidelines look for. But in addition, what we need to know is that this is only pertaining to when you are starting a naive patient on a beta blocker who is an acutely decompensated heart failure. If a patient is, let's say, already have chronic heart failure, they're already on, you know, beta blockers, but they do come to the hospital with some decompensation. You can continue that beta blocker therapy. It's, it's just for the new initiation patients. Dr. Sean Kane 23:35 Absolutely true. It's so goofy, right? Dr. Patel, because there's all these, like, little, tiny rules to know about beta blockers with heart failure, Speaker 1 23:41 yes, and I'm sure you interact with, you know, all these rules, and kind of have a lot of education opportunities, because you deal with this patient population more frequently. For sure, Dr. Kane, a third concern, and you kind of mentioned that earlier, that it's a black box warning on most of the beta blockers is withdrawal issues. And therefore the big, big warning sign is to do not abruptly discontinue beta blockers. And it's really because, you know, once the beta blockers are stopped, there is that increased sympathetic activities that can occur. However, what we need to remember is most beta blockers is going to require about couple weeks of taper regimen. So it's a really important patient education point to make sure that they are not stopping it abruptly, even though they're feeling that fatigue, or, you know, increased tiredness, that they reach out and we make a proper tapering regimen for them. And again, what's on stake is those increased ischemic events, such as exacerbation of an MI or even in some cases, ventricular tachyarrhythmias have also been seen that could result into fatality. Dr. Sean Kane 24:48 Typically, if a patient needs to stop obviously, if they have severe bradycardia, we're going to stop it, but if someone is no longer indicated for a beta blocker, they're going to need to taper off that beta blocker over a period of. A couple weeks to avoid some of these nasty side effects from occurring. Speaker 1 25:04 And in addition to some of these cardiac side effect we mentioned, there are a lot of non cardiac side effect. And as we discussed this, you probably will go back to our anatomy and physiology and, you know, pharmacology that we discussed. But first that comes in mind is these bronchospasms that are because of the beta two receptor, you know, antagonism resulting into that airway constriction. Again, we discussed that this is more common with your non selective beta blockers, but the beta one selective agents at higher doses may lose that selectivity as well, and in these cases, you know, either selective beta blockers are better tolerated Dr. Sean Kane 25:43 terms of peripheral arterial disease, we can see exacerbation of pad caused by beta blockers a little bit more common with non selective beta blockers versus a beta one selective. And the reason for this is that a reduction in cardiac output and beta two blockade can cause vasodilation to the point where the tissues don't get enough flow. So in someone who already has an issue with flow to the tissues like the extremities, this could be a problem. So we can see worsening claudication, cold extremities pulses becoming weaker, even absent, cyanosis, things like that. So typically, patients are going to know that this is happening, but the main effect is going to be that in their toes, fingers, things like that, that they're going to feel like they don't have adequate flow, because their peripheral arterial disease is being exacerbated by the beta blocker. Speaker 1 26:32 Dyslipidemia as a side effect. Again, less common with your mixed beta blocker and alpha one receptor antagonist type or the one with isa activity, but more common with your selective or non selective beta blockers. And as we discussed earlier, it can increase triglycerides to 20 to 40% which is kind of significant, if you think about it, it decreases HDL to about 10% there is maybe little increase in LDL, not nearly as much as the triglycerides, or sometimes no effect. So the verdict on the LDL is not as straight as the triglycerides and the HDL abnormalities. Dr. Sean Kane 27:07 And unfortunately, we also can see some weight gain with these therapies. Usually, this is more common when you initiate therapy, roughly speaking, we're looking at like a 1.2 kilograms. But it kind of is a broad range between losing point four kilos, all the way up to gaining three and a half kilos, from a systematic review, so kind of all over the place, but the typical average amount of weight gain is going to be about, we'll call it two to three pounds for a typical patient initiating a beta blocker, Speaker 1 27:35 and then right along my alley, Dr. Kane, which I have to you know, kind of educate patients about, and kind of continue to monitor, is hypoglycemia, and masking of the hypoglycemia as an effect, as we kind of talked about, how these agents block activity of the epinephrine. Epinephrine is our fight or flight hormone or neurotransmitter, but basically in where you're ready to flight or fly from a dangerous situation, your body needs a boost of energy. So basically, you need more breakdown of the stored glycogen into glucose, or new production of the glucose when you're blocking that activity by having beta blockers on board, when a patient is really, truly experiencing hypoglycemia, the conversion from glycogen to new glucose molecule, or even production of new glucose, it's kind of delayed. So basically, all are not going to recover from hypoglycemia as quickly when beta blockers are on board. Another thing that happens with blocking the epinephrine activity is you lose that adrenergic symptoms that are usually the indicated indications for having some sort of hypoglycemic episode, such as, you know, palpitations, tremors, jitteriness, you know, all that stuff. The only thing that doesn't block is sweating. So then you have to tell the patient, you know, you gotta watch out for sweating. And you have to be in in more practice of, you know, checking your blood sugar more frequently. And again, this issues happen less commonly with the beta one selective drugs, or drugs that have, you know, Isa activity, and as we discussed earlier, coffee is a little bit of an oddball. With that alpha one activity, it actually ends up improving that peripheral insulin sensitivity, so the uptake of glucose is a little bit better. Dr. Sean Kane 29:20 Dr. Patel as a critical care pharmacist, I feel obligated to mention that when we initiate epinephrine IV as a vasopressor for patients, we see tons of hyperglycemia for the opposite reason that beta blockers can cause hypoglycemia. So we definitely see this effect. Either having too much epinephrine gives you hyperglycemia, and then blocking through the beta receptor can cause hypoglycemia in certain patients. Similarly, we can also see effects on potassium. So in certain patients who have hyperkalemia, we may give them something like albuterol, in addition to other drugs to stimulate the beta two receptor to cause an intracellular shape. Shift of potassium. Similarly, with beta blockers, we can block the beta two receptor, and that can block some of that, the shifting of potassium in and out of the cells as well. So we can actually see a potassium effect, specifically hyperkalemia, caused by beta blockers, more common in the non selective beta blockers, but can happen in either one. Typically, I don't find this common clinically, but it is a theoretical concern for our patients. Speaker 1 30:25 Yep, and like you mentioned, Dr. Kane, especially in those patients who have other offending agents, such as an ACE inhibitor or ARB on board too, to keep an eye on it one side effect you mentioned earlier, Dr. Kane, and it could be because of the, you know, CNS penetration of one of those lipophilic agents like propranolol, but depression, fatigue, sexual dysfunction are commonly cited as adverse drug effect. I was pleasantly surprised to find the systematic review. It's actually a recent one that kind of tells you that maybe these are just cited in the labels, and we like to repeat it because it comes up in the label, but not really truly happening in our patients. So again, it may happen with lipophilic agents such as propranolol. And so those early generation of beta blockers rarely seen in the newer ones. The earlier evidence that beta blockers cause depression, fatigue or sexual dysfunction came from case series and some randomized control trials, which had some methodological issues and things like that, but in recent systematic review, they found that there was actually no impact or no increase in depression, a small, significant increase in the risk of fatigue, and that took about one every 57 patients treated per year and small, significant increase in erectile dysfunction, and that was one patient per every 199 patients treated per year in one one of the small study looking at again, your favorite a Tylenol, also found that patients who, quote, unquote, had erectile dysfunctions with the Tylenol and were given a PDE five inhibitor, and those who given placebo had similar effect in resolution of Ed. So it can tell you that, really, it's just a placebo effect of Ed and not really true. And if you look at somebody, you know, we have monumentous outcomes when it comes to morbidity and mortality in such conditions such as no post mi or heart failure, and having one patient have an ED issue when you're treating 199 patients to avoid those repeated, you know, heart attacks or worsening of heart failure, that beta blocker still wins. Dr. Sean Kane 32:42 Dr. Patel, I find that fascinating that potentially some of these side effects that we commonly associate with beta blockers, it's more dogma and kind of historical reasons that we associate them, and it's always interesting when it isn't borne out in the literature, but it's something that's kind of passed along within pharmacy schools and common medical education in general. So I love the fact that maybe some of these side effects are a little bit overblown and maybe not even true, but it's been passed along, because that's how we learned, right? Speaker 1 33:10 That's true. And, you know, it's, it's one of those things where, you know, patients read the leaflet or the label and they think that they have the side effect, you know. And so one of those reports, but this systematic review definitely proven otherwise. Dr. Sean Kane 33:24 You know, another thing to think about with these beta blockers is drug interaction. I mean, the list could go on and on in terms of interactors with our beta blockers. For me, something I fairly commonly see in the ICU is where we have multiple therapies that are blocking the AV node. So it's not so much kinetically that we're changing the beta blocker itself in terms of its half life or disposition. More what's happening is that we just have multiple therapies that are black in the AV node that cause bradycardia. So combining a beta blocker with a non dihydropyridine calcium channel blocker like diltiazem and verapamil, antiarrhythmics, digoxin, amiodarone, things like that, even phenytoin or quinidine, these can also cause a bradycardic effect that could, you know, exacerbate a bradycardia for patient already on a beta blocker. Speaker 1 34:11 Most of you know beta blockers, you know, even though they're not primary antihypertensive agents, but when they're used with other agents, such as, you know, those who have clonidine withdrawal, those who patients are using ergot alkaloids, obviously epinephrine or methyldopa use, it's going to actually result in high blood pressure, instead of trying to do the opposite. Dr. Sean Kane 34:34 We can also see a change in metabolism caused by smoking, probably through the 182 pathway, and then also rifampin as well, so that can increase metabolism of these beta blockers. Speaker 1 34:44 And the beta blockers cardiovascular effect could be also blocked by agents such as, you know, tricyclic antidepressants. So kind of watch out for that. And moving on from drug drug interaction, the drug disease interaction, as we talked about how. For glycemia masking in the diabetes patients, or, you know, poor glucose recovery in type one patients with diabetes is something to keep in mind and as well as educate the patients about. Dr. Sean Kane 35:13 So then finally, Dr. Patel in terms of monitoring, you know, if a patient is initiated on a beta blocker or their dose is increased, clearly, like, the number one thing that comes to my mind is going to be, what is their heart rate on that beta blocker and what is their blood pressure? Even if you're not giving it for a heart rate reduction or blood pressure reduction, it's still going to affect those two vital signs. So you need to know how bradycardic they are, or tachycardic, and what their blood pressure is in terms of, is it safe to continue that beta blocker for the patient? Speaker 1 35:40 Absolutely, you know, and like we said earlier, they're not used for their anti hypertensive effect as much they are for their other cardiovascular effects. So heart rate and blood pressure or something low hanging fruits, we normally do it, but those patients who are on beta blockers for maybe heart failure or post mi other parameters, such as, you know, doing an EKG or echocardiogram, those all could be monitored, but this for particularly as their decreased contractility effect, there are direct measures for their metabolic side effects. You know, you could consider doing weight checks as well as, you know, checking the lipid panel. However, the impact on the weight is not as significant unless they're on other medication that can medications that can cause, you know, weight gain. Dr. Kane, you mentioned there is not a huge impact on the potassium levels. But you know, most likely, we're going to be doing a cmp to do other electrolytes checks, especially in heart failure patients. So we're going to be monitoring those as well, and then right along my alley again, watching out for hypoglycemia, monitoring blood glucose closely in those patients who are at a higher risk will be required. Dr. Sean Kane 36:47 And then you know if they're taking it for migraine. For example, you got to know if it's working. So many of these patients will have a migraine diary to identify how effective the drug is, because if it doesn't work for migraine, then they shouldn't take it. And then, just generally, ADR monitoring. So we went through a number of side effects and can occur from our beta blockers. And monitoring for those side effects is really important, because a patient may not realize that their beta blocker causes a worsening of their peripheral arterial disease, for example, and that's something that they need to know, or you need to monitor, as the healthcare provider for that patient. So that Speaker 1 37:20 being said, Dr. Kane, I think we're ready to wrap up our today's episode with some of the highlights. Yeah. Dr. Sean Kane 37:26 So one highlight for me, especially for students that are just learning about beta blockers, we can kind of logically put these in different buckets or categories, and of the beta blockers that are out there, only a portion of them are really commonly used clinically. So I'd encourage students to think about, what are beta blockers within the top 200 drugs, and then of those divide them into their subtypes. So which ones are non selective, which ones are beta one or cardio selective? Which ones are beta blockers with Alpha One blockade and then not commonly used? But what are the beta blockers that have that intrinsic pathomimetic activity, or ISA? If you ever saw one of those in the wild, that would raise a huge red flag for me, because they're so uncommon, but also a very unique pharmacology to them as well. These subtypes are important because it dictates side effects to expect potentially indications or place in therapy. You know it matters in terms of what the pharmacology is, and that helps you not have to memorize every single fact about every single beta blocker in the market. Speaker 1 38:25 When it comes to dosing, keep in mind we're going to start low and go slow, and while the antihypertensive effect could be dose specific, in order to really get that morbidity and mortality benefit for heart failure patient, you have to follow the initial doses and target doses as outlined in the guideline directed medication therapy. Definitely don't want to start them as a new agent in acutely decompensated heart failure patients. And definitely do not want to abruptly stop the therapy. It has to be taper over one to two weeks if they're going to be on chronic beta blocker therapy. Dr. Sean Kane 39:01 And then, just to highlight, you know, we don't use beta blockers as first Lange anti hypertensives, based on the 2017 ACC ha hypertension guidelines. But if patients have compelling indications, they may be on beta blockers for those compelling indications and happen to have hypertension. So for example, heart failure, post MI, afib, migraine, tremor, things like that. There are indications for beta blockers. So these are not off limits, but they're also not first line therapy for undifferentiated hypertension, and we can Speaker 1 39:31 provide a very long discussion about their safety while they are omnipresent, Omni treating agents, their side effects are also very wide when it comes to cardiac side effect, bradycardia is more common and non cardiac side effect, you know, kind of bronchospasm or bronchoconstriction, weight gain, dyslipidemia could be seen. More of the severe side effect are going to be heart block because of the AV node. Uh, conduction activity, exacerbation of the, you know, acutely decompensated heart failure. And then if you were to do acute withdrawal on somebody who's been on a chronic therapy, then the risk of increased morbidity and mortality due to ischemic events or arrhythmic events. Dr. Sean Kane 40:16 Well, Dr. Patel, I think that does an excellent wrap up of, you know what a typical healthcare provider needs to know about beta blockers. I would encourage our listeners to head over to HelixTalk.com we do have that survey, a very brief survey on vaccine hesitancy for an upcoming episode. We also have the mailing list. So if you want to get an email when new episodes come out, you're welcome to do that as well by signing up and kind of the normal spiel. So we're on Twitter at HelixTalk. If you want to get some clinical pearls in your Twitter feed. We also love the five star reviews and iTunes that helps us kind of grow our audience and reach more healthcare providers that want medical education in their ears. So please do consider going to iTunes and providing us those awesome five star reviews. So with that, I'm Dr. Kane and I'm Dr Unknown Speaker 41:01 Patel, and as always, study hard. Narrator - Dr. Abel 41:05 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. 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