Speaker 1 00:05 Lange, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University College of Pharmacy. Narrator - Dr. Abel 00:11 This podcast is produced by pharmacy faculty to supplement study material and provide relevant drug and professional topics. Speaker 1 00:19 We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. Narrator - Dr. Abel 00:27 This is an educational production copyright Rosalind Franklin University of Medicine and Science. Speaker 1 00:32 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 - Dr. Abel 00:47 And now on to the show. Dr. Sean Kane 00:51 Welcome to HelixTalk. Episode 10. I'm your co host, Dr. King, and I'm Dr. Schuman, and I'm Dr. Patel, and today we're talking about kind of a fun topic, our clinical pet peeves. These are things that kind of drive us crazy, and we really want to educate the audience to help avoid some of the mistakes that we commonly see in clinical practice. So I'll go ahead and get started with a few of my clinical pet peeves. The first is the idea of a sulfa allergy, and whether that sulfa allergy cross reacts with other things that have sulfonamide groups or moieties on them. Speaker 2 01:24 It's a really good topic, because I get this question in the clinic all the time, Dr. Sean Kane 01:28 and I've heard at least one story of a new graduate pharmacist who started working at CVS or Walgreens and had this drug alert pop up that said that this patient was filling lasix or hydrochlorothiazide. They had a sulfa allergy listed in their profile whether or not that was appropriate, because, you know, loop diuretics and thiazide, like diuretics, do have sulfonamide moieties on them, and theoretically that could, you know, cause a problem. So the new pharmacist calls up the physician who wrote the lasix or the thiazide prescription and gets chewed out by the physician for the ridiculousness of his question. And it really is ridiculous. Speaker 2 02:06 And a lot of the drug interaction tools that are built in into medical records, when you know physicians try to put in the orders, these allergies do pop up. So if the patient profile contains that the patient has sulfa allergy, and if you're trying to put in, let's say, lasix or hydrochlorothiazide, it might pop up as a, you know, sul allergy, but then at that point, that's where you need to exercise your clinical judgment and see if it's a really a true allergy or not. Speaker 3 02:32 I think that's one of those. It's kind of that double edged sword of using, of having access to some of these great databases. Sometimes they can get just enough information to raise a red flag, but without any kind of a context. And so you have to dig deeper, lest you raise all the alarms at that point, and in this case, find yourself maybe at the mercy of a more experienced clinician. Dr. Sean Kane 02:51 And what we're actually finding is that some of the computerized databases are getting a little bit better, so maybe they aren't triggered with things like lasix and hydrochlorothiazide, but there's other drugs out there that do have this flag on them as a sulfa drug, so things like celecoxib or Celebrex, which is a Cox two inhibitor, sumatriptan or Imitrex for migraines. And there's a lot more of these sulfonamide containing drugs on the market that simply do not cross react with what we would consider a sulfa allergy, which is really saying a bacterial allergy or a sulfur methoxazole allergy. So really, for me, the take home point is that when you say you have a sulfa allergy, you're really saying that you have a sulfonamide antibiotic allergy. Non antibiotics are not relevant to that allergy. So that's my pet peeve number one. Pet peeve number two is quite related, and it's amiodarone with iodine allergy. If you actually pull up the package insert for amiodarone, you'll find that it says anyone with an iodine allergy is contraindicated to receive amiodarone. So this is the FDA approved package insert for amiodarone, the drug that's been on the market for decades and decades. The package insert says you can't take this drug if you have an iodine allergy. Interesting. Speaker 2 04:04 So from what I heard and from where I've grown up, in India, the salt itself contains some iodine. So anything that you eat with salt there is Iodine. If you're saying you're allergic to iodine, then that means you can't eat anything with salt either, yeah, this Dr. Sean Kane 04:19 is pretty akin to saying I'm allergic to water or I'm allergic to sodium. You know, iodine is a chemical element, and it's not big enough to be antigenic, and it's something that everyone has in their body. So what really people are trying to say is that they're allergic to maybe iodine containing substances that maybe had other things in them that caused an allergic reaction, maybe a patient had topical iodine as to clean a wound or something like that, and had kind of a hypersensitivity reaction. All of that's fine and great, but completely unrelated to having an iodine allergy. And actually, there was a study done showing that in over 200 patients that had a documented iodine allergy when they received amiodarone. It was completely safe in those patients despite their iodine allergy. So we've got good retrospective data showing it's safe, and we have no prospective data saying that it's unsafe with good scientific basis saying that that warning in the package insert is kind of ridiculous. And finally, my last allergy related pet peeve is penicillin allergy, and I think we've touched on this a little bit, but I think it's worth driving the point home that it's actually very safe to challenge a patient's penicillin allergy with a cephalosporin. So if we were to take 100 people skin test, them with a penicillin skin test, 80 to 90% of the people that said that they had a penicillin allergy would skin test negative. This is a very specific and sensitive test for penicillin allergy. So essentially, that means 80 to 90% of people are liars, or at least they thought they had an allergy, but they truly did not. And my Speaker 2 05:49 biggest pet peeve is towards the healthcare providers who document penicillin allergy in patients chart, they do not document the reaction. I cannot stress enough, and I'm sure Dr. Kane and Dr. Schuman can agree with me too that whenever you identify a patient with penicillin allergy, you have to follow up with the question, what was the reaction? What happened when you took it? Document exactly what happened. There could be rash, which is a minor reaction, versus there could be anaphylaxis, which is a severe reaction, and that is the true allergy to penicillin. Speaker 3 06:20 And then furthermore, one thing I've noticed is somebody who simply has a GI upset, especially in some of those, those older penicillins, that if you, if you experience some knowledge, or even to the point of some, some diarrhea, that that gets labeled in there, and because somebody maybe in the software is looking for the best way to flag it, it goes in there, as in, you know, an allergy, without any context, without any definition. Dr. Sean Kane 06:39 Dr. Patel, I couldn't agree with you more that with the growing role of the pharmacist in performing things like medication histories and reconciliation and discharge counseling, oftentimes it's the pharmacist that's putting in things like allergies. And in my mind, I completely agree with you. It's irresponsible to document an allergy without the reaction associated with that. There's almost no value in doing that. So of those patients that do have a positive, actually true allergy to penicillin, if we were to give them a cephalosporin, the cross reactivity rate is quite low, so anywhere from five to 15% depending on what resource you look at and of that, it's about less than point 1% risk of anaphylaxis. So if you kind of combine all of the probabilities, so 20% probability that they're telling the truth, let's say 10% probability of a cross reactivity, and a point 1% risk of anaphylaxis, your actual risk of a very severe reaction occurring in challenging a penicillin allergic patient with a cephalosporin is about 0.002% which is a very low risk. And there's a lot to be gained from challenging especially in very sick patients, like in the ICU that I work in, oftentimes, penicillin allergic patients will be re-exposed to things like ceftriaxone and a quinolone 5, 6, 7 times, depending on how often they're in the hospital, it's almost a guarantee by the third or fourth admission, they're going to have a quinolone-resistant E Coli in their urine. They're going to have a strain and resistant things like that. And if we can challenge those patients and document that we've challenged a penicillin allergy and they tolerated something like cefepime or ceftriaxone, there's a lot to be gained in terms of better antibiotic coverage. I absolutely agree with that. So kind of moving away from allergies, the other extreme pet peeve of mine, particularly because I'm a critical care clinician, is the idea of Creatinine clearance. And calculating creatinine clearance. So the most important thing to understand about Cockcroft-Gault and creatinine clearance is that these equations were validated and designed in people who have or in patients who have stable renal function, so their serum creatinine hasn't changed in a number of days. That's what those studies were done in. So when you come to my ICU and your creatinine goes from one to 1.5 in a 24 hour period, Cockcroft-Gault is not accurate in those patients, and at that point you have to use a little bit more clinical judgment. There are some equations for unstable renal function, but you can't put a lot of stock in the value of this creatinine clearance equation knowing that it wasn't designed for a patient with an unstable creatinine. Speaker 2 09:08 So in cases where patients are in ICU, or let's say patients are on perhaps hemodialysis, what other type of equations are available that are more reliable than just using Cockcroft-Gault? Dr. Sean Kane 09:19 Yeah, so the most common scenario in the ICU is going to be intermittent hemodialysis, which you don't even calculate Cockcroft-Gault creatinine clearance for. With those patients, you dose them for a hemodialysis patient, or you might find someone on what's called continuous renal replacement therapy, which is kind of a continuous dialysis or CRRT. And in those patients, we actually don't use their serum creatinine at all, and we can actually use the settings on the machine to figure out how much drug is likely being pulled off. It's called the effluent rate, which is similar to the glomerular filtration rate. We can use that for drug dosing as well. So really, Cockcroft-Gault is not appropriate in the hemodialysis patient, not appropriate in the continuous dialysis patient. In the ICU Dr. Dr. Kane. Speaker 3 10:01 Are there any other populations in which you want to be concerned that may be using the serum creatinine? May not give us a full picture of what's really going on in the kidneys. Yeah. Dr. Sean Kane 10:10 So again, thinking about the ICU patient, but also kind of chronically ill patient, you're going to see things like cirrhosis, where creatine has to be converted to creatinine in the liver. If your liver doesn't work very well, you're not going to make much creatinine. If you're malnourished, if you don't have a lot of muscle mass, you're not going to produce the creatine to be converted to creatinine. So again, you're going to have a falsely low level of your serum creatinine. And then also for obese patients. So with morbid obesity, we shouldn't be using ideal body weight, because these patients will have more lean body mass based on their body habitus. You know, it takes a lot of muscle to move around 400 pounds. But at the same time, using their actual body weight is inappropriate either, because all that adipose tissue doesn't make creatine to get converted to creatinine. So the best thing to do in that kind of patient is to use what's called an adjusted Speaker 2 11:01 body weight and I believe there is an equation for it. And the reason I mentioned this because a lot of students make this mistake, very commonly, on the rotation where they will use the same ideal body weight equation for a patient who is actually obese. And in those patiently, we're supposed to use the adjusted body weight equation exactly. Dr. Sean Kane 11:19 Then finally, the other population to think about is the elderly patient. So one of those bad things that have stuck around in the pharmacy world for decades is the idea of rounding a creatinine. So it's not appropriate to round an elderly patient's creatinine from point seven to one, because that same patient, if their creatinine was 1.2 you wouldn't round them to 1.5 or two. So it's unfair that you give someone a 30% bump for patient a, but for patient B, where their creatinine is already at one or above that you don't bump them as well. For those malnourished, elderly, low, lean body mass type of patient, you should be thinking about maybe a 30% reduction in their creatinine clearance, as opposed to just blindly rounding to one, because that's the number that you have always heard about or used so. Dr. Patel, I'm getting so worked up about my own pet peeves. I need someone else to vent a little bit. Speaker 2 12:10 All right, I'm ready for it. Dr. Kane, so my biggest pet peeve is actually the manufacturers, the pharmaceutical manufacturers. Obviously we've all heard of the racemic mixture drugs. And then few years later, you know this racemic mixture drugs go generic, and boom, there comes the active enantiomer drug in the market, obviously more expensive than the drug which has racemic mixture. And then the studies are done to prove that the active enantiomer drug is a little bit better than the racemic mixture drug. So I've kind of laid out three different combinations of, you know, racemic mixture drug versus the active enantiomer drug. The first and the foremost one you probably have heard if you're working with patients who have asthma or COPD is albuterol versus levalbuterol. Albuterol brand name goes with ProAir or Ventolin. Levalbuterol, the brand name is Xopenex. If you compare, I'm going to start out with the cost. Xopenex is way more expensive than ProAir and Ventolin. Now the rationale is that levalbuterol is better than albuterol because it gives fewer tachycardia better tolerability in terms of this tachycardic anxiety type of side effects or and then they have similar or greater efficacy, because again, we are dosing the same amount of active drug instead of giving a racemic mixture. Dr. Sean Kane 13:29 Dr. Patel, why would we see less tachycardia with levalbuterol or Xopenex, as opposed to albuterol or ProAir Ventolin? Speaker 2 13:37 The reason behind the tachycardia here is obviously albuterol, we know is a beta agonist, and our beta receptors are not only in the lungs, they're also resided in the heart. So so the albuterol, especially when it's dosed at a higher doses, can also affect the beta receptors in the heart, and that is why we see things like tachycardia or arrhythmic type of rhythms in the heart by taking a higher Dr. Sean Kane 13:59 doses of albuterol, great. So it seems like slam dunk we should be using leave albuterol. It's the pure form of the drug, and it causes less tachycardia. What could be wrong with that strategy? Speaker 2 14:11 Well, funny thing is, there are a few studies done, and the studies are showing conflicting results. So when we are choosing between albuterol versus low albuterol, we're looking at patient by patient basis. So if your patient is has COPD or patient has asthma and has other cardiac conditions such as arrhythmias, or, you know, atrial fibrillation, or have CHF or any other type of valvular condition, they might benefit with the albuterol compared to the albuterol. There was one proposed mechanism that gives open x to the kids because it doesn't cause the hyperactivity, such as the albuterol does. That myth is totally debunked. Both the medication have the same efficacy as well as safety profile in children. There you go. One is not better than the other. And if you want to save some money, go with the albuterol, which is your pro air or Ventolin. Dr. Sean Kane 15:00 So Dr. Schuman, I bet the VA is just chomping at the bit to give out Zopa next to every patient that they can find, right? Speaker 3 15:06 Of course. I mean, you know, just maybe, just scan a little bit of data should, you know, should be enough, and just, just switch everybody over. The cost, Speaker 2 15:13 alright, the second combination, it's fairly recent, I would say, in about last three or four years, we have a drug in the market called lansoprazole. The brand name is Prevacid. Now you can see that over the counter as well, and the active enantiomer drug dexlansoprazole then came in the market when Prevacid patent was about to be expired, and the dexlansoprazole brand name is Dexilant. So the idea behind the name Dexilant was because it's excellent. So again, the studies are done to debunk this myth as well, and we found that comparative efficacy are the same. The only advantage with dexlansoprazole is it has a dual delayed release mechanism. That means that all the other PPIs, including one suprasal patient, have to either take it on empty stomach, if they were taking once a day dose in the morning, or a little bit before they were ingesting the meal. Versus the ducks and suprasal, because of the dual delayed release formulation, it can be taken with the meal as well. Speaker 3 16:15 So if they've been able to then, of course, they've gone and seen that it has much better efficacy. Then right based upon Speaker 2 16:20 that, not at all the comparative efficacy for both Lanza prism and dexlantoprazole have been proven the same. Dr. Sean Kane 16:25 So Dr. tell I'm going to call shenanigans on you here, because I know that dexalant is a dual release mechanism, where you have this immediate release, then later on you have this other release that's totally different than what Prevacid offers lanso Brazil, which is one and done, it's an immediate release. The drug is gone very quickly in the body, so certainly higher drug levels over a longer period of time with Dexilant, dexlansoprazole, should have better efficacy. Speaker 2 16:53 And a lot of clinicians do believe that, because of the same very reason that you mentioned over here. But we not only look at the drugs pharmacokinetic effects in the body. We look at how patient is feeling overall. So in the studies, when they compared Okay, how many patients got the relief from GERD or how many patients had reduction in pH, there was no difference between these two medications. So we're looking at clinical outcomes, and not really the kinetic profile of these two medications. Just one more. While we are on the topic of about proton pump inhibitor, everybody knows Nexium just came out as an OTC product, so I'm talking about esomeprazole. Brand name is Nexium versus omeprazole. The brand name is Prilosec. We all know Prilosec has been over the counter for a few years now, and Nexium is pretty new. When Nexium was put in the market, the manufacturer was driving it in the market, saying it's much better than Prevacid or any other PPIs that are out in the market. And again, clinical studies have been done and this myth has been debunked. The reason behind the manufacturer of Nexium driving this thought process was that all the other PPIs, including omeprazole, were heavily reliant on the CYP2C19 metabolism. Now we all know CYP2C19/P450 enzyme is highly correlated with polymorphism, and there was a huge patient variability among the PPI agents as well as doses. The manufacturer of Nexium was saying that, okay, well, there is less CYP2C19 metabolism of Nexium itself, and so we're going to have a little bit more predictable effect with the Nexium dose compared to the others. However, there were studies done with variable different doses of omeprazole versus variable different doses of esomeprazole. And the studies have found that there was benefit in terms of pH reduction in terms of Nexium being more in favor of the Nexium compared to the Prilosec, which is omeprazole. But there was no clinical correlation. Again, pH reduction. And I guess this is opening up to the next topic Dr. Gaines gonna talk about is a surrogate marker. So yes, it's great to chase the surrogate markers, but in in real life, we're making patients feel better, right? If we tell our patients, we increase your pH from 2.0 to 4.0 they're not gonna be happy if they're still feeling bad. So we're looking at a clinical picture, and many studies compared the whole clinical picture, there was no difference between omeprazole versus esomeprazole. So I think I'm done with my run of racemic mixture drugs versus the active enantiomer drugs. Dr. Sean Kane 19:34 So Dr. Patel, before we move on, you've listed three different drugs that are enantiomers that were basically patent extenders for drug companies. So in the future, when we see and we will more enantiomers come out, more patent extenders come out, what are some of the characteristics that make these newer drugs that really should set off red flags to clinicians saying, Is this really a better drug? Is it really worth the cost of the medication or. Is it kind of hype from the drug company? Speaker 2 20:02 And I think I would agree with all three points that you mentioned, the clinicians need to have a really keen eye on it. Obviously. Look out for the comparative efficacy. Look out for the patient cost factors as well. I think that drives the point home a lot of the time whether patients can afford the medication or not. And one thing goes without saying, if patient cannot afford it, they're going to find ways to cut cost, which means they're not going to have good compliance with this medication. In turn, they're not going to have good effect of the medication. Dr. Sean Kane 20:33 So Dr. Schuman, before we put you on the soap box, just very briefly, kind of dovetailing with what Dr. Patel said, the idea of a surrogate endpoint, and how dangerous that is for evidence based medicine. So, Dr. Patel, you talked about how this newer Esomeprazole had better pH, but really had no different, no difference in clinical endpoints. We see that all of the time with especially newer medications. And in my opinion, the FDA has done a bad job about saying you need to have hard clinical endpoints as opposed to surrogate endpoints when evaluating and approving new medications. So things like glycemic control, almost all of the newer diabetic medications are approved on the basis of improving your a 1c or improving your glucose, but they're not approved on the basis of preventing kidney disease, preventing micro and macro vascular complications, which is kind of the endpoint we're looking for. Just because your blood sugar is 400 you know, that doesn't matter in itself, unless it causes problems. And I want to see these drugs improve those problems, as opposed to fix the number of blood sugar. Speaker 2 21:38 That is definitely right. And I see medication representatives who come and they sell the medications for diabetes based on what the A and C reduction is, and which is great, but again, does it correlate to the clinical outcome? Dr. Sean Kane 21:52 And probably the worst example of this are the thiazolidinediones or TZDs. These are Actos or Avandia or rosiglitazone and pioglitazone, and they were approved on the basis of a 1c reduction, but in post marketing surveillance, they found that, hey, actually we cause more MIs in patients that take these medications. That's a big problem, because that's the thing that we're trying to avoid, as opposed to cause, Speaker 2 22:16 and that's the end result of diabetes therapy, right? We're trying to avoid this cardiac events Dr. Sean Kane 22:20 exactly so to be brief, other surrogate endpoints that you should be aware of when evaluating a clinical trial, things like gastric pH. You know, we don't care what gastric pH is, but what we do care about is, are their GERD symptoms better? Are they having gi bleeds blood pressure? So any anti hypertensive, it's great if it lowers your blood pressure, but I want to see the patients have fewer strokes, fewer heart attacks, less heart failure over time, and even cholesterol medication. So it's perfectly fine that your LDL and your HDL and your triglycerides look better, but if you're not having fewer cardiovascular events, we haven't accomplished anything except improving the numbers that appear on your laboratory sheet. So I think that for me, one of the big opportunities in terms of preventing drug cost expenditures over time and evaluating new medication therapy is to be cognizant of the fact that it's cheaper for drug companies to have shorter, smaller trials with surrogate endpoints, as opposed to bigger trials that actually show some benefit to the patient. And I think that we should all be aware of that. All right, Dr. Schuman, go ahead on your soap box. Go ahead and let us know what's been bothering you in your clinical practice. All right, Speaker 3 23:27 so I've been very excited about this. One of the things I've noticed is that there's maybe improper use of or application of some of the information we have regarding how various psychotropic medications are dosed and respond in the certain neurotransmitters that maybe come about or are augmented at different doses. So what I'm trying to say is that you have maybe in a low dose of a drug, it may act one way, and then at a higher dose it may look completely different on the body. So I know with Dr. Kane, with dopamine, for example, I know in how it's dosed, occasionally you can see vastly different receptor binding, correct? Yeah. Dr. Sean Kane 24:03 So low, very low doses of dopamine purported to improve renal function, which they don't. And then medium doses are supposed to help with cardiac function. And then really high doses of dopamine are supposed to help with blood pressure. Again, the idea Speaker 3 24:17 being that you're going to try based upon, you know, how it may interact with those different levels. Well, we've tried the same things. Same things in psychiatric medicine, and some of the information may not always be applied. One of them is venlafaxine or effects, or it's a fairly common medication that's used for depression out in the communities. We use it all the time in our facility. What drug classes that? That is an it's an SNRI, so it's a serotonin and norepinephrine reuptake inhibitor. So what's interesting about it, though, is that a dose between maybe 37.5 milligrams, which is generally a starting dose, and then up to somewhere between 150 and 225 it's actually just primarily an SSRI at Dr. Sean Kane 24:54 that dose. So it's not an SNRI, serotonin, norepinephrine, but we primarily just get the serotonin. Energy properties, right? Speaker 3 25:01 And so what you what you do is by but then getting to more of a maintenance those you start to it starts to have a little bit of the affinity towards reuptake of norepinephrine. So you start to see increase there. And then that's where it may have that extra benefit. And thing, for somebody who that the benefit on arousal symptoms, for example, or getting that that second mechanism, if they have failed an SSRI, or maybe that has been inadequate for treating their depressive symptoms. So you add that second mechanism. The problem I see, though, is a lot of times we'll start at that low dose, and you won't really go up on it. And so you end up with that we're taking the drug, and you know, they may fail it, and we may say, Okay, well, they failed an SNRI. Well, no, they haven't, because they haven't actually been used at its full potential. And so with those medications, I believe we really want to make sure that we're getting it up. And again, different people's metabolism may be varied, so case by case basis is beneficial. You really want to start looking at Lisa at 150 milligram dose before you say, oh no. SNRI for them. Speaker 2 25:55 And I have seen this practice very commonly in the family practice clinic that I work at, where physicians would start one medication, and instead of increasing the dose, or, you know, in proper titration fashion, they will just say, Oh, it didn't work. Let's time to add another medication. Funny thing is, though the other medication they add is another SNRI or another SSRI, which brings about drug interactions. And of course that drug interaction, drug drug interaction is serotonin syndrome. So again, a lot of education can also go on part of the healthcare providers. Speaker 3 26:29 And I think part of the confusion is because there's, there are two other SNRIs before now, but the other one that's more commonly used is duloxetine, or Cymbalta, and that one, even at the initial doses, it's about 5050 where it's increasing serotonin and norepinephrine. Again, that's right out of the box. So when you start at the low dose, no matter what dose you're using, it's going to get 5050 of each so baby clinicians who may be familiar with that, then try to apply that same mechanism to venlafax. And again, that's maybe where you run into trouble as well. And so that's where we try to educate that even within the class, these affinities can be vastly different. Even another one mil NASA Pran, which is approved only for treatment, primarily of fibromyalgia, that one's even more norepinephrine than serotonin. So even within that class, you have three agents that are at various levels of that that balance. And so you can use that to your advantage. But again, you really got to consider, instead of just rubber stamping, low dose of each one, thinking they're gonna do the exact same. Dr. Sean Kane 27:21 So Dr. Schuman to kind of flip the coin on you a little bit. Once we exceed this rough threshold with venlafaxine, or effect serve about 150 milligrams a day, do we start seeing adverse effects from the norepinephrine, such as, let's say, hypertension or tachycardia, correct? Speaker 3 27:35 And that, that's all. Another one that too we can educate is if somebody we if we start somebody at 37.5 of ventillo effects. And how are you doing? You're doing great. Well, we don't need to worry. But again, knowing that once you start to cross that number, tachycardia can occasionally occur, I've seen individuals start to see, even young individuals, with a vastly large increase in blood pressure that can occur as you cross into that norepinephrine. Some individuals may feel legit or shaky as well. So certainly that can be something. And then that you may want, you can then tip toe that line, all right, so that's, that's the one age, and then the one that I think is my, my most passion, is going to be a medication called Seroquel. And how does that medication work? Now, this one's pretty complex. So Seroquel is an atypical antipsychotic. So what that means is it works to primarily to block dopamine. So you have an increase in dopamine in an area of the brain called the mesocortical system, excuse me, the mesolimbic system. And in that system, there's too much dopamine, and so we kind of bring it back down by blocking those receptors, which then helps to balance out with with symptoms of schizophrenia. And then what it also does is it blocks this receptor called Five HT to the two a and the 2c and the block here, that two a receptor seems to also have some benefit in balancing out some of the serotonin effects. So there's some areas of the brain actually the need a little bit, excuse me, dopamine. So some areas of the brain that need a little bit of dopamine, and that'd be the mesocortal system the front of the brain, so it gives back a little dopamine there, while kind of blocking it overall, in some of the areas where it's just running wild. And with that, though, with these, these atypical antipsychotics, they bring a whole lot of other receptors to the table that they work on. There are histamine receptors, they can behave somewhat in anti histamine effects, alpha receptors, so changes in blood pressure, as well as these muscarinic receptors. So looking at maybe some changing in the amount of secretion someone produces. But what's really interesting about potay Pain is that it it's varied at, again, at what the doses are. And so this medication, you really don't start to see in engaging the dopamine the serotonin receptor till about 250, to 300 milligrams. And this is a medication that it's dose can range anywhere from, again, 12.5 milligrams already comes in a 25 milligram tablet, so you can have it all the way up to 800 milligrams maximum. So we have a wide range to play with. And so what some providers have done is, of course, you can start a patient at a low dose, see how they're doing, and then get it up into that range. Some providers realize that if it doesn't have those anti dopamine and anti serotonin. Facts, then what we're left with is essentially a medication that's an antihistamine that maybe has a little bit of this alpha blockade as well. And so they think, great, we've got another sleep medication, maybe something like Benadryl, maybe a little bit souped up version of Benadryl. And so it started to become used. In the last few years, there's really been an increase in it being used off label for that indication. Even in Australia, they were running some numbers, and they found that there was a huge increase in patients between 20 to 59 years old who were getting they were dosing that 25 to 50 million they didn't have a diagnosis of schizophrenia or depression or bipolar disorder. And so they were trying to figure out, what are people using it for? And they found insomnia. And the problem with that is, or if you are maybe familiar, there's a whole lot of different metabolic side effects with the with the atypical antipsychotics. Dr. Sean Kane 30:42 Well, before we get to the metabolic side effects, I can tell you that nothing makes me feel better at night knowing that I'm taking a medication for schizophrenia for my insomnia, that makes total sense to me. Speaker 2 30:53 And I really wonder if patients are really told that this is the medication they're going to be using it for insomnia. And before I even go further, you mentioned their dopamine activities, and, you know, activates in one limbic system and kind of deactivates in the other. Schizophrenia is an approved indication. What are the other approved indication? As we already noticed, insomnia is actually an off label use. Speaker 3 31:14 Again, with that one, it does have approval. Can be, could be used as an adjunctive therapy in bipolar disorder, and I believe as adjunct therapy and depression as well. And then it's, it's been, you know, there have been plenty of off label uses in other areas. Sometimes they use it in anything. You know, we could go into a lot about use and behavioral symptoms related to dementia, but that's that would be its Dr. Sean Kane 31:34 own topic. And I think that this kind of highlights the importance of open ended questions during a counseling session. You know, if a patient is filling 25 milligrams of Quetiapine or Seroquel, and you walk to the counter and tell them you're taking this anti psychotic for schizophrenia, that's a little bit different than asking What did the doctor tell you this medication was for? I would imagine that some patients might be quickly turned off and probably wouldn't even take a medication if it's for an indication that either they haven't been given, or a diagnosis that they haven't been given, or it's for something with kind of a stigma associated with it, a psychiatric illness that they don't Speaker 3 32:10 have, that I've had, that come up a few times in the counseling. And again, if you don't have the information, if you're the one that just says, you know, has the counsel, you say, Yes, this is for your reason. I don't have that disease. Or, again, you know, somebody's confused. They may not just take the medication Speaker 2 32:23 at all. And I do see patients in the clinic, and I pick up a bottle and say, Okay, what? What are you taking this medication for? And they will look at me and they'll say, I have no idea. You're the one who prescribed me. So again, patient education goes a great way too. Dr. Sean Kane 32:36 So Dr. shoeman, you were just alluding to the fact that we don't just get an anticholinergic effect from this low dose of Quetiapine, but it has other adverse effects that are associated with its use, especially for chronic use. Speaker 3 32:48 And this is where I think that the biggest evidence needs to go out there comes from, is that, as I said, it has these dose dependent receptor effects. But what the what these atypical antipsychotics, some of them have, and this primarily applies to Lange pen or Zyprexa, Clozapine or Clozaril, and then to clotiapine or Seroquel as kind of some of the main offenders. But that's this, this metabolic syndrome. So they can cause it, an increase in blood sugar. They can cause dyslipidemia, increase in triglycerides, as well as a fairly significant amount of weight gain. And these things have been consistently shown that they're completely apart from any dose dependency. And there's there been some, some really good studies, one in 2009 and one in 2010 that looked at specifically just low dose quit typing. And what they found in one study was an average of five pound weight gain. The other one, at the end of the year, they found an average of 10 pound weight gain in individuals that were just getting 100 milligrams Speaker 2 33:40 or less. So I'm gonna sleep well, knowing that this medication is causing diabetes in me. So that's Dr. Sean Kane 33:45 really interesting, because you alluded to the fact that many of the effects are dose dependent, but weight gain and the metabolic syndrome does not appear to be either dose dependent, or the dose dependency is so low that it's at whatever our normal dosing of that medication is for off label insomnia, and Speaker 3 34:01 that's and so that's what has led me to, you know, to exercise caution somebody, again, if we are trying to use it as a souped up Benadryl that we are being aware of, well, that this one brings some other things to the table with it. And I think there's, there's one more we can just quickly get to that is another one that's very interesting. Is going to be a little bit similar to what tieapen is going to be, mercazapine or Remeron. This one's a somewhat of a novel medication for treatment of depression, and that it's not a standard reuptake inhibitor at all. Really. What it does is it has some effects at some of those some serotonin receptors, by blocking that five ht 2c receptor, but then it also increases norepinephrine through a different mechanism, by blocking the alpha two receptors, so where those receptors usually, by binding them, you know, withhold further release of norepinephrine, to kind of regulate it, similar to maybe a medication like clonidine. And how it works? Well, this, by blocking it, is then going to be allowing for some further release of norepinephrine, which, you know, is the goal for treatment of depression, but that generally doesn't. Curve. So you get about, probably, you know, more around 15 or 30 milligrams and higher, you start to really see that effect. At lower doses. It's just histamine as well, or at least a large part of it. And so that medication as well became used at 7.5 to 15 milligrams as a medication for sleep. And again, the problem was that as people continue to have resistance to sleep, are resistant. You know, the inability to sleep that and that you continue to increase the dose, as you might with Benadryl, and now you're actually doing the opposite. You're potentially getting a little bit more arousal. So you have a medication that's being given at bedtime for sleep, and you're starting to increase norepinephrine, similarly to a lot of medication, which is dosed in the morning. And so if a provider is not aware of that, then you could be completely counterproductive for actually cognitive sleep. And there are some patients who pick up on it, then actually have a request. Well, if I'm using it for depression, I need to be it needs to be an am at a certain dose. And this is going to be variable on the patients, but it's something to be aware of if you're using it for one indication versus another, being where the time of the day you get because you could be completely sinking somebody sleep by as you increase the dose of that medication, Speaker 2 36:02 and whether this mirtazapine or remran is prescribed intentionally or unintentionally for the sleep. I just wanted to mention there is this drug sound like, which is, again, ramelteon. The brand name is Rozerem, so a lot of the times, doctors are going for Rozerem to treat the insomnia, but they end up prescribing Remeron and patient ends up taking at night time, which causes the actually the arousal symptoms. Dr. Sean Kane 36:26 Great point. So Dr. Schuman, it seems like kind of a common theme with your pet peeves is understanding kind of the pharmacology and the dose dependency of that pharmacology and some of the dangers in using off label medications, especially in the psych world, especially if you don't have a good knowledge of how the drugs work and why they work and at what doses they work, and kind of the intricacies of that that wouldn't be seen in something like the package insert. So that concludes our pet peeve Episode Episode 10 of HelixTalk. We're available online at HelixTalk.com we'd really appreciate a five star review in the iTunes Store under our podcast. And with that, I'm going to sign off as Dr. King. I'm Dr. shoeman, and Unknown Speaker 37:07 I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 37:12 Thank you for listening to this episode of HelixTalk. For more information about the show, please visit us at HelixTalk.com you you.