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. 128 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is introducing HelixTalks 2021 drug superlative awards. Today, we're going to be presenting a handful of awards that are superlative awards so kind of most likely to or most known for type awards in the category of medications that are on the market. Dr. Khyati Patel 00:58 And Dr. Kane, we're not too far from all the award seasons. You know, the Emmys just happened, the Grammys just happened, and now we're gonna have Oscars happening. So this episode is right on time to talk about that. Now, I might not be dressed enough for the awards, but I think I'm super pumped and excited to talk about some of these pet peeves we have. Love it. Dr. Sean Kane 01:19 And you know, Dr. Patel, I think it's worth noting how prestigious these awards are going to be. So you know, for an award to really have meaning, there must be a an involved process behind getting votes for the award. So I think in the interest of transparency to our listeners, you know, Dr. Patel, you and I convene hundreds of healthcare professionals virtually, of course, to identify superlative award titles, we used a modified Delphi technique to make sure that everyone was in agreement. We had hours of debate. I'm sure you remember all of those hours of debate, and we came up with award titles. Sent a survey of those awards to 1000s of healthcare providers from multiple professions in the spirit of interprofessionalism, and that's kind of how we came up with the awards today, right? Exactly. Dr. Khyati Patel 02:05 I mean, we just created our own Price Waterhouse Cooper company, you know, to come up with seriously. Dr. Sean Kane 02:12 So perhaps we should be a little bit more transparent that these are basically awards that you and I came up with, and the awards themselves are meaningless. They're all in good fun. And we're going to really be doing this to help the audience understand a variety of different clinical pearls or pitfalls that come up in routine, daily practice. So it's kind of a potpourri of relevant topics masked as having these awards associated with them. Dr. Khyati Patel 02:37 So let's dive right into it. I think I'm gonna, I'm happy to introduce the first category, and that's the drug that's most likely to be remembered, drum roll for covid 19 ineffectiveness, rather than its actual FDA indication. And that's unfortunate, but that drug is hydroxychloroquine, and Dr. Sean Kane 02:58 of course, I think everyone remembers this mostly from the summer where hydroxychloroquine with azithromycin was a potential therapy for covid. 19. This was before we had things like dexamethasone and remdesivir and things like that, but all the way back in March 2020, this is when the FDA released its emergency use authorization for hydroxychloroquine and Chloroquine for the treatment of covid 19, and then it was only a few months later, in June of 2020 that they actually revoked that emergency use authorization. Dr. Khyati Patel 03:30 And there was some a little bit of political drama behind this. You know, we all we already know how this fiasco of hydroxychloroquine had some politics behind it, which unfortunately led to the EUA. But then, really, the rationale was that it's, it's, you know, unlikely to be effective, if anything, it may even cause more serious cardiac side effects. And so that that's, that was the reason it was revoked in the June 2020, Dr. Sean Kane 03:57 so really, Dr. Patel, the rationale for the award today is, you know, you're still going to see hydroxychloroquine in clinical practice, and of course, you're probably going to be thinking about covid 19. But really, anyone listening when you see that hydroxychloroquine as like a home med for a patient, there's totally legitimate FDA approved indications for that hydroxychloroquine. So I think it's worth noting, what are those things, and what does a typical provider need to know about hydroxychloroquine in a non covid 19 type scenario? Dr. Khyati Patel 04:26 And when I think of hydroxychloroquine, Dr. Kane, brand name, Plaquenil, the first thing that comes to mind is all these rheumatologic conditions such as lupus or rheumatoid arthritis. So these are FDA approved indications for its use. Dr. Sean Kane 04:41 And then, of course, we also have malaria, which is kind of odd that we have a medication that kind of suppresses your immune system and lupus and rheumatoid arthritis. But then also kind of a an anti malarial drug. We covered this, you know, many, many years ago, actually, in the HelixTalk episode. But basically this is. An anti malarial agent that can be taken once weekly for prophylaxis or even every day for treatment of malaria, but it's not commonly used, and the reason is that we have geographic resistance of hydroxychloroquine with certain types of malaria. So generally speaking, it's really only used in kind of Central America and everywhere else in the world, the resistance rates are high enough that it is not a commonly used agent. Yeah. Dr. Khyati Patel 05:25 And when it comes for, you know, treatment of this, rhematologic conditions like RA or lupus, it's taken, you know, once daily. It's an easy peasy way to remember to take it. It's once daily dosing. When it comes to ra treatment, it could be used as a monotherapy in some patients, but patients who are kind of more advanced in their disease, they might be using it with other therapies like TNF inhibitors or methotrexate. Dr. Sean Kane 05:52 And you know, thinking back to covid 19, and one of the reasons that the FDA revoked the EUA was because of perceived cardiac side effects, specifically Qt prolongation and the risk of Torsades, but also, hydroxychloroquine, historically, has been known to cause things like cardiomyopathy and other conduction abnormalities, specifically heart blocks. Typically, that's a fairly rare condition, but it is well associated with this medication. Dr. Patel, what are some other adverse effects that come to your mind with hydroxychloroquine. Dr. Khyati Patel 06:24 Some of the common side effects that we encounter with this one is, you know, GI issues, so nausea, vomiting, diarrhea, and really, we can advise patients to take it with food, make sure we're doing the dose titrations, you know, gradually, not all of a sudden, maybe taking it in divided doses can be helpful, too. The other side effect that is kind of like the hallmark of monitoring that we need to remember is send the patient to get an eye exam if they haven't had a baseline eye exam done, because this drug is known to cause retinopathy and even in some severe cases, permanent loss of vision. And so again, this is dependent on the dose and how long the patient's been on it, and therefore we don't exceed the max dose, but we need to make sure that the ongoing eye exams are also scheduled a lot of the time. These eye related issues start to occur five years into so you can imagine this is like five years into the therapy. It's not like the first year or first month of therapy, but baseline eye exam is definitely warranted. And then Dr. Sean Kane 07:30 there's kind of a handful of other rare but serious side effects with hydroxychloroquine or Plaquenil, that would include rash we can see myopathies, neuropathies, then neuropsychiatric events. So this could be any mood change that you come up with, anywhere from suicidality to hallucinations to psychosis. Then finally, hypoglycemia is another possible side effect of this medication. So kind of a lot of interesting kind of runs the gambit of a lot of different organs being affected by the medication. Fortunately, most of these are fairly uncommon, except for the GI upset. But you know, as healthcare providers, we need to be aware that this can cause a variety of pretty unique side effects. Dr. Khyati Patel 08:12 Now, Dr. Kane, that was very interesting, and I'm actually excited to move on to the next category, because that's something that I face in and out during my regular practice. And this one's is the commonly used, but the worst anti hypertensives on the market. And again, I'm going to ask for a drum roll. And seems like we have a tie over here. You know our passion for atenolol, how, how bad of a beta blocker that is has been known through other episode recordings, but it seems like hydrochlorothiazide is also tying up for this award. So I Dr. Sean Kane 08:48 just want to highlight this, that this is the first helix toxoplast of award tie that we've ever had, which happens to also be our second award that we're giving out. But it is a tie award between tenalol and hydrochlorothiazide for the most common but worst anti hypertensives on the market. We got to go through these and understand what is it about these two medications that make them so attractive to use and yet so bad to use at the same time? Dr. Khyati Patel 09:13 So kind of, let's break it down. Dr. Kane, atenolol, right? It's tenormine, brand name. It's a beta one, selective beta blocker. We kind of know it already that we don't go after, you know, beta blockers as the first line, kind of like those four first line anti hypertensive. So we kind of saw this coming. But what were some of the reasons why it was so popular before the guidelines changed? Dr. Sean Kane 09:38 Well, a couple of things. So one, you know, Atenolol is beta one selective, so if you have someone with asthma or COPD, you don't have to worry as much about the beta blocker causing wheezing or preventing their albuterol from working or something to that. Effect. Number two, it's once daily, so you don't have to do it twice a day like a Metoprolol tartrate or Carvedilol. Well, and you don't have to deal with like the extended release or anything to that effect. So it's one state administration beta one selectivity kind of put it on the map in the US. So most recent data suggests it's in the top 50 prescribed drugs in the US. It's also the third most common beta blocker in the US. So this is definitely a very common medication that you're going to see in clinical practice, you Dr. Khyati Patel 10:23 know, then, then let's talk about why we think it's the worst anti hypertensive out there in the market. There is a lot of clinical evidence to point at that, but really thinking about, you know, monitoring the patients and stuff, we're talking about renal elimination. So the drug is renally eliminated. It's 40% unchanged. So you know, in patients who have poor renal function, there is likelihood of accumulation, especially in older patients, leading to more pronounced anti hypertensive effect, so leading to dizziness, drowsiness, even falls. And so that's definitely concerning, and perhaps Dr. Kane on your front where you're encountering a lot of like acute kidney injury patients. You probably are seeing this more often, Dr. Sean Kane 11:10 for sure. So a classic scenario is a patient who gets dehydrated because of overuse of their diuretic, or they get a diarrheal episode, or they get too hot in the sun and don't hydrate enough, and they end up getting a little bit of pre renal, acute kidney injury from low blood pressure. But if they're on Atenolol, it becomes a vicious cycle. So they get a little bit of acute kidney injury that causes them to retain more Atenolol than they normally would. That extra Atenolol that they have drops their heart rate in their blood pressure, which further compromises renal blood flow, which further makes it so that the half life of the drug goes up. So you end up in this cycle where the Atenolol half life goes up and up and up to the point where patients start getting pretty, frankly, bradycardic and hypotensive just because their renal function is inappropriate for the dose of Atenolol that normally would be fine, but is not okay in the setting of acute kidney injury, all of the other beta blockers in the market don't have this problem. Atenolol is uniquely bad, and that renal impairment means that you're going to hold on to that Atenolol for a much longer period of time, and that does not happen with other beta blockers. Dr. Khyati Patel 12:18 Now to the listeners, you probably have your rotten eggs and tomatoes ready to throw at the atenol. But hold off. We have some additional bad information about Aten and all, and that's about its clinical outcomes. Dr. Kane, what can you tell us about what's like the most up to date information in the literature about atenolol? Sure. Dr. Sean Kane 12:37 So you know, I think most people are now aware that, you know, when we had older JNC guidelines, they recommended a thiazide as a first line. And then the most recent guidelines kind of have four drug classes as first line for hypertension. Beta blockers have not been first line therapy for quite some time, and the biggest reason for that is actually atenolol. So, you know, over the past two to three decades, we've had a number of clinical trials that have compared Atenolol versus other non beta blocker anti hypertensives, and they've looked at both your blood pressure reduction. So do they effectively reduce your blood pressure? But they've also looked at the whole reason that we treat hypertension, which is cardiovascular outcomes. So heart attacks, strokes, cardiovascular death, arrhythmia, things like that. So there's a 2020 meta analysis that does a great job. This is by themopolis and colleagues, and basically they took about 24 comparison trials of 100,000 patients. So we're looking literally over many decades of Atenolol versus comparator data. 11 of the 24 studies were Atenolol, and that made up about 80% of the data that they looked at. And what they found was that even though Atenolol drops your blood pressure similarly to whatever you're comparing it to ace inhibitor, thiazide, whatever beta blockers, and basically we're talking atenolol were less protective for mace, which is major adverse cardiac events, strokes and all cause mortality. So basically, if you take a bunch of different trials of about 100,000 people, when atenolol went up against other non beta blocker, anti hypertensives, Atenolol, did worse when it comes to preventing heart attacks, strokes and death, and that's a great reason to not use Atenolol, even though the blood pressure reduction is similar. So there must be something else going on that either Atenolol doesn't offer that others do, or some harm that Atenolol has that we're not appreciating, that doesn't provide you the same quality clinical outcome that you're looking for, versus these other anti hypertensives. Dr. Khyati Patel 14:43 And I do feel bad for the other beta blockers that get the bad rep because of, you know, most of these studies had used atenolol, but that's the that's the reason behind the 2017, ACC/AHA guidelines on telling that beta blockers are not the first line in therapy because of such poor data, and again, that data is both primarily, as we discussed, driven by atenolol, even in some of the stable ischemic heart disease guidelines, you know, there are pretty anti-atenolol, all the guidelines are specifically, and I quote say, atenolol should not be used because it's less effective than placebo in reducing cardiovascular event, atenolol is not as effective as other antihypertensive drugs in the treatment of hypertension, and so guidelines are pretty specific not to let atenolol be the beta blocker that we use or be the antihypertensive that we use for our patients. Dr. Sean Kane 15:35 And if that wasn't bad enough, Dr. Patel, we have a second agent that is commonly used that really shouldn't be for the treatment of hypertension, and that is hydrochlorothiazide. Brand name is microside. This is a thiazide diuretic. What are some of the reasons that we see so much hydrochlorothiazide out there in the market? Dr. Khyati Patel 15:54 I mean, I will tell you, my patients can call HCTZ very easily, four letter short name, you know, easy to kind of, I guess, not spell out, but if you're just using those four letters, it's easy to identify. But another reason is because it's just available on all of these generic lists. You know, it's a generic drug, obviously, but also available as combination drugs. And so if we have patients with a little bit of elevated blood pressure where we need two antihypertensives in order to reduce some of that pill burden. You know, it is combined with, name it, your aces, your ARBs, you know, some of the other type of diuretics out there. So again, it's easy availability. It's easily to identify and to say, when we compare it to other guys, are diuretic. It's kind of like a little bit of a milder diuretic. It still has, you know, tendencies to affect your electrolytes. So cause hypokalemia, hypomagnesemia, hyponatremia, and precipitate some gout attack. But hey, this is the better of the other evils that we have in terms of this category, so probably that's why it's more of a go to thiazide. Dr. Sean Kane 17:09 So you're saying is that because it is not as good in terms of acting as a thiazide diuretic, it causes fewer side effects, therefore patients tolerate it better, and everybody kind of pats themselves in the back that they started this anti hypertensive that the patient is okay with, and yet the reason that they're okay with it is that it's not doing a very good job in terms of being a potent thiazide to help drop that blood pressure. Dr. Khyati Patel 17:32 That sounds about right, but then let's then, you know that warrants a discussion on what are some of the better or potent thiazide diuretics that we should be considering to use if we really want that blood pressure to come down. Dr. Sean Kane 17:47 Well, you know, if you look kinetically, hydrochlorothiazide has a half life of six to 15 hours. And that sounds like a lot until you compare it to some of the other thiazide like diuretics that are out there on the market. So chlorthalidone goes from 24 to 72 hours. Then indapamide, which I don't see a lot of, but it's definitely mentioned in the guidelines, has actually a biphasic half life, so is 14 and 25 hours respectively for its two phases of its elimination. So those two are going to last quite a bit longer and potentially provide longer durations of blood pressure reduction as opposed to blood pressure reduction that is predominant in the morning, for example, when the patient is in the provider's office, as opposed to at night, time where their blood pressure reduction may not be there anymore, but nobody would know it because they're not checking a blood pressure 9pm at night In most circumstances. Right? Dr. Khyati Patel 18:41 And, you know, we normally teach students, you know, don't look at the milligrams. Every drug is a little bit different. But really, hydrochlorothiazide is truly the less potent of the three. Thiazide like diuretics, we're talking about hydrochlorothiazide starting anywhere between 25 you know, 12.5 if your patient is, you know, at risk of hypotension. But 25 to 50 milligram. And really, in order to get to the 50 milligram, which is kind of like the normal dose that your patient may end up needing, some of the combinations don't even get there. They get to the max of 25 milligram of hydrochlorothiazide per day, versus if you compare it to chlorothaladone, which ranges anywhere between 12.5 to 25 milligrams per day, or end up amide, which is merely 1.25 to 2.5 milligrams daily, is what our patients would need. Dr. Sean Kane 19:30 So essentially, Dr. Patel, you're saying that most patients don't end up on 50 milligrams of hydrochlorothiazide, and yet that would be the equivalent dose of kind of normal doses of chlorothaladone and inappamide. So one of the the issues with hydrochlorothiazide is that we probably underdose it, and the reason we underdose it is that the combination dosage forms don't provide bigger doses, and also, if we did give those bigger doses, our patients would have more of the side effects that we're trying to avoid. Right? Dr. Khyati Patel 19:59 So. We are under dosing, not treating the blood pressure because we're worried about some of these side effects and the requirements for monitoring, which would still come with drugs like chlorothalon and endemide. But on the plus side, we will still have better blood pressure reduction. Dr. Sean Kane 20:15 And it's interesting, if you look at the 2017 ACC/AHA hypertension guidelines, they agree. So they don't. They're not big hydrochlorothiazide fans either. They say, quote, chlorthalidone is preferred on the basis of prolonged Half Life and PROVEN trial reduction of cardiovascular disease. So basically, even though hydrochlorothiazide is vastly more common, we're talking like, you know, top 20 in terms of prescribed medications in the US, chlorothalidone is the more commonly studied agent that has better cardiovascular data with it and kinetically has more advantages in what hydrochlorothiazide offers. Dr. Khyati Patel 20:53 And so far, we just talked about its blood pressure reduction ability. You know, kind of compare that with the chlorothalon, but we do have cardiovascular outcomes data when comparing chlorthalidone and hydrochlorothiazide as well. So there is this 2021 meta analysis by Rauch and colleagues that looked at some of these cardiovascular outcomes, the MACE outcomes, the stroke, the heart attack, the cardiovascular death, all of that combined and found out that chlorothaladone reduced these maize outcomes by 21% as opposed to your hydrochlorothiazide. And this p value was, you know, statistically significant. So we know that it does reduce cardiovascular events better. We know it does reduce blood pressure a lot better than hydrochlorothiazide, but we also know that it causes more of these electrolyte abnormality, the metabolic side effects. So if you choose to, you know, just go with chlorothalidone, or choose to change your patients from hydrochlorothiazide to chlorothalon. After listening to this, make sure that you and your patient is equipped to do proper monitoring for the drug. If your patient is not able to come to the clinic lab for routine monitoring, then perhaps another solution needs to be found, because we really need to monitor electrolytes Perfect. Dr. Sean Kane 22:13 All right. Well, I think it's time Dr. Patel for our number three superlative award. And the award title here is the most confusing dosage forms. And there are plenty of dosage forms out there that are confusing, so I am excited to see which one you and I picked. So we'll have our drum roll, and the winner is valproic acid. Before we get into why, let's get a little bit of background of valproic acid to kind of set the context of when is this agent used. And then later, we'll say, Why is it so obnoxiously confusing about valproic acid and its dosage forms? So we'll start with indication. So valproic acid is indicated for bipolar disorder as a mood stabilizer epilepsy, and it treats actually multitude of different kinds of seizures, including partial, generalized and absent seizures, and also migraine prophylaxis, where it's taken kind of chronically, to prevent migraines. Dr. Khyati Patel 23:10 And whenever I think of valproic acid, Dr. Kane, I'm thinking about left and right. This box warning right. And so this yellow male syndrome is what I think of in terms of poric acid. So we're looking at hepatotoxicity, you know, increase the LFTs and stuff cause pancreatitis. So we're looking at some of these gi disturbances, and in pregnant patients, especially, you know, when we're dealing with epilepsy treatment, it's huge when it comes to teratogenicity, and so we might have to change the patient from that drug to another drug that's not teratogenic. Dr. Sean Kane 23:48 And if that wasn't enough, we see a host of other side effects of this medication. So like many of our other epilepsy medications, we see plenty of neurosensory side effects, like dizziness, drowsiness, cognitive impairment we also see, and this is common with all of the many of the anti epileptics GI upset. So it's common that we'll take this with food. We'll titrate the dose fairly slowly. Sometimes we'll divide the dose to make it more tolerable for the patient. Dr. Khyati Patel 24:13 And so in addition to those two, there are some effects on the blood counts. So we're looking at lower platelet counts, causing thrombocytopenia, and very oddly, it actually elevates serum ammonia levels in patients. And this elevation could be, you know, asymptomatic, but in patients who already have other liver diseases, such as, you know, cirrhosis or have hepatic encephalopathy, this ammonia level changes could end up being symptomatic, where a patient might present with symptoms of encephalopathy, the confusion, the you know, the inability to detect place, you know, person, time, etc, etc. Dr. Sean Kane 24:55 Then we can also see rash, and this is kind. Goes with the territory. With antiepileptics, especially the older antiepileptics, we see plenty of rash associated with this medication, just like many of the other ones. Dr. Khyati Patel 25:08 And whenever I see valproic acid, I'm always thinking about drug interactions, especially the SIP or the protein binding interactions. And so like you said, Dr. Kane, it's commonly used in epilepsy treatment because it's kind of like pan sensitive, and it comes to different type of seizures, but relatively used with phenytoin. We know phenytoin also binds very strongly with protein, and so you know when you're trying to use the two together, they kind of compete for the protein binding site. And so levels of this drug will need to be monitored as well, Dr. Sean Kane 25:42 and a typical level would be 50 to 100 although it can depend on what you're treating and how refractory the patient's symptoms are and things like that. Dr. Khyati Patel 25:51 So then Dr. Kane, that's that's basically the basics of valproic acid. What is so confusing about the dosage form? Dr. Sean Kane 25:59 Well, it kind of comes down to two different things. So a lot of it deals with the fact that we have different salt forms of valproic acid. So we have literally valproic acid, or the free acid form, and we also have valproate sodium, which is the salt form. And then we also have a mix of the two, where you mix valproic acid and valproate sodium. We call that mix, dival Pro X sodium. What's interesting is that you know, when you take this, when it gets into your blood, all of these salt forms, or acid, free acid forms, are going to dissociate into the exact same molecule. This is, historically, that's how the drug manufacturers prepared valproic acid, or pro eight sodium or dival Pro sodium, they just prepared it in different salt formulations. Dr. Khyati Patel 26:46 And so with all of these different generic salt formulation comes different brand names as well, right? So that adds more to the confusion, yeah. Dr. Sean Kane 26:56 So we have Depakote, which is probably the more common brand name that most people are familiar with, and that is dival Pro X sodium, where it has both versions of the salt form. Then we have depakine, which is valproic acid only, and we have Depa con, which is valproate sodium only. And then, if you want to get it even more confusing, the dosage forms of those brand names also vary as well. So we have Depakote, which has two different kinds of delayed or extended release tablets that are not bio equivalent. We have a delayed release Dr. tablet, we have an extended release er tablet, and the ER tablet lasts a little longer, so you can actually dose that once a day versus the Dr. tablet is twice a day. Then we also have a delayed release sprinkle capsule, which can be dosed twice a day as well. So we have basically three different delayed or extended versions of Depakote, which is, again, dival Pro X sodium, the combination salt form. Dr. Khyati Patel 27:56 And so those are Depakote dosage form, Dr. Kane. Now depakinin, which is about proic acid, is available in immediate release capsules, as well as a syrup which basically kinetically similar to the immediate release formulation. And then depakon, which is about pro it sodium. So that's a sodium salt, is available in the IV solution, again, very similar to the immediate release formulation. Dr. Sean Kane 28:24 So again, I think it's worth mentioning that we have these effectively three different salt forms, although one is just a mix of the two, then we have brand names that relate to the salt forms. But within each brand name we have a variety of different dosage forms that kinetically may be different than each other, and certainly are different between the different brand names that dictate basically how often you have to dose that formulation per day. Dr. Khyati Patel 28:47 So Dr. Kane, if I am a prescriber, very hopeful, positive world, and I'm trying to pick an agent, I would be really confused. But I feel like there is a happy ending when it comes to valproic acid in general, when we are dealing with all these different formulations and names, what is that happy ending? Dr. Sean Kane 29:07 Yeah, so fortunately, the manufacturers, very early on, kind of did a very nice thing. And what they did was they all agreed that no matter what dosage form they pick, all dosage forms would be expressed as valproic acid, or in other words, when you give 200 milligrams of Depakote, that's equal to 200 milligrams of depakine, which is equal to 200 milligrams of depican, even though they have different salt forms and the salt forms way differently, you always express the dose in valproic acid, and you don't have to do any goofy salt form conversions. It's all done for you. Dr. Khyati Patel 29:41 Okay, so that's a relief that it's a one to one conversion, despite all these brand names, generic names and formulations. But I'm thinking the ER capsules, which is extended release, are probably, you know, taken once daily, versus the some of the other immediate release or other er release formulations might be taken. A little bit more often. So that's that's the difference that we still have to keep in mind. Dr. Sean Kane 30:05 Yeah, and I mean, technically the ER capsule is 10% less bioavailable, so it has a bioavailability of 90% instead of 100% so technically you have to give a little extra or account for that when you're converting. But all of the other forms are one to one conversion. You just have to take care of the frequency of dosing. So for example, if a patient is on 500 milligrams twice a day of an delayed release capsule. So 1000 milligrams a day, you take that 1000 milligrams a day, and then you divide it based on how often you have to dose that particular dosage form. So er capsules is once a day. All of the other delayed release products are twice a day. The immediate release products are going to be three to four times a day. And also the IV product is going to be three to four times a day. So based on the formulation that dictates how frequently you dose it, as long as your total daily dose is the same, you can do a one to one conversion, which is a nice silver lining to this otherwise really messy story about this particular medication. Dr. Khyati Patel 31:06 Yeah, and I can imagine Dr. Kane, even though there is availability of all these different formulations and brand and generic salt combos, but at the end of the day, we want patients to adhere to the therapy, and I think the best adherence is going to be, you know, when we are simplifying the regimen. So while there are other formulations available, the ER capsule, which is taken once daily, might be the more preferred way to go to improve patient adherence. Dr. Sean Kane 31:32 Well, why don't we move on to our award number four of five, and the title for this is the most innovative pro drug. So pro drug is where it's a medication that's converted to another more active form down the road. So our drum roll for this award, and the winner is Val Acyclovir. So Dr. Patel, when you hear Val Acyclovir, what things come to your mind? Dr. Khyati Patel 31:59 Well, from the name, I know it's very similar to Acyclovir, and in obviously, with that name, it reminds me that it has FDA approved indications to treat the V, which is Varicella Zoster virus. So we're talking about shingles or chicken pox or HSV, which is the herpes simplex virus. So we're talking about genital herpes, oral herpes, like the cold sores, both for the treatment of the acute episode as well as kind of use it as a suppressive or preventative therapy to prevent future episode. Dr. Sean Kane 32:36 And what makes this kind of an innovative pro drug is that it's actually a double prodrug. So it's a pro drug inside a pro drug. So we'll start with pro drug part one, which is Val Acyclovir, the drug that we're talking about, or Valtrex. So Val Acyclovir is L valine, an amino acid that is combined with Acyclovir. And basically what happens is that that valine amino acid will get cleaved off as part of hydrolysis during first pass metabolism, either in the intestine or in the liver, and that actually allows for effectively, like an extended release product. So the conversion takes a couple hours to fully take effect, and during that time, it's effectively like a slow release of Acyclovir. And what's neat about this is that you more or less get an extended release version of the drug without actually putting it in a dosage form that is extended release. So you can crash Val Acyclovir and it won't impact the kinetics, because the extended release piece of it is actually the chemical structure itself, as opposed to, you know, how they put the drug inside a capsule or a tablet, or something like that, Dr. Khyati Patel 33:43 and with that property, Dr. Kane, I'm sure, well, Acyclovir, it doesn't need to be dosed very often, either, so that allows for kind of stretching out the frequency for dosing. So we're looking at giving it twice daily, as opposed to, if we compare that to the Acyclovir that's given three to five times a day. I mean, five times a day, that's a lot. Think about that. If patient is taking it for a longer period of time, that's just not a pill burden we are looking at and poor adherence, perhaps. Dr. Sean Kane 34:15 Now, if that wasn't enough, that would be a normal pro drug, right? That can tell we have plenty of pro drugs out there on the market that the molecule goes to liver, something gets cleaved off now you have an active compound. That's a very common story with many medications on the market. What really made valleycyclovir win this award today is its second pro drug like feature, which is actually Acyclovir. So Once valleycyclovir gets converted to Acyclovir. Acyclovir then is converted again. This is our double pro drug, but it only gets converted in cells that are virus infected. And what happens is that that Acyclovir inside infected cells will then be converted to a more active antiviral molecule that then in turn. Has its antiviral effect only in infected cells. Dr. Khyati Patel 35:04 So you're saying that in the normal cells, the drug doesn't exert any effect, but in that those virus infected cells, the thymidine kinase from the virus actually converts the drug into its active form, and eventually that's the Acyclovir triphosphate, Dr. Sean Kane 35:23 exactly, and Acyclovir triphosphate is literally the active compound that has an antiviral property to it. So chemically, it's similar to purine deoxynucleotides. So in this case, it's similar to deoxyguanosine triphosphate, and it will actually block viral DNA synthesis by competitive inhibition or inactivation of the viral DNA polymerase so it actually binds to the enzyme that the virus uses to make more DNA and then also it can incorporate itself into the DNA chain and terminate prematurely that DNA chain. So even if that DNA polymerase enzyme is working. It can make it so that it makes a mistake, essentially, and it doesn't continue making that DNA chain, which obviously the virus needs to make more DNA in order to replicate and infect other cells. Dr. Khyati Patel 36:13 So Dr. Kane to kind of summarize, it seems like Val Acyclovir is some of these Amazon pack packages that I receive that are like boxing within a boxing, and there's just like packaging after packaging, right? So this is two double packaging over here. It's a pro drug inside a pro drug. The Val Acyclovir is converted into Acyclovir by the work of our liver, and that allows us to dose it in just two times a day, rather than doing it five times a day. And then the Acyclovir is eventually by the virus phosphorylated so converted into the active form Acyclovir triphosphate, that kind of interferes with the DNA synthesis of the virus and kind of blocks the viral replication. And I think it's just pretty amazing, Dr. Sean Kane 37:03 absolutely, so cool, and that's why won its award. This is a pretty novel, very neat double mechanism that I think goes under appreciated by the typical clinician out there. Dr. Khyati Patel 37:14 Well, I'm happy to move us along, Dr. Kane, and introduce today's last category, not the last ever, and it's an interesting it's not an it's not it's not a drug, but it's going to be the hottest inactive ingredient. And we're going to do a drum roll, and once again, we couldn't pick one. We have a tie with the environment we're dealing with, which is covid, which is kind of like the highlight of this year's award. We're looking at couple different inactive ingredients. So our first inactive ingredient is pretty mouthful as sulfo butyl ether, beta cyclodextrin, shortly, s, B, E, C, D, which is found as an Excipient in remdesivir, again, covid. Hello, and the second one is polyethylene glycol, which is your peg molecule. We are all aware of polyethylene glycol, but most importantly, we've included that in this award, because it's used as an inactive or Excipient ingredient in what some of our mRNA vaccines. So Dr. Kane, can you tell us what this crazy long sbecd Excipient is, and how is it important for remdesivir to work? Dr. Sean Kane 38:31 Yes, so the reason that SP ECD is one of our hotter excipients this year is because of its formulation in remdesivir. So sbecd is a derivative of cyclodextrin, which is a fairly common Excipient that is used to help lipophilic drugs solubilize into more aqueous solutions. And historically, this was actually another hot topic in a drug called voriconazole. So IV voriconazole also used the same Excipient. And if you look at the FDA packaging, they call it something a little bit different, beta Dex, sulfo butyl ethyl sodium, which is the exact same thing. But if you look in many tertiary drug references, like up to date, you're going to see sbecd instead. And the reason that this matters, both for IV voriconazole and for IV remdesivir was that sbecd is renally eliminated. And the concern is that if you are a patient who has renal impairment, you might hold on to this cyclodextrin derivative. And what we know is that other cyclodextrins, not necessarily sbcd, but others are definitely associated with nephrotoxicity, sometimes even hepato toxicity by basically disrupting cell membranes in areas that they accumulate in. So if you look at the IV voriconazole package insert, they actually have a warning saying that you might not want to use it if your credit and clearance is less than 50 because of the concern that you may start accumulating this Excipient called sbcd and. And basically the packaging says, consider risk versus benefit. Consider using oral as opposed to IV, because oral voriconazole does not contain sbcd, and we have used IV therapy in those with renal impairment. And of those patients, it doesn't appear to be obnoxiously nephrotoxic, but generally speaking, there's not a lot of patients that can't take oral, that have an invasive enough infection that you need to use IV. So it's a pretty small patient population anyway, but it didn't appear to be terribly nephrotoxic, but I'd say we probably don't have enough data, which is why it's always going to be a risk and benefit thing. Dr. Khyati Patel 40:35 So that's a good perspective to have Dr. Kane, especially a drug like voriconazole that's been established. But how is this ingredient relevant to remdesivir, which, again, that's been out there, but more so relevant now with the covid. Yeah. Dr. Sean Kane 40:51 So just like IV voriconazole, remdesivir also contains SBE CD, and there's kind of two issues here with remdesivir. One, remdesivir was not studied in patients with creatinine clearance is less than 30 so we're not even really exactly sure how to dose it, to be honest with you, because it does have a renally eliminated active metabolite. But then two, we're worried about that SBE CD in the sense that it may accumulate in patients getting remdesivir, and it potentially could cause nephrotoxicity. Dr. Khyati Patel 41:19 So kind of just comparing how much SBE CD load or dose a patient would get along with these drugs, we're looking at about 6000 mg per dose of remdesivir, which, again, is given once daily. Voriconazole is also given once daily, but the sbecd dose per the dose of voriconazole is about 5000 mg. The difference here is that the remdesivir is given on a shorter day duration, or course, five to 10 days, versus the IV voriconazole. Some patients might receive this even longer than 10 days, and so they might have the accumulation of this ingredient. Dr. Sean Kane 42:00 Yeah. So I would say, in short, we're not exactly sure how big of a deal that sbcd accumulation is, given that it's a fairly short course of therapy, but we don't really have an oral alternative, unlike with voriconazole, so remdesivir is only available IV, and even if you kind of take sbcd out of it, we don't exactly know if we Pick the right dose of remdesivir in those renal impairment patients, given its renally eliminated active metabolite. So kind of a question mark here, but certainly sbcd is kind of the Excipient that is now more common, especially in the hospital environment, with pharmacists who are now potentially debating the role of IV remdesivir among patients with renal impairment. Dr. Khyati Patel 42:42 Well, that was a that was a good one, Dr. Kane, and the other one is polyethylene glycol. So like we said earlier, you know, we all know polyethylene glycol products such as MiraLAX or some of our bowel preps included. You probably remember the number that's behind it too, which is 3350 this polyethylene glycol we're talking about has a different molecular weight, which is what that number is, and it's 2000 and that's included in a couple of the mRNA based vaccines manufactured by Pfizer as well as moderna. And really the reason the polyethylene glycol molecule is added we're kind of like whenever we are adding polyethylene glycol to any drug, we calling it pegylated, and then adding Pegylation, or doing Pegylation, basically is we're kind of expanding the lifespan of those lipid nanoparticles which are carrying these mRNA messenger RNAs, and so creating the longevity we are kind of evading the body's natural immune system the liposomes that would otherwise kind of capture these nanoparticles and eat them up. And so the vaccine may not be as effective. Dr. Sean Kane 43:51 And what's really put this in the news is, you know, this is normal, right? Pegylation is nothing new. But what's new about this is that for those, literally, one in a million people who receive these mRNA vaccines who have anaphylaxis. Some experts or researchers believe that that Pegylation from Peg 2000 or polyethylene glycol with the molecular weight of 2000 Some experts believe that that Pegylation is actually the thing that is leading toward the increased risk of this rare but serious anaphylactic like reaction, I would say the jury's still out here in terms of, is it the Pegylation of that lipid molecule, or is it something different with respect to these vaccines, given that they're basically a brand new technology, I would say we don't know, but this is high up on the list in terms of, does that polyethylene glycol predispose patients to getting that anaphylactic reaction, or is it something different? We don't know, but this is definitely a hot topic. Dr. Khyati Patel 44:45 Yeah, and just to kind of give perspective, you know, these anaphylactic reactions are still very rare. We're looking at maybe one per million, so you're absolutely right. Dr. Kane, the jury is out there. Dr. Sean Kane 44:57 Well, why don't we kind of, briefly, just. Run through the 2021, awards that we've given out today at Dr. Patel. So the first one was the drug that was most likely to be remembered for covid 19 ineffectiveness, rather than its actual FDA indication, and that was hydroxychloroquine. Dr. Khyati Patel 45:13 And the second category of the award we gave out was a drug that's commonly used, but it's the worst anti hypertensive on the market, and it was a tie between atenolol and hydrochlorothiazide. Dr. Sean Kane 45:26 And then our third award was the most confusing dosage forms, which were valproic acid, valproate sodium and dival Pro X, which it's all the same thing, it's all the same drug Dr. Khyati Patel 45:38 and not but not the least my Amazon packaging. In the packaging, the most innovative pro drug was valacyclovir. Dr. Sean Kane 45:47 And then finally, our fifth award was also tied. This went to the hottest inactive ingredient, and it was a tie between sulfo butyl ethyl beta cyclodextrin, or s, B, E, C, D, which is much better to say which was an Excipient in remdesivir and also polyethylene glycol or peg, which is an Excipient in those new mRNA vaccines? Dr. Khyati Patel 46:09 Well, Dr. Kane, I think it was great. I wish I had my popcorn or a glass of soda on me, but next time, I'll be better prepared. And thank you. This was exciting, Dr. Sean Kane 46:18 fair enough. And you know, we've only handed out five awards. We have plenty of other awards that we'd love to hand out in the future, but you as a listener, if you have suggestions on an award, title or a drug that you think deserves an award more than what we've talked about today, send us an email. Can get our email addresses at HelixTalk.com Leave us an iTunes review. We read those, so we would definitely read that. If you have a suggestion, we would love to hear from you guys in terms of what awards you think we should be giving out the next time we do these superlative awards. So with that, I'm Dr. Kane Speaker 1 46:49 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 46:53 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, search for HelixTalk and place your review there Narrator - ? 47:04 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.