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 183 I'm your co host, Dr. Kane, and I'm Dr. Patel, and this episode is titled, The Ultimate Guide to loop diuretics, an in depth drug class review. So obviously, today we're talking about our loop diuretic drug class, everything from the pharmacology to the medicinal chemistry to the pharmacotherapy and everything in between. Dr. Khyati Patel 00:52 All right, well, let's get on the loop and I'm excited. Dr. Sean Kane 00:55 So obviously we have to start by talking about what are the drugs that count as a loop diuretic, and by far the most common one is called furosemide or lasix. But there's a couple other ones out there as well. Dr. Khyati Patel 01:06 Yeah, those are bumetanide (brand name Bumex), torsemide (brand name Demadex), and then not as common as these three we have ethacrynic acid (brand name Edecrin). And obviously this one is not as common. We're going to talk about that more in detail later. Dr. Sean Kane 01:25 And all of these are going to be indicated for the treatment of edema. Usually, this is for peripheral edema, so swelling of the feet and ankles, but also for pulmonary edema, so fluid in the lungs would be typical for heart failure patients. We can also see it in cirrhosis or chronic kidney disease patients. And at the end of the day, these drugs work by making you pee out water so that you get rid of the water that is kind of accumulating in these different areas of your body. Dr. Khyati Patel 01:52 And in this episode, we are particularly talking about loop diuretics. But there are other diuretics out there. Dr. Kane, so how in particular the loop diuretics differ from the other ones. Yeah. Dr. Sean Kane 02:03 So those other diuretics would be like a thiazide or a thiazide like diuretic. This would be heterochlorothiazide or chlorthalidone. We also have our potassium sparing diuretics, so amiloride, triumph, trene, spironolactone, there's a couple others out there as well. The key point with loop diuretics is that loop diuretics are almost always used for edema, so we don't use them to treat hypertension or elevated blood pressure, and we use them because they're our most potent diuretics in terms of getting rid of fluid, but they don't last very long, so the duration of effect is not very good, and their anti hypertensive quality is not nearly as pronounced as these other diuretics that are out there? So again, we use our loop diuretics for edema, not for blood pressure, and typically the other thiazide and thiazide like diuretics, and maybe the potassium sparing diuretics, depending on what's going on, those are more commonly used for hypertension as opposed to edema, although they do treat edema as well, Dr. Khyati Patel 02:59 and we're gonna focus on the mechanism, because that explains how it gets rid of water and then some of the side effects that come in. But these also work a little bit differently than the other type of diuretics, right? So they only work in the loop of Henle versus the other diuretics work in the other part of the glomerular apparatus, and Dr. Sean Kane 03:17 that's why they're called loop diuretics, is they work on the loop of Henle, as you Dr. Khyati Patel 03:22 mentioned, Dr. Kane, primary use of these diuretics is treatment of edema. And so can we discuss the why behind it? Why does it? Why are they so effective? Dr. Sean Kane 03:31 Yeah, so the way that the kidney works, in terms of how much you pee out, is largely based on how much sodium gets from your blood into the glomerulus, into your tubule system, and then how much of that sodium gets reabsorbed into your blood? So let's put a number to it. If 100 molecules of sodium are in your blood, and almost all 100 molecules are going to be filtered at the glomerulus, so they're destined to become urine, but your body really loves sodium a lot, and it doesn't want to get rid of those 100 molecules, even though those 100 molecules are ready to turn into urine as they go through the proximal tubule, the distal tubule, the loop of Henle, the whole process, literally, 98 or 99 of those 100 molecules will be reabsorbed. Instead of becoming urine, they'll be reabsorbed back into your blood. So we call that the fraction of excreted sodium, or phena. So na for sodium, and it basically describes what percent of the sodium that gets filtered in the glomerulus actually ends up as urine. And that number is typically one or 2% so one or 2% of sodium that gets filtered ends up as sodium in your urine later on. Dr. Khyati Patel 04:41 But when we add loop diuretics, it drives the FENa up to about 20 to 25% so this is compared to that one to 2% normal. This is a massive increase in how much sodium is actually excreted in the urine, exactly. Dr. Sean Kane 04:56 And you can't pee out salt crystals, right? So the water. Is going to go along with that sodium. So we can numerically quantify the diuretic or natural effect of these loop diuretics as that phena, so 20 to 25% now if you compare that to a non loop diuretic, so this is our thiazide like diuretics as an example, the phena goes up from one or 2% to something like three to 5% so again, our loop diuretics are making you pee out 20 to 25% of your filtered sodium versus thiazides three to 5% and normal is one to 2% so that's why our loop diuretics are so effective, is that they really, really, really make you pee out way more sodium than our non loop diuretics that are on the market. Yep. Dr. Khyati Patel 05:38 And then again, water follows the sodium. So there is also bigger water loss with the loop diuretics. Dr. Sean Kane 05:43 So then Dr. Patel, the question is, naturally, okay, so I understand that it ends up making you waste more sodium. How does it actually do that? So from a pharmacology perspective, what is its mechanism and why is that so special? Dr. Khyati Patel 05:56 So as we discussed earlier, they work in this particular part of loop of Henle, and they inhibit this sodium potassium chloride co transporter. We also call it symporter. It's located on the ascending side of the loop of Henle, on the luminal side, that's where the urine is being made. Normally, this CO transporter reabsorbs the sodium potassium and chloride. However, the loop diuretics ends up blocking this CO transporter, so these ions are ending up in the urine instead of being reabsorbed back into the blood. Dr. Sean Kane 06:29 And it turns out that this proximal loop of Henle is like the most important part of sodium reabsorption, because our thiazide diuretics work on the distal tubule, which is after the loop of Henle. And that is important, but not nearly as important to sodium reabsorption as the loop of Henle is. So that's why our loop diuretics are so important, is that they're blocking this more critical pathway for sodium reabsorption, and it just happens that that's also involved in potassium and chloride reabsorption as well. Dr. Khyati Patel 06:56 And these three ions are not going to be reabsorbed. They're going to be ending up in the urine, and water loves to follow these ions, so we're going to also see excretion of water. Dr. Sean Kane 07:07 And what's cool is because we know how the drug is working, so you're not going to have as much sodium, potassium and chloride in your blood because you're peeing it out instead, that actually informs the side effect profile that we observe with our loop diuretics. So it turns out that the sodium and chloride, because water is going along with it, the ratio of sodium chloride and water that you lose is about similar to your blood. So you end up not, on average, having disorders of your sodium or your chloride, but you do have disorders of your potassium. So the more potassium you lose in your urine, that means that you're not reabsorbing it, your blood levels of potassium will go down because you're not reabsorbing that potassium, and you're going to have hypokalemia. And this is actually crazy common with loop diuretics, to the point where many, many patients on a loop diuretic have to be on a potassium supplement like potassium chloride, to basically take back the potassium that they're losing from that loop diuretic in their urine. We have Dr. Khyati Patel 08:04 learned Dr. Kane that potassium and magnesium kind of go hand in hand, so they also end up causing hypomagnesemia, low magnesium. But if you think about the CO transporter, it is only sodium chloride and potassium co transporter has nothing to do with the magnesium how do they end up causing hypomagnesemia? Dr. Sean Kane 08:22 Yeah, so this one's kind of interesting. So what happens is, when that CO transporter is active, potassium goes into the luminal cell, so now the cell has more potassium than it normally would, and it actually uses that almost as currency, to help reabsorb magnesium. So by having extra potassium, it's able to reabsorb magnesium, but if it doesn't have the potassium, because we blocked that CO transporter, now it doesn't have that currency to pull magnesium into the cell, and you'll lose magnesium and calcium and other divalent cations because it doesn't have the currency that it needs to have magnesium reabsorption. Therefore, you'll get hypomagnesemia, low magnesium in your blood, in addition to the hypokalemia, the low potassium in your blood. Dr. Khyati Patel 09:06 And so you may also see some patients who are using loop diuretics may end up needing magnesium supplementation as well. Dr. Sean Kane 09:13 Now what's kind of cool though is I mentioned divalent cations are involved with that second process. So definitely we see low magnesium, but we actually do not typically see low calcium. So Calcium is a divalent cation. You do lose it in your urine. So why is it that we wouldn't see hypocalcemia when we are using a loop diuretic? Dr. Khyati Patel 09:34 We do have couple of compensatory mechanism that's occurring in the in the body that is going to increase our serum calcium. So one of them is that our vitamin D, it's going to increase our, you know, absorption of calcium from the intestine. And then also we have the parathyroid hormone that's going to reabsorb the calcium from the from the kidney. So this is a reason we don't get to see hypocalcemia from use of. Loop diuretics. Dr. Sean Kane 10:01 Kind of an interesting factoid. We do use loop diuretics for hypercalcemia of malignancy. So these are patients that have cancer. The cancer releases certain hormones that causes your serum calcium to go up. The body knows that the calcium is too high. There's just not a lot that it can do about it. But in those cases, we will often give them saline, normal saline, and a loop diuretic to basically flush out that extra calcium. And because the body knows calcium is high, it's not going to try to re equilibrate to that higher calcium by releasing PTH or using vitamin D, because it knows it's too high, so that we actually use it therapeutically to get rid of calcium and hypercalcemia of malignancy. But in a typical patient, where the serum level is normal, the body has mechanisms for homeostasis to make it so we don't see hypocalcemia for these patients. Dr. Khyati Patel 10:47 That's definitely very neat how loop diuretics can impact all of these electrolytes, yet some turn out to be normal. So the big picture here is that it does cause hypokalemia and hypomagnesemia that we need to be worried Dr. Sean Kane 11:01 about, and of course, we have to monitor for that. So when you start a patient, you're going to be checking those ion levels in their blood to make sure that they're not too low, and if they are, you're going to have to do something about it. Dr. Khyati Patel 11:12 Any interesting things about how these loop diuretics different in terms of their pkpd that you know would turn into some dosing consideration or patient education considerations, sure. Dr. Sean Kane 11:25 So one thing that's kind of cool is that all of our loop diuretics are really protein bound. They're bound to albumin. We're talking like 95% or more protein binding. Now normally, I honestly don't care that much about protein binding, but in this circumstance, it's actually interesting what's going on. So when a drug is highly protein bound, it means that it will stick to that protein, and it's hard for it to cross membranes. It's harder for it to interact with receptors, and it typically is not going to be filtered at the glomerulus. So that matters, because if your furosemide, or your loop diuretic, is bound to albumin as it crosses by the glomerulus, that furosemide is not going to be filtered and end up in the urine, and it has to go into the urine, through the glomerulus, into the tubules, to interact with that CO transporter protein that we talked about. And if it's not in the urine, it can't do that, and it won't have a diuretic effect. So kind of the conundrum is, well, if it's really highly protein bound, it doesn't go through the glomerular filtration. How does it actually interact with the CO transporter that it's looking for if it doesn't get dumped into the urine at the glomerulus? Dr. Khyati Patel 12:29 And that's where the oats come in. I Dr. Sean Kane 12:32 probably learned about oats in pharmacy school, but to be honest with you, I don't remember Dr. Khyati Patel 12:36 it at all. Yeah, they're pretty neat. They're called Organic anion transporters, and so this is where they're actively secreted. The loop diuretics get actively secreted in the proximal tubule via these anion transporters called oats. Dr. Sean Kane 12:52 Yeah, so organic anion transporter oats. Again, I probably learned about this in pharmacy school, but I really don't remember it, but it's actually really, really important for our loop diuretics, because this is how some drugs end up in the urine, especially if they don't get filtered through the glomerulus into the urine. And loop diuretics are that way. So it relies on this CO transporter to get dumped into the tubule, even though the furosemide was not filtered at the glomerulus. Dr. Khyati Patel 13:20 And another example is NSAIDs, right? They're also filtered or excreted via odes as well. And this is kind of concerning, because we always hear how NSAIDs can undo the antihypertensive or, you know, they have more water retention properties and stuff. So it's trying to do on, you know, trying to do opposite of what loop diuretics are trying to do here. Dr. Sean Kane 13:42 And the problem is, not only are the NSAIDs causing that salt and water retention, but they also compete for the the oat transporter, so you can only transport so many molecules across the organic anion transporter. So if the NSAID is doing it and they're getting dumped into the urine, then your furosemide is not and your furosemide is not going to exert its therapeutic effect. Or conversely, if some other drug is relying on oat transport to get into the urine, you are occupying it with your furosemide, then that other drug is not going to be dumped into the urine. Dr. Khyati Patel 14:14 Yeah, so drug interaction is probably the biggest thing that you can get out of here. The other one is uric acid. It also uses oats to get secreted. And if you have your oats occupied by furosemide, the uric acid is going to be retained in the blood you know, potentially causing gout attack. And so we do get to see that it's not a contraindication for using loop diuretics, but it's a precaution, especially in those who have frequent gut attacks, we need to be careful. Dr. Sean Kane 14:43 And Dr. Patel, again, as someone who either forgot or never learned about oats, I always assumed that the uric acid effect was because the loop diuretic is changing how uric acid is excreted into the urine, and it is, but it's not like we're blocking a receptor to get rid of more uric acid. In this case, we're just occupying the transporter to cause secretion into the tubule system, so at the end of the day, kind of. But it's very different than how the loop diuretic is working on sodium reabsorption. As an example, yeah, more Dr. Khyati Patel 15:13 clinically speaking. Dr. Kane, how are we dosing? Or how are we using loop diuretics? Well, one thing Dr. Sean Kane 15:20 to think about is that we have an S shaped dose response curve. What that means is that at really low doses, it doesn't cause any diuresis, and you have to have some minimum dose to have a diuretic effect. So ideally, would inform how you dose these patients. So if you give a small dose and nothing happens, you definitely need to give more. So you're kind of titrating to effect. But on the other side of the S shaped curve, at the high end, if you have too high of a dose, at some point, you get diminishing returns and a ceiling effect, meaning, if you give a high dose or a very high dose, it might produce the exact same diuretic effect for a patient, and at that point, you're just getting more side effects, as opposed to More efficacy, right, right? Dr. Khyati Patel 16:00 Ideally in a healthy subject, I believe the 40 milligrams of IV furosemide, let's just take that would cause about three to four liters of urine production over three to four hours. So that's kind of like your normal response. Two liters per day is a normal urine output for a healthy person. So if you give them this IV furosemide, you increase it by one or two more liters Dr. Sean Kane 16:23 over a short period of time. Yeah, it's pretty quick. So again, that's in healthy subjects, where they're diuretic, naive that have normal renal function. They're not super dimitous, but that does give a sense of 40 milligrams, which is a typical furosemide dose, is going to give you a couple liters, if not four liters, of urine output over a fairly short period of time. But again, some patients are going to respond better, worse, things like that. But if that gives the audience some sense of the kind of urine output that we're going to see, this is not a drug that someone wants to take right before they go watch a movie in a movie theater, because they're going to be up a lot in that first couple hours. So it can be quite potent. A population that needs a higher dose would be a CKD patient population, and the reason for that is that that urine output is highly dependent on how much sodium gets filtered and then would normally be reabsorbed, but isn't reabsorbed because we're blocking that reabsorption in CKD patients, they don't filter as much sodium because their glomerular filtration rate is lower. So if they have a lower filtration rate, the amount of sodium is going to be less than the ascending loop of Henle, and there's less opportunity for the loop diuretic to do anything. So in those circumstances, you have to give bigger doses to have a more profound effect, if you're looking for the same amount of diuresis. Dr. Khyati Patel 17:33 And it's kind of counterintuitive, because we know too much diuresis with loop diuretics can end up causing an Aki. So while, yes, we need higher doses, these patients are going to be needing higher doses, but with extra monitoring. Dr. Sean Kane 17:49 And really the key to the dosing perspective is appreciating what we talked about, the S shaped curve. The dose response is going to vary between individuals, but the key is that you titrate the dose based on what you're looking for. So net fluid loss in the ICU is probably the biggest thing that we look for. So net fluid loss is how much you peed out minus how much you took in. So if you peed out four liters and you took in two liters of fluid, your net fluid loss is two liters four minus two so you've lost two liters compared to what you took in. And generally speaking, for an edematous patient, we're looking for one to two liters of net fluid loss over a day, which sometimes you you want them to lose more, and they might lose more, but they're more prone to metabolic abnormalities like hypokalemia, hypotension, things like that, if you overdo it and you diarist them too quickly over that first day, right? Dr. Khyati Patel 18:42 And then the risk of Aki, all that kind of goes up too. So you're you're paying attention to what that goal is, but you're also looking at the patient's body weight, right? And that body weight might be coming from the level of edema they have, as well as clinically speaking, you know, how worse are their symptoms. Typically, these patients with lot of fluid retentions are going to have issues with dyspnea or tapnia. So we're going to take a look at their clinical features, how they're feeling, and then we also look at lower extremity edema. So by assessing the pitting edema or looking for rails on the auscultations and stuff. So all of that is going to kind of drive your dosing strategy for these loop diuretics. Dr. Sean Kane 19:27 And then there's actually a lot of different things that you can do if you give a loop diuretic and it doesn't work to whatever your therapeutic effect is. So the obvious one is that you give a bigger dose, and we've kind of alluded to that, but there's other things and other strategies, especially in hospitalized patients, that we can do so as an example. And this is a whole topic in itself, we might consider, in addition, if a higher dose fails, we might consider an IV infusion, where they get it continuously, 24 hours a day. We might switch from furosemide to bumetanide, which is a more potent loop diuretics. We might add a thigh. So that we block sodium reabsorption in the in the ascending loop of Henle and the distal tubule both. So we kind of maximize sodium blockade at two different parts of the tubule system. There's other strategies as well, but all of these, in general, are going to make it so that you have a higher likelihood of achieving your diuretic goal. For a patient Dr. Khyati Patel 20:19 and Dr. Kane, when you give that combination with Diaz, I diuretic, example, I've commonly seen, you know, people would add metolazone on top of the furosemide, like taken three times a week, or something like that, to augment the fluid loss that the lube diuretics can provide, Exactly, yep. So we talked about some of the loop diuretics, the related electrolyte abnormalities, but kind of covering side effects from overall perspective, yes, we are losing electrolytes, but we are also losing water. So dehydration is a common issue that we get to see, and because we are losing important cations such as potassium and magnesium that are important for the muscles, patients may even complain of muscle cramping, kind of like those Charlie horses at night, too. Dr. Sean Kane 21:04 And you know, if a patient's complaining of that, you better check their potassium, their magnesium. And magnesium, as an example, is not on your Chem seven, so you're going to want to get a lab assessment that includes your magnesium as part of that. Yeah, absolutely. You know, another side effect is metabolic alkalosis, and this is again, more common than on the inpatient side, because this typically only happens when a patient becomes over diuresed, where you've diuresed them too much. And what happens here is that a loop diuretic, in addition to the ion effects that we've already talked about, loop diuretics also make it so that your urine is more acidic, so it's going to increase hydrogen ion excretion into the urine, and if you get rid of more hydrogen ion or more acid, that means that you're going to have more base or more bicarb in your blood. So higher bicarb in your blood is called a metabolic alkalosis. So we actually measure this, and if the bicarb level starts to rise, we've probably overdone our diuresis for these patients, and we may need to back off, or there's some drugs that we can give to adjust that bicarb as well. Dr. Khyati Patel 22:05 And while this one is pretty rare, ototoxicity has also been reported with the use of loop diuretics, and so patient may have ringing in the ears. We call it tinnitus, vertigo, or even hearing impairment. But luckily, these are all reversible, meaning you stop the drug and it kind of reverses it. However, there are some risk factors that patients may be at a higher risk of this ototoxicity, such as if they have renal impairment, if you're using very high doses, or you're using those rapid IV administration infusions, they may be at a higher risk. Dr. Sean Kane 22:41 The last two side effects to note are what we already talked about, hyperuricemia or even gout attacks. We talked about that that's because uric acid is secreted into the tubule system using oats, those organic anion transporters and loop diuretics can occupy those so that the patient can't pee out as much uric acid as they normally would. Then the last one is photosensitivity. So when patients take these medications, they're more prone to getting sunburned if they're exposed to sunlight. So just being aware of that sunscreen things like that would be important counseling points. Dr. Khyati Patel 23:14 So Dr. Kane earlier, we mentioned we have four different loop diuretics. Are there particular differences to keep in mind or note among among those four, Dr. Sean Kane 23:23 yeah, and there must be right. Otherwise. Why would a drug company come up with any more than one? But one difference is going to be route of administration, dosage form. So three of the four are available IV and po so furosemide, bumetanide and ethacrynic acid are available as IV and oral formulations. Technically, ethacrynic acid sodium is the IV form, and then ethacrynic acid PO, but it's the same drug, just different salt form. So the difference there is that torsemide is only available as an oral formulation. Dr. Khyati Patel 23:53 And then some differences come in from the absorption as well as the bioavailability perspective. And this is where those you know, IV, two po switches, or dosing differences come in the torsemide, bumetanide, and at the chronic acid, they're like 100% bioavailable. So, you know, one to one, but furosemide, it's about 50% this 50% is really an average. It really depends. We've seen the range is anywhere between 10% to 90% which is a really big range, if you think about it, but technically there, if there is more edema, more water retention, there is less absorption of the furosemide. So furosemide varies a little bit, but the other three is usually pretty good bioavailability, Dr. Sean Kane 24:37 and that's actually one of the reasons why, when patients come in with acute decompensated heart failure, we give them IV, as opposed to oral is that we know that just in general, but especially with furosemide, the absorption is worse if they're very edematous, if they have lots of got edema, the absorption of even food is reduced. So we have to be careful and make sure that they get the full dose by giving the IV. Dr. Khyati Patel 24:58 Yeah, and outpatient wise. If they are taking these drugs, we don't really have food versus no food recommendations. However, know that there is some impact on the absorption. Dr. Sean Kane 25:09 The duration of effect is a little bit different. So furosemide and bumetanide last about six hours. And whether it's an old wives tale or not, I've always heard that lasix was named because it last six hours? I don't know if that's actually true or not, but roughly six hours for furisonide and bumetanide. Some sources will have bumetanide slightly shorter, like an hour or two shorter, but then torsemide tends to be the longer, acting one, something like at the six hour mark. But other sources say it could last double the duration, so up to 12 hours. It really depends on what drug reference you're using for the duration of effect. Dr. Khyati Patel 25:44 And then we have potency differences too, and between the bioavailability and potency. You know, these are important to know when we are considering agent selection, as well as formulation conversions too. So our bumetanide, which is our most potent one, IV or Po, we use the one milligram dose. Dr. Sean Kane 26:01 And then torsemides, it's only currently available as an oral formulation. So the equivalent dose would be 20 milligrams oral, which is the same as the IV of furosemide, which is 20 milligrams of IV, but that's different than the Dr. Khyati Patel 26:14 oral Yeah. And the oral furosemide is that one to two conversion, so it will be 40 milligrams if we are going with the oral route. Dr. Sean Kane 26:21 And then finally, ethacrynic acid is 50 milligrams, so it's our least potent, and it has 100% bioavailability, so the IV and the PO dose are equivalent at 50 milligrams. Dr. Khyati Patel 26:32 So talking about ethacrynic acid, we talked about earlier, Dr. Kane, it's not utilized as much. How is this different? Yeah. Dr. Sean Kane 26:40 So when it first came out, the big claim to fame, and many pharmacy students probably learn about this in medicinal chemistry, three of the four loop diuretics, Furosemide, tortoisemide, bumetanide, they all have a sulfonamide moiety. Moiety just means like a piece, right? So they all have this sulfonamide component. And the thought was that if you are sulfa allergic, that you would also be allergic to these sulfonamide containing loop diuretics. And the thought was that it's contraindicated, because clearly you're going to have a reaction to that, and therefore you should get a non sulfonamide containing loop diuretic. And that's where ethylcrynic acid comes in. It's chemically different. It does not have a sulfonamide moiety. So it turns out 99.9% of the time when someone says that they have a sulfate they have a sulfa allergy, they're talking about Bactrim. So Bactrim is sulfa. The facts is all trimethoprim. And actually, in the US population, three to 5% of people in the US are allergic to sulfa containing antibiotics like Bactrim, but to say sulfa, in terms of sulfa allergy with Bactrim, that's a different reaction than a sulfonamide reaction, chemically, those are different, and what's going on from an immune standpoint is different, Dr. Khyati Patel 27:48 yeah, I think that that is the difference here, is that it's not really the sulfonamide component, but what is adjacent to that sulfonamide moiety, right? So we are not only talking about this Bactrim, but other non antibiotic sulfonamide containing drugs like the furosemide, the celecoxib, the hydrochlorothiazide, or even sulfonylureas like glipizide, Glyburide comes into play too. They all do not have that adjacent component that is responsible for leading that reaction. Yeah. Dr. Sean Kane 28:19 So really, the true distinction here is, is the patient allergic to a sulfa antibiotic? In which case it's okay to give these sulfonamide containing non antibiotics, like a loop diuretic? Or have they had a reaction to a loop diuretic in the past? In which case, then you might actually choose ethnic clinic acid because it is chemically different. And for the listeners that don't believe us, because you learn this in pharmacy school and you want to learn more. There are two articles that we have in the show notes, RICHO and 2011 and Strom 2003 both of these go into more detail about the med Chem of this and actually a cohort study showing that it's safe to give someone who has a sulfa allergy a sulfonamide containing non antibiotic that that cross reactivity is not there, right? Dr. Khyati Patel 29:05 And another reason not to use ethacrynic acid more commonly, is the cost for that 50 milligram IV dose. The AWP is about $5,000 which raises my eyebrows, really big. Dr. Sean Kane 29:18 It makes my eyes water. Doctor, we're talking like alteplase level cost of a drug here of ethnic clinic acid, where, to be honest, like 99.9% of the time these patients could get furosemide IV for pennies. So that cost is just bonkers. And the cost is also really high for the AWP of the tablet, several, several dollars per tablet depends on what source you're looking at and the manufacturer, but either way, it's a very expensive drug, and it's expensive for kind of no reason, right? Dr. Khyati Patel 29:48 And then we have maybe a little bit more ototoxicity associated with this one compared to the other three. So in addition to what we just discussed about the sulfur reaction, these could be additional reasons why we don't get to see ethacrynic acid as commonly used. Dr. Sean Kane 30:03 So really, the big picture here is almost never you should use ethnic chronic acid, and if someone orders it, it's probably because they don't know the literature, which is referenced in our show notes, the only time I could ever see it realistically being used and accepting the eye watering $5,000 AWP per dose would be if they have a documented allergy to one of our other loop diuretics, like furosemide, bumetanide or torsemide, not just allergic to sulfa, which is different, Dr. Khyati Patel 30:30 and it's great to have discussed, you know, the nuances of loop diuretics and the difference between all this different agents and stuff, but clinically speaking and clinically speaking, as in looking at the health outcomes, whether it be cardiovascular morbidity, mortality, what differences have we seen among some of these agents? Dr. Sean Kane 30:48 So prior to 2023 so this is pretty recent stuff, there were a number of small, underpowered or low quality studies that suggested that torsemide might be better in terms of better clinical outcomes compared to other diuretics, mostly furosemide. And if you're interested, we have a review article by buggy and colleagues in 2015 it's in our show notes. But basically they thought that the better clinical benefit may be driven by some favorable biochemical changes, specifically less renin angiotensin aldosterone system activation, and that led to potentially better clinical outcomes. And again, some of these smaller trials with bigger limitations and lower quality trials than what we might be used to seeing in clinical practice. Dr. Khyati Patel 31:31 And so in 2023 we had the transform HF randomized control trial that was published that looked at torsemide and furosemide side by side in an open label, pragmatic style. Study Design in about 2800 patients, they were hospitalized with heart failure, Dr. Sean Kane 31:51 and this is perfect. So this is how evidence based medicine works. So you have a hypothesis driven by smaller trials or lower quality trials or uncontrolled trials, and you look at it, right? You do a full study. And so the study randomized patients to furosemide or torsemide. The investigator got to pick the dose. So it was pragmatic, and they followed them for 30 months after their index heart failure hospitalization, and Dr. Khyati Patel 32:13 they were really looking at those Meteor outcomes, right? The primary endpoint was all cause mortality, and there was no difference. The rate of death was 26.2% in the furosemide group versus 26.1% in the torsomide group. So really no difference there. Dr. Sean Kane 32:29 And they looked at a bunch of other endpoints related to mortality, hospitalization at different time intervals, like at 12 months as opposed to 30 months. They had a variety of subgroup analyzes. All of these were no different. So at the end of the day, there is no clinical difference between torsemide and furosemide, and yet, the author still had plenty of limitations that are described in the article about loss to follow up, not adherence, and other things that would open up the door for future research. But at this point, I would accept this RCT over these lower quality prior articles and conclude that torsemide does not bring a better clinical benefit to the table compared to furosemide, Dr. Khyati Patel 33:08 and I conclude as well. So to kind Dr. Sean Kane 33:11 of wrap up today's episode, some of the key concepts are we have for loop diuretics on the market, Furosemide, torsemide, bumetanide and ethnic acid. And these are the ones that you use when you want to treat edema. They're not used for hypertension, but they are used to get rid of fluid that patients have, typically in their legs and lungs, to make them feel better. Dr. Khyati Patel 33:29 And the way they work, in the loop of Henle, they're going to increase the loss of sodium chloride, potassium hydrogen, magnesium as well as calcium ions into the urine. But clinically speaking, we we see the manifestation of hypokalemia, hypomagnesemia, as well as metabolic alkalosis. Dr. Sean Kane 33:49 From a dosing perspective, they haven't these loop diuretics have an S shaped dose response curve, so you have to have some minimum dose to achieve any diuresis, and at some point, giving more just has a ceiling effect in terms of you don't continue getting more and more diuretic effect, but you can see more side effects at those really high doses, but at the end of the day, the most important thing is that we're assessing the patient's response and then individualizing the dose of the patient based on side effects and the efficacy that we're observing, Dr. Khyati Patel 34:17 right and the last, but not the least, we have this ethacrynic acid, which is incorrectly used in patients with sulfa allergy, really any other loop diuretics that contain sulfa moiety are very safe to use in patients who've had allergies to sulfa, such as allergies to the Bactrim type antibiotics. Dr. Sean Kane 34:37 Then finally, we concluded with transform HF, which is cited in our show notes. And basically it shows that between furosemide and torsemide, there's no clinical benefit between the two loop diuretics. You can pick whichever one suits your fancy, whichever one you prefer. So with that, again, we have some show notes at HelixTalk.com Again, this is episode 183 we love the five. Our reviews in iTunes. We have a mailing list you can sign up for at HelixTalk.com so with that, I'm Dr. Kane Dr. Khyati Patel 35:06 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 35:10 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 to Narrator - ? 35:21 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.