this is Dr busty and we're going to be doing a drug class review with a focus on the Loop Diuretics um we're going to kind of do a basic review of normal uh renal physiology and how urine is basically formed and concentrated and what it does with the electrolytes specifically with sodium and water um so we'll be focusing on mechanisms of action we'll do a basic drug review and then we'll kind of go in through some clinical pearls related to the drug side effects and clinical considerations and certain scenarios and so when you think about the kidney um it's made up of you know millions of nephrons and the area where a lot of these nephrons take place um or in this area here where you see the blood flow kind of narrowing down and if we were to sort of zoom in into that area this is the nefron that we would see where you have the glomerulus up here and you have the blood flow coming into the glomerulus here and what that does is that's the renal a an arterial that creates the profusion that puts you know filtrate into the proximal renal tubule in addition there is secretion in this area of the proximal renal tubule of substances in and out um that starts to create some of the uh absorption of of sodium water electrolytes also acidbase balance is happening here and approximately 60% of sodium in water being reabsorbed in that proximal renal tubule then as it enters in the loop of Henley down here uh that's where a lot of shifts also start to occur and we have where the Loop Diuretics work um right here on the sodium pottassium 2 chloride pump and this is where about you know 20% maybe up to 40% of sodium water is being reabsorbed and then once the urine filtrate makes it up here to the distal convoluta tubule that's where about five to you know 5 to 10% of sodium is being reabsorbed with water and then it enters in the the collecting system where water is basically um being reabsorbed at a certain level depending on the hydration status and it's the urine is being concentrated out um and so that's kind of the the big picture of what's happening but the kidneys play a central role in not only fluid but also electrolyte and acidbase balance and so when we look at the Loop Diuretics there are three that are still largely used in clinical practice I did not include on this table ethenic acid for the purposes of while it is technically uh on the market it is almost near impossible to find most institutions don't stock it and um I've quite honestly never once ever see it needed to be used clinically um in any patient in any scenario whatsoever so I don't know that it's really clinically relevant to talk about it other than it is one of the drugs and I'll briefly mention in the context of allergies here in a minute um so when you think about we got feride bumetanide and then torside so each column represents a different Loop diuretic their generic name followed by the brand or marketed historical name um and when you then look at the individual rows these are the various characteristics that make up those different drugs and so you can see that these drugs have a sealing effect um and one of the reasons why there's a sealing effect is because there's a risk of autotoxicity at higher doses with chronic exposure um we also see that the um doses may not be um may need to be adjusted based on the renal function uh because as this drug just like thide diuretics they have to get secreted into the tubule and if you can't get to the tubule to get secreted they're not going to work um and so that accumulation just occurs and the autotoxicity increases the other important I think clinically relevant Point here is this row on bioavailability this is talking about the absorption and if you look at the individual agents feros amide has the lowest bioavailability and is also subject to influences of gut Adema more so than T torside and bumetanide you can see with bumetanide and torside that the bioavailability is significantly better and is less under the influence of gutema and so when you think about the fact that if a drug doesn't get absorbed it doesn't make it to the side of action it doesn't really matter at all what the anything else about the drug because if it doesn't get there it doesn't work and you can see that 30 to 50% excuse me 30 to 50% of the drug that you administer by mouth of feride is lost essentially in the stool it never makes it really in or is eliminated in some other pathway whereas you can see much more of the drug is going to be making into Central circulation with bumetanide and torside Al certainly if you give these drugs IV then you're administering it directly into Central circulation it's a bioavailability of 100% but when you're giving it by mouth in patients for chronic management as an outpatient and they have any changes in their G bowel Integrity or other things that might influence the absorption then you're going to see that Lasix in particular froide is going to take a hit and so they may be actually compliant with the medication and taking it every day like they're supposed to and at the appropriate doses but yet they're not urinating or diuresing themselves off of the extra fluid now there is a differences in uh the amongst agents in potency if you look up here at the different milligrams per day you can see that bumex or bumetanide has the lowest amount or is more potent um and that has to do with the ec50 or ed50 the how much drug do I have to give to exert a pharmacologic effect and you can see with bumetanide you don't have to give very much in fact it's 40 times more potent than feride is and torside is four times more potent than feride and so if you want to convert patients from One Drug to another uh let's say they're on you know uh Lasix or a feros amide you take the total daily dose of Lasix and you divide by 40 and that gets you the approximate equivalent dose of oral administered bumetanide if you go to torside you take the total daily dose of Lasix that the patient's on and you divide it by four and that gives you the approxim an equivalent dose of torside or Demodex okay now as it relates to giving feride IV versus Po and as it relates to dosing generally when you think about the fact that up to 50% of the drug is never absorbed when you take it by mouth so if you're on 20 milligrams a day of Lasix poo or by mouth then that's roughly equivalent to 10 Mig given IV and that's because when you give it IV 100% of the drug is being AB absorbed into or put into Central circulation and when you take it by mouth as much as 50% of it never makes it in and so that's a typical ratio when you're switching people from an oral dose to a equivalent IV dose kind of how clinicians do that um you can see that some of these drugs are affected in part by their absorption of the drug of food as well as maybe a little bit of gadea and then you can see their durations are a little bit different with torside having a longer duration of action compared to all the agents now when you look at the duration of Lasix it says 6 hours okay and that's so that's how it got its name it last 6 hours lay six last 6 hours uh that probably won't be on a test but you know it's kind of cool trivia all right so how do these drugs work okay so we've briefly talked about the renal physiology we briefly discussed what are Loop Diuretics and you know dosing issues and absorption issues but where they work once they get into the body and you've administered the drug well they they they get into the blood and they go to the kidneys and they're secreted in the in the proximal renal tubule and they've got to get inside of the Lumen okay and the urine filtrate because they work on the luminal side of the nefron at the asending Loop of Henley and so when you look here they get in there by active transport uh and then they when they get to the asting loop of Henley they're going to be focusing on inhibiting this Co transporter or sorter here on the loop luminal side okay of the thick ating Loop of Henley and if we look in that area that's where about 20 to 40% of sodium is roughly being absorbed um it varies obviously dependent on the um uh delivery of the drug to that the tissue at the time um and what that does is it increases the sodium low that stays in the urine filtrate which then what follows sodium water and so then you get a pretty significant diuresis so let's look at where this is at so you form the urine filtrate up here in the proximal renal tubule it moves down the proximal renal tubule into the loop of Henley and then we're going to be zooming in right here okay this is where the Loop diuretics are going to work and again 20 up to 40% of sodium and water is being reabsorbed there okay so when we zoom in remember it had to get into the Lumen okay it had to get into the luminal side so this is where the urine filtrate is is present it's moving it just came up from the ascending Loop of Henley it's and it's going by um headed towards the distal convoluted tubal and this is the basolateral side which has the blood flow and all that other stuff in the renal pinka and here's your sodium potassium two chloride transporter or sorter you can see that that's quite a number of cations that are being affected as well as anions um and when you do that you create electrical chemical differentiation from inside the cell and outside the cell across the different layers of the tissue and so what ends up happening is that affects the paracellular reabsorption of magnesium and calcium so when you give somebody a loop diuretic and you block this you also block the paracellular okay paracellular reabsorption of calcium and magnesium and that is why patients on Loop Diuretics can develop not only hyponatremia but can develop hypokalemia hypo calcemia and hypo magnesia um and that becom becomes very relevant because all of those electrolytes and catons in particular can also in low levels cause QT prolongation clinically in patients and so it does matter in addition to that we know that the body's ability to maintain the amount of total body stores of potassium is influenced by the presence of magnesium so when magnesium is low it will affect your ability to maintain potassium in the body now given the fact that we lose a lot of potassium with some of these Loop Diuretics many times these patients sometimes will need supplements of potassium chloride replacement for that reason uh now sometimes they may be on medicines that cause hyperkalemia like ACE inhibitors arbs renin Inhibitors aldosterone antagonist and that might set offset the loss from the loop diuretic but if they're not on those medications or they're still having potassium loss then the general ratio is somewhere around giving them 10 mil equivalents of potassium replacement for about every 40 mil equivalents of feros amide equivalent that you're using um that's the rough sort of ratio um so that you maintain that potassium but you can give all the potassium you want um if the patient's magnesium stores are not adequate then you won't be able to replenish the potassium so when you have hypo calmia you should check a magnesium and make sure that the magnesium level is normalized or replaced so that when you give the potassium replacement it actually can correct it all right um now when when you think about this is happening here okay in this area then that means the sodium load coming up to the distal convoluted tubu up here the DCT is going to sense all that sodium and when it senses that sodium it's going to go holy cow what in the world's going on there's way too much sodium present in that urine filtrate we have got to get that sodium back in and so the distal convoluted tubal which normally reabsorb 5 to 10% of sodium may now upregulate uh sodium chloride Co Transporters to pull more of that sodium in and that's where diuretic resistance starts to take place um and so you can see that here as the urine filtrate comes by the DCT cells distal convoluted tubule cells will say hm that's not normal okay we got can't get we got to get some of that back okay remember it doesn't know that you're trying to get rid of that sodium it's trying to do its job and so you can have an increased movement of reabsorption that causes diuretic uh resistance now as the urine filtrate does Go On by and starts to head towards the collecting tubule you see that there's other areas where the the nefron will try its best to regulate electrolytes you can see that there's still has a little bit of permeability to sodium here and this is where the influence of ultimately aldosterone works we have the uh free water absorption uh or free uh Aqua porn up regulation that absorbs free water to concentrate urine but we also have the ability to reabsorb potassium that was being uh lost at the asending Loop of Henley and in doing so you will kick out more hydrogen ions and that can cause acid base disturbance so as you lose hydrogens you will become more alkalotic and so you can sometimes um see that happening so diuretic resistance the mechanisms here are we increase the urine concentration delivery at the distal convoluted tubal and the DCT cells up here start to upregulate the reabsorption of sodium and water at that area so it goes from 5 to 10% maybe up to 10 to 15% and so you lose a little bit of the diuretic effect at standard doses of the loops and when that starts to happen you can do one of two things you can either increase the I'm sorry one of three things you can increase the dose of the Loop diuretic that you're using to overcome that two you can increase the frequency of administration of the loop diuretic and then number three you can premedicate the patient with a thide diuretic which will come up here and block that reabsorption then you give them the loop diuretic and what happens is they pass on right by and those doors are all closed and there is no reabsorption and you start urinating like crazy now you have to be careful if you do that where you co- admit Minister a thide diuretic with a loop because that can cause a significant amount of diuresis and so much diuresis that you put them in a a pre-renal azotemia because you over diores them and they become vascularly depleted their vascular volume gets low to where the blood vessels tighten down and constrict and there's lower profusion then to the kidney it's called Uh preal asmia and they can go into renal failure now the traditional thy that's used or talked about is metazone or zoroy um it's just one of the more potent uh thy diuretics on the market but you can quite honestly use any thide diuretic and accomplish that so we do do it but you need to be very careful in how you do it and sometimes in the context of heart failure patients who have diuretic resistance where they accumulate a little bit of fluid we just need to get rid of that fluid so they don't cycle and get into themselves into a heart failure exacerbation well give them a dose or two once or twice a week that will get rid off extra fluid that sometimes occurs because we're all humans and they're going to make some mistakes in in and ingest more sodium and water than they probably should have um but that will get rid of some of that extra fluid but you just got to be very careful that you don't put them in acute renal failure and I've seen it numerous times so you should never ever for the most part ever be co-administering a thide plus a loop diuretic on a daily basis that is likely to put somebody into renal failure the other thing that can happen you can you can see like when you over diores or begin to over diares somebody they start to have something called contraction alkalosis okay and this is where they their their pH or their bicarb levels start to go up and that has to do with the contraction of the of the water in various compartments and so you look at most of the water in the body okay 60% of our body uh water uh our body weight is made up of water you can see that uh the majority of it sits in the intracellular environment and then that other 20% sits in the extracellular environment and this bicarb right here is important because when you over diarrhe something you contract this compartment down because it's lost the fluid in the interstitium and the plasma and so what ends up happening is this concentration of the bicarb looks like it goes up and it's called contraction alkalosis and it's due to the fact that it's just more concentrated because you got rid of so much free water from overuse of the um of of the diuretic in that situation so keep that in mind when you're talking about adding these to one of these drugs um these drugs will need dose adjustments over time and that's why you see this range because you will develop some some degree of diuretic resistance just be careful and how much you give because over time if you start to approach these ceiling of uh doses then that's where that risk of autotoxicity really starts to kick in so the side effects are going to be influenced by the dose the frequency of administration and that patient's renal function uh we talked about hypokalemia and that you might need to replace uh you know approximately uh 5 to 10 mil equivalents per uh 20 so that would be 10 you know if you were on some 10 to 10 to 20 mil equivalents if someone's on 40 milligrams there's no one set rule you have to adjust it for the patient based on their magnesium level based on their other medications um there's a lot of factors that go into the amount that you want to replace but you don't want to give them too much potassium because too much potassium can obviously cause problems as well hypocalcemia hypomagnesemia and again when you're when you're low in the magnesium levels you're not going to be able to fix the potassium and then renal failure can occur if you dose it wrong and it's not being monitored because you over diares the patient and then autotoxicity at higher levels the metabolic alkalosis comes from uh the fact that you in that very last part before the collecting duct where there's that attempt to kick out the hydrogen ions to reabsorb some of that potassium loss um that occurs and therefore you lose hydrogen ions they become more alkalotic okay uh and of course if you over diares them you can see contraction alkalosis uh but that's for a different mechanism it's not the same mechanism as here uh what about sofa allergies or sulfonamide allerg allergies well if you look at the sulfonamide mo right which is a s sulfa group when people say they're allergic to sulfa what does that mean that is this S2 nh2 this group right here okay so this is the sulfonamide mo all right um and when you look at them and typically in there are sulfonamide containing drugs that are antibiotics or antimicrobial agents and then there are nonantimicrobial agents that contain sulfonamides they are different in the N1 substituent and the N4 auramine group and how they're located and as a result of that there is um a feeling and there's evidence that suggests that there's not there's not the same risk so if someone is sulfa allergic technically you're talking about sulfonamide groups and so technically Loop Diuretics have the sulfonamide group but they have differences in these other groups on the side that are different from the anti microbials agents that contain sulfonamides and so the cross reactivity risk is very low kind of like penicillin and cross reactivity to sephos sporin it's about 1 to perc maybe up to 3% the newest data is suggesting that it's low same thing with these drugs the cross reactivity of someone who's sofa allergic to an antibiotic like s trimethoprim sulfamethoxazol I.E Baum that patient may not is likely not to be allergic IC to Loop diuretic so if you look here the Loop Diuretics have that s SO2 nh2 here fosite but it lacks the N1 substituent group okay that's missing over here it also does not have the N4 aamine same thing with torside you see that there's differences and here's the you know sodamide group and again here it is again and it's just not the same as an antimicrobial agents like Baum and so this is sulome oxol that's found in trimethoprim suom oxol I.E Baum and you can see that they these groups this orientation around the sulfonamide is now being recognized as the culprit for allergic reactions and the only reason I mention this is that because if you read certain books and product package inserts and warnings it says if you have a sanide allergy that you should possibly avoid the use of these and that's where ethinic Aid historically has been its claim to fame is that it it lacks you don't see an so SO2 nh2 group at all there is no sulfonamide moadi and ethenic acid but quite honestly patients who have reported to be sulfa allergic end up not having allergic reactions if you co if you administer them one of these Loop Diuretics so the belief is that clinically the risk is very low I didn't say it was Zero it's just very low and so if you have somebody who's had an allergic reaction to Baum or something like that it is acceptable clinically to consider the use of these Loop Diuretics but with obviously some degree of monitoring but most patients end up tolerating it just fine now the other clinical scenario or situation I think is worth mentioning is in the context of um High does use uh when you look at them high does diuretic therapy has been a marker for increased mortality uh during the hospitalization of heart failure in part that may be due to the fact that some of these other side effects I mentioned with electrolyte abnormalities acidbase disturbances volume status changes um that can do that and so the reason why when patients come in the hospital that we normally give it IV is because they have gut edema and with that gut edema if they you see lower extremity edema they may be short of breath and have pulmonary edema from their fluid overload but they also have gut Adema which can affect the oral bioavailability so we bypass the gut and we give it IV so that the concentration of the medication makes it to that uh into the kidney and gets secreted into the tubule and the EUR filtrate so it works on that luminal side on the asending loop of Henley and what ends up happening is they diares we get rid of the extra fluid the edema on the outside goes away the shortness of breath improves and their gut EMA starts to improve and then you switch them over back to their oral agent because now their gut Adema is improved the bioavailability has improved and so that's why we initially give it IV but you have to be careful how much you give IV how frequent so that you don't over diores uh the patient on occasion these patients sometimes even benefit continuous drips because of diuretic degrees of diuretic resistance and that's not normal for most patients but if you have severe diuretic resistance going on then that may actually be a better alternative uh treatment approach now the other clinical scenario that matters is sometimes when you give I V lasic acutely especially in somebody with decompensated heart failure with pulmonary edema plural affusions you know they're shorter breath and you want to reduce the preload if you give uh Lasix or fosmid IV push it has been shown to cause some reductions um in and right ventricular filling pressures basically it reduces the preload because of vasodilation in the uh veins well that might relieve the congestion in the pulmonary vasculature and reduce the pressures inside the right side of the heart but it also has some bad consequences as a result of that you have to be very careful on how fast you administer the medication so it initially helps people to feel a little bit better but what ends up happening is you reduce cardiac output a little bit and that activates the RAS system the renin Angiotensin and aldosterone system that can then cause compensatory increases in Al sterone sodium water reabsorption that actually don't help you um and so the good is these patients receive these reductions and filling pressures if they're really really really congested um it it works as early as 15 minutes after the administration which can cause some increased forward flow the bad okay listd here is that it activates the RAS system and Ras activation in a heart failure patient generally is not a good thing so let's summarize Core Concepts Loops diuretics okay they differ in their oral bioavailability with with fosite having the worst oral bioavailability compared to the other ones and all of them seem to be influenced a little bit at some degree by gut Adema and giving it IV bypasses that we know that they work in a thick asending Loop of Henley on the sodium pottassium 2 chloride uh sorter that's that's located there and it can also then indirectly impact paracellular reabsorption of calcium and magnes magesium the reason that we get good diuresis is because of the amount of sodium and water that's being reabsorbed there uh it does have a sealing effect due to the risk of autotoxicity you have to watch out for electrolyte abnormalities and deficiencies specifically in potassium calcium magnesium and if you're deficient in Cal hyp potassium you need to check your magnesium and replace the Magnesium if you're going to fix the potassium and then remember you need to give somewhere on the range of about 10 5 to 10 mil equivalents for every 20 to you know 40 mil equivalents of lasic that you're U milligrams of lasx or froide that you're using uh again that's going to be influenced by that patient's renal function influenced by their other drug Med medications influenced by their kidney function there's a lot of factors that go into what that dose is so it's not a hard and fast ratio for every single patient but in generality that can happen and over diuresis especially in the context of co-administration of of aai can put patients into renal failure and contraction alosis and they do not not seem to have the same degree of sulfonamide orientations as to antimicrobial agents containing sulfonamides and the risk of or cross reactivity for allergies is much lower so hopefully you found that overview of the Loop Diuretics to be very useful uh both from a pharmacologic understanding but also clinically because there's a lot going on there we use these drugs all the time