Diuretics

foreign engineers in this video today we're going to be talking about diabetics that includes every diuretic imaginable we're going to talk about them if you guys do like this video you benefit from it it makes sense to you please help us and the best way you can do that is by hitting that like button commenting down the comment section please subscribe also I really highly suggest you guys check out our website we'll have a link in the description box below it'll take you there we got some awesome notes some amazing illustrations that our engineering teams kind of put together and I think it's really going to help you guys to enhance your learning experience get those illustrations have the notes beside you follow along with me as we go through and kind of write things on the Whiteboard I really think it'll help but without further Ado let's talk about diuretics when we talk about diuretics diuretics are basically you're trying to be able to cause elimination of something you're trying to eliminate sodium you're trying to eliminate chloride water things like that in the urine and the way that we have to do that is by targeting particular parts of the Nephron so we got to briefly my friends kind of go back over the anatomy the physiology of some of the tubular reabsorption processes that are occurring we're not going to go crazy if you guys want to know way more about this go wash on our renal physiology playlist but for right now we have the different parts of the Nephron I just want to point out a couple parts here one of these is this part here so we kind of have what's called our Bowman's capsule then we go into this part here called the proximal convoluted tubule the proximal convoluted tubule is extremely important I'm going to denote this as the PCT the proximal convoluted tubules where a decent amount of like sodium reabsorption occurs right so if you think about the actual sodium reabsorption that occurs within the proximal convoluted tubule will represent sodium here as kind of a blue line and then we'll represent what usually follows sodium because it generates an osmotic gradient will represent that as water here in this kind of like blue line here so generally what happens here is in the proximal convoline tubule you generally reabsorb a decent amount of sodium and then subsequently you should reabsorb a decent amount of water in this section of the actual Nephron approximately if we really were to kind of approximate how much sodium is actually reabsorbing the proximal convoluted tubule it's somewhere around 65 percent of the sodium that gets reabsorbed here so if you could imagine imagine we did have a diuretic that directly inhibited sodium reabsorption it would cause a massive loss of sodium in the urine and subsequently a massive loss of water in the urine we don't actually have a very specific diuretic that targets directly sodium reabsorption and water absorption it does it indirectly but there is a diuretic that does work in the proximal convoluted tubule and we'll talk about that one but if we had a way of being able to inhibit sodium and water reabsorption directly it would cause a massive loss of sodium into the urine and would cause a massive loss of water into the urine unfortunately we don't have a drug that actually directly does that but there is a drug that works to place some role in inhibiting some of the reabsorption processes that do occur in the proximal convoluted tubule and we'll talk about that it's called Carbonic anehydrous Inhibitors so again the first site of diuretic action here that is involved in direesis is going to be at the proximal convoluted tubular level and one of the drugs that specifically works there is going to be let's actually do this one in red this is going to be what's called your Carbonic anti-hydrase Inhibitors okay so that's an important one it doesn't indirectly reabsorb block the reabsorption of sodium and water it does something else it does particularly something with bicarbonate and it causes some sodium excretion and water excretion but not a ton either way that's the first site of the Nephron now generally a lot of nutrients are also absorbed there so glucose amino acids bicarbonate should be reabsorbed there and that's a really really important one I'm going to represent that in black as well so bicarbonate there's a really really important one that also gets reabsorbed in this section here and that's really the thing that we're going to inhibit with the Carbonic anehydrase Inhibitors but nonetheless we go into the next part here so then you go into What's called the descending limb of the loop of handling if you guys remember that plays a primary role in water reabsorption so primarily the only thing that really is kind of occurring here is water movement out of the descending limited Loop of henle we're not going to really use any specific drug here we'll talk about a drug that actually can involve part of the proximal convoluted tubule and the descending limb that's called Mannitol or urea we'll talk about that one a little bit later okay it's kind of an interesting one all right then we go from the loop of Henley the descending we go up so now we're going into the ascending limit Loop of henle when we get into the ascending limit Loop of henle there is an actual very important drug that works here and again there is going to be some sodium reabsorption that occurs here and there's going to be a decent amount of water reabsorption occurs that occurs here in the ascending limit Loop of henle so when we talked about this before what we're really using for the proximal convoluted tubule we'll talk about this a little bit later is carbonic anehydrase that's inhibiting bicarb reabsorption when we get into this part here in the ascending limit of Henley we actually are directly blocking sodium and water reabsorption here and again what site is this again this is the ascending limb of the loop of Henley so this part here is called the ascending limb of the loop of Henley now when we talk about sodium reabsorption in this section of the actual nephron it's approximately 25 percent so 25 of the sodium is reabsorbed in this section of the loop of henle and we do have a drug that directly blocks sodium and water reabsorption there very powerful diuretic but again there is a particular site there what is that site again that is over here another side of the diuretic action is called the ascending limb of the loop of henle and the particular drug that we will talk about that acts right there is going to be a drug called Loop Diuretics so these are going to be called Loop Diuretics that's their name kind of working within the loop right so this will be your Loop diuretics all right and we'll go over their mechanism of action a little bit more detail we're just basically kind of laying a foundation here all right then as things continue to travel so generally you'll have some type of filtration that occurs here at the glomerulus into the Bowman's capsule so sodium and water will be moving through the proximal convoluted tubule 65 of the sodium is reabsorbed here as well as water if it's not reabsorbed here it'll continue to move down the descending limb water reabsorption will occur in the descending limb it'll go up the ascending limb about 25 percent of the sodium and water should be absorbed in this section of the loop of henle then if it doesn't get reabsorbed here it continues into the distal convoluted tubule so now we're going to move into the distal convoluted tubule when we get to the distal convoluted tubule there's actually two points here so we have What's called the late distal convoluted tubule and then we have over here the early distal convoluted tubule in both of these sections you are going to have some degree of sodium and water reabsorption so there is going to be some sodium reabsorption that occurs here in the late and early distal convoluted tubule and subsequently there is also some water reabsorption that occurs and the early in the late distal convoluted tubule we can actually inhibit the reabsorption directly in the early distal convoluted tubule and the late distal convoluted tubule and we have drugs that specifically work there to block sodium and water absorption and block sodium and water reabsorption what are those okay so when we talk about the early distal convoluted tubule this one actually accounts for about five percent of the sodium reabsorption and then for the late distal convoluted it also accounts for about five percent of the sodium reabsorption so that could kind of get you close to about a hundred percent if you think about that right so 65 plus 25 so it'll give you around potentially close to about 90 percent and then you get an additional five and ten so it's going to go around 100 so generally that's where the sodium reabsorption and subsequently the water reabsorption are going to occur based upon percentages so when you think about it the early distal convolution late distal convoluted tubule if they block sodium and water there it'll cause sodium and water to be lost into the urine but not as much as compared to the actual ascending limit Loop of henle but nonetheless what's the other two sites here that I want you guys to remember another site is called the early distal convoluted tubule and again the drug that works particularly at this site here is going to be what's called your thiazide diuretics so your thiazide diuretics and then the last one here is going to be at the late distal convoluted tubule so this is going to be the late distal convoluted tubule and this one is going to be your potassium sparing diuretics so this is going to be your potassium sparing diuretics and again we'll go over these there's two groups within this one one are called aldosterone blockers and the other one are called emac blockers but we'll go over them but if you guys get the whole point here if we're somewhere to ask you just the basic Point okay if we talk about the nephron we know that there's different points of wrong the nephron such as the PCT the loop of henle and the distal convoluted tubule where sodium and water reabsorption occur now at these particular sites the percentage is different Lots 65 percent in the proximal convoluted tubule 25 in the loop of henle and then five percent in the early distal convoluted tubule and five percent the lead distal convoluted tubule one of the big things to remember I just want to add on here is in the later part of the distal convoluted tubule that sodium reabsorption is dependent upon the presence of antidiuretic hormone so generally in the distal convoluted tubules especially in the late portions here is very dependent upon aldosterone so we're going to put here aldosterone okay so very very important here is dependent upon the presence of aldosterone for sodium reabsorption and ADH for water reabsorption but nonetheless we have an idea of the different parts where sodium and watery absorption are occurring and we know some of the sites by which these drugs actually work one more that I did not mention is the osmotic diuretics that's Mannitol so let's come over here to this small little diagram so in this small diagram what actually happens is Mannitol is this very large kind of solute molecule and what happens is whenever Mannitol it moves through the afferent arterial then it moves through the glomerulus it actually gets filtered out across the glomerulus when Mannitol gets filtered out across the glomerulus it's a decently sized kind of like large solute molecule and what it'll do is it creates a very powerful osmotic gradient and that powerful osmotic gradient will actually pull some water into the proximal convoluted tubule and then it'll also continue to move down so it's so large it can't be reabsorbed it'll actually move down into the descending limb and then it'll also cause a large reabsorption or large kind of like pulling of water into the tubular Lumen here and so what ends up happening is Mannitol causes a massive diuresis a massive degree of diuresis of primarily large amounts of water molecules so that's one of the big things about Mannitol is Mannitol does work at two particular sites and the kidney tubules it's not primarily used as a diuretical talk about its actual indications a little bit later because what it actually does is it's more particularly used for reducing intracranial pressure and reducing kind of acute increases in intraocular pressure so we'll talk about that but Mannitol can work particularly at the proximal convoluted tubule and it can work at the descending limb of the loop of henle so the drug that would actually work particularly at these two sites here to really cause a massive kind of like sucking or pulling of water into these actual tubules and then out into the urine is going to be your osmotic diuretics okay and that's going to be things like Mannitol and urea and we'll talk about that a little bit more later but we got the basic just right so we have a basic just of the different sections of the actual nephron okay where sodium water reabsorption is occurring and we know where diuretics will specifically act at those sections so we know proximal convoluted tubules Carbonic anehydrase ascending limit with the Henley is Loop Diuretics early DCT thiazides late DCT potassium sparing and then technically osmotic diuretics can pull lots and lots of water into the proximal conlit tubule and lots and lots of water into the descending limited Loop of henle and that can cause a massive loss loss of aquauresis so it's going to cause a massive loss of water within the urine and so that's one of the big things with osmotic theoretics but now let's get into a little bit more detail about the mechanism of action so what we're going to do is we're going to zoom in on the proximal convoluted tubule we're going to zoom in in the loop of henling the early DCT the late DCT and we're going to show you how these drugs actually help to promote some degree of excretion of sodium chloride water other electrolytes Etc let's get into that so first one is the proximal convoluted tubule now when we actually talk about this we're going to have some degree of filtration so this is going to be from the Bowman's capsule filtrates moving from the Bowman's capsule into the PCT when things are moving here the primary ion that we actually do care about that actually does get excreted across the glomerulus is something called bicarbonate so we're going to have a molecule here called bicarbonate now bicarbonate is a very interesting molecule what happens is in this proximal convoluted tubular cell we also have another kind of like transport protein and this transporter basically what it does is it's a sodium proton kind of antiporter and what it'll do is it allow for sodium to move into the cell all right through this transporter so sodium will come into the cell when sodium comes into the cell what also is going to happen is a proton is going to be pumped out of the cell okay into the tubular Lumen so this is the tubular cell that we're zooming in on this is the actual capillary blood where things can be absorbed and this is going to be the Lumen of the actual tubular cells okay so that's the Lumen of the tubular tissue and this is actually going to be the tubular cell this proximal convoluted tubular cell will excrete protons and reabsorb sodium because again these things are being filtered from the glomerulus when they get filtered across the glomerulus the sodium will actually get reabsorbed protons will be excreted and then bicarb will continue down here when bicarb moves down what it'll do is it'll combine with this proton here so then what I'm going to do is I'm going to take this proton that I actually have that's now out here and I'm going to combine it with my bicarb when you take protons and bicarb what do you actually get the combination of these make something called carbonic acid okay called carbonic acid now carbonic acid does disassociate and when it disassociates it disassociates into two particular molecules one of these molecules is called CO2 and the other one is called water now what happens is in order for this process to occur we have a very special enzyme that catalyzes and speeds up this particular particular step here this disassociative carbonic acid into CO2 in water is very highly catalyzed by this enzyme on the cell membrane you know what this enzyme is called Carbonic anehydrase this enzyme here is called Carbonic anehydras it's going to stimulate this step now once it does that when carbonic acid disassociates into CO2 in water CO2 is lipid soluble so bicarb is charged it can't be reabsorbed it's too charged there's no specific transporter that allow for bicarb to be reabsorbed across this tubular cell but if I turn bicarb indirectly into CO2 now I have a molecule that actually can be directly absorbed and dissolved and move passively across the cell membrane so that's what CO2 is going to do it's going to move across the cell membrane now you know that there's water inside of cells so what's going to happen is the water is going to combine with the CO2 inside of the cell when it does that and these two actually combine guess what they make they make the same thing to happen here called Carbonic acid guess who stimulates and catalyzes this particular step there's a component of this enzyme in the cell it's going to be Carbonic anehydrase now once I form that now this thing is very unstable and it can easily disassociate guess what it can disassociate to my friends protons and into bicarb now this bicarb is essentially this bicarb that I wanted to reabsorb but I couldn't do it directly but now I have the bicarb in the cell and there is a transporter on the basolateral membrane that can allow for me to get bicarb into the bloodstream and when I push bicarb into the bloodstream I move a negative ion out of the cell so I got to bring a negative ion into the cell so I bring chloride in right and then the same way in order for sodium to be able to move into the cell and protons to move out of the cell sodium has to move down its concentration gradient in other words I need sodium concentration in the cell to be low and I need the sodium concentration outside the cell to be high how do I do that well good thing I got this pump back here on the basol lateral membrane that pumps sodium out of the cell and pumps potassium into the cell that's my sodium potassium atpase so the sodium potassium at DPS is what allows for my sodium to be on the lower end which allows for sodium to be reabsorbed and then protons to be excreted via secondary active transport and then the protons combined with the bicarbonate carbonic acid disassociating the CO2 and water CO2 gets absorbed goes back and makes bicarb so that it can be reabsorbed you're probably like Zach my head is hurting how in the heck is this going to help me with diuresis I got you this is where the drug comes in so now we're going to use the drugs called Carbonic anehydrase inhibitors and let's see now after introducing this so now that we understand the basic physiology what we're going to do is these drugs are going to inhibit so I'm going to draw this later here I'm going to inhibit that particular enzyme the Carbonic anehydrase will now be inhibited okay things get filtered sodium gets filtered bicarb gets kind of filtered across generally what should happen is the bicarb should combine with the protons and make carbonic acid then carbonic acid should disassociate into CO2 and water and then CO2 should be reabsorbed and then reformed into carbonic acid to actually help this process well now what I'm going to do is I'm going to inhibit this enzyme so now I'm no longer going to be able to stimulate the CO2 in water to make carbonic acid so this process is now inhibited that means I'm going to have less protons that I'm going to be able to excrete less bicarb that I can reabsorb means that less bicarb gets into the blood if I don't pump protons out here across with this sodium transporter am I going to be able to allow for sodium to come in if I'm not pumping protons out no so does sodium actually get reabsorbed here no so sodium won't get reabsorbed so this this blocks the sodium so then sodium stays High out here as well and I'm not going to be able to get the sodium into the cell I'm not going to be able to pump the protons out if I don't pump the protons out can I combine a proton with bicarb to make carbonic acid no then if I don't have carbonic acid can it disassociate into CO2 and water and then get reabsorbed no and so then I don't reabsorb CO2 I continually perpetuate this process so the whole thing that happens here is I will not take bicarb and reabsorb it because if I inhibit this enzyme both these you know the actual one that catalyzes this process in this process I won't be able to excrete the protons and then if I can't excrete the protons I can't convert this bicarb into carbonic acid and then into CO2 to reabsorb so then I will not bring CO2 across the cell I won't make carbonic acid I won't reabsorb bicarb and I won't excrete protons and then I won't allow for this reabsorption process to occur so you see how it's kind of a Perpetual cycle so the end thing here is that because I can't actually form this thing here this bicarb if I don't make it this way the bicarb stays in this form and then gets excreted out into the urine so what's going to happen is I'm going to lose a lot of bicarb into my urine a lot of bicarb and very little bicarb will actually get reabsorbed the other concept is if I can't pump the protons out I can't reabsorb the sodium inwards so sodium will not get reabsorbed here and so what will happen the sodium will also be lost into the urine and if sodium is lost into the iron what should it pull with it water should be pulled with the Sodium as well so when you think about the effect of a Carbonic anehydrase inhibitor sorry it's going to cause diuresis but the way that it's going to cause diuresis it'll cause a little bit of sodium loss and a little bit of water loss nothing intense but it's going to cause a massive bicarb loss let's put three arrows here just to kind of accentuate how significant that is is very significant right so Carbonic anhydrates are going to inhibit this enzyme the basic effectors if you inhibit this enzyme you inhibit in the intracellular and the tubular kind of effect pathway so if I inhibit this enzyme I will not be able to take CO2 in water make carbonic acid make bicarb make protons if I don't reabsorb bicarb my bicarbon the blood decreases if I don't have protons I can't excrete protons to combine with bicarb to make carbonic acid so I don't make carbonic acid I don't make CO2 in water and I don't have CO2 to be reabsorbed so bicarb then stays like this and gets excreted on top of that I also if even if some of this actual carbonic acid does form here I can't actually convert it into CO2 and because I can't convert it into CO2 because I inhibited this enzyme this enzyme here is inhibited via this Carbonic antihydrase inhibitor even if I do have some of this carbonic acid being formed because a little bit of the protons a little bit of the bicarb do form I'm not going to be able to allow for this to be converted into CO2 and water because I'm inhibiting this process so either way the whole concept is I'm not going to be able to reabsorb bicarb and I lose it into the urine so it causes a massive loss of bicarbonate a mild loss of sodium and water into the urine that is the effect of Carbonic anhydrous Inhibitors okay I hope that makes sense let's move on to the next one so now we move on to the next one which is the ascending limb of loop of handling so this is talking about the Loop diuretics now how does the physiology occur here well here we're going to have a tubular cell so this is ascending limb a loop of Henley cell this is going to be the blood so this is the peritube of the capillary blood or the vasor rectal blood and this is going to be the Lumen of the loop of henle now what happens in this site here is there's a special transporter you see this transporter here in blue this is called the sodium potassium two chloride co-transporter so what this does is this will push sodium into the cell it'll push potassium into the cell and it'll push chloride into the cell now once the sodium is moved into the cell here where will it go well we don't want it we want the sodium inside of the cell to be at lower concentrations so that sodium can easily move into the cell so we want to allow for sodium to move down its concentration gradient so the way that I'm going to do that is I'm going to take this sodium and I'm going to pump it out and I'm going to use this thing called the sodium potassium atpase and so this sodium potassium atps will allow for sodium to be pumped out and potassium to be pumped in okay that's pretty cool right the other concept here so now I'm going to have lots and lots of potassium in the cell so the potassium should build up because you've got potassium coming in here coming into the cell from the sodium potassium two chloricotransporter and potassium coming in across the sodium potassium into pieces all right what about the chloride the chloride my friends is going to come into the cell but the chloride also has to be reabsorbed and so the chloride will actually be reabsorbed across these channels which may have some degree of like bicarb moving across but either way you're moving chloride into the blood you're moving sodium into the blood and generally what should naturally follow the sodium and chloride water so you should allow for water reabsorption to occur here okay now what about this potassium what's the potassium doing but that seems kind of interesting here so there's lots and lots of potassium kind of sitting within the cell now right because we had a lot of potassium coming in Via these two Pathways the sodium potassium two chloride co-transporter and the sodium potassium atpase which is going to increase the potassium in the cell so now potassium is going to be really really high inside of the cell and it's going to be lower in the tubular Lumen so what happens is some of the potassium will actually leak out via this kind of like little potassium transporter and it'll leak some of the potassium out of the cell causing the inside of the tubular Lumen to become positively charged right now because of that positive charge here there is other ions that are nearby you know what these other ions are you have other ions that are nearby and these are called calcium and magnesium now calcium and magnesium are positively charged they don't want to be in the same vicinity as a lot of positively charged ions due to the potassium leaking out of the cell so they don't want to stay in in the tubular Lumen they're like hey man too much positivity here I got to get out of here and so what they do is is they both move via the paracellular route in between the tubular cells and into the blood so generally you should try to move calcium and try to move magnesium into the blood via this paracela route because what happens is these positive charge here is trying to inhibit them from moving forward throughout the tubular Lumen okay so that's the natural physiology that's occurring here in the ascending limit Loop of henle now insert Loop diuretic okay Loop Diuretics come in and what they do is the Loop diuretics are going to specifically inhibit this transporter so we're going to put in now the Loop Diuretics how are they actually going to be helpful in this process so Loop diuretics are going to inhibit the sodium potassium so what are they going to have it the sodium potassium two chloride co-transporter if I inhibit this transporter can I bring sodium into the cell no so I prevent sodium from coming into the cell do I get sodium into the blood no so there's less sodium that gets reabsorbed here do I bring chloride across no I inhibit the chloride reabsorption do I bring chloride into the blood no so less chloride if less sodium and less chloride are being reabsorbed am I going to pull am I going to create an osmotic drag to pull water along with it no because I lost my sodium and chloride drag so now there's going to be less water that's actually going to be pulled in this direction so now what's going to happen is the sodium the potassium I'm sorry the sodium and the chloride are going to stay in the tubular Lumen so now I'm going to have a lot of sodium that stays here lots of chloride that stays here and guess who's going to kind of follow along with them throughout the rest of the tubular tract lots of associated water and so what I'm going to lose if this were to continue through the tubular cells I'll say that it continued throughout the tubular cells what am I going to lose into the actual urine then effectively I'm going to lose in the urine lots of sodium I'm going to lose lots of chloride and I'm going to lose lots of water into the urine okay now we're not done this is where it's pretty cool if I inhibit the sodium reabsorption I don't have sodium available to move across the sodium potassium atpase so less sodium is moving across here less potassium is moving across this pump that means I'm going to have less potassium via this pathway if I inhibit this pump so I inhibited the chloride reabsorption sodium absorbed from what if I inhibit potassium reabsorption via this transporter I don't bring as much potassium into the cell and now there's less potassium via this pathway so now the amount of potassium that's present in the cell is much less than normal if there's much less potassium that means there's not as much of a gradient for it to want to move out of the cell that means that the positive charge is decreasing there's less positive charge so if you want to think about it if there's less positive charge there is more of a negative or relative negative charge do you think this negative charge is going to want to repel calcium and magnesium now no I'm not going to repel the calcium and magnesium as much now and so since I'm not going to repel the calcium and magnesium from continuing to get reabsorbed I'm going to not allow this reabsorption process to occur so I'm not going to allow for calcium and magnesium to move across the tubular Lumen because now magnesium and calcium are attracted to the positive charge so they want to stay in the tubular lumen so they're going to continue throughout the tube of the Lumen and then get be peed out so what else will I see in the actual urine I'll see lots of calcium and I'll see lots of magnesium oh my gosh doesn't that make sense so with that being said when you think about Loop Diuretics what you're actually getting here is the inhibition of this pump but when you inhibit this particular co-transporter subsequently you're going to lead to less sodium less chloride reabsorption less watery absorption so now you're going to have some more sodium more chloride and water in the urine if I don't if I inhibit these I inhibit the movement of potassium into the cell so I have less potassium to leave this cell less kind of repulsion of the magnesium in calcium so now it's not going to be reabsorbed it's going to stay in the tubular Lumen where the negative charge is and you're going to pee that out too and you're going to lose lots of calcium magnesium so that's a really cool concept about Loop Diuretics and how it's going to help you to kind of cause this diuretic effect all right so so far we've covered Carbonic anehydrase Inhibitors we've covered the Loop Diuretics we've covered the two sections they work at let's now move into the distal convoluted tubule all right so the next one early distal convoluted tubule what's kind of happening and we got to do basic physiology I know it's annoying but it's really helpful because once you understand the Fizz you just basically plug in the drug and then just oppose everything else it's very simple right so as we have things coming through so we were moving through what parts we were moving through kind of in a systematic fashion here so that you guys understand here where at this point where we filtered things out of the actual what Bowman's capsule we went through the proximal convolence tubule we went through the descending limb we went through the ascending limb and now we're at this portion right here and then we'll go into the collecting duct right so so far we talked about Carbonic anehydrase Inhibitors inhibiting bicarb sodium reabsorption and leading to a little bit of water loss we talked about how Lube diuretics will inhibit sodium potassium chloride co-transporters and how it'll lead to sodium loss chloride loss water loss on top of that you also inhibit calcium and magnesium reabsorption now we're going here to how the sodium and chloride reabsorption is being inhibited at this spot and then also water reabsorption so as things are coming through here so you should have some movement of particular ions as we're kind of coming from this point here to here okay so we're going to have some ions or things moving through this area so particularly it's going to be sodium chloride water and some other things so what happens is you get to this point here and there's a special transporter here it's called a sodium chloride co-transporter and what it's going to do is it's going to take sodium that's here and it's going to move it across this transporter subsequently you're also going to have some chloride and the chloride should move across this particular transporter and then sodium will then enter into the cell usually kind of down its concentration gradient so now sodium and chloride should be in this cell it's actually just for the sake of kind of like putting this here just because I have the diagrams here we're going to put chloride up here sodium here but either way it's the same concept we get sodium and we get chloride into the cell well then what happens is the chloride has to get out of the cell and into the bloodstream via this chloride kind of Transporter which will put chloride into the bloodstream here then sodium has to move out of the cell and into the bloodstream and it does that via this sodium potassium atpase right so that's how we get the sodium into the bloodstream now subsequently if you're pulling sodium and chloride across this tubule you're also going to subsequently be dragging what with it water so you should also drag some degree of water into the actual blood because again what we're doing here is this is going to be the early distal convoluted tubular cell this is the blood and this is the Lumen of the distal convoluted tubule early part we're pulling sodium across here we're putting chloride across here we're pulling water across here right so effectively that's what you should be doing is increasing the chloride reabsorption sodium reabsorption and water reabsorption another thing that I wanted to quickly add on here because thia's eyes play a role within this as well and it's very important because we'll talk about it when it comes to like indications and adverse effects but there's another particular ion that gets filtered so we talk about sodium we talked about chloride we talked about water but there's also an important ion here called calcium that calcium reabsorption in the distal convoluted tubule is dependent upon a particular hormone we're not going to go over this kind of like in Crazy detail but there is a particular hormone here that does regulate the activity of the calcium channel here and this is called parathyroid hormone so it does help to kind of like control the absorption of calcium but nonetheless let's say that the calcium absorption is occurring with the presence of pth when calcium gets absorbed and it moves across the actual tubular Lumen into the tubular cell the question is is okay how does the calcium get out so there's a transporter on the basol lateral membrane it's a really cool one and what it does it pumps the calcium into the blood and then what it does is generally what you should be doing is if you're bringing sodium into the cell and then you're using the sodium potassium atps to pump the sodium out of the cell the sodium concentration in the cell theoretically should be lower so then what happens is sodium will move down its concentration gradient into the cell which allows for calcium to move out of the cell so there's a sodium calcium exchange if you will now here's where thiazides now just throw a wrench in this whole physiology process by saying okay I'm going to give the patient a thiazide diuretic how does this actually help how does it work my friends so thiazide diuretics are going to inhibit this sodium chloride co-transporter if I inhibit the sodium chloride co-transporter do I bring sodium and chloride into the cell no so I inhibit sodium and chloride reabsorption if I inhibit sodium chloride reabsorption I have less chloride in the cell to move out into the blood so I decrease my chloride that's actually getting reabsorbed if I have less sodium being brought into the cell I have less sodium to pump out via the sodium potassium etpases and I have less sodium that moves into the blood if I have less chloride and less sodium being reabsorbed across the tubular cell I don't have as much water to reabsorb across that tubular cell by that osmotic gradient that sodium and chloride creates so therefore less water is reabsorbed across the tubular cell then so now think about that if that's the case then what am I losing into the patient's urine I'm losing sodium decent amount of sodium I'm losing chloride decent amount of chloride and I'm losing water now the other concept here that's really cool is how does this affect calcium because we already know that Loop thyroid is called calcium loss right and magnesium loss well thought I said already do something really interesting okay if I inhibit the sodium chloride Co transporter I inhibit sodium from coming into the cell right and now if there's less sodium that's coming into the cell then what does that do to the amount of sodium concentration in the cell bin I have less sodium being brought into the cell that effectively will lower this effectively will lower my sodium concentration in the cell you know what that's going to do remember I told you that sodium moves down its concentration gradient through this exchanger so now if sodium is moving from high concentration to even lower concentration here what's going to happen I'm going to bring more sodium into the cell if I bring more sodium into the cell I have to allow for more calcium to be exchanged out of the cell so that means when I bring the calcium in I'm going to push a lot I'm going to increase my absorption of calcium and I'm going to cause a ton of calcium to be exchanged across the sodium calcium exchanger theoretically what does that do to the amount of calcium that goes into my bloodstream then I increase the calcium absorption Isn't that cool so the whole concept I want you to understand here is when you inhibit the sodium chloricotransporter you inhibit sodium and chloride reabsorption that causes it to get lost in the urine but you also pull water with it when you inhibit this transporter you don't bring as much sodium into the cell that makes the sodium concentration in the cell lower now the sodium that wants to move down its concentration gradient via this exchanger is going to move more powerfully and more consistently and if you have more sodium coming in you have to have an equal amount of calcium coming out so a lot of sodium comes in a lot of calcium goes out and that means the calcium concentration in the cell gets lower and that pulls more calcium into the actual tubular Lumen so as you pull more calcium out you're going to theoretically as you pull more of this calcium out lower the calcium level in the cell which is going to cause an increase in the calcium reabsorption across this cell an increased exchange via the sodium calcium exchanger and cause an increase in calcium in the blood and so what will happen to the calcium here you'll have less calcium present within the urine it's pretty cool right all right but that's how thiazide diuretics work let's move on to the next part here so we move into the late distal convoluted tubule now if you kind of remember our diagram here at this point we've covered Carbonic anti-hydrase Inhibitors we've covered Loop Diuretics we've covered thiazide diuretics so now we've covered 65 of the sodium reabsorption 25 5 and now we have the remaining portion here if we get to the later distal convoluted tubule we're going to inhibit the remaining five percent of sodium chloride reabsorption and subsequently watery absorption at this site so let's now zoom in on that segment and look at it all right basic physiology here when you have things moving through here so again we're going to have some degree of sodium some degree of chloride some degree of water and things like that moving down through this actual tubular lumen here's going to be the distal convoluted tubular cell the late part and then here's going to be the blood where it should be around the peritubular capillary blood all right this section here we have different types of cells we have principal cells and then you have intercalated cells technically this is what's called if you really want to remember this is technically what's called a principle cell so principal cells are involved for electrolyte balance intercalated cells are involved in acid-base bounds we'll talk about that a little bit later but what I want you to remember here is this principal cell is very dependent to some degree on aldosterone so you guys remember that we have our adrenal cortex and our adrenal cortex makes a particular molecule called aldosterone now when aldosterone is secrete it's a steroid hormone and what I'm going to do is I'm going to represent aldosterone by that Circle there okay when aldosterone is secreted it moves through the blood and that it can cross directly across the cell membrane because it's a steroid type of hormone and bind with a particular receptor that receptor that a binds to will then click in to the DNA and activate particular genes in the DNA and then when you activate these particular genes this will increase the synthesis of particular types of proteins one of the proteins this actually represent this in red one of the proteins that it actually synthesizes is called a sodium channel so here's one of the proteins the second Channel it synthesizes is a sodium potassium atpase and the third channel is a potassium channel on the apical cell membrane okay so there's three channels that'll help to synthesize and the presence of aldosterone so again we'll bind onto an intracellular receptor activated transcription Factor stimulate the genes to make particular proteins now once these proteins are activated and expressed we now have a channel here that's open usually these are not there in very powerful amounts but whenever you have aldosterone it's going to increase the expression of this now once this channel is here this is called a e Knack channel so an epithelial sodium Channel when sodium is present at this portion here what it's going to do is it's going to move via this channel from the tubular Lumen into the tubular cell once the sodium is brought into the tubular cell we want to get it into the bloodstream to reabsorb the sodium because that's where five percent of the sodium reabsorption occur so in order for me to pump the sodium via this channel here I have to pump potassium inwards so this is via the sodium potassium atp's and this pumps the sodium into the blood all right but it pumps potassium from the actual blood into the cellular tissue the next thing that happens here is I have this potassium in the cell that I'm actually bringing into the cell from the blood that potassium can actually that's right here right we're going to have this potassium it's going to be right here now it's in the cell it's going to want to move down its concentration gradient so it's going to want to move out of the cell into the tubular Lumen and so then I'm going to excrete some of the potassium out of the actual cell and into the urine right so that's the concept there now generally when I reabsorb sodium across this cell what would I also subsequently pull with me if I have this process so if I reabsorb sodium I should subsequently pull one other molecule into the particular bloodstream as long as ADH is present water so this is generally what should actually happen here now what I'm going to do is and I should actually have less potassium within the bloodstream right so the other thing is I should have less potassium let's put this one up here I should have less potassium within the bloodstream because I'm excreting the potassium I'm pumping it into the cell and then pumping it into the tubular Lumen so there should be less potassium in the actual blood but I should reabsorb sodium reabsorb water and discrete potassium usually in the presence of aldosterone now what I'm going to do is I can have two drugs one of the drugs is what's called an aldosterous I have one drug category for the potassium sparing diuretics there's two drug categories one is an aldosterone antagonist so one is called nedosterone antagonist the second potassium sparing diuretics are called e Knack blockers so of aldosterone blockers and enact blockers all right how does this work if I give an aldosterone antagonist what this will do is is it'll inhibit this process here it'll block the aldosterone from being able to bind onto the receptor and activate transcription factors it'll then inhibit so it'll inhibit this particular process so now you won't be able to bind onto the genes and activate the synthesis of particular genes to make particular proteins such as Enoch channels potassium channels and sodium potassium pumps so then I'm going to inhibit the potassium pump from being formed sodium potassium pump I'm going to inhibit the enact channels from being formed and I'm going to inhibit the potassium channels from being formed if that happens will I have sodium channels available to reabsorb sodium no so then I don't reabsorb sodium if I don't reabsorb sodium and I don't have the sodium potassium pumps available to pump the sodium out of the cell and into the blood what's going to happen to the sodium inside of the blood it's going to decrease if I don't reabsorb sodium across the actual tubular Lumen tubular cell into the blood am I going to subsequently pull water in the presence of ADH across no so then I don't reabsorb water if my sodium potassium pump is inhibited not only do I not pull sodium into the blood but I don't pull potassium into the cell so then I have less potassium available into the cell on top of that I inhibit this particular Channel and so now I can't excrete potassium into the actual urine and so I don't lose potassium into the urine so what happens to the potassium within the blood well I can't pump it into the cell and I can't pump it out of the cell so the potassium within the blood increases this is why it's called a potassium sparing diuretic because you're not going to reabsorb sodium and so therefore you won't reabsorb water effectively so what am I going to lose within the urine I'm going to lose some sodium and I'm going to lose some water but what will I not lose I will not lose potassium so there will be very little potassium present within the urine so that's a really cool concept well that's how Doctrine antagonists work what about the other category of potassium stranded such as Enoch blockers believe it or not it's the same concept if I think about this block the enact channels okay so I block this enact Channel can I bring sodium into the cell no if I can't bring sodium into the cell now I don't have sodium available in the cell so I have less sodium to pump out of the cell and subsequently less potassium available to pump into the cell so the same concept here will occur that I'll have less potassium coming into the cell and I'll have less sodium moving across the sodium potassium pump because again all the enact blockers do is block this channel you'll still have this Channel and you'll still have this channel but look what it does indirectly you block this channel you have less sodium if I have less sodium I have less sodium to move across this sodium potassium pump so less sodium gets reabsorbed plus if I reabsorb less sodium I don't push as much potassium into the cell so I have less potassium entering into the cell if I have less potassium entering into the cell even though this channel is still open there's going to be less potassium excreted so there will be some degree of potassium loss even with these enact blockers so you'll still have potassium that'll be lost but look how little potassium will actually be lost very little potassium will be lost because you have very little potassium that's got pumped into the cell therefore less intracellular potassium that means that there's less potassium to move down its concentration gradient out into the urine so you see how enact blockers indirectly decrease potassium excretion and again reduce sodium reabsorption water reabsorption and cost sodium and water wasting but not potassium wasting that is the cool concept with these drugs so that is how the again potassium sparing directly such as the adoption antagonists and Enoch blockers particularly work within the nephron so at this point my friends we have covered Carbonic anhydrase Inhibitors Loop Diuretics thiazide diuretics potassium sparing diuretics and we even briefly discussed the osmotic diuretics like manitol and urea and really how they work in the proximal convoluted tubule and how they work in the descending limit Loop of Henley and they're very large impermeable molecules that suck water into the tubular cells I mean sorry in the tubular Lumen and cause massive Aqua ureesis not really sodium loss Aqua ureasis massive massive loss of electrolyte free water and that can really cause significant dehydration but again that's how Mannitol and urea would work which are the yellowsmotic theoretics now what we need to do is now that we've built the mechanism of action let's talk about how do these particular mechanisms of causing bicarb loss sodium loss water loss all this type of loss all this type of loss all this type of loss help people in particular disease States one by one with each type of diuretic and then what we'll do is we'll talk about the main indication of diuretics which is fluid dyresis how do we actually specifically attack and approach fluid diariesis and then later we'll go into the adverse effects of each drug category let's get into it all right my friends let's start up with the first category of diuretics that we talked about a little bit which is the osmotic that released this is Mannitol and urea all right so those are the two particular drugs that I want you to remember for this category and again we talked about how their mechanism of action is not really design particularly for as a diuretic so fluid diuresis they really can cause massive loss of water in your urine but that's not their true indication but nonetheless we talked about how they work in the proximal convoluted tubule and the descending limb of loop of Henley and really pull a lot of water into the kidney tubules but you know what else they do so let's say that we have manitol urea we get this molecule it's a very large kind of molecule that you can actually kind of creates a lot of osmolarity so what this really does is it really increases the osmolarity so it really kind of increases the osmolarity of the blood now when you increase the osmolarity of the blood or the osmolality of the blood what you do is you make the blood kind of create this very strong gradient to pull water into it so this would be something like Mannitol or urea they're very large solute molecules especially Mannitol and what it's going to be primarily doing is creating an osmotic gradient that pulls water from extra vascular spaces so it basically it's going to pull it from things like tissue cells or interstitial spaces so from in the cells and the interstitial spaces it's going to yank tons and tons of water so what it'll do is it'll yank water from areas of tissue such as brain tissue or such as things like the vitreous humor in the eye and it'll rip tons of water into the actual bloodstream so effectively when you think about this what the Mannitol is actually going to do or the urea is going to do specifically I would actually want you to primarily remember Mannitol is the most commonly utilized one it's really going to increase the water in your uh your vascular space and pull tons of water from tissue such as the brain tissue and such as the vitreous humor now why would that be beneficial to pull tons of water and dehydrate your cells in your interstitial spaces and the vitreous humor in the eye and the brain tissue here's why and patients who have a lot of cerebral edema so they have what's called increasing intracranial pressure what you want to do is is reduce the pressure inside of the brain so oftentimes this can be too big brain kind of like uh generally sometimes large Strokes so large like ischemic Strokes are very large hemorrhagic Strokes or subarachnoid hemorrhages or cerebral edema in situations of diabetic ketoacidosis but either way lots of cerebral edema what you can do is is you can reduce some of the edema in the brain tissue by pulling water from the interstitial spaces in the brain and from the actual brain tissue and shrink the actual brain to reduce the intracranial pressure so that is one particular reason that we could utilize this drug is to help to effectively pull water which what will this do help to lower ICP okay so that's particularly the indication the other situation is when patients have very high pressure in their eye okay so in situations of where maybe they have acute glaucoma or increased intraocular pressure whenever they have very very high intraocular pressures what you can do is you can give mannitone will help to be able to yank some of the fluid from the vitreous humor which is in the posterior segment of the eye and that'll help to kind of shrink that portion and decrease the pressure inside of the actual ocular socket and so what this may do is is this may decrease the intraocular pressure so this could be used in situations such as cerebral edema so the indication of this and the brain tissue is it may be particularly for cerebral edema any type of cerebral edema and we're going to try to reduce the ICP or it could be utilized in situations such as glaucoma acute glaucoma where there's high intraocular pressure and you're trying to pull fluid from those tissues makes sense right now when you pull the fluid from these tissues you significantly increase your actual plasma blood volume because this Mannitol creates a very powerful osmotic gradient that Yanks a lot of water into the actual vasculature so then imagine now you have a ton ton of water that's moving through your vascular space then what happens is if this moves into the glomerulus and gets filtered easily across the glomerulus what are you going to filter across the glomerulus you're going to filter across this Mannitol so that's one thing you're going to filter across the Mannitol across the glomerulus but what else are you going to filter across tons and tons and tons of water so what else will I have tons of water that I yank from my tissue spaces and so this is going to cause a massive volume of water that's getting filtered across the actual glomerulus but on top of that I'm also going to have Mannitol in the kidney tubules what did I tell you that Mannitol does and the kidney tubule specifically in the proximal convoluted tubule so in two parts B proximal convoluted tubule and the descending limb of the loop of henle now it's going to yank tons of water from the interstitial spaces and from the cells of the proximal convoluted tubulin distal limb of the loop of henle and yet and then what is it going to do it's going to cause a massive loss of water so it's going to cause massive Aqua urethis so what is this going to be containing tons and tons and tons of water will be lost this will be water that came from the tissue spaces in the brain tissue spaces of the vitrus humor other tissues within the body and water that got pulled from the proximal convoluted tubular cells and from the descending limit Loop of henle and the interstitial spaces around that so it's going to cause massive water loss this is called aqua uresis now very briefly I want to just quickly talk about some of the complications that you can have from this well especially since you're losing like a massive amount of water from your body you're really draining your intravascular volume so if your kidneys are functioning and all of this blood volume that you kind of have now from pulling water from these tissue cells and it's in the vascular space and it actually your kidneys are completely functioning it'll filter all that water off and more Mannitol into the cuticupas and really drain your blood volume so effectively what this could potentially lead to adverse effect wise is this could cause significant volume drop so this can cause hypovolemia sometimes to the point where it can actually even significantly drop the patient's blood pressure the other concept here is if you lose tons and tons and tons of water across your actual kidneys what else could it do you're dropping the water so what this also could do is this could actually cause a a loss of water in comparison to the actual sodium inside of your blood and so what this could actually do is this can cause hyper natremia within the blood so watch out for hypernatremia as another potential complication now this is if the kidneys are intact so what I want you to remember is this is particularly going to be happening if the kidneys are good they're good to go they're functioning well so all the volume that you're actually pulling from the tissue spaces you're peeing out so it can lead to hypovolemia and hypernatremia due to the excessive loss of water and then now your sodium is going to go up because you lost a ton of water so it's kind of like a relative hypernatremium if the kidney tubules are not intact or your kidneys are not functioning here's where it's bad so now your kidneys aren't functioning they're all jacked up if these puppies are all jacked up now the water that you're supposed to be taking from the extra this all this kind of vascular space and kind of excreting it out this is all lost so this water here that you're supposed to be taking and peeing out you can't do it anymore you're now losing that ability so now all this volume stays in your vascular space if the kidneys are in re if you have renal failure and you give the Mannitol to them it'll massively increase your your actual blood volume and you know what that'll do that'll cause some of this fluid to leak out of the vasculature and into particular tissue spaces and you want to know what one of the most common tissue spaces it'll leak out into the lungs and it'll cause massive pulmonary edema so I want you to watch out for that that if a patient has some type of acute renal failure or if they have end-stage chronic kidney disease and they aren't able to excrete the water that they pulled into their from their tissue spaces into the blood volume or they weren't able to allow for the mantle to pull some of the water out via the kidney tubules and then cause them to release Aqua cause Aqua ureesis that fluid will stay in the vascular space leak out into the pulmonary interstitium and cause pulmonary edema so these are the things that I want you to watch out for also this is weird right it can cause hypernatremia and hypovolemia if your kidneys are functioning if your kidneys are not functioning it can cause the blood volume to massively increase so it's almost opposite of this one and then if your blood volume massively increases it'll cause pulmonary edema but if you hold on to all of that water and you can't pee it out what happens to the relative relationship between sodium and water now now you're having a lot of water and a relative decrease in the amount of sodium so it can cause hyponatremia so watch out for that I know it may seem slightly confusing but watch out that whenever the kidneys are not working it may cause hyponatremia within the blood and pulmonary edema if the kidneys are not functioning if the kidneys are functioning it'll cause hypovolemia and hypernatremia okay that's Mannitol and urea primarily Mannitol given in situations of ICP crisis intraocular pressure crises to reduce cerebral edema acute glaucoma if we give these medications they're going to cause massive loss of water into the actual urine if the kidneys are functional which can lead to decrease in blood volume dehydration and a relative hypernatremia if your kidneys are not functioning they can't excrete all of that large volume of fluid and water that's in your vascular space they stay in the vascular tree because you can't pee it out and then it causes pulmonary edema and a relative hyponatremia all right now let's move on to the next drug category all right my friend so Carbonic anehydrase Inhibitors what are the particular drugs in this category the main one that I want you to remember is acetazolamide really that's the only one I think actually so acetazolamide is the big one here we talked about carbonicating hydration Inhibitors we know that they act at what particular section of the actual kidney tubules or the Nephron they specifically work at the proximal convoluted tubule but do you remember 65 of sodium is reabsorbed in the proximal conlude tubule but it doesn't directly inhibit sodium reabsorption it inhibits the Carbonic anti-hydrase enzyme and what that does is if you inhibit the Carbonic anti-hydrase enzyme you don't reabsorb what bicarb and so what do you lose a lot into the actual urine bicarb but you also if you inhibit the Carbonic antihydrase enzyme you also do lead to less potassium I'm sorry less proton excretion and less sodium reabsorption so you do lose a little bit of sodium in the urine and subsequently you'll lose a little bit of water as well but the main thing that you lose is a lot of bicarb now if you lose bicarb in your urine what happens to the amount of bicarbonate within the blood now because you're not reabsorbing the bicarb so you're basically this process where you're supposed to be pulling bicarb into the blood is decreased so what happens to the bicarbonate level within the blood it's going to be lower if the bicarbonate level in the blood is lower due to not a lung issue but due to an actual kidney tubule issue then what is that called what happens if your bicarb is low this will do what to your pH this will subsequently increase your no I'm sorry this will decrease your pH this will decrease your pH because again the reason why is if you have less bicarb you have less base and so you have more of the protons around to be able to not be bound up with the bicarb because you remember this equation right that we take basically protons plus the bicarb and when you tie them up it makes something called carbonic acid and that disassociates into CO2 and water well if we have less of this bicarb we're going to have more of the protons over here present and so that's one of the downsides here so if we have less of the bicarb we're going to have to have more of the protons that won't be complex with the bicarb and once the high protons going to do it's going to drop the patient's pH and so this leads to a condition called metabolic acidosis but it's not due to an increase in the anion gap so we call this a non-anion gap metabolic acidosis now why is that actually kind of helpful is that helpful there is a benefit to it one of the benefits to this is that whenever you have this lower amounts of bicarb and it actually causes the pH to become more acidic what this does is this acts on particular chemo receptors what's called Central chemoreceptors and when you act on these Central chemoreceptors you actually stimulate these Central chemoreceptors and what they do is they increase the actual rate of respiration and the depth of respiration so now because it's acidic because your blood is acidic you want to be able to try to make the pH go up and so what it'll do is it'll increase the actual flow to the actual lungs and what you're going to try to do is you're going to try to increase the respiratory rate and the depth so you're going to try to breathe faster and deeper and the whole point to this is there's two points you're going to increase your title volumes right your minute ventilation is going to increase and so hopefully you'll bring in more oxygen to come across and actually move across the lungs and into the actual blood so hopefully with increasing your tidal volumes you'll improve your oxygenation so that's one theory behind that is that you'll increase the amount of oxygen that gets absorbed across but the other thing is that you'll blow off more CO2 so more oxygen will move across the blood but also so more O2 will be inhaled but there'll also be more CO2 that's exhaled and if you blow off more CO2 then what's going to happen to the CO2 level within the blood then the CO2 level within the blood is going to decrease if there's less CO2 what happens is you're going to shift this reaction to the right and then decrease the amount of protons and so that'll help to be able to kind of create what's called a respiratory alkalosis so the effect here is that you're trying to make the patient breathe a little bit faster and this creates something called a respiratory alkalosis so you're trying to make the patient breathe at a faster rate to increase their oxygen inhalation but also try to make their pH go up okay so it's trying to compensate for the low PH that you see with acetazolamide why in the world would this be helpful there's one particular indication and this is in patients who have increased risk of altitude sickness an altitude sickness or basically they develop what's called high altitude pulmonary edema so whether it's altitude sickness or another condition related to it called high altitude pulmonary edema you can give this particular drug because when you give this drug when as they go up to higher altitudes there's less availability of oxygen and so they can develop kind of a hypoxemia and sometimes they can develop in a pulmonary edema if you give them acetazolamide prior to them actually kind of ascending it can kind of get their blood a little bit more acidic which increases their tidal volumes their respiratory rate the respiratory depth to be able to blow off some of the CO2 to make their pH kind of a little bit increase to compensate but also bring in more oxygen to improve their actual ventilation and also hopefully improve their oxygenation so this is one of the things that we can actually utilize it's actually pretty cool there's one more indication for it and we'll talk about a little bit later so one of the indications of causing this metabolic acidosis is treating altitude sickness the other one is we can use this in what's called diuresis so we can use this in a process called fluid dyresis it's kind of an adjunct though therapy and we'll talk about how we actually do it what it does is it treats a patient who has high pH so patients who have what's called a metabolic alkalosis we can give this drug because it will decrease the pH we'll talk about a little bit later all right what else can acetazolamide do so this is related to the diuretic effect right so this will actually cause help with diuresis and altitude sickness via the diuretic effect there is another effect that this drug may have that has nothing to do with the diuresis it's what it can do on kind of preventing or reducing the production of particular fluids what it can do is it can work on the eye and it can actually decrease the kind of uh what's called the aqueous humor production so it can reduce the aqueous humor production and if we reduce the aqueous human production we reduce the amount of fluid that's present within the kind of the anterior chamber of the eye which can help to reduce intraocular pressure so it can reduce intraocular pressure especially in States like glaucoma the other thing you can do is it can also work particularly within the ependymal cells within the cerebral who makes cerebral spinal fluid and it can actually decrease CSF production and if it decreases CSF production that may be beneficial and patients who have high intracranial pressure so high intracranial pressure that is but it's actually not do to a primary kind of like it's not due to any kind of disease not due to a disease process like if there's no kind of like a structural lesion or obstruction or any kind of process like that so it's a disease that's actually idiopathic you've excluded every other cause that's causing their intracranial pressure to be high and it's called idiopathic intracranial hypertension also known as pseudotumor cerebri so this is really what it's actually going to treat it's going to reduce the CSF production and patients who have ICP that's not due to an actual disease process it's idiopathic and because of that our pseudosumor cerebral it would actually reduce the CSF production and reduce the intracranial pressure so it'll actually reduce the ICP all right so when we talk about Carbonic anehydrase Inhibitors or acetazolamide it's actually going to cause a lot of bicarbonate excretion into the urine mild amount of sodium and water excretion but because it kind of really causes a lot of bicarb excretion in the urine it reduces the amount of bicarbon in your blood that causes a metabolic acidosis not anion gap related because it causes an acidosis that can actually increase your chemo receptor sensitivity and cause your chemo receptors to activate your respiratory Center to breathe at a faster rate in depth so you hyperventilate to breathe in more oxygen to improve your oxygenation and breathe out more CO2 to be able to kind of compensate for the acidosis and create a respiratory alkalosis to compensate this can be used in altitude sickness high altitude pulmonary edema as well as a diuretic effect to treat what's called metabolic alkalosis with Loop Diuretics and Thia diuretics it also reduces aqueous human production to produce intraocular pressure and glaucoma and reduces CSF production to produce ICP and patients who have no underlying lesion or disease process that causes their ICP to build up it's called idiopathic intracranial hypertension okay now that we talked about these ones let's move on to the next category drug called Loop Diuretics all right let's talk about diuretics particularly Loop Diuretics at this point so we talked about kind of your osmotic diuretics we talked about the Carbonic anehydrase Inhibitors now let's hit particularly the Loop Diuretics so names we already know the the with these ones they're the kind of cheated a little bit furosemide so you got your furosemide here this is probably going to be the most common legalized one also known as Lasix then you have your torsomide but matinee is also a pretty good one very very powerful one and then the last one here is going to be ethocrinic acid and I repeat ethocrinic acid now with this particular drugs here with the Loop Diuretics what I want you guys to think about here is that they are very very effective at causing a massive amount of sodium and water loss into your urine we knew that because we talked about how they work at the ascending limb of the loop of henle and they directly block the sodium potassium to chloricotransport that causes a massive loss of sodium massive loss with chloride massive loss of water into the air so they're the most powerful diuretic in theory if there was a diuretic that directly blocked sodium and water reabsorption in the proximal convoluted tubule that would be the most powerful diuretic but we don't have one and if you're thinking it's Carbonic anhydrogen is remember I told you it does not directly block sodium and water absorption it blocks bicarbonate reabsorption which causes a little bit of sodium and water loss but Loop diuretics are very powerful so they can cause a lot of like fluid loss so that's really good when you want to take fluid off of somebody who isn't like congestive heart failure or they're in chronic kidney disease and acute kidney injury they're not making much urine or their volume over a little bit cause they've been getting hit with tons of fluid boluses for hypotension in the hospital whatever it may be you're trying to get some of that fluid off these are very good drugs well we have to quickly talk about though is the concept of the kind of like pharmacodynamic pharmacokinetic aspects of these drugs so whenever you give these drugs okay one of the interesting things about them is that they have a very specific dose response relationship so here we have a curve you thought this wasn't coming back I know I know it's a pain in the nut but we're going to talk about it so here we have the dose that you're going to give the drug on the x-axis and then the response on the y-axis when you give this drug let's say that you give kind of a low dose and it doesn't give you the good kind of response that you want it's not kind of going up but then you start to increase the dose and increase the dose and then you start seeing an increase in the response and then as you increase the dose you still see an increase in response and you increase the dose and you increase the response but then eventually you keep increasing the dose and you see no change in the response this is a very interesting thing that you can see with all of these diuretics the dose that you gave that opened up the gates to produce urine is right here where we start to see this uprise this is your threshold dose this is your threshold dose so this is basically the dose that you give that will really allow for them to be able to produce some adequate amount of urine and then as you increase the dose increase the dose you still get a good response good response but then once you hit the maximum dose you hit you give them like let's say that here I'm just giving you an example you want to cause a patient to Diaries and so maybe their threshold dosage is 40 milligrams I'm just giving this as an example and you increase it to 60 to 80 to 100 to 120 and then at 120 milligrams you get no change in the amount of urine that they produced so at 120 milligrams or 100 milligrams let's say that the threat this point here where it stops kind of increasing the response let's say here this is your ceiling this is your sealing dose meaning that let's give an example that this is a hundred and twenty milligrams so anywhere from 40 milligrams once you start that the patient's producing an adequate amount of urine if you increase to 60 they increase the urinary output even more if you increase to 80 they increase if you increase to 100 they keep putting out more urine but once you hit 120 milligrams the amount that you actually produce is the max amount of urine that they will produce it doesn't matter if you go to 140 160 180 200 milligrams they will not produce any more volume of urine that they produced at 120 milligrams so that's one of the interesting concepts of giving diuretics what it's basically telling you is if you give a patient a diuretic to try to make them urinate and you give them 20 milligrams and they don't produce an adequate response don't give up that might not be their threshold dose double the dose give them 40 milligrams to see if they produce an adequate amount of urine if they do then they had a response to that so maybe their threshold doses is above 20. it's 40 milligrams but if you want them to have them make more urine they're not making an adequate amount double the dose again give 80 milligrams and they start producing more urine that's a good response but you're still not kind of getting them Diaries enough double the dose again if you get to a point where you're doubling the dose and the amount of urine that you're producing is the same at that double dose as it was from the prior then you're at the sealing dose at that prior dose and there's no need to keep increasing the dose you're not going to get more diuretic effect that's the concept but I hope makes sense with diuretics the next concept here is that whenever you think about each one of these diuretics they have different levels of potency I think is the best way to say it their efficacy has been shown to be relatively the same but it's the potency of the drugs that's a little bit different so let's actually use these in different kind of Curves here so let's say here we have one curve and we're going to start this one here that it only requires a low dose to get to its maximum kind of efficacy and then we'll go to this next one here where this one you need a little bit of a higher dose to produce its maximum of efficacy and then here we'll have another one which you require a decently high dose to produce its maximum efficacy so what you'll notice is as you kind of go this way the potency is starting to decrease so as you move this way you're requiring a higher dose as you go this way which means it's going to have a lower potency right but they all have the same Emax so their efficacy is all the same what is important to remember about this is that these are the most commonly utilized Loop Diuretics Frozen mitors might be metanoid and the most potent one that you can give at a very low dose to produce its maximum efficacy is going to be this red one here this is going to be we're going to just use the first letter here but you met9 then the next one which you can give it a lower dose and still produce a maximum efficacy is going to be torsomide and then the one that you can give at a decently high dose to produce the e-max the same e-max effects as these is going to be furosemide they have the same efficacy but you just have to find the equivalent dose that produces that Max efficacy so that begs the question what is the equivalent dose that I need to be able to think about whenever a patient is on a particular diuretic let's say that I just pick a dosage this is the way that I I learned it is that you can kind of pick 40 milligrams of furosemide is equivalent to approximately 20 milligrams of torsomide which is equivalent to approximately one milligram of bumetanide so when you think about that that's absolutely insane so if for example I prescribed a patient two milligrams of bumetanide for fluid dyresis that's going to be how much Lasix that's a that's a ton of Lasix right so you give two milligrams of bumetanide that's about how much of this that's an insane amount of furosemide so when you think about that it's an important thing to remember that furosemide is going to in comparison to Matt and IBM that is 40 times more powerful than furosemide and then torsomide is two times more powerful than furosemide so that's an important concept to really understand when you're thinking about the equivalency between these two drugs so that's why again we use this graph here we can utilize these lower doses of this particular drug to produce the maximum efficacy lower doses of this one in comparison to furosemide to produce its maximum efficacy and you have to give a little bit of a higher dosage again of furosemide to be able to produce its maximum efficacy one additional concept here is with respect to bioavailability furosemide the bioavailability that will represent with f for these is about 50 for furosemide and it's generally like about greater than 80 percent so almost close to a hundred percent for bumetanide and torsomide so basically when you give this kind of Po you got to really realize that whenever you give this via a PO version you have to half the dose so giving 40 milligrams of furosemide IV you'd have to give 80 milligrams of it in a PO form to be able to get that dose so remember it's just half the PO form would be two times in this situation the PO form would be two times the IV dose okay so that's important to remember because again if I gave 40 milligrams of furosemide po I'm only going to absorb 20 milligrams of it whereas if I give the torsomide or the bumetanide it's pretty much almost approximately equal to the IV dose it's very very similar okay so that's an important thing to be able to remember what you think about these drugs with respect to kind of their pharmacodynamic kinetics and Dynamics all right so we know now that whenever you give a diuretic again you have to give a specific dose to be able to allow for them to decrease as you go up you may continue to get responsible once you increase the dose to a point where the response is the same so in other words I gave 80 milligrams and they produced 400 cc's of urine I give 100 milligrams they produce 400 cc's of urine the ceiling dose with eight was 80 milligrams I don't need to give any more because I'm not going to get any more of a response and then again on top of that noting the potency of these drugs is very important that bumetanide is the most powerful then torsomide then furosemide so I can give lower doses of bumetanide then torsomide than Furosemide okay and then again remember that the equivalencies is 40 21. and the bioavailability of torsomide and bumetanide is almost close to 100 so the PO to IB kind of conversion is almost exactly equal but whenever you give furosemide it's about 50 bioavailable so again if you want to give the PO version you have to be able to give them two times whatever the IV dose is because that's an important thing to remember okay all right my friends that's the big thing for these drugs with respect to pharmacokinetics and Dynamics now obviously we know that the main indication of these drugs is diuresis we'll talk about that in a little bit I promise another indication for these drugs besides causing fluid dyresis is they can excrete particular types of molecules so you know whenever patients have what's called hyperkalemia so they have high potassium levels within the blood so whenever patients have high potassium levels within the blood you can try to treat hyperkalemia a couple different ways one is you can try to shift it into the cells one is you can try to poop it out and then the other way is you can try to urinate it out and so what we can do is we can give furosemide because if the the potassium is kind of you know taken into the the urine and it's excreted generally what actually happens is when you give any kind of loop diuretic they're going to inhibit this sodium potassium to glycotransporter so you reduce the reabsorption of sodium and chloride so what happens is you get more sodium and more chloride that reaches the distal convoluted tubule particularly sodium and whenever you get to the distal convoluted tubule have more sodium to reabsorb Across the distal convoluted tubule now whenever positive ions are moving out of the tubular Lumen into the tubular cell you're losing positive ions in the tubular Lumen so you need to replace that so guess who moves across to be able to allow for the sodium to come in potassium so potassium is actually going to be lost in the urine a lot with Loop Diuretics so potassium will cause a lot of caliuresis potassium excretion okay they do that because they inhibit the sodium reabsorption in the ascending limb that means a lot of sodium makes it to the distal convoluted tubule a lot of sodium is reabsorbed in the principal cells and a lot of potassium is essentially excreted out of the principal cells and a lot of potassium is lost into the urine so it treats hyperkalemia by causing potassium excretion okay the other concept but we don't utilize it as much anymore is that you can also be utilized to excrete calcium again so when patients have hyper hypercalcemia again calcium is usually going to be kind of filtered across move down the descending limb move up the ascending limb and again whenever you give a loop diuretic you inhibit these Transporters which then causes less sodium chloride to be reabsorbed less potassium to be excreted into the tubular Lumen and that makes the inside of the cell of tubular lumensari more negative which keeps calcium and keeps magnesium in the tubular Lumen and causes calcium and magnesium to be lost so you're going to have a lot of the calcium that remains in the tubular Lumen and then a lot of calcium that gets peed out so this will effectively cause a lot of calcium to be excreted into the particular amounts of urine so this can also treat hypercalcemia however we don't find this to be as commonly utilized as much as it used to be in the past but this is definitely a very common indication of giving Loop Diuretics is to cause potassium excretion not as much so as in the recent years of giving calcium for for calcium hypercalcemia causing calcium excretion but now that we understand the indication of Loop Diuretics some of the indications which is again hyperkalemia hypercalcemia causing them to be lost into the urine we understand the pharmacokinetics and pharmacodynamics we're going to talk about the most common indication of Loop Diuretics which is fluid diuresis but we're going to do it in combination with other diuretics I promise it'll make sense when we get there until then just trust me let's move on to thiazide diuretics talk about those a little bit and talk about some of the other kind of miscellaneous indications for that drug category all right my friends so now let's move into thighs identity so thiaz diuretics there's a bunch of different drugs in this category as well so a couple of them that I want you guys to remember for these ones is the most commonly utilized one is going to be Hydrochlorothiazide so we commonly utilize this as kind of an HCTZ okay so that's one another one is called chlorothiazide so chlorothiazide another one is called metolazone and then another one is called chlorthalidone and there's another one there's an another additional one called indapamide as well but these are your thighs idiotics there's a lot of these and they very commonly utilize I like to utilize these a lot but what I want you to remember is again thiazide diuretics do what they block the sodium chloride co-transporter in the early distal convoluted tubule that leads to sodium chloride and water loss into the urine and they don't actually cause calcium excretion to actually retain calcium so they can actually cause hypercalcemia so there's another indication for this we're going to talk about the effect of the fluid dyresis from this drug a little bit later but what I want you to understand is there's other additional indications of this drug believe it or not it actually can cause vasodilation how it does it I have no stinking idea I try to look for the evidence of this but we I don't know exactly how but if we have our arterial system if you think about this it's kind of two kind of benefits to this if we take the arterial smooth muscle cell and we give a thiazide diuretic it may work by some particular action to be able to cause smooth muscle relaxation so if it cause smooth muscle cell relaxation this will cause what type of effect vasodilation if you vasodilate what do you do to your systemic vascular resistance within the arterials you would cause a drop in the systemic vascular resistance which does what to your blood pressure this will drop your blood pressure this will drop your blood pressure so there's one particular interesting thing that you can see from the arterial side with these like thiocide diuretics so again if I were to put here Hydrochlorothiazide as this drug it may induce a smooth muscle cell relaxation which may cause vasodilation that vasodilation may then cause a reduction in systemic vascular resistance and reduce the BP okay well that's one interesting concept the other thing here is that if I block the sodium chloride co-transporter I block in the in the early distal convoluted tubule I decrease sodium reabsorption into the blood and then subsequently a decreased watery absorption so there's less water within the blood that means I have less blood volume what does this effectively mean I have a decrease in blood volume that means that I don't have as much fluid to bring to the heart so I effectively reduce the preload if I reduce the preload okay again to the left side of the heart as well I have less preload that means I have less stroke volume less cardiac output and then effectively less blood pressure right so if I drop my blood volume I drop my in diastolic volume I drop my stroke volume I drop my cardiac output and I drop my blood pressure so you're seeing kind of an effect here that I can reduce blood pressure with thiazide diuretics what would that be good for hypertension so that's one particular indication for thiazide diuretics is it can be utilized in what's called essential hypertension pretty cool concept right especially chlorothiazide chlorthalidone Hydrochlorothiazide metolazone not as much but again these are good drugs at treating essential hypertension because again they can cause arterial vasodilation and they can actually cause reduction in a mild modest reduction in blood volume which can reduce preload reduce stroke volume reduce what cardiac output and then reduce blood pressure all right cool another cool concept here is that I told you that these drugs also again block sodium chloride and water reabsorption right because they're blocking that sodium chloride co-transporter so you're going to block the reabsorption of these particular substances but it was mainly the sodium that was really interesting if we block the sodium reabsorption it led to less sodium inside of the cell that means that more sodium could come in the cell and more calcium could be reabsorbed so the other effect that we talked about when we talked about the mechanism of these drugs is that we also increased calcium so effectively when you give these particular drugs you're inhibiting this transporter here and the effect is that you're decreasing the sodium chloride and water reabsorption but you're increasing calcium reabsorption so that means that less calcium is going to be present in the urine why would that be beneficial you know in patients who have kidney stones because they form a lot of calcium kind of like oxalate or calcium phosphate stones may be beneficial so it could be beneficial in patients who have what's called calciuria sometimes this is like a familial kind of process but it increased the risk of renal stones so if I can give them this drug like a thiazide diuretics it may decrease the calcium and decrease the incidence of nephrolithiasis and that's a pretty cool concept the other thing is if I actually cause less calcium to be lost in the urine and more calcium in the blood I may have more calcium for my osteoblast to deposit calcium into the bone tissue that may be beneficial in patients whose bone tissue is very porous and weak and very fragile such as in osteoporosis so it's important to remember that there is again three additional indications to thiazide diuretics besides fluid dyresis they can treat hypertension essential hypertension by causing vasodilation of the arterials and reduce blood volume which would cause reduced preload reduce stroke volume reduce cardiac output reduce blood pressure they also cause reabsorption of calcium into the blood and cause less calcium excretion which may be beneficial in patients who have lots of calcium in their urine that increase the risk of kidney stones so it reduces nephrolithiasis plus and patients who you need to have more calcium for the osteoblastic deposit calcium into the bone such as an osteoporosis this may be beneficial so that is the concept of these drugs again I want to stress here that I will cover the effect that they have on removing fluid from the body in patients who have CHF chronic kidney disease fluid overload States we will get to that but for right now no the extra indications in the names of these drugs all right let's move on to the next category of drugs which is your potassium sparing diuretics armor friends let's now talk about potassium sparing diuretic so these are the puppies that are working at the later part of the distal convoluted tubule they're either blocking the aldosterone which is what kind of drugs category spironolactone apler known these are some of the drugs in this category spironolactone the lactone and another one is called eplerone and then another one is the enact blockers so these were blocking out Doctrine which was reducing the sodium potassium pump formation this is reducing the enact formation this is reducing the potassium Channel formation on the apical membrane this is blocking the enact channels directly which indirectly leads to less potassium moving into the cell less sodium potassium adps activity and then less potassium being excreted via the luminal channel and this is going to be amyleride and then I am not a big fan of this drug really should stay away from this drug this is called triamterene but these are going to be your potassium sparing diuretics now again we'll talk about how these are utilized in fluid diuresis we'll talk about how Carbonic anhydrases are used and Inhibitors we'll talk about how Loop diuretics are used we'll talk about how thyroids you use and we'll talk about how potassium sparoderetics are used in fluid direesis and like CHF CKD acute kidney injury nephrotic syndrome fluid overload States Etc but let's talk about some of the other accessory or kind of additional indications of these drugs so we talked about how Loop diuretics are used in hypergalemia hypercalcemia we talked about our thiazide directs they're using hypertension and then also causing less calcium to be excreted the theorem which can lead to less kidney stones and also it can also treat help to benefit patients who have osteoporosis with potassium sparing diuretics especially the aldosterone blockers these are really cool so what you can see here is that what if a patient has a disease State and in that disease State they have a tumor or some type of process here called concentrating this is called con syndrome and this causes them to produce a massive amount of aldosterone so it causes what's called hyper aldosteronism and whenever they have all these high amounts of aldosterone what this can actually do is this can work on many different types of intracellular receptors and cause many different types of effects so high productionism obviously one of the big things that we see is the effect that it can cause a lot of sodium reabsorption a lot of water reabsorption a lot of potassium excretion a lot of metabolic alkalosis so there's a lot of different things that we could see as an effect of that right so some of the big things that you can see with Khan is again this is called con syndrome it's a syndrome in which there is a massive amount of adoption released from the adrenal cortex and then again the things that we can see as a result of that is hypernatremia we can see an increase in water reabsorption which can cause an increase in blood volume and blood pressure we can see less potassium present within the blood we can see a patient developing a very high pH like a metabolic alkalosis so this is a lot of different things that you can see as a result of this what if we gave a particular drug such as spironolactone or eplerone to block the aldosterone not just and helping to Aid in diuresis but also helping to block the aldosterone side effects that's coming from hyperaldostrianism this would be a very beautiful indication to be able to give the aldosterone blockers so this would be the aldosterone blocker effect now the other interesting thing about this kind of concept here is that with these drugs you may see some potential benefit in hypertension very mild utilized primarily in patients who have CHF so yes they can be utilized in hypertension the primary indication by which they truly would be utilized in patients with hypertension is patients who have chronic hypokalemia and CHF because these will spare the potassium loss so it'll help to increase your potassium levels and also they've been shown to reduce cardiac remodeling in patients who have CHF so it really can be utilized in hypertension but again it's not going to be your first line agent more particularly in comorbidities such as patients who have heart failure and hypokalemia but again nonetheless let's talk about another concept here so here but we'll we'll add this in here not only can we use to treat con syndrome so that's one indication a second indication if you really wanted to add this into your list is it can be utilized in patients with hypertension plus low potassium plus CHF this may be a beneficial specifically for aldosterone blockers not as much amyloride and triamterene there hasn't been enough evidence to support those all right especially in CHF another indication for these drugs specifically the enact blockers so another indication exactly how they do it I wish I knew I wish I understood how exactly they do this there's some theory that it may modulate the written angiotensinaldoctrine system process but amyloride and triamterene may treat a particular condition here so the enact blockers they may treat a condition where ADH is actually present it's being produced it's acting on the V2 receptors on the kidney tubules but the effect that it's having on the kidney tubules is diminished so the kidney tubers aren't having adequate V2 receptors to respond to ADH so ADH is actually present but they're not responding to the ADH and so this disease is called nephrogenic diabetes insipidus and enact blockers May prevent this type of processor can be utilized to treat patients who have nephrogenic diabetes insipidus another drug that you can utilize is the thyroidics they may also be beneficial and nephrogenic diabetes insipidus but again not a super well-known fact as to how they do that all right but nonetheless what I really want you to understand of the potassium sparing diuretics again is the names of the drugs okay know that first also knows some additional accessory actions of them the adoption blockers very good at treating hyperaldosterone States no right especially in con syndrome but they also are very beneficial in reducing mortality especially in patients who have CHF it's been shown to reduce mortality if you have hypokalemia they'll spare the potassium and if you have hypertension they may provide some benefit there very specifically though this is the aldosterone blockers and then amyler at a transfering the enact blockers they may work in some specific way to treat patients who have nephrogenic diabetes insipidus okay at this point we have covered all of the diuretics we've covered their names we've covered their mechanism of action we've covered some other additional functions besides fluid dioces so again quick recap manitol urea we talked about them reducing ICP reducing intraocular pressure and again causing massive diuresis in those situations Carbonic antihydrase inhibitor treating altitude sickness high altitude pulmonary edema and again reducing intraocular pressure and glaucoma and treating idiopathic intracranial hypertension we talked about Loop Diuretics being utilized in hyperkalemia hypercalcemia and we've talked about thighs and diuretics treating hypertension especially essential hypertension and also causing less calcium to be excreted to treat patients who have increased calcium with renal Stone risk as well as helping to reduce the significance of osteoporosis potassium sparing diuretics we talked about the aldosterone blockers preventing or helping treat con syndrome and treating hypertension as long as they have heart failure and hypokalemia and then again the enac blocker is being beneficial in nephrogenic diabetes insipidus you want to add on there thighs eyes can also treat nephrogenic diabetes exhibitus all right we're on to my favorite part of this lecture believe it or not however deep into this lecture we are at this point but we're at the most important point that I need you to understand here when we utilize diuretics to pull fluid off of the body how do we do this and why do we do this we have a patient who's coming in or is in in the hospital and they're having evidence of potentially like a significant amount of pulmonary edema a significant amount of peripheral or generalized edema within their belly or within their legs we need to be able to try to remove some of that excessive fluid because if they have a lot of pulmonary edema and pleural effusions maybe it's causing respiratory distress maybe if you had a lot of fluid building up within their abdomen this is actually causing a lot of congestion within the abdomen reducing urinary output if it's kind of causing a lot of swelling and distinction of the actual legs this may cause a lot of pain and discomfort so in those particular indications we may want to start trying to pull and remove some of the fluid from their body this would be an indication for fluid dyresis now why would this potentially happen so why could someone develop a lot of fluid that can actually accumulate within their lungs leading to things such as pulmonary edema so we can have a lot of fluid that kind of develops within the interstitial spaces within the lungs and within the alveoli or maybe they also have pleural effusions so maybe they have a lot of these affluids that are accumulating within their pleural cavity here in situations like this such as maybe plural effusions and these are maybe causing a lot of like respiratory distress for the patients this is definitely going to be one of the more common indications of why you would want to initiate or elicit fluid dyresis so maybe these problems are causing some degree of respiratory distress so you can see pulmonary edema and pleural effusions accumulating or maybe they have a lot of like peripheral or pitting edema within their legs or sometimes another thing I can find is that sometimes if patients have a lot of congestion within their actual body sometimes they can have a lot of fluid that backs up into their abdomen and sometimes they can cause a lot of like you know um distension of their abdomen so sometimes we can see big old bellies and kind of a distension of the abdomen as well so you may even see some type of hepatomegaly or ascites so you may see some type of ascites or a padomegaly these are a lot of kind of like your central kind of congestion either way you're seeing a lot of these congestive symptoms the patients coming in they're in respiratory distress because they have fulminant pulmonary edema and pleural effusions or they look like the Michelin Man because they're filled up and they have massive amount of generalized kind of peripheral pitting edema and they have a lot of fluid within their belly causing hepatomegaly and ascites in these particular situations you may want to remove some of the fluid from their body and reduce the amount of distress that they may be having but the question is is why are they developing this pulmonary edema peripheral edema pleural effusion Society zapatomegaly the most common cause for this is going to be heart failure so if a patient has some type of like dysfunction of their left ventricle so for example they have heart failure whether this is heart failure with a reduced ejection fraction so they have systolic dysfunction where they can't contract blood out of their heart or whether they have diastolic dysfunction so they have a very thick ventricle and they have impaired filling and high filling pressures so whether this is a heart for familiar with a preserved or reduced ejection fraction they have heart failure and their problem is is they're not getting blood out of their heart or they're not filling the heart properly so these are the particular problems as they're having a difficult time being able to squeeze blood out of the heart or they're having a hard time being able to fill the heart if that happens fluid will back up via the pulmonary circulation and lead to pulmonary edema and peripheral sorry pleural effusions that's a problematic issue if the patient also develops heart failure and this causes them to back up and then they end up with kind of like problems of the right heart as well so now they also have right heart problems then fluid will back up into the right atrium and then down into the inferior vena cava which will cause ascites hepatomegaly and big old swelling of the legs and arms and so this can lead to a lot of the generalized peripheral edema and these particular situations that would be one problematic issue as to why this would happen so systolic or diastolic heart failure okay another problem is what if the patient has what's called acute kidney injury or chronic kidney disease so what if another potential problem here is that the patient has what's called CKD like really bad chronic kidney disease or an acute kidney injury so they're basically not very good at producing urine so if their problem is they can't adequately produce urine then all the fluid that they're supposed to be having kind of filtering through them and they're supposed to be making is not happening so their urine production is poor and so they're not eliminating fluid from the body if they're not eliminating fluid from the body they're increasing the amount of blood volume that the patient has if they're increasing their blood volume then they're increasing the filling of the heart and what if the heart already has some degree of systolic dysfunction or diastolic dysfunction then it's going to worsen their pulmonary edema or if they don't have any problem or dysfunction but you're constantly feeling the heart and congesting with fluid because you have so much blood volume this is again going to cause problems in this area and cause pulmonary edema or generalized peripheral kind of pitting edema and ascites and a hepatomegaly another problem here is maybe it's not due to a chronic kidney disease or acute kidney injury it's not due to heart failure systolic or diastolic maybe it's because the patient's been in the hospital for a couple days and they've been crushed with like 20 liters of fluid and they've been giving this patient lots of fluid because maybe they're not making adequate amount of urine or maybe they're hypotensive or maybe they appear dehydrated whatever it may be that could be another very very common issue I can't stress how much I've seen this all the time but fluid overload States and situations where it's iatrogenic so massive amounts of IV fluids for the patient can also cause this problem where you're just kind of crushing them with large amounts of fluid and if you're just pushing fluids into their vascular spaces all you're doing is you're massively increasing their blood volume and if you're increasing their blood volume you're increasing the filling of their heart if you're increasing the feeling of their heart you may cause a lot of congestion if they don't have any underlying heart disease it may not be as bad but if you're crushing them with tons and tons and tons of fluid that preload may be too much it may cause excessive congestion of the heart and then decompress back into the lungs or decompress into your actual peripheral systemic circulation such as in the legs the the belly or in the arms can cause a lot of like generalized peripheral pitting edema all right so again three particular problems as to why I see patients developing a lot of like edema symptoms is due to congestive heart failure most common chronic kidney disease or acute kidney injury where they're not making an adequate amount of urine and becoming fluid overloaded because they can't eliminate fluid from their body or they're getting a lot of fluid iatrogenically from intravenous fluid boluses or infusions and it's causing fluid overload States as well again if you have CKD acute kidney injury fluid overload States and have heart failure it definitely will exacerbate this situation but you can have all of these symptoms with just fluid overload or just CKD without any heart dysfunction just realizing that but nonetheless patient has massive amount of pulmonary peripheral edema they come to you all right you're taking care of them they're let's say just to give you an example let's say that you're looking at them and they have pulmonary peripheral edema and also their weight is increased by let's say 10 kilograms I'm just making a massive amount here and let's say that they're they're Ino balance so the amount of fluid that they're getting in versus out for stay so they've been in the hospital is let's say that they're 10 liters positive at this point I need to try to get that fluid off I need to get rid of the fluid in the lungs get rid of the fluid in the pleural cavity get rid of the fluid in the abdomen get rid of the fluid and some of the actual interstitial spaces in the legs and the arms how am I going to do that great question here's what I'm going to do I'm going to start with the most powerful diuretic which is going to remove the largest amounts of volume from the body because again what I'm trying to do when I give diuretics is I'm trying to have them do what I'm trying to have them do what to the urine increase the sodium in the urine increase the water within the urine maybe increase some of the chloride in the urine but get rid of a lot of these particular things because if you get rid of these then what happens is you have less water less sodium in the blood that means you have less blood volume that means you have less preload and that means that if you have less preload you're going to have less congestion of the heart and you're not going to keep kind of decompressing the heart backwards into the pulmonary or peripheral systemic circulations so that's the whole concept here so in order for me to do that I want to work a blocking specific points what's the most powerful one that I'm going to start with the most powerful one that I have to start with with my regimen here is I'm going to start with a loop diuretic a loop diuretic should be first within this kind of regimen why because it's the most powerful and it's going to remove the largest amounts of sodium and water so I'll give a loop diuretic and what is it going to block let's see if you guys remember it's going to block the sodium potassium two chloride co-transporter which is going to block sodium chloride reabsorption as well as subsequently water absorption so what we'll end up in the urine I get rid of a lot of sodium I get rid of a lot of water and I'll get rid of some chloride in additionally I'll get rid of calcium magnesium some other things like that right but I'm going to really kind of decompress and get rid of a lot of blood volume so that would be my first part of the regimen now as I do the loop diuretic again take into consideration threshold and ceiling doses so maybe you give them a particular amount of the drug it's not enough maybe you have to increase the dose increase the dose until you get an adequate response but once you hit a particular dose where I give them 80 milligrams and they produce 400 cc's of urine in two hours and I give them 100 milligrams and they produce the same amount the ceiling dose was 80 I don't need to give any more so remember that concept but I've given them this and they're still not producing an adequate amount of urine okay then it's still not kind of getting that balance down what I'll do is I'll consider a second drug and there's even a better indication for this I'll start off with the loop diuretic and then what I can do is I can add on a second drug this is going to be where I add on the thiazide diuretics and there's two indications of why I would add on the thiazide diuretics okay one is I'm going to increase my diuresis so one indication is you're going to increase your diuresis so you're going to augment and enhance the effect of the loop diuretic because if you give a thia's ideal cause more sodium and more water loss right because now I'm going to block the I'm going to block the sodium chloride Co transporter here in the early distal convoluted tubule and cause more sodium and water to be lost in the urine so I'll increase irises here's one more thing believe it or not with Loop Diuretics they cause more water loss than they do sodium loss let's write that down so with Loop Diuretics they actually do cause more water loss so if we actually put like with loss with respect to loss they actually cause more water loss than sodium loss so if you cause more water loss from the body than you do sodium loss what's going to happen to the actual sodium it may cause hypernatremia so believe it or not this is a potential effect here that you may see patients develop what's called hypernatremia within the blood so in that particular situation guess what thiazide diuretics do they cause a good amount of sodium excretion so because of that they actually cause more sodium excretion than they do water excretion so when we think about this they actually with their loss they actually cause more sodium excretion than they do water excretion so what will they do they're lower the actual serum sodium within the blood so if a patient's getting hypernatremic another indication to give a thiocide diuretic is because they have hypernatremia I'm going to cause more sodium loss so I start off with the loop diuretic to pull off fluid they start to develop hypernatremia add on a thiazide already or they're not getting enough diuresis add on a thiazide diuretic okay as you do this you start to notice a potential problem that happens and this is really kind of interesting when you give Loop Diuretics and you give thighs at diuretics they really try to cause a lot of sodium wasting so you really try to get a lot of sodium in this distal part so you're going to block sodium here so you have a lot of sodium that moves from this point you're going to block sodium here so you're going to have a lot of sodium kind of at this point and whenever the sodium gets to the late part of the distal convoluted tubule you have a lot of sodium there when sodium kind of actually gets at this point here it can actually get kind of absorbed reabsorbed because there's lots of sodium in the Lumen and less sodium in the cell so it kind of gets reabsorbed with this distal part this is the distal convoluted to the distal part here and what happens is whenever you kind of cause a lot of the sodium to actually be reabsorbed there's another channel here there's a channel here let's actually do this one in pink here that actually kind of excretes a molecule in combination with the Sodium when the sodium gets reabsorbed it kind of causes the positive charges to be lost because now sodium is moving in the inside of the actual lumens getting negative so it pulls with it protons so now I start losing lots of protons into the urine what else did I say happens as you pull sodium into the cell the inside of the cell becomes the inside of the Lumen becomes negative it pulls protons but guess what else it pulls potassium and you lose potassium into the urine so I start to see two potential effects as I give Loop Diuretics and thiazide diuretics I start to see hypokalemia and I'm losing protons into the urn if I lose protons so then the next concept here is as I actually give loops and thiazides I get two potential problems that arise I cause hypokalemia because lots of sodium gets reabsorbed in the distal convolutely tubule which causes potassium excretion and then lots of sodium gets reabsorbed the distal convoluted tubule which causes proton excretion so this is going to lead to hypokalemia and low protons within the blood this will then lead to if you have low protons in the blood what's going to do to the pH it's going to increase the pH this is called metabolic alkalosis if only there was a drug that I could give that would actually cause metabolic acidosis there is carbonic anti-hydrase Inhibitors so now what I'm going to do is I'm going to add on another drug here so the next drug that I'm going to add on would be my Carbonic anehydrase inhibitors Carbonic anhydrase inhibitors and why would I add these drugs on because they're going to cause a lot of bicarb loss so these increase your bicarbonate loss which does what to the pH what does it do to the pH my friends it causes the pH to go down it causes a metabolic acidosis this is a good indication because what happens is with a loop diuretic and a thiazide diuretics they cause metabolic alkalosis so the Carbonic anehydrase Inhibitors will combat the metabolic alkalosis caused by the Loop Diuretics and thiazide diuretics why is that a problem because whenever the patients start getting metabolic alkalosis whenever they get metabolic alkylosis actually impairs direesis so it decreases the efficacy of the Loop Diuretics and the thiazide diuretics so remember as the pH starts getting higher it actually inhibits the efficacy of lube diuretics and thiazide diuretics so if I try to decrease the ph and get it to at least normal then what am I going to do I'm going to increase the efficacy of my lube diuretics so there's two concepts with this as I cause bicarbonate loss it decreases the pH which combats metabolic alkalosis and improves or increases your diuresis plus you also get a little bit of sodium blockade right so if I block the Carbonic anti-hydrates if I block this I'm going to not only block sodium reabsorption but I'm going to block bicarb reabsorption I'll block this process here and so I'll cause bicarb to be lost in the urine and a little bit of sodium and subsequently a little bit of water so I'm going to get a little bit of an extra diuresis effect and I'm also going to combat metabolic alkalosis but I have another problem my Loop Diuretics and my thighs are diuretics were causing hypokalemia and now I got to give all this potassium back to the patient because I don't want them to develop an arrhythmia so what do I do I can give them potassium I can do that but what if I have another drug that can also increase my diuresis and also increase the potassium and kind of prevent the potassium wasting that the thiazides and Loops are causing what if I had a drug like that I do so that's where the fourth drug comes in the fourth one that you can add on here you can tell this kind of stuff gets me super excited it's pretty cool is going to be your potassium sparing diuretics so this is your potassium sparing diuretics so this could be the aldosterone blockers or this could be the enac blockers but I'm giving these drugs because they're going to increase the potassium retention or decrease potassium loss right so effectively what they'll do is you'll increase your potassium inside of the blood which will combat the hypokalemia that the loops and thiazides were causing and believe it or not guess what the hypokalemia can do it can impair the efficacy of loops and thiazides so if I give them a potassium sparing diuretic it'll keep their potassium levels High which will combat the hypokalemia caused by the loops and the thiazide diuretics on top of that they do block the sodium reabsorption and potassium excretion in the late distal convoluted tubule and lead to a little bit of sodium and water loss so you will get a little bit of an increased diuresis effect so this is my perfect kind of like diuretic regimen when I have a patient who's extremely and distress from pulmonary edema a lot of pleural effusions a lot of generalized systemic pitting edema peripheral edema a lot of ascites hepatomegaly due to heart failure CKD acute kidney injury fluid volume overload and these states you need to direese them start with a loop they may get hypernatremely because it causes more water than sodium loss if you need to increase your diuretic effect and prevent hypernatremia give a Thia is a diuretic as you start to treat them with that they start to get hypokalemic and metabolic alkalosis develops that impairs their effect efficacy of those drugs give a Carbonic anhydrase Inhibitors to cause bicarb loss and decrease the pH to combat the metabolic alkalosis from loops and thiazides and it enhances a little bit of sodium and water loss if they become hypokalemic guess what else you can do and hypokalemia can impair the efficacy of loops and thiazides you can give a potassium sparing diuretic like spironolactone eplerone amylori triamterene and what will they do they will cause potassium retention they'll inhibit potassium excretion cause the potassium levels to go up and if the potassium levels go up that combats the hypokalemia that the loops and thiazides cause on top of that it also blocks sodium and water reabsorption in the distal convoluted tubule and cause a little bit of that to be lost in the urine so it also causes diuresis this is the perfect schematic for a patient who has the need to be Diaries there's one more indication for dyresis which is a little bit odd and wonky and that's when patients have a lot of ascites and kind of a patomegaly and peripheral kind of a pitting edema but it's due to cirrhosis and that situation the treatment's a little bit different let's talk about that now all right my friend so now what we're going to do is we're going to talk about how do we decrease patients that actually have ascites you would think oh it's the same thing Zach you just give them you know furosemide and give them like thighs believe it or not it's not exactly the same it's a little bit different and the reason why is the pathophysiology slightly changes so when patients develop a lot of Edema such as you know for example maybe it's not just societies maybe they also develop so you know a lot of like uh Leg Edema and stuff like that too so maybe they develop a lot of like pitting edema okay within the legs or maybe they develop a ton of ascites okay because of a lot of fluid backing up from their liver into the actual um abdomen so in these particular situations the primary etiology of this is not a fluid overload State it's not a chronic kidney disease State it's not a heart failure type of State in these situations the primary etiology here is that they have cirrhosis so there's some type of cirrhosis type of process and with cirrhosis their liver becomes so fibrotic that what it does is it actually kind of causes the portal vessels that are supposed to enter into the liver and bring fluid kind of through it generally blood through it and then its liver is supposed to kind of remove some particular toxins remove some particular nutrients store some particular things and then secrete some things and then put it into the inferior vena cava that's the whole job of it problem is that all the cirrhosis and fibrosis starts kind of encroaching on some of these portal veins and then you start getting a lot of this fibrosis that kind of encroaches on the portal veins and causes the pressure because it starts squeezing on it it starts causing the pressure of the portal circulation to increase so subsequently what happens is with the cirrhosis it causes an increase in the portal blood pressure now with that being said what happens is the liver says okay hold my beer I got a way to fix this and it says I'm going to release particular types of peptides like nitric oxide and things of that effect which are going to kind of try to cause Vaso dilation of this portal vein to try to help to be able to increase the blood flow because that's the whole problem the blood flow is being affected because I have all this fibrotic tissue around it that's compressing the portal vein so maybe if I try to make the portal vein dilate a little bit it'll reduce the pressure and help to maybe improve some of the flow through the liver the downside of this is something else when you release nitric oxide what it does is not only does it try to cause a vasodilation effect of the portal veins it also vasodilates a ton of like splanchnic vessels like it really vasodilates a lot of the vessels inside of the abdomen and the downside of that is that if you really kind of like let's say that here I have some particular vessels here so this one is supposed to be going to the kidney right but I have all these other blood vessels that are supposed to be going to other particular tissues so maybe I have some blood that's going to be going to a bunch of different organs here so let's say that we kind of put some organs here so a lot of my GI organs here and then this one that's supposed to be going to the kidney all right so this is the blood flow that's supposed to be going to the kidney what I'm going to do is I'm going to get these nitric oxide molecules and they're going to vasodilate these splanchnic vessels so they're going to vasodilate it's going to cause vasodilation which will help to increase the blood flow to these actual organs but what it'll do is it'll reduce the amount of perfusion to the kidneys right because you're taking and kind of diverting the blood volume away from the kidney and then instead going to the organs the downside of that is that you have effectively out of this because you're not going to get as much perfusion to the kidney you're going to have a reduced renal perfusion so the actual renal blood flow is decreased when you decrease the renal blood flow what this does is this activates What's called the renin Angiotensin aldosterone system so then from here my kidneys are going to start pumping out renin which will eventually lead to I'm going to kind of got divert throughout the entire process here it's going to go to Angiotensin II eventually Angiotensin II is then going to try to go and kind of like squeeze your blood vessels and increase your blood pressure and try to perfuse the kidneys it's trying to fix that problem but it also activates aldosterone when it activates the adrenal cortex to make aldosterone aldosterone will then go to the actual distal convoluted tubule and what it's going to try to do in the distal convoluted tubule is reabsorb a lot of sodium excrete potassium and then if you also have ADH present not only will it reabsorb sodium but also reabsorb water so trying to increase your sodium reabsorption and increase your watery absorption the problem with that is is that if you kind of have from this effect an increase in sodium reabsorption and an increase in water reabsorption guess what that's going to propagate it's going to propagate worsening ascites and it's going to propagate worsening so the problem with this is it's going to cause worsening ascites and worsening pitting edema okay that's the problem with this so now what I got to do is is I got to come up with a drug that'll really help me to reduce in some degree this this seems to be the problem here this really seems to be the problem is that whenever the liver has cirrhosis poor blood pressures rise release vasoactive peptides it causes splength vasodilation so it increases the blood flow and diverts it to the actual GI organs but less of it goes to the kidneys less renal blood flow activates the renal Angiotensin aldosterone system aldosterone causes a lot of sodium retention a lot of water retention a lot of sodium and water gets actually kind of retained within the belly and within the legs and before you know it they're walking around with this kind of like fluid-filled kind of like cavity here in their belly and within their legs propagating worsening ascites so what if I gave a drug that blocked aldosterone which reduced sodium and water retention which reduced the society's process guess what we got aldosterone blockers so that is where the primary drug for treating patients who have edema such as ascites hepatomegaly peripheral pitting edema from cirrhosis is actually going to be aldosterone blockers because if I give an aldosterone blocker such as spirinolactone or eplerone I'm going to block the effect of aldosterone on the distal convoluted tubule I will not reabsorb sodium I will not reabsorb as much water and I will not excrete as much potassium so then effectively my kidneys won't retain as much sodium I won't retain as much water and I won't actually have as much of the societies and I won't have as much of this pitting edema Isn't that cool so this is actually the first line drug and you actually give pretty high doses of them so generally very very high doses of these drugs and patients who have ascites hepatomegaly peripheral impeding edema from cirrhosis the drug that you can add on as an additional kind of like supportive therapy here to produce sodium and water retention which one causes the maximum amount of sodium and water loss out of all the diuretics which one causes the maximum amount of sodium and water loss Loop diuretics so the additional therapy that I could add on here would be my Loop Diuretics but these are going to be usually in lower Doses and then again why is this going to be beneficial because with Loop Diuretics this is going to be at lower doses with these drugs what they're doing is they're blocking the sodium potassium two chloricotransporter and causing a massive amount of sodium and water to be lost into the urine which again effectively leads to less sodium and water would actually be retained within the blood which leads to less kind of like sodium and attention and water retention within the belly and the legs leading to lessepado megaly less societies and less generalized in peripheral edema okay so again that seems to be the primary therapy for patients with Diaries sorry due to acidic fluid accumulation or peripheral pitting edema due to underlying cirrhosis these patients may also potentially benefit from like a paracentia a paracentesis so generally when you have a lot of acidic fluid they may benefit from kind of tapping into the belly and pulling off some of that fluid such as a paracentesis and they also May benefit because in patients who have serosis they have less albumin production you may actually benefit from giving these patients albumin as well but again nonetheless what I want you guys to understand is how do you remove that fluid with diuretics it's primarily going to be the aldosterone blockers like spironolactone and then adding on a loop diuretic to enhance sodium and water excretion reducing the acidic fluids all right my friends the last category here is we give these drugs we give this patient a particular Loop thiazide potassium spraying Carbonic anehydrase inhibitor or any of these drugs what are some of the adverse effects that I have to be aware of and how do I make it easy in my brain to remember them I got you let's talk about it all right my friend so adverse drug reactions let's go through them ready first one Lube diuretics all right we talk about Loop Diuretics we talked about how they're going to cause the most amount of sodium and water loss but what I tell you uh is I told you that remember when we talk about loss it causes definitely a lot of sodium loss and a lot of water loss but in comparison because this it's going to cause more likely hypernatremia why just again as a reminder yes you lose a lot of sodium 25 of sodium is actually going to be blocked from being reabsorbed at the ascending limb but you'll also lose a lot of water so because of that water loss is going to be greater than the sodium loss and that's why you'll see hypernatremia potentially with Loop diuretics the other thing is that it can actually kind of pull off a lot of water to the point where it can actually cause them to become hypovolemic so watch out whenever patients sometimes become over diariese you want to watch out for any types of hypovolemia so watch out for any low blood volume that can actually cause low blood pressure so be careful with that the third thing here so again we're really kind of inhibiting this particular transport is the sodium potassium to Clark Transporters that blocks sodium reabsorption that blocks watery absorption we talked about if it blocks sodium and water absorption you're going to lose a lot of blood volume right it also can cause more water loss than sodium loss so you may see hypernatremia especially with repeated dosing the next thing is when you block the sodium potassium to chloricotransporters it also blocked what else from being reabsorbed in between the cells because remember calcium and magnesium so you should also see low calcium levels in the blood and it also should cause low magnesium levels within the blood what was another concept here another one with electrolytes is that because you inhibited a lot of sodium reabsorption a lot of sodium makes it to this distal convoluted tubule so you're going to have a ton of sodium here remember I told you that in the principal cells you'll reabsorb a lot of sodium into the principal cells and you'll reabsorb a lot of sodium into these intercalated cells I talked I told you I talk about these eventually the intercalated cells are the ones that control acid-base balance the principal cells are the ones that control your electrolyte balance like sodium potassium so remember sodium if there's a lot of sodium that gets here because you blocked it from being reabsorbed a lot of sodium will move in via the sodium transporter and a lot of potassium will be excreted into the urine a lot of potassium on top of that if you have a lot of sodium being reabsorbed it also causes a lot of protons to be excreted into the urine and again why does this happen again the whole concept is is as you take a cell and you have to have positive ions flowing into it such as sodium that means that you're going to have positive ions moving into the cell that means that the Lumen is going to become negative when the lumens negative it will pull out positive ions such as protons and such as potassium ions and that's why potassium and protons will be lost into the urine so because of that if you lose potassium into the urine it's going to cause hypokalemia and if you lose protons into the urine it's going to make the pH you're going to have less protons within the blood if you have less protons within the blood that's actually going to cause the pH to go up so it's going to cause a metabolic alkalosis okay so so far hypernatremia hypovolemia hypocalcemia hypomagnesemia hypokalemia and metabolic alkalosis what else this one's interesting as the proximal convoluted tubule you also have an organic acid transporter that is supposed to kind of pump furosemide but it also pumps out what's called uric acid and so sometimes these can compete and so you can't excrete the uric acid as much because you're trying to pump furosemide in there sometimes you can't pump out the uric acid and so uric acid levels actually get accumulating within the blood because you can't pump out the uric acid at the same time you're trying to pump out the furosemide or any of the Loop Diuretics and so because of that the uric acid levels increase in the blood and that causes hyperuricemia okay another effect it's weird but Loop Diuretics May May have some effect on insulin whether it's inhibiting insulin secretion or whether it's inhibiting the effect that insulin has on tissue cells to bring glucose into the cells so weather Loop diuretics inhibit insulin release or inhibit the effect of insulin on the tissue cells you're not going to get glucose coming into the cell and so what happens is the blood glucose levels rise and so this may also cause the patients to develop hyperglycemia hyperglycemia so increased glucose levels within the blood there's one more effect and this is usually a very very high doses it may also cause Oto toxicity so toxicity to the actual inner ear and cause hearing loss usually that's with ethocrinic acid are super super high doses of Loop Diuretics okay but more commonly with ethercretic acid okay the next one let's actually move on to the thighs the direction the reason why I want to do that is because they have a lot of the similar types of effects again when we talk about this what will it do to the sodium well I told you that with this it's actually blocking the sodium chloride co-transporter and it's going to cause a lot of sodium loss in the urine but more powerfully water loss so what I see more of an effect of hyponatremia so I'm going to see low sodium and the blood because it's actually going to cause sodium loss to be greater than the amount of water that is lost okay beautiful the next concept here let's actually make this pretty this was supposed to be a red parenthesis come on man and then we go here same thing low sodium because you're causing more potentially sodium loss than you have water loss this won't cause as much water loss though so you won't get as much of a hypovolemia type of effect so that's a cool thing the second thing what can it do to calcium oh you guys better not forget this if I inhibit the sodium chloride code Transporters I inhibited sodium reabsorption which also led to more sodium coming into the cell this way and more calcium coming out this way and so that causes a lot more calcium to be absorbed so what will this do to the calcium it'll increase the calcium levels so it may cause hypercalcemia it does cause a little bit of Mag to be lost I'm not going to go over the mechanism here it's a little bit interesting but it can cause a little bit of hypomagnesemia what about the potassium well the same thing it's blocking sodium a reabsorption here in the early part of the distal convoluted tubule so by the time it gets to the late distal con late part of the distal convoluted tubule you're going to have a lot more sodium than you usually would so that means a lot more sodium enters into the principal cells a lot more sodium enters into the intercalated cells that makes the inside of the Lumen negative that draws out potassium and draws out protons and so what do I urinate a lot of into the urine I have lots of protons in my urine and lots of potassium ions into the urine so effectively this will cause hypokalemia it'll also cause low amounts of protons in the blood which will cause an increase in the pH causing metabolic alkalosis okay what else can it do the other thing is that you know um thighs and diuretics are also excreted or put pushed into the tubular cells via the organic acid transporter and the proximal convoluted tubule just like Loop Diuretics but guess who else is supposed to be excreted that pathway uric acid and so because uric acid has to compete with both Loop Diuretics or thiazide diuretics you're not going to be able to excrete it because you're supposed to be able to excrete thiazides via this transporter and Loop Diuretics and now you can't excrete uric acid and so it builds up in the blood and so it may cause hyperuricemia oh my gosh man we're getting good the other concept here is that it may again do something with insulin whether or not it actually may inhibit insulin production or inhibit the effect of insulin has on the tissue cells to shift glucose in there it may in some way either inhibit insulin production or inhibit the sensitivity of insulin on the tissue cells and so they don't reabsorb glucose or absorb glucose and so what will this do this will cause hyperglycemia it has no effect on ototoxicity and then one other effect that you actually can potentially consider here is through mechanisms that I'm not completely sure of it may also increase your lipid level so it may also cause hyperlipidemia all right so with Loop Diuretics you get hypernatremia hypovolemia hypocalcemia hypomagnesemia hypokalemia metabolic alkalosis hyperuricemia hyperglycemia ototoxicity with thiazides you get hyponatremia hypercalcemia hypomagnesemia hypokalemia metabolic alkalosis hyperuricemia and hyperglycemia and hyperlipidemia all right potassium sparing diuretics with potassium sparing diuretics it's actually not too bad thank goodness with these ones what you really want to remember here is that what they're doing is in general regardless if it's an enact blocker or whether it's an aldosterone Blocker we already know that it's preventing sodium reabsorption which leads to less sodium potassium so here really quickly really quickly I don't reabsorb sodium therefore I can't pump it out via the sodium potassium atpase so that means less sodium is being reabsorbed that means less potassium is being pumped into the cell that means that there's less potassium to be pumped out of this cell so that means that less potassium is going to end up into the urine so because of that this will cause the potassium level within the blood to increase so it may cause hyperkalemia okay the other concept here is that this is what's really interesting with aldosterone aldosterone has been shown to not only cause stimulation of sodium and reabsorption potassium excretion but it's also been shown to stimulate proton excretion into the urine so if I give an aldosterone blocker guess what I may potentially do inhibit proton excretion and so another potential effect that I can see here is I'm going to see less I'm going to see less proton excretion so if I see less proton excretion the protons in the blood may go up and this may decrease the pH so this may cause a metabolic acidosis another concept here is really cool is that let's say that we talk about the enact blockers either way both of them both the aldosterone and enact blockers lead to hyperkalemia why is that important if the potassium levels in the blood are high what you guys know is is that sometimes we have these Transporters on many different cells in the body and what this does is this transporter is supposed to pump the potassium into the cell and pump the protons out of the cell well the higher the concentration is the potassium within the blood the more potassium goes in and the more protons goes out well if I have hyperkalemia I'm going to be shunting in potassium and shunting out protons so I increase my protons within the blood which leads to a drop in the pH so you can see this with both the enact blockers and the aldosterone blockers so I see hyperkalemia I'm also going to see and metabolic acidosis there's one more effect and this is particularly with the aldosterone blockers because it not only blocks aldosterone it can also block some other steroid hormones particularly in men this may lead to the development of excessive breast tissue called gyneco mastia I want you to remember that primarily with the aldosterone blockers you will not see that with the Enoch blocker such as amyleride and triamtery all right my friends so with this being said the primary adverse effects here is going to be hyperkalemia metabolic acidosis gynecomastia or some type of erectile dysfunction or amenorrhea or menstrual irregularities in females due to the aldosterone blockers not only blocking aldosterone but other steroid hormones okay that's the big things that I want you to remember there the next one and the last one here is carbonic antihydrase Inhibitors with Carbonic anhydrous Inhibitors what we know is they're going to inhibit the Carbonic anhydrous enzyme therefore you're not going to be able to reabsorb bicarb and excrete protons so the proton excretion is decreased and the bicarbonate reabsorption is decreased so I lose a lot of bicarb into my urine and I don't have as much bicarb being reabsorbed into the blood so my bicarbon the blood is less if my bicarbon the blood is less what is that going to do to my pH it's going to decrease my pH causing a metabolic acidosis but I'm going to cause a lot of bicarbonate to end up in my urine you know what bicarbonate in the urine actually can do it can increase the risk of kidney stones it can actually make the urine more alkaline and if you make the urine more alkaline I can actually increase the pH of urine and can increase the risk of kidney stones especially some of the calcium Stones so that's another thing to be able to think about there's one more thing if I block the reabsorption of bicarb and I block the excretion of protons where does that proton problem come at come into play out of play well you know there's another molecule that's supposed to be kind of excreted from the body that can be very toxic this is called ammonia so you can excrete pneumonia right now ammonia generally what it'll do is it'll combine with this proton when ammonia binds with a proton it'll form something called ammonium and the the benefit of this is that when you think about things being absorbed a thing that's charged is hard to absorb right because you need some type of Transporter whereas ammonia this is actually not charged at all so it could reabsorb right across the actual membrane so if I weren't having any protons to bind with the ammonia the ammonia can just get reabsorbed and increase within the blood oh my gosh hyperaminemia is super dangerous but that is a potential complication so watch out for high levels of ammonia within the blood which can lead to encephalopathy it can lead to different types of paresthesias and a lot of like cerebral edema types of effects so again big thing to think about with Carbonic anhydrous Inhibitors is it can cause metabolic acidosis it can actually cause the urine to be more alkaline which increases the risk of kidney stones and it also can cause hyperaminemia and then one other thing is that if you do have some degree of sodium reabsorption that's inhibited to this process you will get a little bit of sodium at the end of the distal convoluted tubule here and so you have more sodium reabsorption more potassium excretion if you really wanted to remember this this may cause a little bit of hypokalemia as well my friends we've covered all the diuretics I know it's been a beast I hope that it made sense I'm so sorry that it went so long but I hope that you guys did help and did help you and you guys enjoyed it we got to do a quick couple of cases and then we're done all right meet me there all right my friends let's do some cases so first question here is an elderly patient with a history of heart disease has difficulty breathing is diagnosed with acute pulmonary edema which treatment is indicated well in general as we talked about with diuretics the one that's actually going to be the most effective at pulling out large volumes of kind of fluid from the body but really reducing the true total volume blood volume within this situation is going to be Loop Diuretics they are going to be the most effective at being able to reduce the actual fluid overload states in the situation of acute pulmonary edema so furosemide should be the best answer acetazolamide is not going to be able to pull that much fluid off again it's good when patients who you're diariesing with Furosemide started to become a little bit more metabolic alkalotic you could add that drug on chlorthalidone is a thiazide-like diuretic so it's going to be more beneficial kind of like an add-on therapy a few patients becoming extremely hypernatremic again we also can utilize these in hypertension and also again these drugs may be somewhat beneficial in patients who have some type of problem where their calcium levels within their blood are low they're osteoporotic and you want to increase their calcium levels so those could be indications and spironolactone is not a super great diuretic for a special acute pulmonary edema so because of that I would not be utilizing that drug so it should be C Furosemide altitude sickness a group of college students is planning a mountain climbing trip to the Andes what is the most appropriate for them to take to prevent altitude sickness well we already know that it's got to be acetazole mine so acetazole might also known as Diamox is going to be a nice Carbonic anhydrous inhibitor and so that's really going to help to be able to again get rid of a lot of the actual bicarb in the urine and so that will help to kind of allow for the pH to become a little bit more acidotic so in these situations here that is going to be the best particular drug in this situation here would be the acetazolamide and so that would be C alcoholic meal has developed hepatic cirrhosis to control the ascites and edema which should be prescribed so this is actually a very interesting one and so you would think okay edema in general edema is going to be best with things like furosemide and that would seem to be true in most particular scenarios however that's not the most effective drug in classic cases who patients who have hepatic cirrhosis in patients who have hepatic serosis sometimes they can actually get these weird hepatoadrenal syndromes where they can have these problems with aldosterone levels being a lot higher and so in those States we actually have found that spironolactone has actually been the best at treating the hepatic related edema so any hepatic related edema especially with these hyperaldostron states spironolactone is actually shown to be the most effective diuretic as compared to all of them so spironolactone would be the effective answer here all right question four 55 year old male with kidney stones needs a medication to decrease urinary calcium excretion which diuretic is the best for this indication so as we talked about below we want to know which one helps to be able to increase calcium absorption basically is the way that we want to think about this so If instead of actually allowing for things like a loop diuretic that's actually going to cause calcium loss spironolactone doesn't really have any true effect at all on calcium triamterene as well so it leaves us with Hydrochlorothiazide and again we know that thiazide Heretics help to be able to again particularly increase calcium absorption and inhibit sodium and chloride and water reabsorption so this will be beneficial helping to be able to increase blood calcium levels kind of a beneficial situation in patients who actually not only are having problems with kidney stones but also patients who have osteoporosis so Hydrochlorothiazide that would be the choice um 75 year old woman with hypertension glaucoma being treated with chlorthalidone amlodipine lisinopril and acetazolewide in clinic today she complains of acute joint pain and redness and her great toe which is diagnosed as gout which medications most likely have to cause the gout attack well this means any drug that actually inhibits the organic anion Transporters in the proximal convoluted tubule that excretes uric acid that leads to hyperuricemia that's Loop Diuretics and that's thiazide diuretics so which one of these is one of those two categories of drugs amlodipine is a costume channel blocker see those little mine is a Carbonic antihydrase inhibitor chlorthalidone is a thiazide like diuretic so it should be chlorothalidum which drug is contraindicating hyperkalemia without the anything that inhibits kind of the renin angiotensinaldosterone pathways so that'd be ACE inhibitors aldosterone receptor blockers and spironolactone so any of the or any of the actual aldosterone antagonists such as eplerone so acetazolamide is a Carbonic anehydrous inhibitor has no effect on the potassium chlorothides that would actually kind of cause hypokalemia at the critic acid it's one of the weird Loop Diuretics and generally those cause hypokalemia and then eplerone is a Doctrine antagonist so that's actually going to block out the Astron which will actually cause less potassium excretion and so that'll cause hyperkalemia 59 year old man with the Intensive Care Unit has a metabolic alkalosis which therapy will treat this condition all right so again you wanted something that's actually going to in a metabolic alkalosis your bicarbs high or pH is actually going to be subsequently high as well so in this situation here you actually want to excrete bicarb from the body so a Carbonic anhydrase inhibitor or a bicarb excretor to direse out in the urine would be the best in that situation so acetazolamide is the only Carbonic anti-hydrocentimeter in this drug categories here so I would do a cetazole mine a male patient is placed on a new medication that and notes that his breasts have become enlarged and tender to touch which medication is most likely is he taking and so in generally these are going to be drugs that are altering the androgens um and so generally aldosterone is a steroid hormone and so whenever you give drugs that are working to block aldosterone at its particular receptor sites but also has anti-androgen activities as well and other tissue sites such as the breast tissue this can lead to these types of effects so we need one of these drugs to be primarily I mean aldosterone antagonist but one that's not a specific aldosterone receptor antagonist it can actually bind onto other anti-androgen receptors and that would be spironolactone so spironolactone is the only one here heart failure with a reduced DF diuretics okay so a patient with heart failure with a reduced ejection fraction research to his medications on the internet oh boy found he was taking two diuretics to be met9 and spironolactone he asked if this is a mistake um with his therapy what is the best response so we've got to go you got to go to Dr Google um so it's never a good idea but it's a good question I think so they are two diuretics but they have two different functions so bumetanide is a loop diuretic so it's going to help with the symptomatic effects of heart failure with the reduced DF so in other words any types of peripheral or pulmonary edema symptoms that they may have the bumetanide is going to be more successful at spironolactone has kind of a couple of functions to go along with that whenever they're on bumetanide they're hypo they may kind of cause they're going to lose some potassium and so we can actually kind of preserve the potassium with spironolactone it also may give them a little bit of an additional diuretic effect but nothing intense but the other thing that we know about spermolactone is that it's actually been shown to reduce mortality and that's a drug that we want to give patients if you can reduce mortality you should do that and it's also been shown to reduce the mortality by preventing a lot of the cardiac remodeling effects remember it helps to reduce preload helps to be able to reduce the aldosterone effect on the heart which causes a lot of the remodeling effect there so I would say that there is benefits of spironolactone by preventing hypokalemia giving a little bit of extra diuresis but on top of that also prevents cardiac remodeling reduces mortality in patients who have heart failure so whichever one answers that spironolactone is used to prevent hyponatremia no could actually be used to prevent hypokalemia spironolactone is used to reduce heart structure changes and decrease the risk of death that we know it reduces mortality so it's got to be bemet9 is used to decrease the potassium loss from spironolactone therapy that's actually again that's opposite spironolactone be used to decrease that from bumetonite therapy and this is a duplication error and only one diuretic should be stopped I mean in one diet no that's not the case so I think that again the correct answer would be B all right last question here so which Artic has been shown to improve blood pressure and resistant hypertension or those already treated with three blood pressure medications including a thiazide or thiazide-like medication so they're already on a thiazide or thighs I'd like medication for their blood pressure and they're on a couple other medications apparently whatever that may be in addition to this I'm not sure but what else could we add on to the thiazide and the two other medications that they're being treated with so um and dapamide is again it's it's basically a thiazide diuretic so I wouldn't want to put them on two of those so that that would not be the correct answer furosemide is not really a true blood pressure medication if a patient's extremely volume overloaded and hypervolemic it may help to reduce the blood pressure but that's not a primary indication for furosemide Mannitol is not a blood pressure medication as well it's primarily utilized in patients who have like you know excessively High intracranial pressure so again it's not going to be one of those particular situations again in situations where they have high ACP they may develop a Cushing's Triad and maybe give a Mannitol and improve their blood pressure but it's not a blood pressure medication that's designed to reduce blood pressure spironolactone actually does have antibertensives properties it's not super powerful but it has some benefit and one of the good things about this drug is that again it can help with reducing mortality in patients who have underlying heart failure it may help to be able to block out the osterum which will help to produce a lot of the sodium and water intake um from the body which helps to produce kind of the preload the excessive blood volume the Venus return reduce the cardiac output and reduce their blood pressure um and again it also gives you some type of um kind of resistance to hypokalemia as well so yeah I would say that spironolactone out of all of these would be the only one that would actually give a true kind of blood pressure modest reduction mild reduction only reason I can't give him dapomite is I've already given the thiazide thighs I'd like to read it firosamide is not indicated for blood pressure Mannitol is not indicated for blood pressure but spironolactone can help with hypertension especially if they have hypokalemia heart failure or any kind of like hepatic edema related issues so this would be good indications for that so I would say it would be D all right my friends so that would cover all of these questions on diuretics I hope it made sense I hope that you guys liked it and an Engineers thank you guys for being so awesome always sticking in there continuing to support us we love you we thank you couldn't do this without you and as always until next time [Music]

Channel: Ninja Nerd

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Keywords: Ninja Nerd Lectures, Ninja Nerd, Ninja Nerd Science, education, whiteboard lectures, medicine, science

Id: 1MLUQPS_71A

Length: 156min 7sec (9367 seconds)

Published: Fri Nov 18 2022