Diuretics & Renal Physiology

Hey future doctors, thanks for joining me on Spoonful of Sugar, a podcast made for medical students, by medical students to help the medicine go down. My name is Ria Mulherker, I'm currently a medicine intern in Philadelphia, and I will be your host today. You might have thought that we did enough with the kidney in season one of Spoonful of Sugar, where we had three entire episodes dedicated to the kidney. We talked about glomerular diseases, aka eye, urinalysis, but here we are again with an episode on diuretics. I really think the kidney is the organ that keeps on giving. Seriously, on board questions, on the wards, you'll notice that everyone has something wrong with the kidneys, and some of the most important drugs that we give in the hospital, some of the most common drugs, have so much to do with the kidney. And that is why renal physiology is so important to understand, and so here we are again. Today, I'd like to discuss renal physiology, and kind of address diuretics in the context of normal renal structure and physiology. As always, when I go through this topic, I'm going to be asking a lot of questions, and I really hope that you'll take some time to think about the answer, try to say it out loud to yourself, and pause the audio if you need more time to think. I really don't want you to feel bad if you're not getting the questions right. Some of these are going to be read by mine questions. Don't feel bad if you don't know what I'm talking about, because really this is a place for everyone to learn more, and for us to practice what we already know. So with that in mind, a lot of positivity, let's get started on kind of a basic overview of renal physiology. I really want you to just kind of think about the normal structure and function of the kidney. What does the kidney do? So we know that blood goes into the kidney through the renal artery, and that blood gets filtered in the renal cortex and the medulla. And essentially, the stuff that we want to keep goes back through the body through the renal vein. And the stuff that we want to excrete ends up going into the collecting duct and into the larger calisies. And finally, at the renal pelvis, it connects to the ureter. And that's really the anatomical structure of the kidney. Now, what is the functional unit of the kidney? Do you know? So the functional unit of the kidney is the nephron. Okay, and the nephron can kind of be divided into two parts, as I like to think of it. So there's the glomerulus, and then there are the tubules. Now, what happens at the glomerulus? So at the glomerulus, remember, this is where the afferent arterial enters, and it turns into capillaries, which are surrounded by a structure called the bummin's capsule. And this is where the filtration happens before blood returns through the efferent arterial. So what does the glomerular filtration barrier look like? There's three main layers that I want you to think about. Do you know what they are? So the first thing that the blood is going to hit is the fenestrated capillary endothelium. And that's formed by the endothelial cells, which are lining the blood vessels. The next structure is the basement membrane, and what makes up the basement membrane? So type four collagen and heparin sulfate. We're going to make up the basement membrane of that glomerular filtration barrier. And then the final layer are the cells on the other side. And do you know what those cell layers are called? What those cells are called, I mean to say? So these are the potocytes, and remember they're called potocytes, they have that POD stem in there, which refers to the foot processes. And these foot processes kind of extend and form gaps. And so really the function of this filtration barrier is to create both a size barrier as well as a charge barrier. And what do I mean by that? So the size barrier is kind of straightforward to understand. Essentially large structures such as proteins and any kind of cells, such as red blood cells, are too large and so they're not going to be able to get filtered through this capsule. And there's also a charge barrier. So all three layers of this filtration barrier are negatively charged. And that prevents other negatively charged molecules such as proteins like albumin from escaping. So really the job of this glomerular filtration barrier, the Bowman's capsule, is to act like a sieve and prevent large things like cells and proteins from escaping. So then what does escape into the tubules? So smaller molecules like water and ions, like sodium, potassium, calcium, bicarb, these are all the things that are going to be escaping into the tubules and then it's the job of the tubules to adjust the reabsorption versus excretion of these molecules. So now let's go through the tubules and kind of think about what happens at each part of the tubules as we travel through the nephron. So the first structure after the Bowman's capsule that we hit is the proximal convoluted tubule. And this is located in the upper cortex of the kidney. So what happens in the proximal tubule? A lot of reabsorption happens. And when you think about the different parts of the kidney, I want you to think about the tenicity of the fluid in the kidney. So in the proximal tubule what we see is isotonic absorption. So here we reabsorb almost all of our glucose and amino acids. We also reabsorb water as well as sodium chloride, bicarb, phosphate, potassium, uric acid. The majority of sodium is absorbed here. And I did say that this is isotonic absorption in the proximal tubule. So how do we keep it isotonic if we're basically reabsorbing everything? So the cells of the proximal convoluted tubule are actually going to generate and secrete ammonia or NH3. And that kind of helps the kidney secrete more acid as the ammonia moves along. And it helps keep the fluid here isotonic. Now in the kidney there's a lot of different ions, there's a lot of different molecules being absorbed. But remember that the most important function of the kidney is going to be to regulate sodium and water balance. And kind of a side effect of that is acid. So if you're getting lost with all the other ions that I mentioned as I'm going through the kidney, try to focus most on the sodium and the water and the acid. I think those are kind of like the three most important things to focus on and then everything else kind of is secondary. So that's the proximal tubule, excellent, isotonic absorption. What's the next structure we hit in the nephron after the PCT? So then we run into the descending loop of Henley. And again, think about this in the context of renal anatomy. So in the cortex we have the proximal convoluted tubule coming straight from the glomerulus. And as it becomes the descending loop of Henley, that limb kind of dips down into the mandula. So what happens here as we take the tubule and go from up in the cortex down the descending loop of Henley into the mandula? What happens to the fluid in the tubules? So here the urine is going to become hypertonic. And why is that? So in the descending loop we're really only absorbing water. The cells that line the tubule of the descending loop of Henley are impermeable to sodium. So urine becomes more concentrated as it descends from the cortex into the mandula. And this is established kind of by a fine chemical balance created by both the ascending and descending loop of Henley. But essentially as the water descends, the cells are impermeable to sodium and we're only reabsorbing water. So think of that urine getting more and more concentrated as it descends into the mandula. And then after the descending limb, it's going to go back up towards the cortex via the ascending loop of Henley. So what happens here in the ascending part? It's kind of the opposite. So urine starts to become more hypotonic as it rises back up into the cortex. And it's literally the opposite of the descending. So in the ascending loop we're impermeable to water and we're only reabsorbing sodium, chloride, and potassium. And there's a special transporter here. It absorbs one molecule of sodium, one molecule of potassium, and two molecules of chloride. So if you think about what the ascending limb does for the loop of Henley, it's essentially creating that high concentration gradient, which is what drives water reabsorption in the descending loop. I know it's confusing to think about, but what I want you to take away about the loop of Henley is that as water comes down through the descending limb, as urine comes down, we're only going to reabsorb the water and make urine hypertonic. And then as we go back up through the ascending limb, we're going to reabsorb sodium, potassium, and chloride and start to make the urine more hypotonic. So where in the kidney do you think urine is least concentrated? Where is it most hypotonic? It's really going to be most hypotonic at the very end of the ascending loop, the thick ascending loop, and the beginning of the distal convoluted tubule. So then let's move on to the next part. What happens in the distal convoluted tubule? So here we continue to reabsorb things. We continue to reabsorb sodium, chloride, and we remain impermeable to water. So we're still hypotonic at this point, but remember that most of this stuff is going to get reabsorbed in the proximal tubule, and the descending tubule is kind of less of a contribution. And then finally we hit the very last structure which is the collecting tubule. So what happens in the collecting tubule? So here we're going to reabsorb sodium, but this time in exchange for potassium and hydrogen. And I want you to remember that water is just going to follow sodium because it follows the concentration gradient. So whenever sodium goes, water follows. And then the other thing I want you to remember is that wherever potassium goes, hydrogen follows. So in the collecting tubule, we're reabsorbing more sodium and water, and we're excreting potassium and hydrogen ions. Now the kidney gets more complicated because there are a lot of hormones that act in the nephron. And so really quickly, I just want to review four different hormones and what they do in the kidney. So what does angiotensin to do? It's one of the most important ones that acts at the kidney. Think about where it acts and what it does. So the job of angiotensin is to make you hyper-tensive, right? And that's kind of in the name, the intensive part. Angiotensin makes you hyper-tensive. And remember, that happens because the renin, angiotensin, aldosterone system gets activated when the kidney perceives decreased blood flow to the macular densa. So what angiotensin to does is it acts at the proximal convoluted tubule and it tries to stimulate sodium absorption. And remember, water is going to follow sodium so it's going to help retain more fluid and make you more hyper-tensive. A little detail that's important to remember is that angiotensin-2 works at a sodium hydrogen exchanger. So what ends up happening is sodium gets absorbed, hydrogen gets excreted and we end up absorbing more bicarb. So the actions of angiotensin-2 are going to cause a contraction alkylosis. And this is something that's important to remember because it can also be a side effect of a lot of the diuretic drugs that we give. Let's talk about the next hormone, aldosterone, which is also part of that same ras pathway. What does aldosterone do? Aldosterone is going to act on a mineralocorticoid receptor in the collecting tubule. So there's two types of cells in the collecting tubule. There's principle cells and then there's intercalated cells. So in the principle cells, essentially what we get is sodium reabsorption and potassium excretion, and then in the alpha intercalated cells is where the hydrogen ion is going to follow. And remember what I said before, sodium gets reabsorbed where sodium goes, water goes. And potassium gets excreted and wherever potassium goes, hydrogen ions go. So we are, aldosterone makes us retain sodium and water and it makes us lose potassium and hydrogen. The next hormone I want to talk about is ADH or vasopressin. What does ADH do? So ADH is interesting because it only acts on water. ADH binds a V2 receptor also in the collecting tubule and it actually cause vesicles containing aquaporin channels to go and bind the membrane on the luminal side of the tubule. So when ADH binds these cells, it's going to cause expression of these aquaporin channels and that is literally a channel for just water to come back in and get absorbed. So remember that aldosterone and angiotensin are going to affect both sodium and water and ADH acts just on the water. And then the final hormone I want to discuss doesn't actually influence sodium and water balance but it affects calcium. That's the hormone I'm thinking of. PTH or parathyroid hormone, this is another one that's very important in the kidney. So parathyroid hormone, what it does is it blocks phosphate reabsorption in the proximal convoluted tubule and in the distal convoluted tubule it promotes calcium reabsorption. Deep breath guys, that was definitely a lot and I know we haven't even gotten to the pharmacology yet. I really think that if you understand renal physiology then the drugs come pretty easily. It's all about understanding what the functions are of each part of the nephron. And so as we get into this next part of the episode I'm going to continue to follow the track to the nephron and we're going to kind of go through it again but this time we're going to address the diuretics kind of in the order of the pathway from the glomerulus to the collecting duct. So let's start over at the beginning of the nephron and start with the proximal convoluted tubule. So what drug, when is the diuretic, acts at the proximal convoluted tubule? Acetazolemide, very good if you remembered that. What's the mechanism of action of acetazolemide? So this is a carbonic and hydrace inhibitor and it acts at the proximal convoluted tubule. Essentially it causes diuresis of bicarb. When would we use that? When would we want to get rid of bicarb? So if you're alkylotic it can be used to treat metabolic alkylosis. It's also used to treat glaucoma, altitude sickness and a condition called pseudotumor cerebrary. Better adverse effects of acetazolemide. So it can cause acidosis, but that's kind of a desired effect, right? Because we want to get rid of the bicarb. It can also cause hypotholemia. It can cause formation of calcium phosphate stones. And there's a specific type of allergy that patients can have, in which case we're not supposed to use acetazolemide. Do you know what allergy I'm thinking of? Cylphyalurgy. We don't want to use acetazolemide in patients who have sulfalurgy. And unfortunately a lot of the diuretics are going to cause sulfalurgy. This next one too. What diuretic is going to act in the loop of Henley? So loop diuretics. Loop diuretics are actually going to act in the thick ascending loop of Henley. What are the names of some common loop diuretics? Can you think of any names? So furocemide or lasex is one of the most common. The brand name lasex actually tells us the half-life of furocemide, which is about six hours. There's furocemide, there's bumetanide, there's torsomide. And all of these are going to kind of have oral forms, as well as IV forms. That is the mechanism of action of loop diuretics. So it's in the name, right? It acts at the thick ascending loop of Henley. And what happens there? Remember, we absorb ions through that co-transporter. So the co-transporter that brings in sodium, potassium, and two molecules of chloride. So it's going to block this co-transporter. And by blocking absorption of sodium, potassium, and chloride, it's actually going to abolish that hypertonicity or that increased gradient that's created in the medulla. And so that prevents water from being reabsorbed in the descending loop. So it essentially prevents reabsorption of water and it causes diuresis. And remember that these are very, very effective diuretics because so much sodium reabsorption happens in the thick ascending loop. And so as a result, we're going to get more water reabsorption as well. So by blocking that co-transporter system, we are performing very effective diuresis. It's also important to know what happens to calcium as a result of administering loop diuretics. Do you know what loop diuretics do to calcium levels? So loop diuretics are actually going to cause you to lose your calcium. There's a sentence in first aid. I don't want you to forget it. Loops, lose calcium. So kind of ingrained that into your mind that loop diuretics are going to make you lose calcium. When would we use loop diuretics? What conditions do we use to treat? Really anything that gives you edema. So remember, these are very effective diuretics, so they're going to help lose fluid very fast. So we give them four patients with heart failure. We give them in patients with cirrhosis, because cirrhosis can make you retain a lot of fluid. If you have pulmonary edema, for example, patients sometimes will get flash pulmonary edema, loop diuretics are very good to quickly remove fluid from the body. What are adverse effects of loop diuretics? So they're not to be given in patients with sulfa allergy. They can also cause auto toxicity, so they can cause deafness. They can cause hypocholemia, hypocholemia. bomagnazemia basically losing your ions, they can cause metabolic alkylosis, think about that contraction alkylosis which we talked about earlier, they can cause gout, and then these can actually damage the kidney itself and cause something called interstitial nephritis. So we really try to avoid giving these in patients with kidney injury. Is there an equivalent of loop diuretics that we can give to patients who have sulfa allergy? Do you guys know of a drug like that? So the answer is yes, which is why I'm asking the question. But the drug is ethycrinic acid. So ethycrinic acid functions as a loop diuretic, but it doesn't cause sulfa allergy. Why don't we use it regularly though? Why don't we just use ethycrinic acid instead of ferosamide, torsamide, and so on? So it can cause worse auto toxicity, which is why we try to give loop diuretics when possible, but if not possible, then we would use ethycrinic acid. Let's continue moving along the kidney. What diuretic is going to act at the distal convoluted tubule? So these drugs are called thiozides. What are the names of some common thiozide diuretics? So hydrochlorothiozide, which has thiozide in the name, then there's also chlorothalodone and metolazone. Okay, hydrochlorothiozide, sometimes abbreviated HCTZ, chlorothalodone, and metolazone. What is the mechanism of the thiozide diuretics? So as we said, these act at the distal convoluted tubule, and they inhibit sodium chloride absorption kind of in the early distal convoluted tubule. Now, remember, less sodium is absorbed in the distal convoluted tubule compared to the loop of Henley, and so these are less effective. They have a smaller, nature-eretic effect as compared to the loop diuretics. So they're still diuretics, but they are not as effective as the loop diuretics. And what about calcium? What do they do to calcium levels? So these drugs are actually going to increase calcium absorption. I'm not going to get into the mechanism of how this happens, but just remember that loop diuretics make you lose calcium, and thiozide diuretics actually increase your calcium absorption. So they have the opposite effect on calcium, and when do we use thiozide diuretics? So remember what I said? They're not as effective diuretics as compared to the loop diuretics, so we really don't use them for patients with indemnitist states like heart failure, cirrhosis, you're not going to see that. More often they're used as anti-hypertensive agents, and they're actually very effective anti-hypertensive agents in certain populations, and they're one of the first drugs that we jump to sometimes to treat high blood pressures. What are adverse effects of thiozides? So these can also cause hypocholemia, hyponatremia, metabolic alkylosis, like the loop diuretics. But then there's an ammonic in first aid, again, which I really love, which is hypergluc G-L-U-C. They cause hyperglycemia, hyper lipidemia, hyper-eurysemia, and hyper-calcemia. So again, they cause hyper-eurysemia, and so we really don't want to give them to patients who have gout. These can also actually cause a sulphur allergy as well, but unfortunately I don't know of an alternative like ethycrinoc acid, which we can use as a substitute for thiozides. So that is the distal convoluted tubule, and let's finally move on to the very last segment that I want to talk about, which is the cortical collecting tubule. What diuretics act here? So these are the diuretics known as potassium sparing diuretics, and there's actually two kinds. They come in two different flavors. So the first type is aldosterone antagonist, and do you guys know the name of the aldosterone antagonists? So there's spironolactone and epleronone, and the mechanism is really in the name. They both have that ONE ending that rhymes with aldosterone, so spironolactone and epleronone are the aldosterone antagonists, and then what's the mechanism of the other type of potassium sparing diuretics? So these ones block the sodium channels in the cortical collecting tubule. And do you guys remember their names of these? Their names are triumterine and amyllaride, and these are not very commonly used, the second type. So why are these drugs as a whole? Why are they called potassium sparing diuretics? What do they do to potassium? So these drugs are not going to cause excretion of potassium. They're actually going to cause reabsorption. So whereas with everything else that we talked about, the loop diuretics, the thizide diuretics, we saw hypocholemia, with these drugs, we're actually going to see hypercholemia. Now when will we want to use these drugs? So if potassium levels are low, for example, if patients have hyper aldosteroneemia, we would want to use spironolactone or a pleironone to block aldosterone. And then a big one to remember is spironolactone. It's actually used in conjunction with fero-semide to treat hepatic ascites. What are adverse effects of these? The potassium sparing diuretics. So hypercholemia and potassium levels are not something to take lightly because potassium is very important for heart rhythms. And so hypercholemia can actually be very dangerous and it can cause cardiac arrhythmias. So we really do not want to take hypercholemia lightly. Now spironolactone actually has a special side effect that we worry about. Do you guys remember what that is? Bironolactone can cause gynecomastia as well as other anti-androgen effects. Now sometimes spironolactones actually used because of the anti-androgen effects. Those are desirable, for example, in patients with polycystic ovarian syndrome. But what if a patient is being treated with spironolactone and the anti-androgen effects are undesired? So let's say you're treating a gentleman and he starts developing gynecomastia. What would you do at that point? You could stop spironolactone and switch him to a pleridone. So excellent job guys. We survived our journey through the nephron twice. The first time we talked about the physiology of the kidney normally, and the second time we kind of talked about the diuretics and what they do. So my big takeaways from this episode, there's only one kind of diuretic that causes acidosis. And do you remember which one that is? Acid is holomide, it causes excretion of bicarb. And then why do all the other diuretics cause alkylosis? So remember we talked about the mechanism of contraction alkylosis. When kidney sees less volumes, it causes the macular denser to activate the renin angiotensin aldosterone system. And angiotensin II was going to act at the proximal convoluted tubule, cause sodium, hydrogenion, and exchange, and bicarbary absorption. And so that is the mechanism of contraction alkylosis. And the other thing is that whenever potassium levels are low, the sodium, potassium exchange during the cortical collecting tubule is actually, interestingly, going to exchange sodium for hydrogen ions instead. And so we lose acid that way as well and get paradoxical acid area. So we're absorbing bicarb in contraction alkylosis and we're releasing hydrogen ions. And so we're going to get alkylosis from all the other diuretics. The other important ion that's really important to know is calcium. So what is the effect of loop diuretics on calcium? They're going to cause hypocalcemia, because remember, loops lose calcium. And what about the thiozides? What do they do? Because hypercalcemia, remember, they cause hyperglycemia, hyperlipidemia, hyperglycemia, as well as hypercalcemia. So then which drug would you want to give loops versus thiozides in a patient who has calcium, phosphate, kidney stones? Loop diuretics, very good, because loops lose calcium. Really excellent job guys. Believe it or not, I'm completely out of questions and I have nothing else to ask you. This can be a really, really tough topic. For me, it was particularly challenging to get used to the specific drug names and remember important details about the side effects. In this episode, I try to give you some of the most important takeaways about these drugs, but remember that learning anything in medicine takes a lot of practice and repetition. So I encourage you to apply these concepts to practice questions or flashcards, whatever works for you. If it helps repeat listening to this episode, really do whatever it takes to get that practice and repetition to kind of drive these concepts home. Thank you so much for listening. This really concludes our episode. If you found this episode helpful or if you're listening to Spoonful of Sugar and you're liking what we're doing, please follow us, like us, subscribe to our podcast, give us a rating or review. If you have questions, comments, concerns, you can always visit our website it's boonfullofsugar.org and post them under the comments for this episode and finally I wish you guys the best of luck with studying remember that SOS doesn't always have to be a cry for help it can also stand for a spoonful of sugar to help the medicine go down