DIP Episode 150 - Comprehensive USMLE Renal Pharmacology 3

Okay, good morning, my name is Divine, I am a resident. This is episode 150 of the Divine Intervention Podcast. And in this episode, this will be episode 150, it will be the third part of the comprehensive USML reno from a college review. I should be done with this and this podcast now one more of the short podcast. The last podcast will probably be like 15 or 20 minutes long. So let's go ahead and jump right into it. So last time we talked about the proximal convoluted tubule. So I think it makes a lot of sense to jump to the next part of the nephra which is the thin descending limb of the loop of Henley. So the thin descending limb of the loop of Henley is permeable to just water, okay, it's impermeable to salt, right? So there is actually a medallary con, and the thing is you may say, okay, how is he just permeable to water? The reasoning behind this is that there is a medallary concentration gradient that is super hypertonic so it causes you to reabsorb water, right? So the thing is if you go ahead and put like a non-reabsorbable sugar like Manateau on the urine side, then you kill that gradient or reabsorption across the medallah, right? Because that non-reabsorbable sugar is automatically active and the medallary concentration gradient is also smutically active. So it's almost like a tug of war between two smutically active substances. So you kill the gradient across the medallah, you don't reabsorb more water in the thin descending limb of the loop of Henley.

So by doing that you have increased urine production, right? But the thing is it's not like when you give people Manateau, it's not like you, you know, just give it straight into the kidneys, no. When you give a person Manateau, the thing that happens that it initially goes to the blood. So because it goes to the blood and it's a non-reabsorbable sugar, you'll smutically draw water into the bloodstream and if that happens, you will increase in transula volume. The problem is people that have certain disorders will have a lot of trouble dealing with this increase in transula volume, especially patients with heart failure, especially patients with heart failure, right? So it can exacerbate a CHF. So Pomenary Adema is a classically tested exam side effect of Manateau, right? So it's actually contraindicated in patients with a history of heart failure. Another thing you can also use Manateau for, right, is you can use it to accurately decrease intracranial pressures, all right?

Although the thing is if they give you like, because I've seen MBME questions where they talk about a person that has like several adema from a stroke or something and then they're asking about the means of decreasing intracranial pressures like the quickest means and then they give you all the answer choices hyperventilates, give Manateau, give us a zolomide, bloody, bloody, bloody, the quickest means this is very high out to know the quickest means of decreasing intracranial pressures acutely is actually to hyperventilate the patient, right? Because if you think about it, when you hyperventilate the patient, the acututention decreases, the acututention decreases in the blood that will cause a viso-construction of the blood vessels that feed the brain, right? So by doing that, you decrease blood flow to the brain and you have a transient decrease. So it's not like, oh I do it and it's a magic pill forever now, you obtain a transient decrease in intracranial pressure. The thing is, it's really not every blood vessel in the brain that has this property, right? The blood vessel, I mean, in fact, let me put it this way, it's not every blood vessel that has this property, right? It's just there are some blood vessels that feed the brain, we have the ability to order a gullet appropriately, right? Because they have like some chemoreceptors and stuff like that that can respond to CO2 levels.

And with this whole business with CO2 levels and other regulation, I think it probably be who's me to, you know, talk about some high-year things here, right? So the thing is, I know also like I guess since we're also talking about Manateau, right? I told you that Manateau is a non-reabsorbable sugar. Well, guess what? Another high-yout non-reabsorbable sugar that you should try to know pretty well for exams is a Serbital and where the Serbital comes from, Serbital actually comes from glucose, right? So glucose is converted to Serbital by an enzyme known as all those reductase, right? And the thing is Serbital is osmoticly active, so it draws water into cells, right? So this is why patients with diabetes, they have a cataracts and you may say, okay, but divine, can't you? I metabolize that Serbital a little further. You can actually, right? So if a cell has this enzyme known as Serbital dehydrogenase, that can convert the Serbital to fructose, right? So you don't get osmotic damage. But the thing is the cells in the eyes and the kidneys they lack Serbital dehydrogenase, so once they convert glucose to Serbital, under the action of all those reductase, the Serbital is stock and you have osmotic damage to those cells. That is literally how diabetes messes up your eyes and kidneys. Now, so sort of talking on the carbon dioxide front, right? So the thing is if, for example, a person has like opioid overdose, right? What happens to their respiratory rate?

I would hope you're telling me that it goes down. Respiratory rate actually decreases, right? So the thing is if a person overdoses an opioid, that essentially causes a respiratory acidosis, right? Because that's carbon dioxide levels go up. And in that respiratory acidosis, right? As the CO2 levels continue to rise, the normally you would say, oh, yeah, if my CO2 is rising, you know, the way my body responds on that normal circumstances is to increase my respiratory drive, to increase my breathing drive. But the thing is opioids. Opioids remember opioids act on mere receptors and those mere receptors are G protein coupled receptors, but they are GI, can inhibitory G protein receptors. So when an opioid binds to those mere receptors, it shuts down because it's an inhibitory G protein coupled receptor. It shuts down the respiratory centers in the medulla, right? And if you shut down those respiratory centers in the medulla, you essentially do not respond appropriately to elevations and carbon dioxide and your respiratory drive remains a depress. But when a person has opioid overdose, you may say, okay, so the thing is that they anything that's supporting their respiratory drive a little, actually believe it or not, there is. And the thing that's actually helping them a little at the is because by being, you know, all zoned out on opioids, right? They have like, they have like a relative kind of hypoxia, right?

So they have like a decrease in partial pressure of oxygen in their blood. So that thing somewhat helps with increasing respiratory drive. So this is why you don't just want to give a person that's overdose on opioids like a supplemental oxygen because that can actually further decrease their respiratory drive. Right? So you really, the primary treatment for opioid overdose is NAR Loxone. Okay? And sometimes you've been trying to trick you on an exam by putting NAR Loxone and NARL tracksone. NARL tracksone is not appropriate, is not appropriate to use opioid overdose before the NARL tracksone kicks in the patient with long dead. So you don't want to do that, right? So let's examine like, okay, like why you don't want to give supplemental oxygen? The thing is, carbon dioxide in the medulla can control respiratory drive, right? But the thing is the peripheral chemoreceptors, right? So carbon dioxide, medulla, contrary respiratory drive, those are more examples of your central chemoreceptors. On the flip side, we also have peripheral chemoreceptors, those peripheral chemoreceptors, they're actually more responsive to oxygen than they are to carbon dioxide. So the thing is, when you give these people that are all long-throwed on opioids, like very high levels of oxygen, so I guess the antithesis to hypoxia is hyperoxia.

If a person becomes hyperoxic and they have like these increased levels of oxygen, they can actually tell you about it that you know that these people have more than enough oxygen on board, so that will further depress the respiratory drives. So that's just something to keep in mind as in the opioid overdose. NARL oxaline is the primary treatment, given supplemental oxygen is not always the smartest, not always the smartest agent, and the thing is the jury is you know kind of out on this, there's like a lot of literature that says, well maybe this may be correct, this may be your own bloody bloody blood, but at least I've you know read a decent amount of literature and this seems to be the mechanism behind the explanation for not giving people supplemental oxygen if they are zoned out on opioids. So since we've done the thinnest sand and limb, the thin, desendant limb of the loop of Henley, let's jump over to the thick ascendant limb of the loop of Henley, right? So the thing is you know we have on the urine side we have like the sodium potassium two chloride transporter, it's a triple transporter, and again it should make sense that it's a triple transporter because sodium has a positive one charge, potassium has a positive one charge, and the two chlorides have individual negative charges, right? So that balances things out. Again remember you almost always want to try to maintain electronic neutrality wherever possible.

So the sodium potassium at two chloride a transporter, it brings sodium potassium and two chloride ions literally into the thick ascendant limb of the set, right? So the thing is when all these things come in, there is actually a transporter that causes potassium to pop back out, right? So it's like almost like the potassium is taking a U-turn, it gets in through the NEK2 CO transporter, and then it pops back out through another transporter that's still again on the epi-cool side, we can call that the urine side, and then that potassium as it comes back out, you know it has a very strong positive charge, so it actually causes calcium and magnesium to be reabsorbed by a paracelular pathway, right? Between those cells that constitute the thick ascendant limb of the loop of Henley, right? So your loop diuretics work at this level, they work by blocking the sodium potassium to chloride transporter because if you block this transporter, you don't really absorb all these ions and they are very smutically active, so that draws water alongside, and then boom, you pee a ton, right? That's how the act is as diuretics. So what are some representative examples of these are sodium potassium to chloride blockers, right? We have drugs like furor somide, right? We have drugs like Bumetanide, we have drugs like Torsomide, and then we have another one known as if a crinic acid.

If a crinic acid is high, you'll know because it's actually the only one of these four drugs I've just mentioned that is not a sulfur drug, so you can actually use it to treat people that have a sulfur allergy and need a diuretic, like a loop diuretic. Only problem is of all the diuretics, if a crinic acid is the most auto-toxic, and if I'm not mistaken, I think also the most nephrotoxic, right? And to be perfectly honest, I think it's actually like super high-yout for purposes of exams to remember the drugs that have this potent combination of being nephrotoxic and auto-toxic. And if I'm not mistaken, if a crinic acid is one of them, another group I will aminog like oxides, right? So drugs like gentamysin, neo-mysin, amy-kysin, tuber-mysin, streptomycin, and then don't forget the drug as this platin, it's a platinum compound. I remember it's one of those things that can cause, you know, it's nephrotoxic, you can prevent that by giving this drug, and known as amy-fostin. And then also, then chomysin also has that, you know, potent side effect combination of nephrotoxic and nephrotoxicity. So you may see divine, why do some drugs seem to like collocalize nephrotoxicity together? The thing is these drugs, the ultimately torch certain transporters that are found both in the kidneys and in the ears, right? So it's like, if you're torching the same transporter, if it's located in different parts of the body, you have the same effect ultimately.

So that's just something I guess to keep at the back of your mind. And one thing you may want to keep in mind, right, is again, like you probably remember this adage that loops loose calcium, right? Everyone has heard of this demonic, and again, it should make sense, right? Because again, if you block that transporter, that potassium is not going in and not coming out to cause a paracelular reabsorption of calcium and magnesium through that fancy shmancy paracelular pathway, right? So people that get take look at the heretics, they become hypo calciumic, right? So look at heretics, probably know the smartest thing in the world for a person that has a history of nephroletiasis like kidney stones, right? Because loops, right? I just told you that they cause hypo calciumia. So they cause less calcium in your blood. Where is that calcium that is supposed to come to your blood stain in? It's stain in the urine, right? So loops cause hypo calciumia and hypercalcury, right? So again, people that have a picture of kidney stones look at heretics, not the smartest idea in the world, right? And then loops also cause hypo magnesiumia, right? And then again, loops because they depress your blood volume, right? By doing that, they will, you know, cause hypo profusion of the afrin material, so you're in a dutance, and our doctrine system is all wrapped up, right?

So you ultimately have hypo kidney, I feel like I beat this, this thing to the, beat this horse a real heart in the first renal pharmacology podcast. So I'm going to keep moving on. And again, remember these things will also cause a metabolic alkalosis, right? Again, don't mix this up with acidosolomy. Acidosolomy, it has the unique combination of causing, you know, a non-anion gap metabolic acidosis, most specifically a type two renal tuberculosis, and hypochyline, okay? So it's not like every other diuretic that says, oh, hypochyline, metabolic alkalosis, acidosolomy, dorsolomythe, the carbonic and hydrism inhibitors different, okay? Causes metabolic acidosis with hypochyline. Okay. Now, remember right there is also a disease that's kind of like similar to taking a lube diuretic, it's called a butter syndrome, it's inherited an odosomal recessive fashion, right? Yeah, just something to keep in mind. So those people have very similar electrolyte abnormalities to represent taking a taking a lube diuretic. And one key thing I think you want to keep at the back of your mind with this sodium potassium or two chloride transporter is that it is actually one of the primary creators of the medallary concentration gradient, right? It creates about 60% of it, right? And the thing is you may say, okay, so the one who creates the other like 40% the thing that actually creates the other like 40% is a urea.

So, EDH actually increases the reabsorption of urea in the nephron, and that urea actually contributes quite powerfully to the medallary concentration gradient. But this sodium potassium two chloride transporter is a big big contributor of the ionic side of the gradient. And again, you may say to find out why would EDH help me reabsorbed urea? Well, again, look at what is EDH's job, right? The job of EDH is to increase the reabsorption of water at the level of the principal cell of the collectin duct. So it should make sense that EDH should contribute to increasing the concentration gradient in the medallary of the nephron so that you have very good, at least you essentially is almost like feeding like rating feet stock so that you're better able to do your job in the future. So really with loop diuretics, the medallary concentration gradient decreases quite significantly, right? So reabsorption of the of water in the nephron is very minimal. So this is actually why that's the mechanism behind loop diuretics being the most powerful diuretics, we have the most powerful diuretics because the prevent the reabsorption of ions, right? So water follows alongside but they also essentially obliterates the medallary concentration gradient because again, that sodium potassium-2 chloride transporter is a big contributor to the medallary concentration gradient. Now, last thing I'll say about loop diuretics and I guess I will just sort of talk about it with thiazides at the same time.

The thing is loop diuretics thiazides, diuretics, you actually both excrete these compounds with transporters. That kind of help you get rid of uric acid, right? So the thing that happens is if the rid of excretion of uric acid actually goes down when a pressing is on a loop or thiazide diuretics, so people that are taking any of these diuretics, they have an increased risk of gout, right? Because uric acid is increasing in the blood, right? And that again raises the risk of like gaudia attacks especially in individuals that are susceptible. Okay, so let's go ahead and jump to the distal convoluted tube. So the thing is if you're looking at the cell, like each of the cells that constitute the distal convoluted tube, on the blood side or again the apical side. Now we have, well, no, the blood side or you can see the basal side, the B's match, you have the sodium potassium ATP spot, right? I guess three sodium cells out of the cell and two potassiums into the cell. On the blood side, you also have something called a sodium calcium exchanger. That sodium calcium exchanger is an example of a secondary active transport mechanism. The thing that happens is that that exchanger, because remember sodium is primarily an extracellular eye, that exchanger brings sodium down its concentration gradient into the cell and you take advantage of that gradient energy of sodium to pump calcium ions out of the, to get calcium ions out of the cell.

Okay, that's why it's called a sodium calcium exchanger. It's essentially a sodium calcium anti-porer. But again, it's a very high yield mbim example of a secondary active transport. And then on the urine side or the apical side, you have a sodium chloride same powder, okay, that brings sodium and chloride into the cell. And then you also have a calcium channel on that urine side, that apical side, that just literally brings in calcium. And the thing is that transporter, its activity is actually increased by parathyroid hormone, right? By parathyroid hormone. So you can already begin to see one of the mechanisms behind parathyroid hormone raising and persons blood calcium levels. It increases the activity of that calcium channel, so that helps you to be absorbing calcium in the nephra. And if that happens, your blood calcium levels go up. Okay, I remember yesterday, I also, either yesterday or two days before. I also mentioned that PTH increases the activity of one alpha hydroxylase, right? So when that happens, you will have increased conversion of calcium dial to calcium trial. And if you have that happening, so you make more active vitamin D, that helps you to reabsorb more calcium and force it in the gut. And I said that this job is essentially done at the level of the proximal confloretubial. So that's just something to keep in mind. So the thing is thiozydioridic state work by blocking this sodium chloride as a simple.

Okay, so if you block the sodium chloride simporter, sodium and chloride does not get reabsorb, they are smutically active, water follows alongside, you'll be out on a lot of blood volume. Okay, but again, remember, thiozydes are not as good as loops, right? Because they do not really obliterate the medallary concentration gradients. That sodium chloride simporter contributes a very limited amount to the medallary concentration gradient. And you'll see the critical importance of understanding these subtle differences between loops on thiozydes as we progress. So what are some examples of our representative of thiozytes? I'm sure a person listening to this podcast is probably yelling out HCTZ hydrochloroapyrizydine in their minds. Here's the deal. Your friends at the MBME, they realize that every human being, even people that are not even in the field of medicine, have memorized the term hydrochlorothyrizyde. So I can almost promise you, it's highly unlikely that you see hydrochlorothyrizyde on your exam. You will likely see the other ones that don't sound like thiozytes, but they are actually thiozytes, right? So drops like a clothalidone, right? Clothalidone is one, another one is metolazone, and then another one is indapamite, okay? So clothalidone metolazone and indapamite are examples of thiozyde diuretics. Now the thing is, remember for the thickest end of the limb of the loop of failure, I said that. Badder syndrome is like taking a is like taking a loop diuretic.

Well, you have another disease here for the distal convoluted tubial gyroman syndrome. Gyroman syndrome is actually like taking a thiozyde diuretic and just like badder syndrome, it's inherited in a lot of more recessive fashion. Believe it or not, they test the mechanism of inheritance of these diseases. Now the thing is, so one thing that the classically test on exams and is commonly thought wrongly actually in many medical curriculums and many people just seem to not understand. So they just memorize it is that thiozyde calls hypercalcemia and hypocalciuria. So thiozyde calls hypercalcemia and hypocalciuria. So you may see, divine. How is this? Like why is this so? Well here's the thing. When you take, so think again, I mentioned two transporters that you find on the basal or the blood side of a DCT cell and two transporters that you find on the epical or the urine side of a DCT cell. I said for the blood side, you have the sodium potassium ATP spot and then you also have the sodium calcium exchanger. On the urine side, I said you have the sodium chloride symporter and then you have a calcium channel. So the thing is, if you take a thiozyde diuretic and you block that sodium chloride symporter, what happens to the intracellular concentration of sodium in a distal convoluted tube yourself? It decreases, right? It decreases. So if that decreases, remember sodium is primary and extracellular ion.

If the intracellular concentration of sodium is decreasing, what happens to the gradient for sodium between the intracellular environment and the extracellular environment of a DCT cell when you take a thiozyde diuretic? I would hope you're telling me that it increases. So let's say for example, there are 10 sodiums on the outside and on the normal circumstances without thiozytes, there are three sodiums on the inside. The gradient is the difference, that's seven. But if you take a thiozyde diuretic and block that sodium chloride symporter and let's say, oh, there's 10 sodiums on the outside, right? And you're actually making it even more, it may go from like 10 to 12 because that sodium is not making its way into the cell. And then because sodium is not making its way into the cell, let's say what you have on the inside is like one sodium, right? You see that gradient has become like 11 or like 10. It's got a much higher. So when that gradient goes higher, it should then make sense that a transporter that depends on the gradient energy of sodium will work even better because you're increasing the gradient. So you're amping up the energy of that gradient-based transporter. And remember, I said a few minutes ago that that sodium calcium exchanger, right, works through a secondary active transport mechanism. So when you take a thiozyde diuretic, you increase the sodium gradient across the membrane of DCT cell.

That actually increases the activity of the sodium calcium exchanger. So in doing that, you will bring more sodiums on from the basal side, right? So from the blood side into the DCT cell and you pump out more calcium, right? So by pumping out more calcium, you will actually lower the intracellular concentration of calcium in a DCT cell. And because you have a calcium channel on the urine side of the DCT cell, right? By lowering that intracellular calcium, you actually encourage more reabsorption of calcium in the urine because the channel just works based on concentration gradients. So this is how thiozyde diuretics can cause hypercalcine and hypocalcura. This is in contra distinction to loop diuretics that cause that cause a hypocalcine and hypercalcura. So make sure you don't mix those up like me. You can already see how confusing it can be. You can see why your friends at the NBM would love to take a gander of this. And again, you don't have to be honest with you. I've never really tried to memorize any of these things because you just make sense if you think about it. Okay. And then, so because thiozytes, they help you reabsorb more calcium from the urine. They're actually pretty good for people that have kidney stones, right? They're actually pretty good for people that have a propensity to form in our kidney stones. Now, the thing is thiozytes, right?

So thiozytes, they cause something called like there's this pneumonia, you've probably memorized that they cause a hyperglucle. Right? So they cause like hyperglycemia, hyperlipedemia, hyperheorecemia, hypercalcemia. We've already talked about the mechanisms behind the hypercalcemia, right? And we've talked about the mechanism behind the hyperheorecemia because like, okay, they compete for the same transporters that excrete a uric acid in the nephrine. So those two make sense. So I've always wondered as a med student like, okay, well, we're those this hyperglycemia and hyperlipedemia comfort. And with some diggin, I was actually able to find some explanation for this. But to understand the explanation for this, we need to take a small step back and talk about talk about some endocrinology, probably like a one minute lecture on endocrinology. So the thing is, I'm going to end this lecture on the thiozites. I don't want this to go on for too long. So the thing is, in the pancreas, okay, let me just lay it out this way. Phyzidei-radix have been known to open up potassium channels, okay? Phyzidei-radix, the apotassium channel openers. Remember that's the apotassium channel openers. And if you think about it, if you open up potassium channels, right? That will cause potassium to flow down its concentration, gradient from inside of a cell to outside of a cell. That will cause cellular hyper polarization, right?

So ultimately, that can essentially cause a cell, you know, to be like a little less active because it's not a deep polarizing, it's not deep polarizing very well. And the thing is, this is actually one of the reasons why phyazides actually decrease systemic muscle resistance, because by causing these like cellular hyper polarization, the cell can relax and you can have like visual, like smooth muscle relaxation and visual dilation. And this is why, classically, you're told to, you know, maybe avoid taking NSAIDS with phyazides, because when you do that, you're essentially taking, you make less persta-glandins. Remember NSAIDS inhibits cyclopsis genies. So you make less persta-glandins and persta-glandins are visual dilators. So by giving an NSAID, you're essentially counteracting the visual dilute effect of a phyazide, okay? You're countering that visual dilute effect of a phyazide with essentially the visual constrictive effect of an NSAID. And then why, so how does this open-inputation channels cause in cellular hyperpolarization? How does it cling to this hyperglycemia hyperlipidemia? Here's the thing. The thing is in the pancreas, right? We know that glucose is converted to glucose 6-phosphate with glucose kinase. And then we know that after that, you know, you go down like policies, you make a crap ton of ATP, that ATP in the pancreatic eyelets of longer hands closes potassium channels. Those increased levels of ATP be close potassium channels.

When you close those potassium channels, well, potassium will not be able to get out of the cell anymore. And if it doesn't get out of the cell, the membrane potential will increase, and that pancreatic eyelets cell will depolarize. When it depolarizes, right? So the voltage changes, so a voltage-gated calcium channel will become activated. Coussium will come into the cell and then you ultimately squared out that insulin. That is really how you make insulin from the pancreatic, from the beta cells that constitutes the part of the pancreatic eyelets of longer hands. So you can already begin to imagine that if you hyperpolarize these cells, right? When you take a thier side by like opening up those potassium channels, then you'll never fire as a cell, right? Because again, you're essentially contracting that ATP blocking the potassium channel business, right? So you open up those potassium channels, the cell doesn't depolarize it, it stays hyperpolarized. So you have a decreased release of insulin, right? So think about it. When you have decreased release of insulin, you can already begin to find that, oh, you have trouble handling your blood glucose levels, right? So you get hyperdlycemic and then remember insulin actually helps you actually mix your deep sites, take up triglycerides to study them as fat, right?

So the thing is if you have again decreased release of insulin, you're not encouraging your at deep sites to really have to store your lipid as fat, like as fat, so you end up having like high levels of lipid in your bloodstream, okay? So that is the mechanism behind the hyperdlycemia and the hyperlipidemia that you'll find in with thiazideiorethics is just a direct application of biochemistry and some cell physiology there. So, you know, those are again big things you want to keep at the back of your mind with with the thiazides. Now, the last thing you want to keep at the back of your mind with thiazides, I think I may have said earlier that if you're comparing luptiorethics and thiazideiorethics, the thiazideiorethics actually have the stronger association with hyponitrimia, okay? If you're comparing luptiorethics and thiazideiorethics, because some of you may be thinking, oh, luptiorethics, you know, they're the most powerful diuretic, so that means because you're getting rid of all the sodium, they must be like the, they must be associated with a higher incidence of a hyponitrimia, that's actually not true. Your thiazides actually are associated with a higher risk of a of hyponitrimia, so let me explain one. Right? So, the thing is we know the thiazides, right? You plug that sodium chloride in order you find that the distal converter is trivial. When you do that, you get hyponitrimia, right? Because you're literally dumping sodium in the urine. So, why are thiazides?

Why do they have this stronger association with hyponitrimia? Well, the thing is, when you take a thiazide, you don't mean sodium in the urine, well, you don't necessarily change the medallary concentration gradient. The medallary concentration gradient is still alive and well, because again, remember, I told you that the sodium potassium two-chloride transporter, that you find that the level of the thickest sendent lamp of the loop of family plays a primary role in this process. So, the thing is, when people take thiazides, right, they become volume down, right? Because you're literally thinking a diuretic. But, so, when you become volume down already mentioned that the activity of your reading and your tensile endosterone system goes up. Remember, one of the jobs of endotensin two is to go to the super-optic nucleus of the hypothalamus for its release of the H. So, if all these things happen, that's not really awesome, right? Because that you are losing sodium in the urine, but guess what? Your medallary concentration gradient is still intact. So, when you're reading and your tensile endosterone system comes online, you will avidly reabsorb eternal water in the nephron because again, the gradient is still there, right? So, at the end of the day, you're losing sodium where you're gaining water back. When you have these two things happening or hand in hand, you can already begin to see how hypoenitriemia may be something that may happen.

A person taking a thyrside may have a pretty high risk of developing. And this is actually something that's very relevant clinically because it's actually a fairly popular side effect in people taking a thyrside at diuretics. If you're contrasting this with the loops, you don't have any problems because in loops, yes, you're losing sodium, but your medallary concentration gradient is being depleted, right? So, you are not, even if you're running and your tensile endosterone system comes back online. There's literally no medallary concentration gradient, or you can see there's a severely hampered medallary concentration gradient for them to reabsorb a water. So, that's why you have much less risk of hypoenitriemia with loops in comparison with thyrside diuretics. So, I think I'm going to go ahead and stop here. There'll be one last podcast. I suspect it will probably be like 15, 20 minutes long and then it will be done with Renault from ecology. And as I mentioned at the end of every podcast, I do offer one on one tutoring for many exams. So, step one, two CK, two CES, step three. And then I offer tutoring for pre clinical med school exams and 30 year clerkship shop exams. I have, and I also do this thing. I call, I guess, longitudinal tutoring where I work with like a first, second, or 30-year med student, where tutor you longitudinally with like your courses, your shelf exams. But at the same time, I tutor you for the USME Lis with each of your blocks.

So, see for example, the first year as you're taking like a self-e physiology block, I'll tutor you for like your self-e physiology like med school exam. But at the same time, I'll also teach you like self-e physiology as relevant to the USME Lis step one. And I'll also expose you to a host of like, you know, like question styles and testicant strategies that will just make you super well prepared when you hit your dedicated period. So, I do this with like first second year med students and also 30 year med students. 30 med students is more like tutoring you for like your clerkship exams. But again, at the same time, I'll prepare you very strongly for step two CK. So, most of these people, they have like very short dedicated periods, they end up like absolutely crushing their exams. And then if you have like a college body that needs a tutoring for like Gen CAM, O-CAM, Physics, Bio CAM, Histology and Physiology, I'd offer one on one tutoring for those. And if you're a medicine resident, you need tutoring for like the internal medicine training exam. I tutor the ton of people for the IT Es that we held earlier this month and late last month. Or if you're a medicine resident, you need tutoring for the ABIM board exam. I'd offer one on one tutoring for that. And then if you're a medicine applying to residency, so like an ERAS application or a college student applying to a medical school, so like an AMCA application, I'd offer like one on one advice in for that.

So like personal statement writing, help with like letters of recommendation, editing your application, more interviews, I'd offer all those things. So, either send me an email or a message through the website or you can send me a quick email, divine intervention podcasts with an SAD end at gmail.com. So I do hope you've gotten something from this podcast. Have a wonderful rest of your and I will see you in the next podcast. God bless you. Thank you.

They block the Na+/K+/2 Cl- cotransporter in the thick ascending limb of the Loop of Henle.

The Na-Cl symporter; it is located in the distal convoluted tubule (DCT).

Hyperventilating the patient, which acutely decreases PaCO2 and causes cerebral vasoconstriction.

High levels of oxygen (hyperoxia) can further depress the respiratory drive by affecting peripheral chemoreceptors.

Loop diuretics cause hypocalcemia/hypercalciuria; Thiazides cause hypercalcemia/hypocalciuria.

Serbitol dehydrogenase (lack of this enzyme leads to sorbitol accumulation).

Hypercalcemia/Hypocalciuria. Blocking Na-Cl symporter increases intracellular Na+ gradient, enhancing the secondary active transport of Ca2+ via the Na+/Ca+ exchanger in the DCT.

Thiazide diuretics. This occurs because volume depletion activates RAAS, and since thiazides do not obliterate the medullary gradient, water reabsorption continues despite sodium wasting.

Sodium (Na+), Potassium (K+), and two Chloride ions (2 Cl-). This is the NKCC2 cotransporter.

Furosemide, Bumetanide, Torasemide.

Cataracts and kidney damage (osmotic nephropathy), due to the lack of serbitol dehydrogenase.

Thiazides cause cellular hyperpolarization by opening K+ channels, leading to vasodilation. Combining them with NSAI Ds (which inhibit prostaglandins) counteracts this vasodilatory effect, increasing the risk of renal vasoconstriction.

Hypercalcemia/Hypocalciuria. Blocking Na-Cl symporter increases intracellular Na+ gradient, enhancing the secondary active transport of Ca2+ via the Na+/Ca+ exchanger in the DCT.

Thiazide diuretics. This occurs because volume depletion activates RAAS, and since thiazides do not obliterate the medullary gradient, water reabsorption continues despite sodium wasting.

Sodium (Na+), Potassium (K+), and two Chloride ions (2 Cl-). This is the NKCC2 cotransporter.

Furosemide, Bumetanide, Torasemide.

Cataracts and kidney damage (osmotic nephropathy), due to the lack of serbitol dehydrogenase.

Thiazides cause cellular hyperpolarization by opening K+ channels, leading to vasodilation. Combining them with NSAI Ds (which inhibit prostaglandins) counteracts this vasodilatory effect, increasing the risk of renal vasoconstriction.