DIP Episode 72 - Endocrine Physiology and Pharmacology Part 1

Okay, welcome. My name is Divine. I am a PGY Wanna Transitional Year resident going into radiology. This will be the 70th second episode of the Divine Intervention Podcasts. I'm going to say that this is going to be a podcast that's related to endocrineology and endocrine from ecology. And this again will likely be a two-part episode because I'm actually going to spend some time in the very beginning to talk about some physiology which will make the pharmacology a lot easier to understand. And basically in today's podcast I'm going to cover calcium from ecology and physiology. I'm going to cover thyroid from ecology and physiology. And then I'll start on the drugs that I used to treat diabetes. I will go all the way to met forming. The other drugs I'll cover them in the next podcast and then also the adrenal drugs and what not. So let's begin. So let's talk about calcium physiology to start with. So the thing is remember that PTH is like the big hormone that controls on your blood calcium levels, especially it brings up your blood calcium levels. So where does PTH come from? PTH comes from the parathetic gland. And remember the parathetic gland actually has a calcium sensing receptor. Okay, has a calcium sensing receptor. If it senses low levels of calcium in the serum, you will secret more PTH if it senses high levels of calcium in the serum, you'll secret less PTH. Now PTH does a ton of stuff, right?

I said that in general PTH's job is to increase your blood calcium levels and to decrease your blood phosphate levels, right? So that's why PTH is occasionally known as the phosphate trashing hormone. So how does PTH go about accomplishing these objectives? The thing is PTH, right? It increases calcium reabsorption in the nephron. That's one thing it does. Another thing PTH does is that it activates. And actually if you're thinking about PTH increasing calcium reabsorption in the nephron, it's actually very high yield to know that PTH does this by activating a calcium channel that is found at the distal convoluted tube. Okay? In fact, if I'm not mistaken, I believe I talked about that transporter in the context of how phyazides can cause hypercalcemia. I believe I described that potential like mechanism behind that in my renal review. That's like some episodes back. And then PTH, right? A trashes phosphate. And the way PTH has the ability to trash phosphate is by inhibiting that sodium phosphate, um, same powder that you find at the proximal convoluted tube. That same powder uses the sodium gradient. So sodium is going from a high concentration outside the cell to inside the cell. And then it uses secondary active transport to bring phosphate in. That sodium phosphate same powder at the proximal convoluted tube is inhibited by PTH. Okay? So that's the mechanism behind PTH helping you trash phosphate. Another thing PTH does is that it activates one of our hydroxylates. Okay?

One of our hydroxylates you find it in the in the kidneys. And the job of one of our hydroxylates is to take 25 hydroxyl vitamin D, also known as calcium diol that's made in the liver and converts it to 125 dihydroxyl vitamin D. That's what's known as calcium trial. Calcy trial is the active form of vitamin D. And then calcium trial increases the reabsorption of calcium and phosphate in the gut. Right? And the thing is PTH may say, oh, divine. How does PTH raise your blood calcium levels? I already talked about how it increases reabsorption at the level of the kidneys, right? At the distal convoluted tubule. I also talked about how it activates vitamin D so that you increase calcium and phosphate reabsorption in the gut. But one of the thing vitamin D does, I mean one of the thing PTH does is that it activates directly activates your osteoclasts so that you can resort bone. And again, also is your blood calcium levels. But how does PTH go about this job? Right? Basically, the way PTH does this is that it actually activates osteoblasts and then those osteoblasts proceed to activate osteoclasts. So how does that process work? The way that process works is that you activate the osteoblasts with PTH. And then when those osteoblasts are activated, they release a ton of the release something known as rank ligand, okay? Rank ligand. That rank ligand has the ability to bind to a receptor found on the surface of osteoclasts known as the rank receptor.

When rank ligand binds to that rank receptor, that activates osteoclasts to go ahead and resort bone. So think about it. If you're a person that has osteoporosis, you probably don't want rank ligand to ever see the rank receptor that you find on osteoclasts. So they don't resolve your bone more and get into even more trouble. So the way that your body prevents that, I mean, the way you can pharmacologically prevent that is with a drug known as a de-nossium map. De-nossium map is a drug I'll talk about shortly. I guess I'm talking about it now, but it's a rank like it's a monoclonal antibody against a rank ligand. So it binds up the rank ligand so that you never have the ability to have rank ligand interacting with the rank receptor. And then another physiology time here, right? So you may notice that women have a low, like very low risk of osteoporosis before the age of 50, but they have a very high risk of osteoporosis after the age of 50. The thing is, in women, prior to the age of 50, you're producing a ton of estrogen from your ovaries. Well, that estrogen increases the synthesis of a protein known as osteopor tegrin. Okay? Osteopor tegrin is a protein that whose synthesis is increased by estrogen. So if you're a pre-menopausal, you have a ton of estrogen, you have a ton of osteopor tegrin. It so happens that osteopor tegrin actually binds up rank ligand. So that prevents the interaction between rank ligand and the rank receptor.

And if you don't have that interaction, you'll not have bone res option. So that's potentially the mechanism behind pre-menopausal women having a lower risk of osteoporosis, right? And obviously, if you're an obese post-menopausal female, you also have a lower risk of osteoporosis, okay? Very likely by this mechanism as well. So actually being obese, right? Because you are more weight-bearing, it actually decreases your risk of osteoporosis. But being obese actually increases your risk of osteoarthritis, okay? Just one of those weird things you want to keep at the back of your mind. And classically on the USM Ls, they can give you a question about an oryxic patient. Patients with anorexia nervosa, they actually have an increased risk of like early onset of osteoporosis. Just one of those weird things that they test on the exams, I want to keep at the back of your mind. So let's talk about a few diseases, right? And like your calcium balance in those diseases, right? So let's assume a person has liver disease, right? So think about this. If a person has liver disease, they are not making 25 hydroxy vitamin D, they are not making calcium dial, right? So they basically have no feet stock for the production of calcium trial. And if you don't make calcium trial, then you will not reabsorb calcium and phosphate in the gut. So you'll be hypocalcymic. So your blood calcium levels will be low. If your blood calcium is low, right, that should raise your PTH.

Well, if your PTH goes up, then what do you think will happen to your phosphate levels? Your phosphate levels will actually go down, okay? Because your kidneys are working just fine, right? So as your PTH levels go up, you'll have hypophosphatemia because you are appropriately trashing the phosphate because your PTH is high. Contrast that with a person that has kidney disease, right? So if a person's kidney disease, your liver is working just fine, right? So that liver makes one alpha, I mean, that liver makes calcium dial, right? So like the 25 hydroxy vitamin D, but there is no one alpha hydroxylase to work on that calcium dial to make it into active vitamin D, which is known as calcium trial. So because again, you're not making active vitamin D, your calcium and phosphate will not be reabsorbed in the gut. So you have hypocalcemia. So your blood calcium levels will be low in kidney disease. And if your blood calcium levels are low, guess what will happen to your PTH? It will go high, right? So your P2 H will go up. But this is where you need to be careful. Yes, PTH is known as the phosphate trashing hormone. So yes, if your PTH is high, your phosphate should be low, right? But the thing is, if you have kidney disease, your kidney is the organ that helps you trash phosphate. So if you have kidney disease, even if your PTH level is high, your phosphate level will actually be high as well, right? Because you cannot appropriately trash that phosphate.

So kidney disease and liver disease are both causes of secondary hyperparthyroidism, okay? They are both causes of secondary hyperparthyroidism. But the way you differentiate between kidney disease as the cause of secondary hyperparthyroidism and liver disease as the cause of secondary hyperparthyroidism is to look at the levels of phosphate because your calcium is low in both, your PTH is high in both. What your phosphate will be high in kidney disease as a cause of secondary hyperparthyroidism because you cannot appropriately trash the phosphate. But in liver disease, your phosphate will be low because your kidneys are working so you will appropriately trash the phosphate when your PTH is high. Make sure that makes sense to it's a very high-yield concept to know for basically your medical future. I mean, these are things that come up on exams fairly frequently. And then another disease I'll talk about is like a person has like scrimal cell cancer, right? Of the lung. In fact, not just for the lung, but most scrimal cell cancers produce something known as PTH RIP, right? So parathyroid hormone, relief peptide. So the thing that PTH RIP does is basically acts like PTH, right? So the thing is, in scrimal cell cancer of the lung, right? Where a person is making PTH relief peptide, what do you think will be trove their blood calcium levels? Well, I'm hoping your thing will be high, right? Because again, PTH RIP will do what PTH does, so your blood calcium levels will be high.

And if your blood calcium levels are high, will be trove your blood PTH. Your PTH will go down. Remember, PTH is not the same thing as PTH RIP. So PTH levels actually low in patients that have scrimal cell lung cancer, producing PTH RIP in a perineoplastic phenomenon, okay? And because those people have low PTH, where all the trove are phosphate, what do you think? Their phosphate will actually be high, exactly. Their phosphate will be high, okay? Their phosphate will be high. So it's just one of those weird things that you need to keep at sorry, their phosphate will be low, whoops, their phosphate will be low because PTH RIP works like PTH, right? So you will trash phosphate because your kidneys are working fine, so your blood phosphate levels will be low. Now, let's assume a person has a disease known as familial. You should never get this wrong on an example, because literally the answer is in the term. What assume a person has this disease known as familial, hypocalcyoric, hypercalcine, right? What do you think will be trove their blood calcium levels? It will actually be high, okay? But because they have, I mean, the path of physiology of FHH basically involves like a sense in defect in the calcium sense in receptor, right? So your calcium sense in receptor, even if you have like high blood calcium levels, it doesn't understand that you should decrease the release of PTH. So your PTH levels are really high.

So your PTH will be high in FHH, and your blood calcium levels will be high as well, okay? And again, because PTH is a phosphate trash in hormone, your blood phosphate will be low. So, what if a person has primary hyperparthyroidism, right? So primary hyperparthyroidism, primary hyperparthyroidism, right? Arise this because you have a parathyroid adenoma, right? That's causing that's basically have this adenoma that's autonomously secreting a ton of PTH. Well, if that is the case, your PTH will be high. So because your PTH is high, your calcium will be high, right? Your blood calcium will be high. If your blood calcium is high, right? Because you also again have high PTH, your phosphate will be low, okay? So let's think about this for a second. So you may see divine. How do I tell because I mean think about this for a second. In primary hyperparthyroidism, your PTH is high, your blood calcium is high, your blood phosphate is low. Well, guess what? In familial hypocoucury, hypercalcemia, your PTH is also high because your calcium sensor receptor is not working, your blood calcium is also high, your blood phosphate is also low. So let me see, divine. How do I differentiate between these two? That's where you need to look at the urinary calcium, okay? If a person has primary hyperparthyroidism, okay? A person has primary hyperparthyroidism because they have a ton of calcium in their blood, they'll have a ton of calcium in the urine, okay?

And because again, the calcium sensor receptors are working just fine, right? They're really, this is a lot of calcium. Let's get rid of some of it in the urine, right? So those people actually have high urinary calcium. Confests that would people that have FH who cannot appropriately sense that they have hypercalcemia on body. In the kidneys, they're because your normal response to hypercalcemia is to waste more calcium in the urine. But if your calcium sensor receptor is not working, then that normal response does not kick in too gear. So actually, instead of wasting calcium in the urine, you reabsorbed more as much calcium as possible from the urine in FH. So those people actually have low urinary calcium. Again, that's super, super high yield to know for example. So let's just sort of summarize all of this. If a person has primary hyperparthyroidism, their PTH will be high, their blood calcium will be high, their blood phosphate will be low, their urinary calcium will be high. If a person has FH, so familial, high, poor, calcium, your REC, hypercalcemia, their PTH will be high because their calcium sensor receptor doesn't know when to slow down on encouraging the release of PTH. So their PTH is high because their PTH is high, their calcium is high because their PTH is high, their phosphate is low, but because their calcium receptor doesn't work right, they actually increase the absorption of calcium in the urine. So they have low urinary calcium.

If a person has a squamous cell lung cancer that is secreting PTH Rp in a panoplastic fashion, those people's PTH Rp will be high and because their PTH Rp will be high, you'll get a PTH response. The blood calcium will be high, the blood phosphate will be low. And actually because your blood calcium is high, right, and because your kidneys are working fine, your calcium sensor receptors working fine, your urinary calcium will also be high, okay, in PTH Rp panoplastic business with squamous cell lung cancer. But these people that have squamous cell lung cancer, they will actually have low PTH, okay, because that hypercalcemia will appropriately suppress the release of PTH from those people's native parathiric glands, okay, PTH Rp will be high, but PTH itself will be low in those people. And then in secondary hyperparthyroidism that arises from kidney disease, your PTH, because you don't have one alpha hydroxylase working, you're not making an active vitamin D, so your Bihapocalcemic, so your blood calcium will be low because your blood calcium is low, your PTH will be high. Yes, your PTH is high, but your phosphate will actually be high because your kidneys are not working, so you do not appropriately trash the phosphate. Contrast that would liver disease as a cause of secondary hyperparthyroidism.

The person's, if you have liver disease, you're not making calcium dial, so if you're not making calcium dial, there's no feedstock for calcium trial, so there's no feedstock for active vitamin D, so you will not reabsorb calcium and phosphate in the gut, so your blood calcium will be low, if your blood calcium is low, the PTH will be high, because your kidneys are working right, you will appropriately trash phosphate, so your phosphate will be low, okay, very high yield to know that. And I guess we can also talk about tertiary hyperparthyroidism. And now you see divine, where is the pharmacology here? I promise you, like, if you understand all this, like all the stuff I'm saying is super, super high yield. I will very likely have like a dedicated endocrine review podcast, but I just thought I should just go ahead and talk about these here, cause these things are just things that confuse people a lot, and the repetition always helps. So let's talk about tertiary hyperparthyroidism, right? So the classic scenario for tertiary hyperparthyroidism on MBM Es is that they'll talk about a patient that has that has had like chronic kidney disease, right? I told you that chronic kidney disease causes secondary hyperparthyroidism, right? But let's assume those people then get a kidney transplant, right? If you get a kidney transplant, one alpha hydroxylysis is back on board, right? So your calcium physiology should work right.

So if your kidney comes back on board, you're making an active vitamin D, you're like, oh, okay, so my calcium should be fine, my PTA should return back to normal levels and all that stuff, but that may not be the case. So think about it, right? So just sort of think of like habit you have. If you've done something consistently for like decades and decades and decades and decades, right? It's hard for a person to just suddenly just stop doing that thing, right? So I sort of think of that in the context of the pathyroid for a person that has had chronic kidney disease for years and your parathyroid glands are used to make an autonomous calcium, I mean, a ton of PTA, right? Even if your kidneys come back online, the transplant that kidney is at least in this case, your parathyroid glands are no longer responsive to normal signals. So in tertiary hyperparthyroidism, your PTA is high, okay? If your PTA is high, guess what? Your calcium will be high. If your calcium is high, guess what? Your first feed will be low because now you have good kidneys so you can appropriately trash the first feed. And then if your first feed is low, what do you think your urinary calcium will also be in tertiary hyperparthyroidism? Your urinary calcium will be high. So basically, tertiary hyperparthyroidism has the same lab values as primary hyperparthyroidism, okay?

Although the treatment and the thing is usually if you read the question carefully, the history will be able to tell you that, oh, this is what I'm dealing with, right? And the thing is in terms of primary hyperparthyroidism, usually the way you treat that is to remove the parathyroid at a normal, right? And the problem is soft for those people. However, if a person has tertiary hyperparthyroidism, you actually do not remove the parathyroid at like, it's, I'll say in general, people that have tertiary hyperparthyroidism don't necessarily have a parathyroid at a normal as the cause of that tertiary hyperparthyroidism. So instead of removing like some at a normal, no, that's not what you do for tertiary hyperparthyroidism. In tertiary hyperparthyroidism, you actually remove three and a half parathyroid glands. I know you're like divine three and a half. Yes, you read me right. You remove three and a half parathyroid glands because usually you have hyperplasia of the entire parathyroid gland, like the four parathyroid glands in the setting of tertiary hyperparthyroidism and also in chronic kidney disease. Now that I mentioned that one other good idea that came to my mind is this is again tricky, like common tricky exam situation that you see on the USML is right. So if a person has primary hyperparthyroidism usually, usually it arises in the setting of a parathyroid at a normal.

So this is actually very high, you know, the most common cause, very high of the most common cause of primary hyperparthyroidism is a parathyroid at a normal. However, in patients that have MEN1 syndrome, in patients that have, in fact, any of the MEN's syndrome that present with primary hyperparthyroidism, the most common cause of primary hyperparthyroidism in patients with MEN syndrome is parathyroid hyperplasia, okay, not parathyroid at a normal. Parathyroid at a normal occurs with primary hyperparthyroidism in the general population, okay. But parathyroid hyperplasia is the most common cause of primary hyperparthyroidism in patients with MEN syndrome. And then the last thing I will say before I sort of begin to delve into the pharmacology is that in tertiary hyperparthyroidism, I said you can remove 3.5 parathyroid glands. One other thing you can do is you can try to modulate the activity of the calcium sensing receptor. And the way you can do that is with a drug known as CINACALSET. CINACALSET is a calcium sensing receptor modulator that can actually help in the treatment of tertiary hyperparthyroidism. It basically sort of tells the calcium sensing receptor that calcium is a little too high. Let's stop the sort of dumb down on the release of PTH. Okay, so let's move on then. Sorry, one more thing, one more thing. Sorry, all these high-odideas are coming to my mind now.

So if a person in the hospital has hypercalcemia, the most common cause is malignancy, okay, just one of those things you want to keep at the back of your mind. Okay, so back to the real world, although it could, I will say I mean, yeah, think about hypercalcemia malignancy, but I feel like many people have seen in the hospital, at least being an intern, with hypercalcemia was from chronic kidney disease. No, no, no, no. You know what? Just scratch that. Just forget that I said that. Think about malignancy. I think I was thinking in the wrong direction there. Okay, so back to this. So just again, a few key conditions, like osteoporosis, remember, your calcium balance will be normal. If a person has like a Pajet's disease of the bone, right, your calcium will be normal. If basically all your calcium labs are normal with the exception of outforce, outforce will be elevated. And then I already talked about MEN1, right, remember parapanet, and MEN1, those people have P2, T3 adenomas, right? So most common leads are prolactinoma. They will also have parathyroid hyperplasia, okay, not adenoma parathyroid hyperplasia. And then they can have like pancreatic neuroendocrine tumors, so they can have like gastrinomers that present as the Zolongelicin syndrome for that you want to give a PPI, right? Or they can have Vipomas.

Remember, Vipomas present as the WDHA syndrome, where people have like watery diarrhea, hypochylemia and echlohedria, for that you want to go ahead and give up your tight. They can have insulinomas, remembering insulinomas are associated with weepostriate, right, of like hypochylemia, symptoms of hypochylemia, and then relief of those symptoms with the administration of glucose, okay? For insulinomas, you want to give diazoxide, remember diazoxide is a potassium channel opener, right? Because if you remember, the way you see crediansulin in the first place is that glucose will come into pancreatic beta-iletsel. As that glucose comes in its converted to glucose 6-phosphate by hopefully you're not saying hexokinism or you're saying glucose kinase, and then that glucose 6-phosphate helps you make ATP, and then that ATP goes and closes up an ATP-dependent potassium channel, and then that cell depolarizes, and then when the cell depolarizes, you squared out insulin, okay? So if you open up that potassium channel with diazoxide, then the cell will not depolarize. If the cell does not depolarize, then guess what? You will not release insulin, okay? So diazoxide cannot really be used to treat insulinomas, but if you remember from the podcast from yesterday, right? So episode 71, where I talked about onc from a college, I said that there is an itrosouria known as streptozosin, streptozosin is an alkalinity, basically it's an alkalinity agent, right?

It's also used for the treatment of insulinomas, it is very toxic as a drug to the pancreatic beta-iletsel, so you can also be used in the treatment of insulinomas. And then another pancreatic neuroendocrine tumor that may be observed in MEN1 is a glucagonoma, right? So basically, they will give you a person that has like onerally, like relentless diabetes and skin rash, right? The boss phrase for that skin rash is a macrolitic migratory arithema, okay? And then in MEN2 A, those people have fibromosytomas, remember, fios, they present with like the episodic headache and hypertension, usually in a younger person, and remember that fiochromosytomas, right? They don't chop in the anterior medias thinum, they chop in the posterior medias thinum, because they are neuro-based tumor, right? And remember that fios will be derived from neurocress cells. Those are very nice embryology details that could be tested on step one. And then remember that in MEN2 A, those people can also get medallary thyroid cancer, right? And remember the tumor marker from medallary thyroid cancer is calcetone, right? And calcetone, what does calcetone induce your blood calcium levels? Well, remember that calcetone in calcetones down your blood calcium levels, okay? So hypocalcemia may actually be a presentation of MEN2 A, okay? And then in MEN2 A, you can also observe a parathyroid hyperplegia.

In fact, I'll tell you this, patients that have MEN2 A or 2 B, they need to get a prophylactic thyroidectomy, because the chances of getting a medallary thyroid cancer is like 100%. Like, it's not a matter of if they will get medallary thyroid cancer, it's just a matter of when, okay? So those patients almost always should recommend a total thyroidectomy for those people. And then MEN2 B, right? Those people again still have the fiochromocytomas, they still have the medallary thyroid cancers, they also have like new cochonuromas, right? And also like a marphanoid body happiness, right? Don't forget that other things that can cause a marphanoid body habitals include diseases like homocystinuria, usually that's like a marphanoid body habitals with intellectual disability, and then Marphan syndrome where they have a marphanoid body habitals but without intellectual disability, right? Just one of those weird things you want to keep in mind for you exam. Okay, and hypocalcemia, right? Again, hypocalcemia, so again, NAM actually starting from ecology. So hypocalcemia, right? Classically, arises from chronic kidney, can arise from like chronic kidney disease already explained the mechanism. If a person has hypocalcemia from chronic kidney disease, right? You want to go ahead and give, like, you know, like give them calcium supplementation, give them calcium trial, right? So calcium trial is 125 dihydroxy vitamin D, right? That'll fix their problem, okay? Hypocalcemia, right?

Again, like I said, if a person has like medallary thyroid cancer, that's a secretive autonocalcytony, those people could also have a hypocalcemia, right? Because calcium toning, calcium tones down your blood calcium levels. Now, if a person has hypocalcemia, right? How do you try to hypocalcemia? You can give calcium toning, calcium toning certainly helps. Another thing you can do is you can actually give a furor some height, furor some height, right? Remember, loops loose calcium, right? Because they block that sodium potassium two chloride transporter at the level of the thickest sendin limb of the loop of Helene, right? So if you blocked that transporter, right? You will not reabsorb those positive ions. And when you don't reabsorb those positive ions, you will not extrude, you will not extrude potassium that will then help you paracelularly reabsorb calcium and magnesium, okay? So you actually lose a lot of calcium in your urine if you're on a loop diuretic like furor some height, okay? So furor some height can actually help quite a bit in a hypercalcemia. And then bisfoss phonets, right, can be used for the treatment of hypercalcemia. The thing is bisfoss phonets, they cause hipoptosis of osteoclasts, right? So you don't break down your bone anymore. And the thing is you can actually use bisfoss phonets to treat like Pajet's disease, right?

So Pajet's disease, classic example presentation, will be like an old person that has like hot smoth feeling well and they have like crinionic deficits, like they have like decreased hearing and all that stuff. For those people, think about giving them bisfoss phonets. Bisfoss phonets are the drug of choice for the treatment of Pajet's disease. And also please don't forget that you can, I mean in Pajet's disease, those people can have something known as a high output heart failure, right? Because those people's bones become hypervascular. So that causes like a functional decrease in systemic vascular resistance. So that then ultimately cause a high output heart failure. So of those again, these are things you want to keep in mind for your example. Now, if a person has like hypercalcemia of malignancy, right? So from like PTHRP, pern, your plastic phenomenon or from multiple myeloma, for example, for those people, the way you treat that hypercalcemia of malignancy is actually to go ahead and give this phosphonets. Although I will say that in multiple myeloma, that hypercalcemia that they get is not necessarily from PTHRP. It's actually more from interlooking one that's made by those by those plasma cells, right? So that interlooking one causes, it's also known as, I believe another name for interlooking one is osteoclast activated in factor. So when you activate those osteoclasts, that will cause you to resort bone and that will increase your blood calcium levels actually.

In a person that has multiple myeloma that has hypercalcemia, you can give them this phosphonets, but actually steroids work extremely well in that population as well. Just one of those like, I don't see that ever showing up on a USM anybody if he did, you'll get it right because you listen to this podcast. And then if a person also has osteoporosis, right? Osteoporosis, you can also treat with a with a phosphonet, right? Remember the cut of T-score. Phosphorosis is a T-score of negative 2.5 or less, right? If people have those like low T-scores, you need to place them on a phosphonet. And just I guess a high-youthin I'll go ahead and say here is that again. I know you may see the vine, you're not really dipping your hand in much from ecology here, you know, just talking about all these other scenarios. Yes, I know, but the thing is they don't always just test like direct pharmacology on the USM and it's right. They try to integrate concepts together, right? So I think that's probably the best way to actually learn this stuff, right? So what's another way they can test this phosphonets before I talk about the side effects of this phosphonets? The thing is if a person is on chronic steroids for like an autoimmune disorder or some kind of rheumatologic disorder, for those people, if a person has to be on chronic steroids, or let's say they have like NST, COP, or really bad asthma, where they have to take like dileoral steroids.

You need to place those people on two kinds of drugs. One, you need to place them on this phosphonets because remember steroids actually increase your risk of osteoporosis. And then you also have to place those people on PPI's, right? When a person is taking chronic steroids, you need to place them on PPI's because steroids increase the person's risk of peptic ulcer disease. Okay, now what are the side effects of this phosphonets? They're just two you need to know. One is that this phosphonets can cause something called an erosive esophagitis. Okay, and they can also cause like osteonecrosis of the jaw. Okay, if you're thinking more about like hip osteonecrosis, think more about steroids causing that. Stereosteonecrosis of the hip, or you can see like Eva's colonicrosis, whatever, but this phosphonets tend to cause more phanosinecrosis of the jaw. I don't really know why how that happens. And then I already talked about the no suma, right? Again, you can use it to treat hypercocemia, it binds up rank ligand, has basically a similar mechanism of action to osteoporotyping, I already described that. And then if a person has like, again, really bad osteoporosis, I said, first line is a a bit phosphonet, right? But another thing you can actually use to treat osteoporosis is drug known as teriparatite. Okay? Teriparatite is a pth analogue, right? So this is a concept you should maybe try to explain like linking your mind.

Whenever you give something in a pulsatile fashion, it upregulates a pathway. But if you give something in a continuous fashion, it shuts down that pathway. For example, if you give a person pulsatile gnrh, that will up regulate the activity of the HPG axis. If you give a person continuous gnrh, that will downregulate the activity of the HPG axis. Same thing obtains with pth, when you give pth in a pulsatile fashion, that actually causes a buildup of bone. If you give pth in a continuous fashion, that actually causes resorption of bone. So this is where teriparatite comes into play. When you give teriparatite, which is a pth analogue, in a pulsatile fashion over like a year or thereabouts, that can actually really increase your bone density, okay? And that can be used as treatment for osteoporosis. Okay? In fact, it can almost like reverse osteoporosis a person has. Now, the thing is, you need to be careful though. You cannot give like, I mean, you're like, oh man, this sounds like a great drug. No, you cannot give teriparatite forever. Because think about it, you're essentially given a growth factor, a stimulating factor for bone. So guess what? Teriparatite, if given for a long enough period, can cause osteosarcoma, okay? So you need to be careful with that. You just give it, I think like the maximum time for you can give teriparatite for like two years or something like that. So that the person does not get osteosarcoma, which is clearly not a good tip.

Now, what are the things that can cause osteosarcoma, right? So like pages disease, right? I say pages disease can cause high up with our failure, it can also cause osteosarcoma teriparatite. As I just mentioned, can cause osteosarcoma. And then if a person has like an RB gene mutation, right? Like a retinoblastoma gene mutation. Remember, it's a tumor suppressor gene. If a person has that gene mutation, they can also get osteosarcoma. In fact, the classic way they test that on the USML is is they will describe a kid newborn that has like a white reflexes instead of a red reflex. And then you're thinking about osteosarcoma. I mean, you're thinking about retinoblastoma. And then they will ask that this patient is at increased risk of which of the following malignancies in the future. And that'll be an osteosarcoma. Okay? Just again, one of those how you think you want to keep at the back of your mind. Now, I guess I should also mention this disease osteopetrosis. Osteopetrosis, right? It's it arises from a carbonic and hydros too mutation, right? Remember, carbonic and hydros too, you osteoclasts, we use that enzyme a lot to to basically make like acid that can resorbone. That's how osteoclasts resorbone. So, if you have a mutation in that enzyme, your osteoclasts don't work right. So, they don't have the ability to resorbone. And if you cannot resorbone, that's a it's pretty not a good thing, right? Because your bone will just be not right to basically.

In fact, osteopetrosis known as a brittle bone disease. This is one of those bizarre things you want to again keep at the back of your at the back of your mind. Osteopetrosis is actually treated with bisphospholates. That's what I'm talking about it here. Now, let's go to that's really all I'll say about calcium from ecology and physiology, I guess. So, now I'm going to talk about thyroid from ecology, okay? But before we can talk about thyroid from ecology, we have to talk about thyroid physiology first, okay? But this would be a much shorter discussion, well, hopefully than calcium physiology. So, how do we make thyroid hormone, right? The thing is, iodide, right? Again, this thing all starts with the sodium potassium ATP spump, right? The sodium potassium ATP spump pumps three sodiums out of the cell and brings two potassiums into the cell, right? So, sodium is primarily an extracellular ion for that purpose. So, because sodium is really high outside the cell, we can use its gradient energy to bring that sodium into the cell and as it's flowing down its gradient into the cell, we can use secondary active transport to bring all the stuff into the cell, like iodine, for example, right? So, iodine, like iodide, right? So, I- comes into the thyroid follicular cell through a sodium iodide sympoder, okay? That's an example of secondary active transport. And then, when the iodide gets into the cell, it becomes oxidized, right? So, it goes from I- to like elemental iodine, right?

It's like I-2, right? Remember, if you sort of throw back to a general chemistry from college, oxidation occurs when you have a decrease in your, I mean, when your oxidation number becomes more positive, right? So, if you're going from iodide, that's a negative one charge to iodine, that's a zero charge. The oxidation number has become more positive, okay? And that's the oxidation step of thyroid-common synthesis. And then, after that, you have something known as organification. Organification basically happens where you join that iodine to thyroid globulate, okay? You join the iodine to thyroid globulate, okay? And when you do that, you begin to make things like mit and date. I always make one of my friends that went to MIT for undergrad with this. So, like, yes, if you listen to DID as well, it sort of applies to you. So, you form like mit and dates, right? And if you join a date and a mate, you would make T3. If you join two dates, you'll make T4, okay? And if you notice, I'm not talking about any enzymes for this. Basically, the enzyme that does all this thyroid-common synthesis is thyroid peroxidics, okay? That's a very big thing you want to know for exams. And then, when you make, the thing is, the more active form of thyroid hormone is T3, not T4, okay? But if you look at a person's serum, you generally find more T4 than T3, okay? The thing is, if you want to go from T4 to T3, you can do it in the thyroid gland, or you can actually do it in the periphery.

The one you probably care about for exam purposes is the one in the periphery. If you want to go from T4 to T3, you use something known as a 5 prime diodymics, right? So diodymics get rid of one iodine, okay? So the 5 prime diodymics, there's a peripheral one that helps you convert T4 to T3, and then T3 is the metabolic-active form of thyroid hormone. And remember that Hashimoto's thyroid diet is, right? So Hashimoto's is the most common cause of hypothyroidism in the US, okay? It's actually associated with anti-therapyroxidysa antibodies. Now, I want to talk about something that's really important, and it's a protein known as thyroid globulin. The thing is, thyroid globulin, the protein, is released at the same time as thyroid hormone, okay? Just like when you release insulin from the beta cells in the eyelets of longer hands. As you're releasing insulin, you're releasing C Peptide at the same time. When you're releasing thyroid hormone from the thyroid gland, you also release thyroid globulin. So think of thyroid globulin as the C Peptide of your thyroid gland. Let me see, divine. Why do I care about this? Let me tell you why you should care. Classic USML exam question is to describe a person that has like, let's say they have like Graves disease, right? Or they have like a hyperthyroid, like, like, let's say like they have like a, you're trying to distinguish between a person that for example has like Graves disease or some other cause of a thyroid toxic phase.

From a person that is factitiously injecting thyroid hormone, right? To like fake symptoms, say for example, they have like a 1,000, right? So the thing is, if thyroid hormone is coming from your thyroid gland, your thyroid globulin levels will be high. If thyroid hormone is not coming from your thyroid gland, your thyroid globulin levels will be low. If I was saying more about this when I do the endocrine review podcast. So if a person is injecting thyroid hormone, the thyroid hormone levels will be high, obviously, when the thyroid globulin levels will be low. But so that's kind of a dissonance, right? So that's how you know that they're injected, right? Like they're snacking on their centroid or something. But if a person has like Graves disease or they have like the quivering thyroiditis or they have like the thyroid toxic, thyroid toxic phase of Hashimoto's, right? The thyroid hormone levels can be high, but the thyroid globulin levels will also be high as well because that thyroid globulin, I mean because that thyroid hormone is actually coming from the thyroid gland. Okay, and then there's some like raius scamp things you should, you can also think about with those, but I'll talk about that in the endocrine review podcast. Okay, so, but actually one thing I should say here is, please do not confuse thyroid globulin with phyroxen binding globulin. Okay, phyroglobulin is different from phyroxen binding globulin.

Phyroxen binding globulin or TBG basically like binds up thyroid hormone in the circulation. Okay, and one way I think they love to test with thyroxen binding globulin is that if a person is pregnant, right, or they're on OCP, basically anything that causes a high-press regenic state will actually raise your levels of phyroxen binding globulin. Okay, so your TBG levels will go up. But actually for those people, they have free thyroid hormone levels will still be normal. Okay, in fact, you know, let me make this clear because this thing just comes up way too much on exams. There are three things you need to think about. If a person has a stachy nose CPS or the appregnant or whatever, their phyroxen binding globulin levels will be high, they are total phy- because the thing is, right, TBG binds up thyroid hormone. So they are total thyroid hormone levels will be high as well. But their free thyroid hormone levels will be normal. Okay, so again, I repeat that. If a person is on OCP or the appregnant, their TBG levels will be high, their total thyroid hormone levels will be high, their free thyroid hormone levels will be normal. Okay, and again, I'll potentially explain the reasoning behind that in the endocrine review podcast. Okay, so now let's go to the anti-theraid medications. So the anti-theraid medications, the big one you want to know is PTU, right? PTU, basically PTU may thymazole, they both inhibit thyroid peroxidides, right?

So you basically stop making thyroid hormone. But in contrast to my thymazole, PTU actually also has the ability to inhibit that peripheral 5-prime diodeonase that I talked about that helps you convert T-4 to T-3. Okay, in fact, if a person has thyroid storm, you want to go ahead and give those people PTU instead of methymosole because PTU theoretically will help with inhibiting that 5-prime diodeonase. However, if you get a thyroid storm question on your exam and you read the Q-stem and propranolol has not been given yet, you need to give that propranolol first. Propranolol, this is like Florida, high yield, propranolol is the first drug that is always given in the setting of thyroid storm. I'll repeat that again. Propranolol is the first drug that is always given in the setting of thyroid storm. So, and why is this? The thing is, I mean, propranolol obviously will prevent whatever aridmias, right? That may happen with the hyperthyroidism, they remember. Hyperthyroidism can cause a fib. But propranolol also inhibits that fancy 5-prime diodeonase, right? That converts T-4 to T-3. So, in thyroid storm, you give propranolol, you give PTU because PTU can also do that 5-prime diodeonase inhibition business. And in thyroid storm, you can also give steroids, steroids inhibits that 5-prime diodeonase. And you can also give a potassium iodide because you take advantage of something called the wolf trichof effect.

The wolf trichof effect is where given an iodine load paradoxically causes a hypothyroidism, okay? So, those are the things you can use for thyroid storm. You can use propranolol number one. You can give PTU, you can give steroids, and you can give potassium iodide. Don't confuse the wolf trichof effect. We're given an iodine load causes hypothyroidism with the yacht-based off phenomenon. We're given an iodine load causes hyperthyroidism, right? I mean, that's the mechanism behind amyodorant cause in hyper and hypothyroidism. Amyodorant can take advantage of the wolf trichof effect to cause hypothyroidism or it can take advantage of the yacht-based off phenomenon to cause hyperthyroidism, okay? And another interesting, I guess, tidbit with regards to PTU is that PTU is actually safe in the first trimester of pregnancy. You may read in some resources that PTU is always safe in pregnancy. No, it's not. It's only safe in the first trimester. After the first trimester of pregnancy, you need to switch the patient to methemazol, okay? You want to switch the patient to methemazol because in the first trimester, that's where we're like super, super worried about aplasia cuties, which the risk is actually higher with methemazol, but in the second third trimester, you're not really worried about that, so in those circumstances you then switch to methemazol.

Methemazol is actually the preferred anti-thyroid medication compared to PTU, but PTU is your best choice in two situations and two situations only on exams. One situation is if a person has thyroid storm, the second situation is if a person is in the first trimester of pregnancy. Okay, and remember that PTU can also cause a granulose eye doses, okay? So let's sort of keep that at the back of your mind. Methemazol pretty much the same drug in hippy styroproxidase, it's safe pretty much at every time other than in thyroid storm or in the first trimester, so you can give it in trimesters 2 and 3. It can also cause a granulose eye doses, it can also cause aplasia cuties, okay? And then I already talked about how amyoda runnyzazol is called hypo and hyperthyroidism. Lithium is associated primarily with hypo thyroidism, and just one of those things is again getting the back of your mind. Now let's talk about diabetes, okay? So I'll probably finish the podcast in the next like 3, let's see between 3 and 5 minutes. So let's talk about how I would treat type 1 diabetes, right? Type 1 diabetes, you're not making insulin, right? So all those oral hypo glycemic agents not gonna do squat for you, you need to give those people like legit insulin, okay? Although actually I take that back, there is one drug known as Pramlin type, Pramlin type is actually a treatment for type 1 diabetes, it's actually the only like oral medication that you can give to a type 1 diabetic.

No one really knows how it works, but it actually like decreases like the rise in blood glucose that accompanies a meal, okay? It's basically like an analog of something known as amylin, and yeah, it's used to treat type 1 diabetes, also used to treat type 2 diabetes as well. And I guess sort of like an unreleafed point. The thing is remember, if you're comparing type 1 and type 2 diabetes, type 2 diabetes is actually the one that's associated with amyloid being found in the pancreatic eyelids. So if you get a question where they say, oh, they did histology, and they had like Congo red positive staining with the, you know, like a prograin biorefringents in the pancreas, you really want to think about type 2 diabetes. The thing is that amyloid, that you're finding in the pancreas is actually coming from the amyloid, okay? So just an unreleafed point to solo keep at the back of your mind. Now, if you're going away from premelent type, right? You want to give like type 1 diabetes, legit insulin. It is like again, floridly high yield to know the different types of insulin and the adoration of action. In fact, there are four types of insulin. There's insolence that are ultra rapid acting, there's insolence that are rapid acting, there's insolence that are intermediate acting, and there's insolence that are long acting, okay? The ultra rapid acting insolence, there's like like less, no, less pro, okay?

There is another one known as aspart, and there's another one known as glolizing, okay? So less pro, aspart and glolizing. And then the rapid acting insolence is just regular insolence, literally called insolence regular. And then the intermediate acting insolence, there's only one you need to know, it's known as NPH, I think it's like neutral, predominant, haggidona, something ridiculous. Just remember NPH and you're probably good to go. And then the long acting, there's three you need to remember, right? So there's glargin, okay? There is a deremir, so D-E-T-E-M-I-R, and then there is another one known as degludeck, D-E-G-L-U-D-E-C, okay? The classic thing that we do on an exam is to show your graph with insulin, and then show you the pick onset of action after it's given, and the duration of effect, you need to memorize that graph. Just look up a picture of that in your first state, it's a pretty classic graph, but it shows up all the time on exams, you definitely need to know that graph. Okay, so maybe pause this podcast and go look at that graph just for reinforcement, okay? And then let's talk about type 2 diabetes. I know this podcast has gone on for almost an hour now, I honestly don't expect to go this long. So just talk again, I'll just talk about metformin and then there'll be it. In fact, you know what? Yeah, I'll just talk about metformin because it's kind of tricky. So, metformin, metformin is a big one-night, right? The drug class is a big one-night class.

No one really knows how metformin works, but if you're thinking about your biochemistry, you could potentially propose a mechanism for how metformin works. So let's talk about this for a second because this has a very nice biochem time, right? So the classic boss phrase you'll see many pharmacology texts in your first state, whatever is that metformin decreases hepatic gluconeogenesis. Well, how might that be the case? The thing is, in my biochem reviews, I talked about a cycle known as the curry cycle. Okay, I talked about the curry cycle. The thing is the curry cycle takes place in the liver. What does the curry cycle do? Basically, the curry cycle takes like lactate from like muscle, from red cells and converts that to pyruvate and then converts that like, so it converts the lactate back to pyruvate obviously, that'll be under the activity of lactate dehydrogenase. And then in the process of gluconeogenesis, you convert that pyruvate back to glucose. Okay? Well, the thing is, if you're an organ that does the curry cycle by default, you need to be an organ that can do gluconeogenesis. And it so happens that the two organs that can do that are your kidneys and your liver, right? Your liver is probably like the bigger guy in that situation. So we said that metformin decreases hepatic gluconeogenesis. So let's say you're basically cutting off the gluconeogenesis that happens in the liver, literally, that's what metformin does.

The thing is, if you're cutting down on hepatic gluconeogenesis, that gluconeogenesis phase of the curry cycle will not work. Okay? If that gluconeogenesis of the curry cycle does not work, then everything that is upstream of that in the curry cycle will build up. So your pyruvate will begin to build up. And if your pyruvate builds up, guess what will build up as well? Your lactate. Your lactic acid will build up. So this is the potential mechanism behind metformin causing a lactic acidosis, a life threatening lactic acidosis. Okay? So metformin can cause a high anion gap metabolic acidosis. Basically, again, a lactic acidosis. This is one in general. The person has real feelings. If a person is getting his anoreal kidney right, you probably do not want to give them an informin. Another classic way to test this concept on exams is they can talk about some like a histro diabetes, like tattoo diabetes, as getting an imaging study. Right? Let's assume like they have a pee or whatever. You want to do like some kind of cat scan that involves a CT scan that involves a contrast. Remember that contrast can cause intra-renal AKI. Okay? So for those people, you need to hold that metformin. In fact, if a person is getting a potential in a frotoxic agent, you need to hold metformin. In fact, I'll tell you this as a clinical prayer for the future. Always do med- medication reconciliation on your patients. Right?

If a patient is coming to the hospital and they have metformin, just stop them at forming and please them on insulin. Okay? For patients coming into the hospital, that's something that I pretty much always do. Stop their metformin and just place them on insulin. Regardless, it doesn't matter. Just stop their metformin. Trust me. You don't want to deal with the lactic acidosis that can arise with metformin. It can be life threatening in some people. And then the next thing I'll say about metformin, right? So you hear that it decreases hepatic gluconeogenesis. So I've talked about how you can link that to lactic acidosis as a side effect of metformin. But another thing people say, at least again, if you're really a first aid, you read your pharmacology text is that metformin increases insulin sensitivity. What's the potential mechanism behind that? The potential mechanism is that metformin actually increases the activity of an enzyme known as AMP kinase. So like AMP kinase. Right? So how does this increase insulin sensitivity? Well, let's talk about the mechanism. The thing is, remember your glucose transporters. We have a glute four of those glucose transporters. One of the important ones are the glute four transporters. Remember, we'll find them on the dipocytes and on the surface of a skeletal muscle cells. That's a, it's an insulin dependent glucose transporter. The thing is insulin actually helps you put more glute four on the surface of your skeletal myocytes.

But the thing is think about it. If you're exercising, your skeletal muscle needs a ton of glucose, right? So that you can exercise well, right? So the thing is when you exercise and guess what? You actually put a ton of glute four transporters on the surface of your skeletal myocytes. But I know you may already be asking a question in your mind, but define, wait, if you exercise, you're using up glucose. So your blood glucose levels go down. So if your blood glucose levels are going down, your insulin should not be up. Your insulin will actually be down. So if your insulin is down, how is this glute four transporter getting to the surface of a skeletal myocytes? That's an important question. The thing is during exercise, skeletal muscle actually inserts more glute four transporters on its surface in an insulin independent fashion. Okay? And the thing that makes that happen is AMP kinase. Okay? AMP kinase. And you may even wonder like, divine, why is this thing called AMP kinase? Think about it. Again, if you're exercising, you're using up ATP at a very high clip, right? As you're using up that ATP, right? Guess what you'll be making a ton of AMP? AMP activates that kinase. That's why it's called an AMP kinase. Okay? So if metforming is helping you activate AMP kinase, but activating AMP kinase, you're putting more glute four on the surface of your skeletal myocytes.

If you're putting more glute four receptors on the surface of your skeletal myocytes, you're bringing in more glucose. Okay? But you're doing that without insulin. So let's say before, oh, you need it, it's like you're basically taking over the functions of insulin in a non-insulin dependent fashion. Okay? So this is the mechanism behind metforming, improving insulin sensitivity. That's a, it's just one of those things that you may not see on you exam, but I can almost foresee them making this a question that is cell biology or biochemistry related. And this will likely throw many people off. Okay? So just one of those things, was one tweak, does one taking the time to sort of buckled on and explain this. So to round up this podcast, the big side effects of metformin lactic acidosis, especially in patients with renal failure, and the GI upset. Okay? Metforming can cause a GI upset. So I think I'm going to stop here. I know this was long. And before I round off, don't forget I offer one-on-one tutoring for the USMLA exams, step one, step two, CK and CS and step three, and also the medicine-entrining exam and the medicine board exams. And then also the application prep for med school. So that's the Amcass application and residency, that's the ERAS application. I have a lot of experience doing these things, preparing people for interviews and whatnot. So please feel free to send anyone my way that requires any of these services. I do it on a one-on-one basis.

So I wish you all the best. I hope the Lakers win their game against whatever team they're playing today. I believe it's the Uter Jazz. So I'll see you guys in the next podcast. Have a wonderful day and God bless. Thank you.

To increase blood calcium levels and decrease (trash) blood phosphate levels.

The RANK receptor.

Because the failing kidneys cannot appropriately excrete (trash) phosphate, even when PTH is high.

Primary hyperparathyroidism results in high urinary calcium; FHH results in low urinary calcium due to CaSR defect.

Propranolol (a beta-blocker).

5'-deiodinase.

By activating a calcium channel found at the distal convoluted tubule.

Low (because the kidneys are working and appropriately trashing phosphate).

Squamous cell lung cancer (a paraneoplastic phenomenon).

Bisphosphonates.

Low urinary calcium excretion.

Diazoxide (or Streptozosin).

By activating a calcium channel found at the distal convoluted tubule.

Low (because the kidneys are working and appropriately trashing phosphate).

Squamous cell lung cancer (a paraneoplastic phenomenon).

Bisphosphonates.

Low urinary calcium excretion.

Diazoxide (or Streptozosin).