Diabetes Drugs – NCLEX/USMLE Review

Welcome everybody, today we will be talking about the different types of diabetes drugs. We have quite a list to discuss today. We’re gonna start with insulin, the big insulin and as we work down as soon as we get down kind of to the bottom of the lists are not as important. However, these kinds of top five are going to be your big diabetes drugs. These are gonna be your mainstay.

So there’s type one diabetes and there’s type two diabetes mellitus. And the difference between these two types is that for type one you cannot make your own insulin, the mainstay for treatment is going to be insulin. However, for type 2 diabetes you have decreased insulin tolerance pretty much. The insulin that you normally make isn’t as effective, so how do you treat it well? We’re gonna use insulin. So type 2 is a little more complex for treatment, also a good lifestyle modification is the number one stay so if you’re ever asked a question what is the first treatment that you should do for type 2 diabetes? It’s insulin, it’s not insolent, not insulin my apologies it’s diet and lifestyle modifications exercise to change your food, change the way you eat. However, for type 1, the mainstay for treatment is going to be insulin.

so, type 2 number 1 is diet, exercise that’s a big point to remember. if anybody asked what the number one treatment is it’s going to be lifestyle modifications. Work first if these lifestyle modifications fail, then you move into drugs. so keep that in mind but otherwise, we’ll talk about the main talking points, the key buzzwords, the stuff that will get you test points. We will go over stuff that will get you the main buzzwords and the main concepts. My goal is to get you tested. I don’t care what level you’re testing at whether you’re an undergraduate, whether you’re going to a graduate program, or whether you’re taking a board exam. This is the lecture that will get you test points regarding diabetes drugs and explain some of the differences. 

So let’s go ahead and start with the first one insulin very important for type 1 diabetes. Now there’s a whole bunch of different types. There’s going to be rapid-acting. There’s going to be short-acting, intermediate then there’s long. When you think of rapid insulin I want you to think of three main prototypical insulin, like drugs. First, we’re going to start out with lispro, that is going to be a mainland. We’ve also got aspart, and we’ve also got glulisine. So when I say rapid-acting insulin, we’re talking you know stuff that starts immediately and lasts for anywhere from three to five hours, so about four hours of action. so it’s going to be rapid-acting and this is the stuff that you may see in insulin pumps.

Because in insulin pumps you’re monitoring your insulin or your glucose levels. Every so often and you’re going to modify it by using rapid-acting insulin in those pumps. We also got short-acting and some well. What’s the difference well rapid was about four hours of action, however short is gonna last anywhere from you know four to twelve hours of action. It’s gonna be anywhere from a shorter duration to half a day or so. So what is the short-acting insulin? Well, that’s just going to be your regular that’s just going to be the normal insulin that you synthesize naturally by the body. However, you can do synthetic regular insulin especially in the case of type one diabetes where you don’t create your own, that’s just going to be regular insulin.

Alright, we’ve also got intermediate, this is going to be NPH that’s going to be prototypical intermediate insulin. and in long-acting we’ve got our glargine and detemir. Okay and one of the tips that I use to remember the long-acting insulin. So, I’m thinking of a pirate. Pirates like to say Glaaaaar, pirates like to say claar, you know that they are a little rough and they also like to have long-lasting deaths, so glar means death is very long-lasting. So detemir, glargine, that’ll help you remember long-acting insulin, think pirates. so intermediates, intermediates are going to last anywhere from ten to twenty hours, not quite the full day.

Well, long-acting on the other hand, will last anywhere from 14 to 24 hours and this will last almost the full day. So, you’ll only have a one-time injection theoretically. One of the main concepts that I’m not gonna touch is, you can use different dosing and combine these so you might do a low dose of long-acting insulin at the beginning of the day and multiple multiple dosing of short or rapid-acting insulin. It just depends on the clinicians, it depends on the patient but just realizes that you don’t just give one type of insulin for the most part unless if you’re in a pump or in certain situations. Otherwise, you give maybe a long-acting and a short-acting between meals like right after a meal. So, that’s just a variation, but I’m not going to go into that.

So, let’s talk about how insulin works. We just injected normal regular short-acting insulin into the body. How is this gonna exert Its effect? We have insulin receptors. Insulin receptors are going to be trans-membrane. What does that mean? They’re gonna have an extracellular and an intracellular component. They’re gonna span the phospholipid bilayer membrane. so, they’re gonna be exposed to the surface of the cell and the inside of the cell. So, on the cytosolic side, once insulin has bound to the extracellular you know the binding site for this insulin receptor, the intracellular or the cytoplasmic side either one interchangeably has a tyrosine kinase activity. The tyrosine kinase activity is going to add a phosphate onto stuff. So, we’re going to take an enzyme we’re going to phosphorylate it so this tyrosine kinase is going to take an enzyme, it’s going to phosphorylate it and so we’re just attaching phosphates on the stuff. and those phosphates will come from ATP.

So ATP will come from the ADP and in the process this phosphate, the triphosphate is going to become a diphosphate because we’ve lost a phosphate here. The phosphate that we lose gets stuck onto an enzyme, so we have a phosphorylated enzyme, it’s gonna activate stuff. so when you add a phosphate onto that enzyme you’re gonna activate it. so you’re gonna exert some downstream effects and when I say downstream effects you’re going to phosphorylate a whole bunch of enzymes, turn those enzymes into active enzymes. You have downstream effects because these enzymes will be active, so what effects will we see? Well, you may see increased glucose uptake into cells. Now let’s recall what’s the function of insulin?

It’s to take a hyperglycemic state, so you have a high blood glucose level. It’ll drive that glucose into the cell, which is the point of insulin. If you’re going to take a high blood glucose concentration in the bloodstream. So Glu, those stands for glucose you’re going to drive. When you give insulin you’re going to drive the blood glucose into cells. so you’re gonna decrease your bloodstream glucose levels. so one of the downstream effects will be increased glucose uptake, also you’re gonna have more glucose into the cells so what that will do is it’ll drive glycogen formation. now your liver and your skeletal muscle cells will synthesize glycogen. Glycogen is just gonna be your stored form of glucose so if you have increased glucose in a Cell this. The cells will say hey we have excess glucose. Let’s just store it and that’s in the form of glycogen. also remember that when you increase glucose uptake into cells, you take potassium with it. so as you take glucose into cells potassium will go with it into the cell. So you possibly could have hypokalemia. Hypokalemia is decreased potassium in the bloodstream and that could be a side effect of a massive dose of insulin so you have to be careful with that. That’s kind of the mechanism for insulin.

Now let’s move on to a different category: biguanides. so the biguanides are going to be it. They’re going to be a category of the drug but the prototypical drug that you will see in the real world type 2 diabetics, is a major player. I would remember this one the biguanides are gonna be metformin, that’s gonna be a prototypical drug of choice. so the mechanism of action is actually a little unclear. What we do know is that we’re going to use this as a first-line treatment for diabetes. It’s gonna be an oral medicine. It’s going to be one of your first-line treatments, and it’s going to be specifically for type 2 diabetic patients. Now, what does happen when you give biguanides even though we don’t know the exact mechanism of action. we do know that you’re gonna decrease hepatic glucose formation. Now, remember I’m going to go back aside here remember I just said that when you take glucose up with insulin into the cell you’re going to synthesize glycogen. Now glycogen is your stored storage of glucose. Now metformin is going to decrease hepatic glucose formation.

We’re gonna decrease gluconeogenesis, but we’re also gonna decrease glycogen breakdown, which will spit out kind of glucose into the bloodstream increasing Our blood glucose. all of these, all diabetic drugs aim to decrease glucose in the blood. That’s just kind of a general rule of thumb. Our goal is to decrease our hyperGlycemic State, Our high glucose state in the bloodstream. so diabetic patients may have too much glucose in their bloodstream all of these drugs via different mechanisms will aim to decrease the glucose in the bloodstream and metformin works by decreasing your liver’s ability to form glucose. Also, it’s going to increase each peripheral glucose uptake. You have a whole bunch of glucose in your bloodstream. Metformin will increase the uptake of that glucose and your peripheral cells so your muscles for example and that glucose will go into the cell kind of like the same mechanism of insulin. Okay so board questions, if there’s one question that I’ve gotten multiple, multiple, multiple times it would be this; which of the following drugs can lead to lactic acidosis. Lactic acidosis well it’s gonna be your metformin.

They’re going to give you a whole list of different diabetic drugs, they’ll have metformin as one of them. This is your money question right here. I’ve been asked this multiple times and multiple different board question banks. Now lactic acidosis does not forget this, it also causes other complaints such as you know like a bad taste in the mouth. It also can cause GI disturbances but the number one adverse effect of metformin is going to be your lactic acidosis. This is important, this is something that you need to commit to memory. so even though we don’t know the exact mechanism of action for metformin. We do know that it does exert some effects. We know that it’s effective, that’s why it’s going to be our first-line treatment. it’s going to be one of our number one drugs that we use in type 2 diabetes. After they eat correctly and after they exercise. If their diabetes can be controlled with diet and exercise, excellent! we don’t need drugs but if it cannot, we need to think about implementing metformin in their regimen and one of the side effects that we need to monitor with metformin is going to be a lactic acidosis. So that is metformin and that is an important high-yield topic. 

Next, we’ve got another category: the sulfonyl-ureas. Now there are quite a few different drugs, so the biguanides are just pretty much the prototypical metformin for the insulin. For the sulfonylureas, we have quite a few and I’ve just listed them out right now. Okay so, here are some of your prototypical sulfonylurea drugs. now just realize that there are gonna be some first-gen drugs, there’s gonna be some second-generation drugs not that important to distinguish between the two of them. Just realize that there are different categories of the sulfonylureas and you’ll be good. We’re going to talk about the general mechanism of action for these sulfonylureas. so, we’ve got a cell here and that’s going to be a beta cell.

So, the beta cells are going to be your insulin-releasing cells in your pancreas. so, hopefully, you know the difference between alpha and beta and Delta and all those different pancreatic cell types. Your beta cells are going to be your endocrine cells that release insulin into your bloodstream so we’ve got a cell here and you know that we have some glut transporters here. Now there’s a whole bunch of different types of them, not important for right now so I’m just going to keep it basic. we’ve got a glut transporter and it’s going to be on the surface of the cell. what that’s going to do is it’s gonna take glucose and bring that glucose into the cell. so these pancreatic cells even though they’re releasing glucose, what they’ll be doing, is they’ll be taking up small amounts of glucose. These glut transporters specific to the pancreas will kind of be sampling. How much glucose is in the bloodstream? If we have a high amount of glucose into the bloodstream we’ll be taking in a lot of glucose during our sample, kind of our test of the environment. so, if we have a high amount of glucose will go into the cell during our test. Now what typically is going to happen is typically this high amount of glucose is going to cause a high amount of insulin release.

Now, what’s gonna happen in diabetics if you’re going to have this high amount of glucose except the pancreatic cells won’t respond as well.  What we can do is, I’ll go through the basic physiology here. you’ve got a potassium channel, see if I can keep this so, we’ve got a potassium channel here. what typically is going to happen is normally you have a high amount of potassium inside the cell. remember sodium’s on the outside potassium is on the inside and it’s maintained by the sodium-potassium ATPase pump. so you have a pump over here it’s going to ATP. potassium normally this is going to diffuse out of the cell so when that happens we’ve got another channel over here, we’ve got a calcium channel. Calcium typically comes into the cell and it’ll depolarize the cell. And then lastly we’ve got insulin because remember these pancreatic beta cells produce insulin. so we’re going to have a whole bunch of synthesized insulin ready to go and then. it’ll get released once we have some calcium. so what will normally happen, we’ll have a high amount of glucose come in that’ll depolarize the cell. depolarization is going to cause calcium to come in. Calcium coming in is going to cause insulin release, which is the normal physiology of things. Calcium is coming into the cell as our ultimate goal because that will produce insulin release. Insulin goes into the bloodstream, that’s what happens. but however, we’ve got a class of drugs called sulfonylureas.

The sulfonylureas what they do is, they’re going to inhibit this potassium channel. so, in a normal potassium channel potassium is gonna diffuse out of the cell to try and keep the charges normal. However, sulfonylureas are going to inhibit this channel. so this channel cannot happen therefore, our potassium is going to stay inside. The cell we’re going to have an increased concentration of potassium in the cell. now a high positive charge in the cell is going to depolarize that beta-cell. We’re gonna cause depolarization within the cell. when we depolarize this cell calcium is going to rush in because you’re going to have a concentration gradient that calcium I’ve already said causes instant insulin release. sulfonylureas increase insulin release. That’s the main point to remember. That’s your take-home, is what they’re going to do, is you’re going to inhibit this potassium channel. so, they’re going to increase insulin release by inhibiting potassium, and inhibiting the potassium channel is going to increase depolarization. Depolarization will cause calcium influx causing insulin, releasing a big point to remember. Then We’ve got a couple of adverse effects. Let’s kind of take a tiny little area out here. What can happen? Well, you can have hypoglycemia.

Typically in a diabetic your hyperglycemia, you have too much glucose however, if you don’t give the correct dosing for the sulfonylureas, you may have a side effect of hypoglycemia. You have too much insulin being released, so you inhibit this potassium channel really well. You get a depolarization. You get an increased insulin release and you release too much insulin, you’re gonna have decreased glucose in the blood and that will manifest into your hypoglycemia. also disulfiram. So, disulfiram is going to be a drug given to alcoholics. it’s going to block the breakdown of acetaldehyde which is going to be like a toxic metabolite in your liver and when you do that you’re going to get nausea you’re going to get throwing up and that’s what they give to alcoholics to try and kind of mentally convert them to the associating drinking alcohol to throwing up. so every time they drink alcohol you’re going to get a whole bunch of toxic metabolites built up. It’ll cause them to become sick so it’ll cause a disulfiram-like effect. so disulfiram is a drug that’s given to alcoholics. Then lastly you may have GI disturbances as well. so, that’s this sulfonylurea.

In a nutshell, that’s the high-yield information that you should know next we’re going to talk about another the Glitazones. Now they are also known as the thiazolidinediones. So, I’m going to call them glitazones from here on out a couple different categories that are pretty much interchangeable for our sake. Now there is a way that I can remember these two drugs. so we’ve got prototypical drug number 1, pioglitazones. then we’ve also got Rosiglitazone. So notice their endings both end in the zone. Now let me tell you a little story here. This is how I remember my glitazones and their mechanism of action. so me and my friend, we’re both terrible at golf.

I mean we love to play but we’re terrible is really just a drunk fest. When it happens but however, when we’re betting money or whatever at our golf game you need to get in the zone. so when you play golf you need to get in the zone. Why do I say golf necessarily? well, it’s because in golf we’re not very good so far is a really good score for us. So when we’re in the zone, We always shoot for par in golf so the PPAR gamma to be specific. However, for our sake when you’re in the zone playing golf you always shoot for par so the glitazones are going to be going to work by binding the PPAR gamma receptor. Now that’s going to be their mechanism of action. They’re going to bind the PPAR gamma receptor, what this is going to do is we’re going to increase the GLUT 4, remember the different subtypes really don’t matter, they’re going to increase the glute transporters which is going to increase glucose into the cell perfectly. So what does PPAR stand for? It doesn’t really matter! It stands for peroxisome proliferator-activated receptor type gamma, not important at all. What is important is just to realize that you’re gonna increase your PPAR gamma. glitazones will go and bind to this PPAR gamma. what that’ll do is it’ll increase the transcription and the translation. Transcription is it’ll transcribe your DNA into mRNA then, it will translate that mRNA into GLUT 4 transporters. They’ll stick those GLUT 4 transporters up into the cell membrane. What that’ll do is you’ll increase the glucose into the cell that is your target goal. Remember we have too much glucose in a normal diabetic type 2. too much glucose in the bloodstream so our goal is to put it into the cells as reservoirs. Let’s finish adverse effects out. not too many um when you think glitazones think heart problems. you know in all those golf commercials they always talk about heart problems, just remember that. a lot of golf commercials that you see on TV, depending on where you are I guess you have a lot of heart problems. all those old men wanna get back out to the golf course. If heart problems, that are kind of preventing them from getting in the zone to get part in their golf game. also, you know hepatotoxicity is a pretty big one, you’ll see hepatic toxicity so damage to the liver so that’s the glitazones.

 

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