Transcript for:
Overview of Antiviral Medications and Mechanisms

What's up, Ninja Nerds? In this video today, we are going to be talking about antivirals. There is so much to go over. Just like antibiotics, we're going to cover every antiviral. We're going to talk about those against HIV, against influenza, against hepatitis, against the herpes viruses. And so there's so much to cover. So what I urge you guys to do to really understand this stuff, assist in your understanding of this, please go down in the description box below. That'll take you to our website. On our website, we'll have illustrations, we'll have notes for you guys to follow along with and really, really help and aid. in this very difficult topic, okay? So let's talk about antivirals. When we talk about antivirals, we're gonna go over the first category against HIV. So these are gonna be your antiretroviral therapies. Now HIV is a nasty virus. It's a type of retrovirus. When we think about that, retroviruses are basically viruses that take RNA and they can be converted into DNA. Now, what kind of host cells do these usually attack? They attack our immune system, particularly, you know what kind of cells they love to attack? They love to attack our cells called the T-helper cells. So our T-helper cells are the big cells that are constantly being attacked, our CD4 positive cells really. So when we think about this, imagine we have this HIV virus. When the HIV virus works to bind onto our T-helper cells, our immune system cells, it utilizes very specific types of proteins. to gain its fusion and entry into the actual host cell. Now, what are those different proteins? So there's a couple of them. You see this little ball point here, like this little blue point here? This protein right here is called GP41. And then this kind of like longer stick protein, which is its to is called GP 120 now these proteins are integral to the HIV virus to allow for it to bind on to the host cells receptors what are those host cell receptors that it needs to bind with generally this protein which the GP41 will bind with is called a CD4 protein. And then on most of the TA helper cells, there's two types of blue proteins there that bind with the GP120. There's two types. So one of that I want you to remember is called CCR5. So CCR5 is the big one that I want you guys to remember. CCR5, don't forget this one. And the other one is called CXCR4. Now, why is all of this important? important. Once the actual virus utilizes these proteins like the GP41 to bind with the CD4, the GP120 to bind with the CCR5 or the CXCR4, it then fuses with the actual proteins here on the host cell and then gets shuttled into the actual host cell and then releases, you see that little blue structure, that little squiggly line, releases its RNA. So once this kind of fusion occurs, it then allows for the entry of the actual virus. Into the host cell so now look Now that RNA is in the host cell. Okay, that's the that's the issue here So we can actually try to have drugs that can really prevent this fusion and entry of the actual viral RNA into the host cell What are those drugs? I'm glad you asked one of them and called Enfuvitide. And Enfuvitide is a type of like fusion or entry inhibitor. It inhibits the actual entry of the viral RNA into the host cell. And what Enfuvitide will do is, is it'll inhibit this interaction. It won't allow for the GP40. on the HIV virus to bind with the CD4 protein. If that doesn't bind, are you gonna allow for this to fuse, enter, and release the viral RNA to the host cell? No. So that's one big thing to be able to remember. The second thing is this CCR5. Remember, I kinda asterisked that one. That's a very important one. Not all particular types of T helper cells will express this type of CCR5, which the HIV virus will bind to. Not all of them, only some people with the genotype for that. And you have to test for that in order to use this particular drug. But Moraviroc prevents the virus from docking to the cell. That's the way that the first aid USMLE utilizes this. But Moraviroc will basically prevent this interaction. It'll inhibit the GP120 from interacting with the CCR5 receptor. Therefore, the virus can't dock and release the RNA into the actual host cell. So we see how these two drugs work. Moraviroc prevents... the actual virus from docking releasing the rna and then fever tide inhibits the fusion of the gp41 to the cd4 inhibiting the release of the rna into the cell that's one step now that's not it though the rna once inside of the host cell it's very interesting it also releases you see how there's like these little maroon proteins inside of the virus so not only does it release its rna but it also releases off this other type of protein so there's other proteins that It also releases into the host cell when it fuses and releases it. I'm going to draw all these kind of like maroon dots. But what I'm going to do is I'm going to zoom in on one of those maroon dots. You see this guy right there? That's one of those maroon dots. This enzyme is called a reverse transcriptase. We're going to put here reverse transcriptase. Actually, let's make them bigger. So this is a reverse, now what does reverse transcriptases do? Reverse transcriptases are really interesting. They're cool little enzymes here. And they take, so transcription is generally you take DNA and make RNA, right? That's transcription. If it's reverse, I'm taking RNA and making RNA. DNA that's all it is so in this process I'll take and utilize this cute little enzyme and convert RNA over a process here and make something called DNA so that is going to be my reverse transcription process now why is that significant because now i have viral dna viral dna that i can actually put into the host cell and try to incorporate it into the host cell's dna this t helper cells dna that's bad news bears what if i had drugs that could inhibit that reverse transcriptase inhibitor if i inhibit it we'll be able to take rna incorporate into dna make dna i'm sorry and then incorporate into the host cell use the host cells nuclear machinery to make proteins and make more by viral RNA molecules, if I stop this process, I could potentially inhibit that. So I'm gonna use a bunch of drugs to do that. One of the drug categories, so this is a general category, these are reverse transcriptase inhibitors. Here, let's just do one big line from all these big mamas here. So reverse transcriptase inhibitors are going to work to inhibit this cute little enzyme. How does it do that? Let's talk about them. These names are painful, believe me. That's why I wrote them down. I can't remember all of them, have a little way that I can try to help you guys to remember all of these painful names so the first category that I want you to remember in is this is actually the most important one because the hallmark it's the basic foundation of highly active antiretroviral therapy which we'll talk about a little bit and this is your NRTI that stands for nucleoside reverse transcriptase inhibitors now what these drugs do is very very interesting well in order to be able to take this HIV RNA Let's make this pretty simple and to make DNA. So this what's going to do is going to be utilized by this enzyme to be able to make this HIV DNA Now in order to do that to take RNA and to make this DNA I need nucleotides. I'm gonna read the RNA strand When I read the RNA strand, I'm gonna use the particular nucleotides on the RNA strand use nucleotides that I have around and add accordingly to the complementary base and make DNA from that RNA strand. But I need nucleotides. Guess what? Reverse transcriptase isn't that smart. It's not smart enough to be able to recognize the difference between a real nucleotide and a nucleoside reverse transcriptase inhibitor, such as one of these drugs. So when it grabs one, let's say that it grabs a nucleoside reverse transcriptase inhibitor and adds it onto the growing DNA strand that you're trying to build off of this RNA. When it does that, guess what? You can't add any more nucleotides to that afterwards because that nucleoside reverse transcriptase, it actually stops any more DNA formation from this RNA template. and we stop that process so that's how these drugs particularly work now I wish there was a way of being able to remember all of these as I have for some of these other ones. The only thing that I can think of that would actually help us to be able to remember this particular drug category is Zales TD. So if you get your girls the Zales ring, yeah you'll end up in the touchdown. You know you'll end up getting a touchdown, I don't know. But it's basically Zidovudine, Abacavir, Lamivudine, M-Tricitabine, Stavudine, Tenofovir, and Didanosine. there's no particular in some of these there's a very specific core root type of word in the actual name that's easy to remember for these there's not really that particular root word i'm sorry but What I want you to remember is that these particular drugs are going to inhibit the reverse transcriptase from taking RNA and making DNA by stopping the growing DNA template by acting like a nucleotide even though it's not. It'll terminate the actual formation of DNA off of this RNA template strand. That's that drug category. Now the N and RTIs are the non-nucleoside reverse transcriptase inhibitors. These are very interesting. So you see how this like little reverse transcriptase has a little like like pocket around its shoulder. Well what happens is these little drugs, these little buggers will actually bind onto this little allosteric site. You see that little allosteric site, that little pocket there? These NNRTIs will bind onto that little site there. When it binds onto it, you know allosteric When it binds onto it, it changes the shape of the enzyme. When it changes the shape of the enzyme, it doesn't allow for the enzyme to be able to work as well as it should. What is the job of it? The job of it is to take this RNA, read it, grab nucleotides, and make DNA. If we utilize these particular drugs to bind onto this allosteric site, we don't allow for it to have a particular structure that allows for it to properly read the RNA, grab nucleotides, add on to it, and make a new DNA strand. And then a subsequent... DNA strand. So that would inhibit this particular process. And that is the actual drugs here, the NNRTIs. Now, there actually is a way to remember these. So you have nevirapine, efavirenz, ertravirine, and delavirine. Leviridine. Do you notice here that at least in all of these, there's a vir somewhere in it, and it's in the actual center of it. So I want you to remember anytime you see a vir in the center of one of these types of drugs, that would be a NNRTI, a non-nucleoside reverse transcriptase inhibitors. So NRTI, Zales DT, acts as a kind of like a nucleotide, and then when you add it you terminate the formation of further DNA because it won't allow for further DNA to be formed in an RTI allosteric inhibitor binds onto a particular site inhibiting the reverse transcriptase enzyme from being able to properly function and taking RNA and making DNA whoo we got through a beast there okay that's these drug categories so we have the drugs that are basically inhibiting the fusion and entry of the actual HIV RNA into the cell in fever type Mara rock we have the drugs that are inhibiting the reverse transcriptase that takes RNA and makes DNA. NRTIs, NNRTIs. One acts like a nucleotide, but it's not. It's a nucleoside. We're not going to get into the structure of that, but again, they help to be able to prevent the growing DNA strand from your RNA template. NNRTIs, Bind onto an allosteric site and inhibit the enzyme from being able to properly function. Now we move on to the next thing. From here, the DNA of this HIV virus will then get taken up into the host cell's nucleus. Once it gets taken up into the host cell's nucleus, here's the DNA. is your host DNA. This is the host DNA. You see this black enzyme here? This black enzyme, you know what it does? It takes and finds a particular site here on the host DNA and makes a cut. And then when it makes that cut, it then takes the actual viral DNA and incorporates it into the actual host DNA. So then from there we're gonna get something a little bit like this, if you will. We're gonna have kind of a mixture of these two. So now I'm going to have my viral DNA mixed in with the actual host cell's DNA. Isn't that crazy? That's kind of scary if you think about it, pretty sneaky by this actual virus. But what is the name of that enzyme that integrates the actual viral DNA into the host cell's DNA? Because now this is a mix. I have a little bit of viral DNA mixed in there. This enzyme is called integrase. What if I had a drug category that could work to be able to inhibit? Wouldn't it be a beautiful thing if I had a drug category that could work to inhibit this integrase enzyme? Therefore, not a lot of people would be able to inhibit this. for the actual viral DNA to be incorporated into the O cell DNA and why is that a problem? Because if you incorporate this, guess what? Every time you try to replicate this DNA, guess what else you're replicating? You're replicating the actual viral DNA. Every time you transcribe this DNA, guess what you're transcribing? You're transcribing the viral DNA to make more viral RNA. That's bad news bears. So we need to have particular drugs that can inhibit this process. What are those drug categories? So within the integrase inhibitors here, again, we have that same concept here. Here is your host cell DNA. This is a host DNA. I'm going to put host DNA. This is the viral DNA. I'm going to combine these two, take a little cut out of this, add this viral DNA into the host cell's DNA. So now I have the combo there. That's it. what this actual drug will I'm sorry this enzyme will do if I give particular drugs that inhibits that that'll inhibit this process these drugs are dolutegravir, raltegravir and elvitegravir do you guys notice a very specific like similarity between all of these you notice this part here tagravir It's in every single one of them. So we can remember the integrase inhibitors by ending in Tegravir. We can remember the NNRTIs by having a vir somewhere in the center of the actual drug name. So far, we're making some steps, okay? So if you're not sure, you get a question, you're like, I don't remember which one of these are. It's okay if you don't remember the entire name. Just look for one of the actual common root words against all of these. All right. That's our integrase inhibitors. The next one we're going to have to talk about is the protease inhibitors, but let's kind of go over this continual process of how this virus is actually causing problems. So we said that this actual viral DNA will do something else. Let's say that we have this process where we take the actual transcription process. So I have my transcription process where I'm actually going to read the actual DNA, and that includes the viral DNA, transcribe that, and when I transcribe it, guess what I'm going to do? I'm going to transcribe some of the viral DNA and make viral RNA. So now I'm going to have some viral RNA that I'm going to make. Now what happens here? When I actually do that, when I make some of this RNA, so I'm going to start popping out tons of viral RNA here. When I pop out all of this viral RNA, Guess what's going to happen here? This RNA is then going to go out into the cytoplasm and find some ribosomes. When it goes and binds on to these ribosomes, it'll then use the ribosomes to undergo translation. So this process here where we take the actual DNA, the viral DNA, and make more RNA is called transcription. The process where I take the actual viral RNA and then try to make proteins as a result of that is called translation. So this is the transcription process. the translation process. Now, I make these particular proteins utilizing the actual viral RNA. Once I make these, I make these things called polyproteins. Now, these polyproteins are just a clump of proteins. And what we need to do is, is we need to utilize a very specific enzyme called proteases. Because what proteases do is they take and cleave the actual polyprotein so that we can make a lot of different types of structural and functional proteins. So the protein that are going to be important for the actual viral structure as well as other particular types of enzymes. So we're going to use this to make a bunch of structural proteins and we're also going to use this to make a bunch of functional proteins. But this will not happen unless I have what particular enzyme present? The proteases. So the proteases will enable this particular process. They are integral in being able to cleave these polyproteins into structural and functional proteins. If that doesn't happen, I'm going to have to do something else. I won't be able to make all of the integral viral proteins. The ones that are like such as reverse transcriptase, such as some of the actual proteins that make up the actual structure of the virus. So, very important that that enzyme is present. What if I use a drug category that will actually work to inhibit these proteases? And if I inhibit these proteases, they won't be able to take the polyproteins that were translated and they won't be able to cleave them. And so if I can't cleave them, I will not be able to make any. any structural and functional proteins. If I can't make any of these dang structural and functional proteins, what do you think is gonna happen? Then I'm not gonna be able to do what? I'm not gonna be able to use this particular proteins, run it through the Golgi apparatus, and then from here, use this to make my particular virus proteins. So I won't be able to have like my core proteins or the capsomere proteins. I won't be able to make some of the particular enzymes inside of this actual virus. I won't be able to make some of these actual GP proteins here on the surface. And so that's all going. to be inhibited. That's not going to be helpful. I can't actually make a new virus that way. So, I'm going to use these drugs to be able to inhibit this process. Now, if you look at these drugs, there's like a million of them, right? You're like, oh my gosh, Zach, I can't remember all these dang things. Don't worry, I don't remember them either. But if you notice here, adizanavir, durinavir, indenavir, lopinavir, nilfenavir, sequinavir, tepranavir, ritonavir. Do you notice something? You notice navir is at least present in every single one of these. That's what I want you to remember. If you see the ending with navir, you have a protease inhibitor. So in an RTIs, there's a vir in the center. Integrase inhibitors, there's a tegravir at the end. And protease inhibitors, there is a nevir at the end. And again, we know how these drugs particularly work. They actually work to, again, they work on these polyproteins and specifically there's something called gagpol polyproteins. And what they do is they help to be able to act as a protease to cut these actual polyproteins into all the different types of structural functional proteins that are integral into making the actual virus. Now, remember I told you that you have that viral RNA. Some of the viral RNA, guess where that viral RNA is going to go? The viral RNA that we actually have out here, we're going to have that get taken up into the Golgi apparatus. In combination with all of these different types of proteins that we made from it. And then we're going to incorporate that actual RNA into the virus. Then from there, we're going to put it into a vesicle from the Golgi apparatus and then have it move to the actual cell membrane, where it will fuse with the cell membrane and exocytose all of these viruses and release it out into the actual interstitial fluid or into the vascular system to go and infect other cells. If we work, so particularly utilize maybe a combination of some of these drugs to inhibit particular parts of this actual life cycle of the HIV, we can potentially prevent this viral replication and again continual spread of the virus. But what is the particular regimen that we should actually utilize? The heart regimen or the highly active antiretroviral therapy regimen is really based upon the foundation of NRTIs. We need at least two of those NRTIs to be able to perform this process. So it's always going to be two NRTIs no matter what. So you can pick any one of those above. We'll talk about some of the adverse effects and contract indications of some of them that would obviously deter you from using that one, but it's always going to be two NRTIs. Now once you do that you can add on one of the other agents. We can utilize either a N- NRTI and again the utilization of one of those depends upon the side effects or the adverse effects and contraindications that you want to avoid or an integrase inhibitor we're gonna put I and I or a Protease inhibitor we're gonna put PI and again the choice of which one of these you pick can kind of also depend upon HIV Genotype, but it also depends upon the actual adverse effects that you're trying to avoid or contraindications now And that's the baseline heart regimen. What about these other two drugs? That was the purpose purpose of even mentioning these. These are adjuncts that you can add on to this particular therapy. So remember I told you, what was the point of even talking about Moraviroc or Infuvertide? The reason we would add on Moraviroc is again, they have to have a CCR5 receptor. So you can use this in your HIV resistant strange, but particularly it's an add-on. If they have, they have to have a CCR5 positive receptor, but you can utilize Moraviroc. As an add-on in the HIV resistant strains especially to the NRTIs, but they have to have they have to be positive for the CCR5 Receptor if they're not positive. It's not going to provide any extra additional benefit. The other one here is Infubertide so So Infuravitide will add this bad boy on and the HIV resistant strains that again are resistant to the NRTIs. So this is an add on as well, particularly in HIV resistance. very specifically to the NRTIs. That is the basis of the mechanism of action of these drugs, the names of these drugs, the categories of these drugs, and then again, the particular regimen that you... would put a patient on who's been diagnosed with HIV. Again, that is the basis there. We have to now talk about adverse effects, contraindications, things that you should worry about when you put these actual medications on a patient. All right, so now we're going to talk about the adverse effects and contraindications. of these anti-HIV medications. Now, when we talk about these, we'll go over them based upon the category. So we talked obviously about Infiravitai, Moraviroc, NRTIs, NNRTIs, integrase inhibitors, and protease inhibitors. We went over the mechanism of action, the names, don't remember all the names, just remember again the big root word if you can for those. But what I want you now to remember is particularly the adverse effects. So this is obviously important whenever you're getting ready to put a patient on one of these medications, it's important to think about what kind of like medical history they have. And then again, that might actually deter you from using this particular drug. and trying another one. So, NRTIs are the backbone to a lot of your heart therapy, right? The highly active antiretroviral therapy regimen. If you notice, there was always two of those with one of the integrase or one of the proteases or one of the NRTIs. One of the big effects that you can see with all of these is mitochondrial toxicity. So it has some type of way of being able to alter the mitochondrial activity. And so you can see mitochondrial toxicity. Now, there are so many things that the mitochondria does. So. So it's important to remember. One of those things is that it obviously is important for a lot of energy production. So ATP formation, that's super crucial when it comes to muscles being able to function. If you don't have that ATP, the muscles will actually start to have issues with that. And you can develop something called myopathy. The other thing here is we don't know exactly how, but it actually may alter the neurons in some type of way, particularly the peripheral neurons, where they actually have some type of damage as well. And this may lead to peripheral neuropathy. The other thing that's important here is that it's also involved in fatty acid oxidation. So we take particular fatty acids and we oxidize them into acetyl-CoA in the mitochondria. If you cause mitochondrial toxicity, are you going to be able to perform fatty acid oxidation? No. And so then what happens is fats build up inside of particular tissues. And one of the big tissues there is the liver. And guess what happens if you have lots of fats building up in the liver? This can cause steatosis. So you may also see hepatic steatosis. And the other thing here, which is pretty straightforward, for it as well. Think about whenever you have a patient who are a general, whenever you have something like a you have what's called pyruvate. Pyruvate is supposed to get taken up into the mitochondria and convert into acetyl CoA. If the mitochondria isn't allowing for the pyruvate to get converted into acetyl CoA because of the toxic effect, what does it actually get converted into? Pyruvate gets converted into lactic acid and so that can also be another issue where you make lots of lactic acid you can see something called lactic acidosis and so these are the possible effects of these drugs due to the mitochondrial toxicity you can see this in all of these again myopathy neuropathy and then hepatic steatosis lactic acidosis the other thing that you can see here is something called pancreatitis so pancreatitis there's a lot of different reasons for this one do you guys remember when we did the video we talked about i get smashed it was the mnemonic to remember all of the particular causes and the d and i get smashed is drugs well there's There's a lot of drugs that can do this, but one of these is your NRTIs. And there's two particular ones that I want you to remember. One of them is called Stavudine. This is a big one, and I don't want you to forget this next one called Didanacine. These are two of the particular drugs that may actually be able to induce some type of pancreatitis. All right. The next thing here is nephrotoxicity. So these do have the ability to cause some type of nephrotoxic effect and lead to an acute kidney injury. Okay, so nephrotoxicity is another big one that can lead to an acute kidney injury. And the big one out of all of these is tenofovir. Tenofovir. And what's interesting is tenofovir is actually technically not necessarily a nucleoside reverse transcriptase inhibitor. It's actually a nucleotide reverse transcriptase inhibitor. It's actually one of the only ones, tenofovir and something called adefovir. But either way... that's the one that i want to remember and has a nephrotoxic effect the other thing here is there may be some bone marrow suppression so bone marrow suppression you may see this particularly with zidovudine so zidovudine may actually cause a little bit of bone marrow suppression but it actually drops your number of red blood cells and drops your number of neutrophils and so that's another particular thing to remember is you can see anemia and neutropenia particularly with zidovudine now here's the other one that's really interesting this one it's It's a weird one, but abacavir. So abacavir can actually cause something called a hypersensitivity reaction. So you can see a very significant hypersensitivity reaction. So what happens is this drug may actually interact with particular types of mast cells and lead to a massive histamine response. And this massive histamine response may lead to a lot of like nasty effects. One is it may lead to nausea. It may lead to vomiting. It may lead to diarrhea. It also may lead to a nasty rash. It may lead to fever. And it may lead into respiratory failure. Now it's important to remember that anytime you put somebody on a baccalaureate to avoid any type of hypersensitivity reaction, there are certain patient populations that are susceptible to this. And so you want to check like an HLA-B, 5- And generally the patients who have this type of HLA susceptibility gene are at high risk of a hypersensitivity reaction, such as developing nausea, vomiting, diarrhea, abdominal pain, rash, fever, and respiratory failure if you put them on this particular drug. All right, so big things to remember, again, for the adverse effects for the NRTIs, all of them can cause mitochondrial toxicity, pancreatitis is particular to Stavudine and Dianosine, nephrotoxicity with Tenofovir, bone marrow suppression, particularly anemia and neutropenia with Zidovudine, and then abacavir can cause a hypersensitivity reaction, HLA-B5701 haplotypes. So make sure you check this because if not, you give it to them, they can develop fever, rash. They can also develop nausea, vomiting, diarrhea, and respiratory distress. All right, the next category that I want us to be able to talk about about is the NNRTIs, the non-nucleoside reverse transcriptase inhibitors. So you guys remember these ones? Xales, DT, right? So Zidovudine, Abacavir, Lamivudine, Emtricitabine, Stavudine, Tenofovir, and then Didanazine. For NNRTIs, do you remember what they end in? They always are, they have the the root word, it's the Vire, it's in the center, right? So efavirenz, nevirapine, delaviridine. Now, with these, there's a couple different adverse effects that I want you guys to remember. Hepatotoxicity is a relatively common one, and we see this more specifically with F of irons. So F of irons and nevirapine. You're going to notice a common trend that F of Irons will really jack people up because that's one particular thing that you can see here is hepatotoxicity. So you may see a bump in their LFTs. The other thing is that it can actually cause CNS toxicity and we really say that this causes some insane and I mean vivid like dreams to where it's really really weird and so they can develop these crazy like you know odd vivid dreams and so we see this primarily with f of irons so f of irons will give you the hepatotoxicity would also give you CNS toxicity that'll cause like these insane vivid like dreams so f of irons And the last one is going to be the teratogenic effect. So we don't want to give this to a particular patient if they are pregnant. So teratogenic one is efavirenz. And then the other one that I want you guys to remember is delaviridine. All right, that covers the in-in RTI adverse effects. Now let's come down and talk about the integrase inhibitors and the protease inhibitors. All right, so the next thing with integrase inhibitors, again, if you guys remember the integrase inhibitors, this was the ones that actually had what particular thing? The Tegravir at the end. W-Tegravir, Radix. Elvategravir. So with integrase inhibitors what they've been actually shown This is an actually nice one to remember here is that they can actually cause rhabdomyolysis And so if you have someone who's rhabdomyolysis you may expect an increase in their CK Plus if you also have a lot of rhabdomyolysis your kidneys will take up a lot of that myoglobin and put a ton of that myoglobin inside of the urine. So you may expect a lot of myoglobin in the urine and a increase in their actual CK. So look for that in patients who have, are taking integrase inhibitors. Now protease inhibitors is a big one as well. Now, one of the things that this can actually do for protease inhibitors, and again, how do you remember these ones? Do you guys remember? It was ending in nevir. So if it ends in the nevir, then you know they have a protease inhibitor. Atazenavir, ritonavir. sequenavir, many of those drugs. Lepenavir, keep going on. But what happens here is that these drugs particularly can produce, one of them, can produce what's called a crystal-induced nephropathy. And when it produces this crystal-induced nephropathy, it can actually lead to some nasty acute tubular necrosis and lead to a nasty acute kidney injury. And there's one particular drug that I do want you guys to remember for this one. And this particular drug here is going to be indenavir. And indenavir is a very common drug. has been shown to be able to increase the formation of crystals that can actually cause an acute tubulin necrosis and destruction of the actual kidney tubules leading to an acute kidney injury. The next thing that I want you to remember is that all of these drugs have the ability to produce something called lipodystrophy. What happens is you see a lot of this fat accumulation in lipodystrophy and it can produce kind of like a Cushing-like effect where you get the buffalo hump, the swollen moon face and that type of effect similar to Cushing's syndrome. The other one that's really, really interesting here is that this can actually cause very, very high levels of glucose. So you can see something called hyperglycemia. Now, why does this happen? Well, what happens is most of these drugs, they'll inhibit this particular transporter here called a glute transporter. And glute transporters are supposed to be able to take and shuttle glucose into our actual cells. So they want to bring glucose into our cells. But if you give particular drugs, such as these protease inhibitors, they will inhibit these glut transporters. If you inhibit these, can you take glucose into the cell? No. So if you can't take glucose into the cell, where does it stay? stay it builds up inside of the bloodstream this can cause hyperglycemia the last thing here is that you also have a lot of these particular enzymes called CYP450 enzymes that are involved in biotransformation taking a drug adding on different types of molecules like glucuronates and etc and making them a little bit more polar so it's involved in like drug metabolism we can have particular protease inhibitors one of the most specific ones here called ritonavir and ritonavir works to be able to inhibit the CYP450 enzymes. And so what happens is if you inhibit them, you develop higher levels of that drug concentration. And that can be concerning depending upon what type of drug you're taking. If you're taking like warfarin, maybe you have a higher risk of now having bleeding. So it's the common effect they're thinking about other drugs that they're taking if you put them on something like ritonavir because you may be increasing the concentration of that drug because it inhibits the CYP450 enzymes. Okay, that is the adverse effects, contraindications, mechanism of action, indication. all the names of the drugs for HIV, but we're not done. Now what we gotta do is we gotta talk about influenza. All right, so now let's talk about the influenza medication. So influenza is obviously the flu. All right, so if somebody actually becomes infected with influenza, what happens is it primarily is spread through respiratory droplets and gets some part of your respiratory tract, at least like an upper respiratory tract infection, lower respiratory tract infection in some way, shape, or form. So we know that the influenza virus usually gains access into our body and to affecting our actual immune system via the respiratory tract. So what happens is this will bind on to particular cells within the respiratory tract and what it does it'll actually bind into there Get its actual viral structure into the particularly in this case It's viral RNA into the actual host cell structure use it to be able to make more viruses So how do we come up with the particular drugs to be able to target the actual life cycle of the influenza virus? Well, let's go quickly through the actual life cycle So once the actual influenza virus gets into the respiratory tract binds on to respiratory tract cell, how does it actually do that? Well, here's our influenza virus virus. On the influenza virus, we know that it's going to have an RNA inside of it. And we know that it's going to have all these different types of proteins around it. One of the big things to remember here is you see these blue proteins, these baby blue proteins? Proteins I want you to remember is going to just be we're going to put H4. This is the hemagglutinin. All right, so this is a hemagglutinin protein. Then in red here, you're going to have something called neuraminidases. Okay, so these are your neuraminidases. And then here in orange, you're going to have something called a proton ion channel. So we call this an M2 channel. So we're just going to put ion here. We're going to put M2 ion channel. Now, what happens is once this virus is actually spread via respiratory droplets, gets into the respiratory tract and tries to bind onto to some type of cell within the respiratory tract, it utilizes these pink proteins. You know what these pink proteins here are called? These are called sialic acid residues. So this is called sialic acid. Now, with this sialic acid, we need these hemagglutinin proteins on the actual influenza virus to be able to bind with the actual sialic acid residues. Once it binds, once the hemagglutinin binds with the sialic acid via a process called receptor-mediated endocytosis. it brings the virus into the actual host cell, this respiratory tract epithelial cell. Once inside of the cell, we need to be able to uncoat this virus so that we can get that RNA, that nucleic acid, out. We want this nucleic acid, this viral RNA, to be released. We need that RNA to be released so that we can get it into the host cell nucleus. So in order to do that, I need to uncoat this virus. That's where those M2 proton channels come in. So what I'm going to do now is, I'm going to utilize particular M2 proton ion channels to pump protons. into this structure to kind of allow for it to acidify and get this uncoating to occur. So again, these M2 ion proton channels will allow for uncoating of the virus. So let's actually write that down. So this process here is called uncoating. so that we can release the actual viral RNA. Once the viral RNA has actually been released from this actual structure here, it then gets taken up into the actual host cell's nucleus. And in the host cell nucleus, you know that you have host DNA, right? So this is going to be the host. cells DNA inside of this actual respiratory epithelial cell. What happens is this host DNA is always making RNA, right? So through a process called transcription, it'll be making mRNA. Now, you know, in order for mRNA... to actually interact with ribosomes, you guys should know this, right? That we go through a particular like post-transcriptional modification. So in order for this ribosome to truly interact with the actual mRNA, it needs a very specific type of structure. And we're gonna put this structure here in purple here. This is called our five prime cap. So we need that five prime cap in order for this actual translational process to occur. Well, guess what? There is really no five prime cap on that viral RNA. RNA. So this viral RNA is kind of stuck. It won't be able to use the ribosomes to be able to create proteins. So what I need is, I need the 5'cap that's present on this host cell mRNA to be switched over onto that viral RNA. And there is a very cute little nuclease enzyme here. So you see this enzyme right here? This is called a endonuclease. And what the endonuclease will do is, is it'll take and cut this actual 5'cap off. off and transfer that onto the viral RNA. And then the result here is that I'm going to have a viral RNA with a nice little five prime cap on it. And now I can actually utilize the host cells ribosomes to be able to make proteins. So then from here, This is going to be this five prime cap that's actually getting passed over. And now I'm going to allow for this viral RNA to come out of the actual nucleus and then interact with the actual host cell's ribosomes. And now here it's going to be able to use. the host cells ribosomes to be able to synthesize a bunch of proteins and these are proteins that are structural proteins functional proteins I need these proteins to be able to allow for me to assemble a new virus so all these proteins will actually get taken taken to the actual Golgi apparatus, and then we'll also take something called the RNA here, and utilize that to make, again, a new virus. That virus will then go, again, after it forms a vesicle from the Golgi, to the actual cell membrane, fuse with the cell membrane, and try to exocytose it. And we'll get to this part in a second. But we at least got to the RNA here that required this five prime cap from that endonuclease to do this, okay? Now, the other thing... here is that this RNA, we're going to want to try to be able to make more of this RNA. And so there's processes where the actual RNA will actually try to make more RNA, make more RNA, make more RNA via particular RNA polymerases. And so what we're going to do is we're going to continue to keep trying to make More RNA, utilizing RNA polymerases. So now I'm going to make a bunch of this viral RNA. This RNA that I actually am going to make is going to get taken to the actual Golgi apparatus and then go through this process where I can incorporate that with the actual viral proteins to make a new virus. Okay? Now... Here's where it's actually really important that you understand. We can actually have particular, well, actually, one more thing, one more thing. So we have the RNA, we combine it with the actual structural functional proteins, made the actual virus in the actual Golgi apparatus, formed a vesicle, had to go fuse with the cell membrane. When it fused with the cell membrane to try to release it, it gets stuck. So it's trying to get off of the actual epithelial cell so it can go and infect other epithelial cells. But it can't do it. You want to know why? Because that hemagglutinin protein, remember this one? This hemagglutinin protein is still... Still stuck. to the sialic acid. And it can't release away from the sialic acid unless we have another particular protein that comes in and cleaves that connection between the hemagglutinin and the sialic acid so that we can release the virus away from the actual cell so it can go and infect other cells. There was one other that was missing, and that was that red protein, the neuraminidase. So what happens is the neuraminidase protein will actually cut this particular structure here. It'll cut this particular structure here. cut the link between the sialic acid residue and the hemagglutinin. And that'll basically allow for the virus to bud away and be released away from the actual host cell. So this will allow for the budding or the release. if you will, of the virus away from this host cell. So we have a couple different parts here which are really, really important. One is the uncoating, which is due to these M2 ion proton channels pumping protons into this endosome here, allowing for the RNA to be released. into the actual host cell cytoplasm and then move into the nucleus. Second one is we have this five prime cap process. So this is the first step. Second step is this endonuclease that allows for the transfer of the five prime cap from the host cell mRNA to the the viral RNA and then the third step here is going to be the budding and the release of the virus from the actual host cell. We have drugs that can target each one of these particular steps. The first one here is the uncoating. We have particular drugs that can actually inhibit this into ion proton channels inhibiting the ions from being able to get into the actual endosome and then release this RNA. What are the particular drugs that we can utilize to inhibit this particular process? If we inhibit this process you You will not allow for the release of the actual or the uncoating or the liberation of the viral RNA out into the actual host cell cytoplasm and then get utilized by the nuclear machinery to make more RNA and more proteins. These are these particular drugs. And this drug that we can actually utilize is called amantadine. Now amantadine is pretty much only utilized in influenza A. You can see this in a couple other diseases. You may see this in something like Parkinson's disease. But again, big thing for amantadine is it's primarily only used in influenza A. Now the second step here is this part here where you have this endonuclease transfer the 5 prime cap from the host the host cells mRNA to the viral RNA. This endonuclease enzyme if we inhibit it what if we inhibited this cute little enzyme here so we inhibit this process if we inhibit this process it won't be able to transfer the 5 prime cap onto the viral RNA if we don't have the 5 prime cap we won't be able to allow for this to bind with the ribosomes and the synthesis of the proteins will be shut down. What is the name of the drug that would actually do this? Well, it's an endonuclease inhibitor and this is called biloxivir. So biloxivir can be used in influenza type A and B, but generally it has to be less than 48 hours of symptom onset. So if someone develops particular symptoms of influenza and it's at least less than 40 hours since their symptoms actually developed, we can utilize this drug to potentially reduce the severity of the symptoms, but it's not going to prevent the infection. It'll just reduce the severity of the symptoms that they'll have. So again, that's the whole process that I want you guys to remember. Again, just to recap it again, you have here 5'cap on the actual host RNA. You're going to try to transfer that 5'cap onto the viral RNA so that it can be utilized by the actual ribosome to be able to make particular types of viral proteins. When you give this drug, biloxivir, it inhibits this process, the transfer of the 5'cap. So you won't be able to cut this actual 5'cap off and then transfer it over. over onto the actual mRNA. All right, that's the concept there for the second step. The third step here is called your neuraminidase inhibitors. Now, remember I told you that Neuramidase is designed to be able to cut the actual hemagglutinin, which is basically the part of the virus that's stuck to the sialic acid. We can't get the virus to bud off and go and infect other cells unless it has that enzyme that cuts that connection there. What if we used a drug that inhibited that neuramidase from cutting the connection between the sialic acid and the hemagglutinin? Would we be able to release the virus, allow for it to bud off and go and infect other cells? No. So what if I utilize particular drugs? to inhibit this particular process. These are my neuraminidase inhibitors. And these particular drugs are called oseltamivir and another one is called zanamivir. And again, these two particular drugs are only used again in influenza A and B. You can also use this as a prophylaxis, particularly in two situations in adults. And in children, so kids less than, so greater than or equal to five years of age, depending upon particular risk factors. But again, important to remember here for the influenza A and B is this has to be, again, less than 48 hours of symptom onset. So if the patient develops symptoms of influenza A or B, they tested positive, and it's at least been less than 48 hours, you can put them on these drugs to reduce the severity of the symptoms of the actual influenza. But again, it is not actually going to prevent the infection. There is some thought that maybe it can be used prophylactically in certain patients that are at high risk in adults and children who are greater than or equal to five years of age. But again, not a lot of evidence there as well. All right, now let's talk about adverse effects and contraindications. All right, so the adverse effects. Thank goodness that a lot of these drugs, Vloxavir, Oseltamivir, Zanamivir, they really don't have many side effects. They're well-tolerated whenever they're given. It's the amantadine that's actually the one that can actually cause some kind of toxic effects. So amantadine is really the one that's worth remembering for the effects. And what it can actually do is it can cause a... ataxia. It can also cause levito reticularis, which is a type of skin manifestation. And it can also potentially work on the heart to be able to prolong the QT interval, increasing the risk of torsades to points. So when again, when it comes down to amantadine, amantadine can actually cause ataxia. It can lead to levito reticularis and it can also prolong the QT interval. long the QT interval increasing the risk of torsades to points. Alright now that we've talked about that let's move on to the next virus which is the hepatitis medications. Alright so now we're going to talk about the anti hepatitis medications. So you have a patient who has hepatitis the big ones that we actually should know that we can treat with antivirals. is hepatitis B virus and hepatitis C virus. Let's talk first about hepatitis B, the antivirals that work against that, and then after that we'll talk about hepatitis C, its life cycle, and again the antivirals that act against that. So first thing is you'll obviously know that the hepatitis viruses, hepatitis B virus in this case, loves to attack which type of tissues? The hepatic tissues, so it loves the hepatocytes. When it acts on the hepatocytes, it obviously produces a lot of damage, inflammation, and then again increases the risk of hepatocellular carcinoma, etc. How does this happen? this actual virus work though, what's the life cycle? Some crucial points along the way because there is very specific drugs that we're going to utilize to target very particular parts of its life cycle. Okay, so we have here the HIV virus. When the HIV virus, I'm sorry, the hepatitis B virus. Ooh, geez, hepatitis B virus. When the hepatitis B virus works on the hepatocytes, it uses very specific types of protein channels. Like there's like an NCTP protein, if you really want to know that. But basically what happens is once the hepatitis B virus is binding with this, it then uses these proteins to get taken up into the cell. Once it's taken into the actual hepatocyte, what happens is it releases its partially double-stranded DNA. So this is a DNA virus. Once it releases its what's called partially double-stranded DNA. It then will get taken up into the actual host cell's nucleus. Once it gets taken up into the host cell's nucleus, it'll utilize particular enzymes to be able to take this partially double stranded DNA and convert it into a completely circular double-stranded DNA. So then it'll actually convert this into a complete circular double-stranded DNA and we call that CCC DNA if you really want to know that. Now What happens here is from this process, here's what's really interesting. From this process, we're going to take this complete DNA, this complete double-stranded circular DNA, and it's going to be able to replicate itself. So it's going to be able to undergo kind of a consistent replicative cycle. So it'll be able to undergo a lot of replication. So this process here will be its replication. Okay. The other thing that's really interesting about this is that this can also undergo a transcription process. So when an under... undergoes a transcription process will make lots of RNA. Different types of RNA. One of the RNAs that it'll actually make is mRNA. So it'll make a viral mRNA, but it'll also make another type of RNA. And this RNA that it'll also make here besides the mRNA is called pregenomic. RNA we'll talk about what that means in just a second. But what happens is You get this virus again to bind to the actual hepatocytes once it binds in it gets taken up the virus then gets uncoated and released releases its partially double-stranded DNA, gets taken up into the nucleus, gets converted into complete double-stranded circular DNA. That complete circular double-stranded DNA can utilize particular enzymes, DNA polymerases, to replicate itself and make more of it. Then on top of that, it can utilize particular RNA polymerases to make RNA. One of them is mRNA and the other one is called pregenomic RNA. The mRNA will then go and utilize the host cell's ribosomes to be able to make particular types of proteins. And these proteins, obviously, that it's going to synthesize can be structural, that are integral to the actual structure of making a new virus. but it can also be functional. So this can be particular types of enzymes, DNA polymerases, RNA polymerases, proteases, et cetera. And so what happens is these proteins are very, very crucial because we're gonna take some of these proteins and move them towards the Golgi apparatus with the end goal being that we're going to incorporate this into the virus, make a new vesicle from the Golgi, and that's going to contain very structural proteins and functional proteins that are important to the viral structure and function. Now, we have the protein component of the virus. We need the nucleic acid component of the virus. Right now, we have RNA. This virus is DNA. I need to be able to convert this pre-genomic RNA back into DNA. What is the name of the particular enzyme that converts RNA to DNA? That's got to be... to be a reverse transcriptase enzyme. And guess what this cute little blue enzyme is? This is a reverse transcriptase. And what it'll do is it'll take this pregenomic RNA and convert it into DNA. It actually turns into something called negative sense DNA and then been positive sense DNA but eventually we're going to convert this into partially double stranded DNA so that is the goal is to convert this back into the DNA component that it was prior whenever it infected the cell because we want to replicate this virus and make more of it so that we can go ahead and pass this virus on to other cells damage more hepatic cells so this DNA will then be taken to the Golgi combined with all the different structural and functional proteins make a new virus and then from there it'll be put into a vesicle from the Golgi and then fuse with the cell membrane and exocytose the hepatitis B virus more of them so they can go and affect other hepatocytes so we have particular things that we can do to shut this HBV virus from replicating and then passing on to other hepatocytes and damaging more what are those drugs glad yes well the big target here is this bad boy that's the biggest one this is probably the rate limiting step that we have to target is the reverse transcriptases. If we inhibit this, we won't be able to take the pre-genomic RNA, make DNA. It won't have the coding that it needs for it to be able to infect other cells, make more proteins, etc. So if we shut it down right here, we'll... essentially prevent viral replication, formation, infection of other types of hepatocytes. This is a big step. So we need reverse transcriptase inhibitors to be able to inhibit this particular enzyme. If we inhibit this, we will not allow for this step to occur. We won't allow for us to be able to incorporate the actual DNA into the actual hepatitis B virus and we won't have the nuclear machinery that it needs to be able to replicate, make more proteins, and perform all the nasty functions that it does. That's a pretty cool thing. So we have two different drug categories within this reverse transcriptase inhibitors. And this is your NRTIs. That sounds familiar. Nucleoside reverse transcriptase inhibitors. What do they do? Very simple. It's very, very simple, guys. Think about it. Here we have our... RNA. Here's the pre-genomic RNA. We need to convert this into DNA. What does it do? It reads the RNA, reads the actual nucleotides on the RNA, and then adds on nucleotides on the opposite, the daughter strand in this case, to make a new DNA. strand but it needs nucleotides to make DNA off of the RNA template guess what these NRT eyes act like they act like nucleotides their nucleoside reverse transcriptase in the present usually they don't have a hydroxyl group on the end so what happens is you try to add them on okay Okay, let's say that there's a, you know, you try to make a new strand here off of this. You're trying to make a new strand. What's going to happen is you have the nucleotides that are complementary here, and they're just interacting perfectly. But then this reverse transcriptase goes into its pocket, grabs off a NRTI, and tries to add it on here. Adds it on. When it adds it on, guess what? You can't add anything. else to the actual strand because it has no hydroxyl group for you to add another nucleotide onto. And so it terminates the formation of further DNA. You can't make DNA, you can't make the actual coding that you need for that virus to continue to replicate and cause all its nasty functions. And so that's where these drugs come into play. So the two NRTIs that I really want you to remember that work to inhibit this particular enzyme here is lamivudine. Okay, and Entacavir. Alright, so Lamivudine and Entacavir are the two big ones that I want you guys to remember. Now it's hard to, you know, there's no particular beautiful thing that's similar between these two that has a root word. So it's unfortunate that you have to just remember it. But the other ones, the NTRTIs, they're basically just like Entacavir. NRTIs, they just are a nucleotide. They just, again, they have kind of a similar function just to the NRTIs. They basically terminate the formation of more DNA off of your RNA template because they won't allow for further growth of nucleotides or polymerization after them. These ones are nucleotide reverse transcriptase inhibitors. These are nucleoside. So this is adefavir and tenofavir. Do you notice a similarity between both of these? They both have fovir in them. So we can remember these by... The Fovir. Okay, so your NTRTIs have the same function as the NRTIs. It's just they are nucleotides. This is a nucleoside. But they're pretty cool drugs. Now, one of the big things that you have to remember with these particular a Defavir and Tenofovir, you should actually watch out for something called Fanconi syndrome. This is extremely rare but it's something they may test you on on your boards. So Fanconi syndrome is this condition where it's a triad. Okay and again you see this with a Defavir, a Defavir and Tenofovir. And what happens with Fanconi syndrome is it's a condition where where you excrete out three particular things into the urine. You excrete out lots of phosphates, so you have what's called phosphateria. You excrete out a lot of glucose, so you have glycosyuria. And you excrete out a lot of amino acids, so you have amino aciduria. So there is a lot of phosphates, glucose, and amino acids that are excreted into the urine, and this is called Fanconi syndrome. So remember that as a potential adverse effect whenever you're monitoring these patients for particular electrolyte abnormalities, their glucose abnormalities, and particular amino acids. amino acid abnormalities, this can be seen with a Defavir and Tenofovir. Now, that's these drugs working on that particular part of the pathway. The next drug is a little interesting, a little odd, has a lot of different functions, if you will. Here's what's really interesting. You know the basic kind of immunologies, whenever you have a virus that infects a particular cell, so it infects these cells, these cells are now viral infected. When they're viral infected, what they do is they try to alert nearby healthy cells that that there is a virus in proximity and it's causing a lot of problems. And they release a particular molecule that we naturally make in our body called interferons. One of them is interferon alpha, beta. These are the big ones. And what happens is the interferons, they circulate through your bloodstream to nearby healthy cells, nearby healthy hepatocytes that haven't been infected by a virus yet. And they bind onto these cells and via particular second messenger systems, they work to be able to stimulate the host cell's DNA. DNA to make particular types of proteins. So it will increase the particular production of proteins. Now these proteins that it makes are very significant. One of the proteins that interferon alpha makes is, is it makes proteins that will actually act as anti-viral peptides. In other words, they'll break, they'll actually prevent protein synthesis, they'll prevent the actual RNA formation, and they'll do something else. So they'll do three particular things. So what do interferon alphans do? Here's what I want you to remember. There's three particular particular things that I want you to remember with interferon alpha. One of the proteins is it increases antiviral peptides, antiviral peptides, and these antiviral peptides, which are very, very interesting here, can do a couple particular things. One is that these antiviral peptides can actually inhibit protein synthesis. So particularly what they'll be able to do is they'll help to be able to inhibit this particular process. So one of the things that you can see here is that if we were to kind of follow this, it makes these particular proteins interfere on alpha, will inhibit the actual protein synthesis. It also may prevent particularly this process of the RNA. Okay, so it might also be able to prevent the RNA from being able to convert it into DNA. So there might be another particular function here where it may be able to inhibit this particular process by working on very specific enzymes. And the second thing that it can do is it can also increase the expression of very specific molecules on the actual cell membrane. And these are called MHC1 complexes. So it increases antiviral peptides. One of them is it's going to inhibit protein synthesis, okay, of the actual viral proteins. It may also inhibit viral RNA formation. And the third thing that it can actually do is it can increase the expression of. MHC1 complexes. Now why is that important? I'm glad you asked. So you know whenever you have like a cell that's infected, so here's our cell, it's infected with a particular virus. When it expresses these MHC1 molecules, so here's MHC1 molecules, what that does is it'll express a piece of the actual virus on it. And when we have immune system cells, you know these immune system cells called your CD8 positive T cells? So these can be like your cytotoxic T cells. they'll notice this and when they notice this they'll say oh boy something wrong here and I'm gonna go ahead and release particular types of perforins and granzymes and kill this virus infected cell so that's how interferons work interferons are pretty intense they have ability to be able to increase antiviral peptides one of the ways is by inhibiting protein synthesis. Second way is inhibiting the viral RNA activity. Third thing is increasing the expression of MHC-1 complexes which causes more cytotoxic T cells to come to the area and kill these virus infected cells thereby preventing the replication, formation, and spread of the actual HPV virus. Pretty insane, right? Yeah, it's pretty cool. So you can actually use interferon's alpha in two ways. You can use them one way to be able to work against hepatitis B virus, but it also can be utilized in refractory hepatitis C virus, which we'll talk about a little bit later. But with interferon's alpha, what are the particular complications, adverse effects that you can see with this particular drug? One of the things is this teratogenic. So you wanna be able to avoid this in someone who is pregnant. So teratogenic. is one particular thing and the other thing is it can actually suppress the bone marrow drop the production of your red blood cells so called anemia drop the production of your platelets thrombocytopenia and drop the production of your white blood cells leukopenia collectively this is called pancytopenia so you may see pancytopenia as a potential adverse effect of interference so avoid this in women who are pregnant and avoid this in a potential patient who already has issues with anemia thrombocytopenia or leukopenia or monitor their CBC for any evidence of pancytopenia. So again, when we talk about the hepatitis B viruses, when we talk about the drugs that are targeting it, one is the reverse transcriptase inhibitors, your NRTIs, which is the lamivudine, and your, particularly, entecavir. And again, the other one is the NTRTIs. These are nucleotide reverse transcriptase inhibitors. This would be a adefavir, tenofovir. Big thing to watch out for these is, particularly adefavir and tenofovir can cause Fanconi syndrome. The other one is interferon alpha. increases the production of antiviral peptides that prevent protein synthesis, inhibit the activity of the viral RNA, and increase the expression of MHC1 complex, which cause increased cytotoxic T cell activity to destroy these virus-infected cells. The other thing is, again, watch out for in patients who are pregnant and watch out for any pancytopenia with interferon alpha. Okay, now that we talked about that, let's move on to the next one, which is the antivirals against hepatitis C virus. All right, so we're almost done, guys. Hang in with me, okay? We got hepatitis C virus, and we'll finish the hepatitis medication. So with Hepatitis C virus, again, same thing. We know that you have the hepatitis C virus. It's going to love to attack thee. liver cells. So it's going to cause damage to the liver, cause inflammation, and again, potentially increase the risk of hepatocidal carcinoma. Now, when the hepatitis C virus binds to the actual hepatocytes, it uses like a plethora of receptors. There's so many dang receptors, like LDL receptor and SRB1. There's just a plethora. There's no reason to remember all these dang things. Remember that the hepatitis C virus, though, is an RNA virus in comparison to the hepatitis B, which is a DNA virus. So when it binds with these particular proteins, it uses these to be able to undergo an endocytosis mechanism to be brought. into the cell. Once it's brought into the cell, it has to uncoat. Once it uncoats, it will then release its RNA into the actual host cell cytoplasm. So now, where's my markers? Oh my gosh, all of them are over here. Okay, so once we have this RNA get released, here's my beautiful RNA from the hepatitis C virus. This RNA is going to then go and bind with the ribosomes on our rough endoplasmic reticulum. So you see this is a rough endoplasmic reticulum, and then on there they're going to have all these ribosomes studying all the edges of it. This viral RNA, hepatitis C viral RNA, will then go and bind. and bind with these ribosomes. Once it binds with the ribosomes, the ribosomes are then going to utilize the RNA to do what? Translate it and make proteins. But it makes these big, big polyproteins. So as a result, I'm going to synthesize a bunch of polyproteins. Now these polyproteins that we synthesize actually from the actual viral mRNA via this translation. process. So this again, what is this called? Translation. We know this, right? We're going to make a bunch of these polyproteins. Now there's a couple different polyproteins that we should be aware of. First one that I want you to remember is called NS3. Then you have NS4A, NS5A, and then the last one is NS5B. Now, these particular structures are making up this big thing called a polyprotein. Now, this polyprotein, we need to be able to break it down. All right, so once this protease works here, it's going to break down this polyprotein. When it breaks down the polyprotein, it breaks it down. into two components. One is it breaks it into the different types of structural proteins. So obviously these are the different like capsaicin proteins, envelope proteins, all of those things, but it also breaks it into functional proteins. So these are proteases and polymerases, et cetera. So we need both of these in order for the virus to be able to replicate and in order for it to be able to function and obviously infect other cells. So in order for us to be able to form these we have to cleave this polyprotein and this enzyme is integral into actually being able to cut this polyprotein and it loves to particularly work on the NS3 site and the NS4A site. It's called a protease but we actually know what we call this dang thing. We call this an NS3 4A protease. I know it's ridiculous. ridiculous, but that's what we call this little cute pink enzyme. And what it does is it'll actually work to be able to cut this polyprotein, particularly at the sites and the different structural and functional proteins. We actually do have drugs that we can utilize to target that, preventing the cleavage there. We'll talk about that in just a second. But you know what else is really interesting? This NS5A and this NS5B have very interesting functions. NS5A, there's still some kind of debate exactly what it does. There's a thought process, but NS5B, we definitely know what it does. And what happens... What happens here is it's really, really interesting, is you take RNA, right, so we have the RNA that the virus is actually gonna be shedding into the actual cell. And what happens is we think that the NS5A, and we definitely know that the NS5B, are particular enzymes that are utilized to be able to replicate and make more of the RNA. So these are particular proteins that we may utilize to make more of the HCV RNA. So very, very important. So what if I had very particular drugs that I can use to inhibit the NS5A? Will I be able to make more of this RNA? No. What if I have a drug that can inhibit the NS5B? Will I be able to use that? You know what the NS5B is? It's actually an RNA dependent RNA polymerase. That's why we know it definitely is involved in this. So it takes RNA and makes more RNA. If I inhibit that particular protein, will I be able to make more RNA? No. Will I be able to make more virus? No. So this is why these are two important drug sites and then this protease is an important drug site. Now, once I actually have all of these structural functional proteins plus my RNA, what can I do? I can send this RNA. I can send these different types of proteins, all my structural functional proteins, and send it to the Golgi apparatus. From the Golgi apparatus, we'll package it, make a new virus, replicate more of these little suckers, and then exocytose them out to go and infect other cells. My question here is, what are the actual drugs that are actually going to target this protease? What are the drugs that are going to target this NS5A? What are the drugs that are going to target this NS5B? And then we'll finish off talking about this last enzyme. It has a little interesting weird function that doesn't really completely correlate with the life cycle. We'll talk about that one next. All right, so let's talk about these groups here. So we have one particular group called protease inhibitors. So these are protease inhibitors that actually are directly acting. So it will inhibit this NS3,4A protease. Perfect. preventing the cleavage of this polyprotein and the different types of structural functional proteins and to get it targets like right here at that site. So if we utilize particular drugs such as semeprevir, peritoprevir, glipeprevir, see they're so dang hard to remember these dang names, right? I don't even bother doing that. You know what I look for? What's the common theme within all of these? Previr, go with that. So if we have previr, we see that within these protease inhibitors, we know which type of group we're going to talk about in comparison to all these other ones. Now, what these drugs really are interestingly doing, again, is just don't forget. Here's your protease. It works on this polyprotein. You have the four different components here, right? The NS3, NS4A, NS5A. NS5B. It's working to cleave this actual protein at this particular NS3, 4A site, making your different types of structural proteins, making your different types of functional proteins. So if we can inhibit this actual protease, we'll inhibit the actual cleavage and prevent the formation of structural... proteins which are integral to making more virus. So again, protease inhibitors, semiprevir, peritoprevir, glucaprevir, just remember the previrs, okay? Now, the next one is the NS5A inhibitors. Remember I told you that there's kind of a question theory about how they actually work. One of the big things that we know about these is that there is, at least from what we understand, is that this, again, here we have the NS3, NS4A. here right here is going to be the NS5A and then here is your NS5B. We utilize this NS5A they believe to be able to act as a some type of integral protein that's needed to make more RNA. The other thing that we see here is that it may be involved particularly in allowing for the RNA and some of these actual proteins to be taken to the Golgi which is important for assembly. So there's two particular things that we think may be important here. One is it's going to be involved in RNA replication, making more RNA, and also it's important in viral assembly. So if we give NS5A inhibitors, Lidipsever, Velpatasver, Daclatasver, these drugs are going to inhibit this particular protein from undergoing RNA replication to make more HCV RNA. and inhibit the viral assembly of this actual protein, of these particular HCV viruses. All right, do you guys notice, like a very interesting here between all of these, lidipsevir, velpatasvir, declatisvir, do you guys notice a common like root term between all of these? You see there's asvir, Asvir, Asvir, that's the way I would want you guys to remember the NS5A inhibitors. So remember, Pravir at the end for Proteus inhibitors, Asvir at the end for NS5A inhibitors. The next drug if you just want to look here we'll actually hit this part too, NS5B inhibitors. We'll talk about what it does in just a second, we already kind of had a good idea but remember how you look here, so Fosbovir, Dizabovir, what do you notice as a kind of a common theme between both of these? It's the Buvir, right? So they both have Buvir at the end. So again, Previr, Protease, Asvir, NS5A, Buvir, NS5B inhibitors. Now again, here is going to be your NS3, NS4A, NS5A, and here is going to be your NS5B. Remember, this actually acts as a RNA-dependent RNA polymerase, meaning it takes RNA and makes more RNA. So we can utilize this particular enzyme. We definitely know that this is utilized to be able to make more RNA. If we utilize a particular drug, such as one of these, Buvers, it'll actually help to inhibit the formation of more HCV RNA, thereby inhibiting the formation of more HCV viruses. So this is a very, very good drug. Now, you're probably wondering, okay, how in the heck am I supposed to remember which one of these I actually use? Do I always use a protease inhibitor? Do I use an NS5A? Do I use an NS5B? It's actually really complicated. And believe it or not... it depends upon the genotype. And there's like so many different genotypes of the hepatitis C virus. We'll have a link down in the description box for that below. And we'll also talk about it in a case. But I want you to remember, there's so many different genotypes that the type of genotype, is that actual type of genotype determines which type of drug combination you use. So you may be utilizing a protease inhibitor plus an NS5A inhibitor, or a protease inhibitor plus an NS5B inhibitor. One of the very common combos that you'll actually see often times is just super expensive is actually an NS5B and an NS5A inhibitor combination. And that's usually sofosbuvir and lidipsovir. But again it depends upon the genotype. link on that. It just goes way too beyond the lecture here to really go into that much detail about all the different genotypes. But again, I think now that you have a basic understanding of the mechanism of action and the drug categories, let's now move up now and talk about this other random drug here called ribavirin. All right, so the next one is ribavirin. Ribavirin is pretty interesting. So this drug here, it's primarily, to be honest with you, we only use this in refractory hepatitis C virus. So really it's primarily only used in like your refractory Refractory HCV. Alright, and really if we do utilize this in refractory HCV it's dependent upon the particular type of like genotype of the virus, but really it's a part of a triple therapy. So we only utilize this drug as a part of a triple therapy and more of your really resistant refractory hepatitis C viruses. And so it'll be a combo of ribavirin, so it'll be three drugs. Ribavirin will be one of them. The second one will be sofosbuvir, which was a buvir. That was an NS5B inhibitor. So again, we'll put NS5B inhibitor, and this is going to be sofosbuvir. Here, we'll put down sofosbuvir. And the last one is actually, believe it or not, interferon alpha. Remember I told you that interferon alpha can treat both hepatitis B virus, but it also can be utilized in hepatitis C virus. Do you remember what this one did? Increases antiviral peptides to inhibit protein synthesis, inhibits the viral RNA activity, and also increases the expression of MHC1 complexes for cytotoxic T cells. Okay, remember teratogenic N? Pancitophenia for adverse effects. But either way, when we talk about this actual triple combo, we utilize ribavirin in this triple combo. Now what does it do? And it inhibits a very particular type of enzyme. This enzyme is called inosine monophosphate dehydrogenase. So this enzyme, basically what it does, it helps to be able to make guanine nucleotides. Okay, so it helps to be able to take and make something called guanine nucleotides. Now guanine nucleotides are important for being able to help you get rid of being able to make more RNA. So it's a nucleotide. You need this in order to be utilized by NS5A and NS5B to be able to add on. So for example, if I take this RNA and I want to make more RNA, I need nucleotides to be able to make RNA. If I give a drug like ribavirin, what ribavirin does is, is it actually works to inhibit this inosine monophosphate, it's actually inosine 5-phosphate, inosine 5-phosphate, inosine 5-phosphate dehydrogenase. Either way, it's an enzyme, it inhibits it from being able to make guanine nucleotides. If I don't make guanine nucleotides, am I gonna be able to utilize these to make RNA? No. Can I make RNA then? No, and I inhibit the RNA replication and formation, thereby inhibiting the virus from being able to replicate and form. So ribavirin is particularly going to be utilized to inhibit this particular enzyme the inosine 5-phosphate dehydrogenase that inhibits the guanine nucleotides that are being formed that inhibits you from being able to utilize the ns5a ns5b to convert the RNA to make more you're going to inhibit the formation of further RNA. Okay pretty straightforward concept for this guy. Now one of the big things is that as adverse effects of these drugs. Protease inhibitors, NS5A inhibitors, NS5B inhibitors, they're actually relatively well tolerated. Not a ton of like toxic effects of these. You gotta be careful if a patient has like decompensated cirrhosis, that you don't really wanna give these drugs. But for the most part, ribavirin is really the only one that can have some kind of nasty adverse effects. And the big thing to remember here is it's teratogenic. So you don't wanna give this to a person who is pregnant. And then the other thing here, or someone who's, you know, again, don't give this to someone who's pregnant, but the other thing here is hemolytic anemia. It's been shown to be able to increase the risk of hemolytic anemia. So these would be the big things that I would want you guys to remember about the hepatitis, C virus drugs, the direct acting antivirals, and again, primarily adverse effects here is ribavirin, hemolytic anemia, teratogenic, but don't utilize these drugs like a decompensated cirrhosis. That's pretty much the big thing, but relatively well tolerated. All right, so that covers the mechanism of action. That covers. the drug names, that covers the indications, that covers the adverse effects for the anti-hepatitis medications. So let's now move on to the last big category, which is the anti-herpes medications. So the anti-herpes medications, with these, again, when we talk about the herpes viruses, like the family, there's a bunch of these things that we can talk about. Obviously, the one that we know is your HSV could be one particular one. So if we were talking about HSV, you get your varicella zoster virus, you get your CMV. These are the big ones that we actually should know because there's antivirals that I can actually treat these particular diseases with. Now the question that we have to be able to understand here is what kind of infections do these actually cause? So what kind of tissues are they hitting right? So herpes simplex viruses and varicella zoster virus particularly tend to attack very specific types of tissues. So we see like herpes simplex viruses attacking for example we can see herpes simplex viruses attacking like the skin. So you can see particularly like mucocutaneous lesions with HSV one and you can also see this with HSV. So for example, herpes labialis with the herpes simplex 1, you can see the genital lesions with herpes simplex 2. The other thing is it may also attack the esophagus and cause HSV esophagitis. The other thing is it can attack the actual meninges in the brain tissue. And so you may see HSV, encephalitis, meningitis. And you know varicella zoster virus? Varicella zoster virus is really interesting because what can happen is it can actually become, you can get an infection, it can travel along to the actual nerve, stay there until you actually have some type of issue where you're immunosuppressed, you have some type of stressor or anything like that, and it can become reactivated, come down and lead to shingles. So you can get shingles with varicella zoster virus. The other thing is CMV. So CMV has the ability to cause infections particularly to the esophagus and cause esophagitis. It can attack the lungs and cause pneumonia. So you can get CMV pneumonia and it can also attack the actual retina and lead to CMV. V-Retinitis. And so you can see how these viruses can attack various tissues. But the question is, is how does this virus affect the tissue? In other words, how does it get in? How does it utilize the actual host cells, the particular machinery to make more viruses and replicate? And is there any particular enzymes or any particular targets within that life cycle of the CMV, VZV, or HSV virus? that we can target to prevent them from replicating, prevent them from shedding, prevent them from causing nasty effects in these actual diseases. So let's talk about that. All right, so either way, one of these viruses, they bind onto the host cell. Wherever this host cell may be, again, it could be any of these tissues. Once they bind, what happens? Okay, they bind onto these particular receptors. Once they bind, they get taken into the cell via endocytosis. Then via the uncoating, they release what particular structure? Well, you know, most of these viruses... are DNA viruses. And so what happens is they'll release their actual DNA into the host cell. Once the DNA is released into the actual host cell, it'll then actually get taken into the actual nucleus. Once it's taken into the nucleus, it'll utilize particular enzymes. You know, these viruses also contain particular, like what's called nasty viral DNA polymerases. So it'll also release not just this DNA, but it'll also release particular enzymes. enzymes and proteins that are essential to its replication. So here's the viral DNA. The viral DNA will then be utilized by this very special enzyme. You know what this enzyme is called? This is actually a DNA polymerase. But it's important to remember that this is actually a viral DNA polymerase. So what it's going to do is it's actually going to take this viral DNA and do what? Make more DNA. So what's going to happen is I'm actually going to take from this, I'm going to utilize this enzyme and I'm going to stimulate more formation of viral DNA so now I'm just gonna have tons and tons of this actual viral DNA as a result here of this enzyme. Now what can happen is I can take some of this actual viral DNA and utilize particular RNA polymerases. So I can utilize particular RNA polymerases and from this I can make something called RNA. So this is all DNA. All of this is viral DNA that we're just replicating utilizing the viral DNA polymerase. But I can utilize maybe specific types of RNA polymerases to make RNA. Once I make this RNA, this messenger RNA, I can use this RNA, this type of viral messenger RNA, it can then get taken out of the actual nucleus and then go to the ribosomes. From the ribosomes, the ribosomes can use this actual viral mRNA and do what? Synthesize particular types of proteins. So it can synthesize all the proteins that are integral to making the actual viruses, the herpes viruses. These could be different types of structural proteins, these could be different types of functional proteins, but all of these are very, very important to remember. So what are we going to make as a result? A bunch of different things. of different types of protein structural and subsequently functional proteins and these proteins that we're gonna make are gonna be needed to incorporate to make a new virus what we do we'll send these to the Golgi apparatus and then from the Golgi apparatus will to take these proteins combine it with the nucleic acid and make a new virus that virus will then be put into a vesicle butted off of the Golgi and then fuse with the cell membrane and when it fused with the cell membrane it'll release the virus via exocytosis. Now, this is the protein component. We have the proteins that are important to the virus, but we need the nucleic acid. Well, we've utilized this viral DNA polymerase to make tons and tons of DNA. So then guess what I'm going to do? I'm going to push this DNA that I replicated out, and I'm going to push this into the actual... cytoplasm and then I'm going to transport this to the Golgi apparatus and incorporate it with all these proteins to make a new virus and then release it via exocytosis. So you know what we can do? The primary area that we should target, the most important area that is the target site here is going to be taking the viral DNA and making more viral DNA. That seems to be the biggest point. So I should have drugs that target this viral DNA polymerase or in some way target the formation of new DNA because if I can inhibit that that formation of new DNA, I won't be able to use the viral DNA to make RNA. I won't be able to take the DNA and incorporate it into making a new virus. So this is really important. So I might be able to come up with ways to stop making DNA. If I have less DNA, I have less RNA, less proteins, and I have less of the virus as well. So let me think about a particular drug category that I can do that with. That's going to be this first one, the viral DNA polymerase inhibitor, and then we'll talk about some other interesting ones called guanosine analogs. Let's move on to those. So now, the first category here is your viral DNA polymerase inhibitor. So again, it's pretty straightforward. They're going to inhibit this particular enzyme. If we inhibit this particular enzyme here, What are we going to do? We're going to inhibit the actual viral DNA that we brought into the actual host cell, prevent us from making more DNA. If we inhibit the formation of more DNA, we're going to inhibit the actual DNA that can be incorporated into the herpes virus. Plus, on top of that, if we don't have as much of this DNA, we won't be able to transcribe as much of it as less mRNA, less proteins. again, in combination with less DNA that we replicated, we won't be able to make any more viruses. So this is the particular groups that I want you to remember that inhibit the viral DNA polymerase. Now, what are the drugs that we can utilize here? The first one is called Sadofavir. And then the second one here is called Foskarnit. Now, these drugs will inhibit this particular enzyme. What the boards may try to test you on here, Sadofavir acts directly, binds onto the actual DNA polymerase and inhibits. it. But the foscarnet may act like an analog that inhibits this enzyme. And it's important to remember this because they will ask you this on the board as politely, is it's a pyrophosphate analog. But again, the basic concept here is that it is still inhibiting the viral DNA polymerase from making more DNA. It's just this one is directly going to inhibit it. This one is going to act like an analog that will inhibit that enzyme. Now big thing to remember here is indications for these particular drugs. We obviously know that we're utilizing it to treat particular types of herpes infections, but it's very important that you remember that we utilize this in CMV infections and particularly CMV infections. that were resistant to maybe Ganciclovir. So Ganciclovir is one of the guanosine analogs and we'll talk about that in a little bit. But CMV infections that maybe are resistant to something called Ganciclovir. And this would be our infections like CMV, pneumonia, CMV, retinitis, CMV, esophagitis, that Ganciclovir wasn't able to actually treat. So we would give Sudafovir or Foscarinib. The other one is we can use this in acyclovir resistant. HSV infections. So acyclovir is again one of the other types of guanosine analogs and we very very commonly utilize in HSV infections but if patients have some type of resistance to the acyclovir such as in HSV, mucocutaneous lesions, such as herpes labialis or genital lesions or meningitis encephalitis or some type of shingles virus or on top of that esophagitis and they're not responding to acyclovir, we can try things like Sudafib. verifos carnit so that'd be the primary indications for these drugs okay we know the mechanism of action we know the indications what are the adverse effects that you should watch out for with these particular drugs one of the big things is that sedophil has been shown to be able to produce something called crystal induced nephropathy. Okay that might have sound familiar, remember one of the other drugs over there with the, we talked about that a little bit about ago, with the HIV medications the indenivir, so it was one of those particular types of protease inhibitors, this also can produce a crystal Induced nephropathy. And this can lead to acute kidney injury. So one of the big things is to remember this one, and it's also just naturally nephrotoxic too. So with this particular drug, you want to be very, very careful with Sadofavir. Now one of the things that we can actually do with Sudafovir to reduce the crystal induced nephropathy, and they may ask you this on the exam, is you want to give this with lots of IV fluids and also give this with something called probenicid. And it may help to be able to reduce the crystal induced nephropathy. with this drug. This may be a question they could ask you on the exam. The other one is the Foscarin. So Foscarin has been shown to potentially increase the risk of seizures, but the exact mechanism is still kind of questionable, but it's believed that it may produce massive electrolyte imbalances. So it may produce alterations in calcium. It may produce ulcer alterations in phosphate. It may produce alterations in potassium, and it may produce alterations in magnesium. Particularly, they've been seen to cause hypomagnesemia, hypoplasmia, hypokalemia, it may cause increase or decrease calcium and increase and decrease of phosphorus. So again, you can see these particular electrolyte abnormalities, and it's believed to be that these electrolyte abnormalities may potentially produce increased metabolic abnormalities that precipitate seizures that we can see primarily with FosCarnit. So FosCarnit, I want you to remember seizures via electrolyte abnormalities, sedophil, crystal induced nephropathy, but again you can try to reduce that by giving lots of IV fluids and probenecid during giving that type of drug. All right this would be the viral DNA polymerase inhibitors. Now we move on to our guanosine analogs. The guanosine analogs are very very interesting drugs. Let's talk about the actual category. There's a lot of other ones. I just want you to remember the most common ones. And these are, again, your cyclovirs. So for example, you have something called acyclovir. And then there's another one called valacyclovir. It's just kind of one of the pro drugs for this one as well. But I think one of the big things to remember for these actual drugs here... is acyclovir, valcyclovir. Those are probably one of the big ones to be able to remember. There is another one that we utilize here, and we're going to talk about this one. And this is called ganciclovir. And there's another one called famganciclovir. But what happens is, This is acyclovir, valacyclovir. These are primarily indicated in what types of infections. So we primarily utilize these, valcyclovir and acyclovir. Their indications is HSV and VZV infections. So they're primarily gonna be utilized in HSV infections that cause herpes labialis or some type of general infection. HSV infections that cause encephalitis, meningitis, or some type of VZV that also causes shingles. And we can also use this particularly in some type of HSV esophagitis. So this would be your acyclovir and valacyclovir. The ganciclovir is a really interesting type of drug that it's really actually going to treat your CMV infections. So you can see this in CMV infections that cause pneumonia, CMV retinitis, and some type of CMV esophagitis as well. Okay? So these are the big things to think about. Now... Ganciclovir, CMV, aciclovir, visovalciclovir, remember that for the HSV and VCV. Okay. Now, what's really important is how the heck do these actual drugs work? It's really odd, to be honest with you. Let's imagine here is your drug here. These are guanosine analogs. So this is acyclovir, valacyclovir, ganciclovir. They get taken up into the actual cell. So imagine here, this drug gets taken up into the cell. When it gets taken up into the cell, there's a particular enzyme that's present inside of the cell. And this enzyme is a viral kinase. I don't want to get bogged down on this because there's so many different types of viral kinases. If you... you really wanted to know thymidine kinase really acts on the top two, valacyclovir, acyclovir, and then UL97 kinase acts on the ganciclovir. I think that's a little bit too much, but all I want you to remember is that the viral kinases, they take and add phosphate groups onto these acyclovir, valacyclovir, and ganciclovir drugs. And so then as a result here, Here's my drug here. I'm going to add on a particular phosphate and I'm going to keep adding on phosphates. And I'm going to take this and make it look like a nucleotide. And now if this looks like a nucleotide, guess why that's important? What is one of the key things in making more of these actual viruses? We need nucleotides, particularly their RNA and their DNA. So here we have something that looks like a nucleotide. Do you remember this enzyme here? What was this enzyme? This was the DNA polymerase. polymerase. This was our DNA polymerase. This was that viral DNA polymerase that we talked about. It takes the viral DNA and makes more viral DNA. In order for that to happen, what do you need to make more DNA? Nucleotides. Guess what this thing looks like? It acts like a nucleotide. It's a guanosine analog. Acyclovir, valacyclovir, ganciclovir. If we phosphorylate them, they almost look like a nucleotide. And if we try to to add them in, guess what they're going to do? They're going to terminate the actual DNA formation, terminate RNA formation. Because again, this enzyme will take and read the DNA. It'll say, oh, I'm going to add some nucleotides that are complementary. But when it does, it grabs in and accidentally grabs acyclovir, valacyclovir, ganciclovir, adds it on to the growing DNA strand. Guess what? You can't add any more nucleotides onto this structure. So it terminates DNA replication and can also terminate RNA. formation that's a beautiful thing and so that's how these particular drugs will work okay now what are the big things to watch out for when you put someone on one of these drugs big thing is nephrotoxicity so it has been shown to be able to produce a nephrotoxic effect and this is very very specific to acyclovir so when you put someone on acyclovir you see that they definitely can cause a pretty good acute kidney injury if the drug accumulates and so what we try to do to be able to really prevent this is make sure you give this with a good amount of IV fluids. Same thing with the Sadofavir. You give it with IV fluids, but also give probenicid. The other thing here is valacyclovir and acyclovir have also been shown to be able to increase the risk of TTP. The mechanism is not exactly completely known, but if a patient has TTP and they're on one of these drugs, potentially they're looking at it as a potential drug cause. Okay? And then the last thing here is potentially pancytopenia. So shutting down the bone marrow, preventing the production of red blood cells, preventing the production of platelets. preventing the production of white blood cells there is a particular drug that actually may be utilized here and that actually may be responsible here and this is called Ganciclovir so Ganciclovir alrighty so big thing that I want you guys remember for adverse effects here again nephrotoxic acyclovir give it with IV fluids TTP thrombotic thrombocytopenia purpura look for acyclovir and valacyclovir in the actual drug list and then again Ganciclovir bone marrow suppression for these drugs, acyclovir, valacyclovir, ganciclovir, these are guanosine analogs. You phosphorylate them. They look like nucleotides. The viral DNA polymerase has no idea that it's any different from a nucleotide, tries to add it to make more DNA. It adds it, but guess what? You can't add any more nucleotides after that. terminates the actual replication and transcription process. These drugs, they directly inhibit it, so it won't even be able to work to be able to add nucleotides and make more new DNA, or make any types of replicated DNA from that viral DNA that we brought into the cell. This will shut down the actual viral replication, and again, the nasty effects of this virus. That covers the whiteboard portion of this lecture. We're not done yet, though. We gotta put all of this together and do some cases. Let's get to it now. All right, guys, let's do some practice problems. There was a lot of stuff that we covered on the whiteboard, so there was a lot of things that we have. to be able to review and let's see if we can just test their knowledge and put this stuff into true understanding for you guys. All right. So you got an infectious disease attending. He's taking you through your rounds and desires to, you know, he wants to pimp you a little bit. He wants to ask you some questions and see if you got the knowledge about antiretroviral therapy. So he says, okay, I want you to tell me the name of the drugs that block the CD4-GP41 interaction. You say, okay, it's Enfibratide. I know that one. And then he says, okay, what's it used for in the heart therapy? And you say, oh, it's not really a part of the main regimen, but you can say it's an adjunct. It's an add-on in HIV resistant strains to the NRTI. So that would be the Infirvitide. All right, good. That one's done. Boom. Easy. He says, okay, what are the drugs that block the CCR5 receptor and the GP120 interaction between HIV and the Th2 cell? And you say, oh, that's easy. That's Moraviroc. Boom. Done. Because Moraviroc prevents the docking, right? And then he says, okay, what kind of genotypes or positive genotypes do you have to have for the Th cells? It has to be CCR5 positive. I know that. Boom. He says, okay, what are the name of the drugs that actually block this enzyme called the reverse transcriptase that takes and converts RNA to DNA? which is important for the actual virus to be able to incorporate that viral DNA into the host cell's DNA. You say, okay, well, that enzyme is called the reverse transcriptase. I know that if I have two particular drugs, one, it's a nucleoside, so it actually acts kind of like a nucleotide. The reverse transcriptase can't tell the difference, and so it tries to incorporate it into the growing DNA strand. So when it adds this in, you can't add any other nucleotides beyond that point after that one. So it terminates the actual DNA formation. And you say, okay, what are the name of the drugs? And you say, well, you say Zales TD. And you're like, what? what? He says, oh, yeah, that's the way I remember it. Zidovudine, abacavir, lamivudine, m-tricitabine, stavudine, tenofovir, and didanosine. And those are the particular NRTIs. He says, okay, all right, smart guy. Here's the next question I have for you. Which one of these cause mitochondrial toxicity? You say, oh, well, mitochondrial toxicity is actually classified by lactic acidosis, peripheral neuropathy, myopathy, and also hepatic steatosis, as well as lactic acidosis, if I already said that one. And it's all of them that do that. He's like, all right, yeah, you got that one. He's like, all right, which one cause pancreatitis? tights. And he says, oh, that's stavidine and didanocine. He says, which one of the ones actually cause nephrotoxicity? He says, it's anophover. And he says, okay, which one has actually caused like a pancytopenia by trying to suppress the bone marrow? He says, it's zidovudine. He says, all right, guy, I got you here. You got a patient who's potentially has a very specific type of haplotype that is positive for, and if you give them this drug, they get a hypersensitivity reaction where they have fever, nausea, vomiting, diarrhea, and respiratory distress if they are positive for the HLA-B5701 type of haplotype. Which drug would you not want to give them if they tested positive? And you say vacavir. And he just backs off for you a little bit. But then after that, he says, okay, I got more questions. He says, all right, you got some drugs. I want you to tell me the drugs that actually block the reverse transcriptase that aren't actually acting as a nucleoside. They bind to an allosteric site and prevent the enzyme from functioning to convert RNA to DNA. He said, oh, the non-nucleoside reverse transcriptase inhibitors. I always remember them by the vir that is in the center of the word. F of irons, right? Niverapine, Ertravine, and Deliveridine. And so, again, you always see the vir in the center. This is the only one that has the vir in the center of the action. actual name. He says, okay, good. Which of these NNRTIs is actually specifically hepatotoxic? And you would say, oh, well, pretty much like, you know, generally F of irons is the biggest one and nevirapine. He says, okay, which one causes vivid dreams and hallucinations? Kind of like when you're sleeping and you say, oh, that's F of irons. And which one's actually causing the teratogenic effect? And you say F of irons and delaviridine. So these are the big things to remember here for your NNRTIs. Now, the next thing he says, okay, what is the actual drug that inhibits the particular enzyme that integrates the viral DNA into the actual host cells DNA and that's the integration inhibitors and I always remember them by the ending Tegravir Tegravir so again if you go back the actual particularly the inner RTIs always has the vir in the center and then the integration inhibitors always has the Tegravir at the end it's important to remember this with W Tegravir Rad Tegravir now he says okay The next question I have for you is, what is the main adverse effect of these drugs? And you say rhabdomyolysis. So it can actually cause the breaking up of the actual skeletal muscle cells. And he says, OK, what kind of labs would actually test for it to see if they have that? And you check the actual CK, the serum CK, as well as the urine myoglobin. All right, good. Next question, which is the actual drugs that inhibit a particular enzyme that breaks down polyproteins, specifically the GAG-pol polyproteins, that converts them into structural and functional HIV proteins that are necessary for it to be able to function? And you say the protease inhibitors are actually going to inhibit that. And so the protease inhibitors, you always remember with the ending nevir. So it was the vir in the center. That was the NNRTIs. And then the integrase inhibitors is the tegravir at the end. And then nevir at the end is the protease inhibitors. So you got that one down and he says, okay, what are the actual protease inhibitors that actually are associated with CYP450 inhibition? Ritonavir. Which one with hyperglycemia and lipodystrophy? The Cushing-like effect. All of them. And then he asked, okay, which is the one that actually causes crystal-induced nephropathy? And you say, indenivir. And then after that, he says, okay, let's finish this off. He says, what are the three combos that we utilize in the heart therapy? And you'd say it's always based on the NRTIs. We always need two of them and then one of the other categories, which is the integrase inhibitors, the protease inhibitors, or the NNRTIs. The adjuncts that you can add on is infuvertide if they're resistant to one of these regimens and then miraviroc if they're positive for the CCR5 receptor. Boom. Next case. Case study two, you had an infectious disease attending. Again, he's performing well around. He wants to ask you about a question who has influenza. So they test the positive for influenza. He says, what are the drugs that actually inhibit the M2 ion channels that actually allow for the virus to uncoat and allow for it to release its actual nucleic acid, the RNA, into the actual cell cytoplasm? And so they're called encoding inhibitors. And primarily, this is amantadine. The next question he says is, OK, which influenza does amantadine actually cover? Does it cover A or B? And you say, it's only A. And then he says, okay, what are the primary adverse effects? And you say ataxia, you say a prolonged QT interval, and levido reticularis, which is a particular skin manifestation. The next question he asks is, okay, which drugs actually inhibit this enzyme? It's called an endonuclease, which is involved in mRNA synthesis primarily, involved kind of like that 5'cap swapping. And he says, which one is it? And you say, oh, it's biloxivir. It inhibits that particular enzyme. And then biloxivir is really only used for what, he says? And he says, oh, it's only particularly for influenza A and B, but it has to be less than 48 hours of symptom onset because it kind of reduces the intensity and severity of the symptoms. Then the next thing is, which is the actual drugs that inhibit the neuraminidase enzyme that cleaves the sialic acid from the hemagglutinin, releasing the virus, allowing for it to spread throughout the bloodstream and to affect other cells? And these are called neuraminidase inhibitors. This is oseltamivir, zanamivir. And primarily the only use for this is influenza A, B, same thing like biloxifera, less than 48 hours of symptom onset, reduces the severity of the symptoms. And there is some potential thought that it can actually be prophylactic in some adults and pediatrics greater than five years of age or older. All right. All righty. Boom. We covered that one. Third study. You had an infectious disease attending, he's performing rounds, and he now wants to ask you about a patient who has hepatitis B. He says, okay, what kind of drugs can we put this patient on that actually inhibits the reverse transcriptase? Because it acts like a nucleoside or a nucleotide. We say, oh, the nucleosides is lamivudine or entecovir. And the ones that actually are acting as nucleotides, but they do the same exact thing. They act like a kind of a nucleotide in general. And whenever the reverse transcriptase tries to add it in to the growing DNA strand, whenever you try to add a new nucleotide after that drug, it can't do it. It terminates the further formation of DNA. And the nucleotide ones would be tenofovir and adefovir. And the nucleosides would be lamivudine and entacavir. All right. So then he says, okay, which of the actual, one of these drugs that are above here that is actually responsible for Fanconi syndrome, which is classically seen with glucose in the urine, phosphate in the urine, and then amino acids in the urine. And it's primarily going to be your NTRTI, so adefavir and tenofavir. And then which drugs actually form antiviral peptides that were to inhibit protein synthesis? They work to inhibit RNA synthesis, and they actually form MHC1 complexes that lead to the activation of cytotoxic T cells to kill those virus-infected cells. And this is called interferon alpha. Okay? In interferon alpha, the main adverse effects to watch for is don't give this to someone who's pregnant, and it can actually suppress your bone marrow and cause pancytopenia. All right. He says, okay, we got another patient here with hepatitis C. He wants to know, what are the drugs that actually inhibit the NS3 4A proteases that break down these big polyproteins? and to structural and functional proteins that are essential for the hepatitis C virus formation. So it particularly works to inhibit this cute little enzyme right here, NS3,4A protease, which breaks down this polyprotein. Well, it's a protease inhibitor. Yeah, exactly. And so the protease inhibitors will end in prever, prever. For this group, for the hepatitis C virus category, it ends in prever. For the other one, which was back for the protease inhibitors and the HIV, it was ending in never. The prever is going to be particularly for the protease inhibitors and hepatitis C virus therapy. So that would be this particular category. Then he says, okay, which are the ones that actually inhibit the NS5A? And NS5A is believed to be able to prevent this actual protein is involved in taking and converting RNA into more RNA and may be even involved in a virus assembly at the Golgi apparatus. Well, it's called... NS5A inhibitors. And NS5A inhibitors always end with Asver, like Lidipsivir, Velpatasvir, Dacladasvir. All right. So they end in Asver. All right. That's your NS5A inhibitors for anti-HCV therapy. Then we have, what are the drugs that actually inhibit the RNA dependent RNA polymerase, also known as NS5B. This is basically taking RNA and helping us to make more RNA. So it's important in RNA formation. This is going to be NS5B inhibitors, and we always remember these by Buver, like so Fosbuver. All right. So we got Prover for the protease inhibitors in this category. We got Asver for the NS5A inhibitors in the HCV category. And then we have Buver for the NS5B inhibitors, which are the RNA-dependent RNA polymerase inhibitors. Okay. There's one more drug in this category that works to inhibit this enzyme called inosine 5-phosphate. dehydrogenase. And this enzyme is responsible for making guanine nucleotides. And nucleotide is important to be able to make more RNA. If you don't have the nucleotides, you can't make RNA. You can't make nucleic acids in general. So this would inhibit the RNA formation. And so this is going to be ribavirin that does that. And important to remember is the indications of when we use this. And it's only an HCV refractory therapy. So there's very specific genotypes that we would use this in. And it's a part of a triple therapy. which is ribavirin, sosophosphavir, and interferon alpha. Now, you probably have the question, it's like, I don't really know which one of these I actually utilize. Do I use a combo? Do I only use one of them in hepatitis C virus? It really depends upon the genotype, and we'll talk about that in a second, but the next question I have for you is, what are the adverse effects of ribavirin? So what should I watch out for? Big thing is it is teratogenic, and it can cause hemolytic anemia. That leads us to the last question here, is how do we know which drug or combo to use for a patient who has hepatitis C virus? I don't really know. So it really depends upon the genotype that comes back in their labs. So depending upon which type of genotype they have here will determine the combo. Do they get a protease inhibitor plus an NS5A inhibitor plus a, and again, when you see RNA polymerase inhibitor, that's NS5B. So RNA polymerase inhibitor is an NS5B inhibitor. So do I use all three of these? Do I only use an NS5A and an NS5B? Do I only use a protease? and an NS5B. So it really kind of depends upon the specific genotype that we would use this in. So that's an important thing to remember. I wouldn't work too hard in trying to remember these just because it's a little bit beyond, I think, the scope of this lecture. But that's the kind of the combo that we would use. It just depends upon the genotype. All right, the last case here is going to be a patient who has herpes and he's going to be, again, attending, he's going to ask you some questions. He says, what are the name of the drugs that actually inhibit the viral DNA polymerases, which are basically responsible for taking... DNA from the actual herpes virus and making more herpes virus DNA. You're going to inhibit that particular enzyme. And you say that this is foscarinate and sedophil. And then he says, okay, which one of these is actually a pyrophosphate analog? Remember, fos is foscarinate, right? So that's going to be foscarinate. Next thing he says, okay, which kind of indications would these drugs be particularly utilized for? And you say two particular situations. One is in a patient who has HSV, who has resistance to acyclovir. So they've come up with maybe some type of moderation in their thymidine kinase in some way, shape, or form. And so now they can't respond to that. So they have HSV esophagitis, meningoencephalitis. They have some type of severe mucocutaneous lesion of some kind. Or ganciclovir-resistant CMV infections, like CMV pneumonia, retinitis, esophagitis, where their UL97 kinase is mutated in some particular way. So these would be the two particular indications. And then which one of these actually is potentially... related seizures due to electrolyte abnormalities? You'd say Foscarnit. And then which one obviously can cause crystal induced nephropathy and is naturally nephrotoxic? Sudafovir. How do we minimize this? IV fluids and probenicid. All right. Last part here is you have another group of drugs, he says, that actually act as guanosine analogs. And what happens is they get taken up into the cell that's infected with the herpes virus and gets phosphorylated via these drugs. thymidine kinases or UL97 kinases. And when they get phosphorylated, they eventually kind of look like nucleotides. Okay. And so they can try to be added into the DNA that's being formed by the viral DNA polymerase, who's trying to take herpesvirus DNA and make more of it. It needs nucleotides to do that. So these drugs act like nucleotides. They're guanosine analogs that get phosphorylated. They literally look like a nucleotide. And when he tries to add them into the growing DNA, it inhibits further DNA formation. What are the names of these drugs? Acyclovir, valacyclovir, there's even way more, but these are the two most commonly used. ones, and then Ganciclovir. Okay. So the next question is what are the indications of aciclovir and valcyclovir? It's primarily HSV infections. Okay. And then the other thing is what are the primary like adverse effects of these two drugs? Well, aciclovir is extremely nephrotoxic. And so we have to give this with IV fluids to minimize the nephrotoxic effect. And then valcyclovir and acyclovir both have been shown to potentially increase the risk of TTP, thrombotic thrombocytopenic purpura. Okay. And the last thing is ganciclovir. So ganciclovir is actually going to be utilized in CMV infections. Okay. So retinitis, esophagitis, pneumonia, et cetera. And the big thing to remember for this one is ganciclovir. Some of the adverse effects of this one is it may be potentially causing bone marrow. suppression leading to pancytopenia. Okay. So that's important to remember. And that covers this part on our cases on antivirals, man. I know this was a lot. I hope it made sense. I hope that you guys enjoyed it. I love you ninjas. I thank you guys so much for always sticking with us. And as always until next time.