Transcript for:
Antivirals Lecture Notes

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 antivirus we're going to go over the first category against hiv so these are going to 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 are 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 gp 41 and then this kind of like longer stick protein which is bound to is called gp120 now these proteins are integral to the hiv virus to allow for it to bind onto the host cell's receptors what are those host cell receptors that it needs to bind with generally this pink 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 here that bind with the gp 120. there's two types so one 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 once the actual virus utilizes these proteins like the gp41 to bind with the cd4 the gp 120 to bind with the ccr5 or the cxcr4 it then fuses with the actual proteins here on the host cell and then it 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 is called infervetid and infervertide is that type of like fusion or entry inhibitor inhibits the actual entry of the viral rna into the host cell and what enfevertide will do is is it'll inhibit this interaction it won't allow for the gp41 on the hiv virus to bind with the cd4 protein if that doesn't bind are you going to allow for this to fuse enter and release the viral rna to the whole cell no so that's one big thing to be able to remember the second thing is this ccr5 remember i kind of astrix 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 you have to test for that in order to use this particular drug but maravaroc prevents the virus from docking to the cell that's the way that the first aid usmle utilizes this but miravaroc 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 maravaroc prevents the actual virus from docking releasing the rna and then fever tight inhibits the fusion of the gp-41 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 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 viral uh rna molecules if i stop this process i could potentially inhibit that so i'm going to 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 but i 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 is this is actually the most important one because it's the hallmark it's the basic foundation of highly active antiretroviral therapy which we'll talk about a little bit and this is your nrtis 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 was going to do it's 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 going to read the rna strand when i read the rna strand i'm going to 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 sales ring yeah you'll end up in the touchdown you're getting a touchdown i don't know but it's basically zydoviudin a bakavir lamivudine m tricidibine stabudine tenofovir and didenosine 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 strain that's that drug category now the in 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 pocket around its shoulder well what happens is these little drugs these little buggers will actually bind onto this little allosteric site you see a little allosteric site that little pocket there these in an rtis will bind onto that little site there when it binds onto it you know allosteric sites 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 to 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 new dna strand so that would inhibit this particular process and that is the actual drugs here the in rtis now there actually is a way to remember these so you have never efevirans urtravarian and delaviridine do you notice here that at least in all of these there's a veer somewhere in it and it's in the actual center of it so i want you to remember anytime you see a veer in the center of one of these types of drugs that would be a nnnrti 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 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 fuverytide moravarock we have the drugs that are inhibiting the reverse transcriptase that takes rna and makes dna nrtis and nrtis 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 in rtis 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 cells nucleus here 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 going to get something a little bit like this if you will we're going to have kind of a mixture of these two so now i'm going to have my viral dna mixed in with the actual host cells 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 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 allowing for the actual viral dna to be incorporated into the host 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 hose 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 what this actual drug will i'm sorry this enzyme will do if i give particular drugs that inhibits that that will inhibit this process these drugs are dolutegravir routagravir and elvatecravir do you guys notice a very specific like similarity between all of these you notice this part here tegra veer it's in every single one of them so we can remember the integrase inhibitors by ending in tegra veer we can remember the in rtis by having a veer 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 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 poly proteins 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 proteins 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 and being able to cleave these polyproteins into structural and functional proteins if that doesn't happen i won't be able to make all of the integroviral 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 structural and functional proteins if i can't make any of these dang structural functional proteins what do you think is going to happen then i'm not going to be able to do what i'm not going to 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 capsimir 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 a bad that's not 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 things don't worry i don't remember him either but if you notice here addazanovir dorinovir and denver le penavir nuffinover sequinovir to pranavir do you notice something you notice naveer is at least present in every single one of these that's what i want you to remember if you see the ending with naveer you have a protease inhibitor so in an rti's there's a veer in the center integrase inhibitors there's a tegravere at the end and protease inhibitors there is a nevere 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 gagpal 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'll fuse with the cell membrane and exotize exocytosis 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 in our ti's 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 do utilize either a in in rti 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 going to put i n i or a protease inhibitor we're going to put pi and again the choice of which one of these you pick can kind of also depend upon the hiv genotype but it also depends upon the actual adverse effects that you're trying to avoid or contraindications now that's the baseline heart regimen what about these other two drugs that was the 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 rava rocker and fever tide the the reason we would add on morave rock 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 moravirock as an add-on in the hiv-resistant strains especially to the nrtis but they have to have they have to be positive for this ccr5 receptor if they're not positive it's not going to provide any actual additional benefit the other one here is inferior type so infuriating we'll 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 inferior time or avarock nrtis n and rtis integrase inhibitors and protease numbers we went over the mechanism of action the names that 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 um heart therapy right the highly active antiretroviral therapy regimen if you notice there was always two of those with one of the integras or one of the proteases or one of the and in rtis 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 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 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 mitochondria 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 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 as well is 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 it into acetyl coa if the mitochondria isn't allowing for the pyruvate to get converted into acetic wave 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 hepatocytosis 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 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 then i don't want you to forget this next one called didanese 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 or virtual scriptase inhibitor it's actually a nucleotide reverse transcriptase it's actually one of the only ones an alpha bear and something called a defiber but either way that's the one that i want to remember and it 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 zydovidine 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 zydovidine now here's the other one that's really interesting this one it's a weird one but a back of here so a back of your 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 back of your 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 5701 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 cause mitochondrial toxicity pancreatitis is particular to saving the adenosine nephrotoxicity with tinofovir bone marrow suppression particularly anemia neutropenia with zydovieudine and a baccavier can cause a hypersensitivity reaction hlab 5701 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 is the nnrtis the non-nucleoside reverse transcriptase inhibitors so you guys remember these ones sales dt right says idoviadine a baccavir lamivudine m tricidabean stavudine uh tenofovir and then didannacy for in nrtis 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 f of irons never pin delaveradine now with these there's a couple different adverse effects that i want you guys to remember hepatotoxics is a relatively common one and we see this more specifically with f of irons so f of irons and nevirapine now 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 epivirus so f of irons will give you the hepatotoxicity it would also give you cns toxicity that'll cause like these insane vivid like dreams so f of irons and then 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 epivirus and then the other one that i want you guys to remember is deliveridine all right that covers the in in rti adverse effects now let's come down talk about the integrase inhibitors and the protease inhibitors all right so the next thing with integrase inhibitors again if you guys remember the integral inhibitors this was the ones that actually had one particular thing the tegra veer at the end dawg you tegra via rod tiger veer el vitegravir so with integrase inhibitors what they've been actually showing this is an actual nice one to remember here is that they can actually cause rhabdomyolysis and so if you have some of those rhabdomyolysis you may expect an increase in there 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 uh are taking into grace inhibitors now protease inhibitors is a big one as well now one of the things that this can actually do for produce numbers and again how do you remember these ones do you guys remember it was ending in navir so if it ends in the nevir then you know they have a protease number adizenovir ritanovir uh saquinovir many many of those drugs lapinovir 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 denver has been shown to be able to increase the formation of crystals that can actually cause an acute 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 and what happens is you see a lot of this fat accumulation and lipodystrophy and it can produce kind of like a cushing-like effect where you get like 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 transport 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 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 glucaronates 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 ritanavir and rytanovir 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 could 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 rhitonovir because you may be increasing the concentration of that drug because it inhibits the cyp 450 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 we got to do is we got to talk about influenza all right so now let's talk about the influenza medication so influenza is obviously the flu alright 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 into affecting our actual immune system via the respiratory tract so what happens is this will bind onto particular cells within the respiratory tract and what it does it'll actually bind into there get its actual viral structure into the uh 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 onto respiratory tract cell how does it actually do that well here's our influenza 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 like blue proteins these baby blue proteins these 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 and 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 drop it gets into the respiratory tract and tries to bind onto 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 cyalic acid residues so this is called cyalic acid now with this cyalic acid we need these hemoglutinin proteins on the actual influenza virus to be able to bind with the actual cyalic acid residues once it binds once the hemagglutinin binds with the cyalic 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 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 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 uncoding to occur so again these m2 ion proton channels will allow for uncoding of the virus so let's actually write that down so this process here is called uncoding 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 cells nucleus and in the host cell nucleus you know that you have host dna right so this is going to be the host cell's 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 going to 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 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 five prime 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 five prime cap 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 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 right 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 you know 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 combined 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 stuck to the sialic acid and it can't release away from the cyalic acid unless we have another particular protein that comes in and cleaves that connection between the hemoglobin and the cyalic acid so that we can release the virus away from the actual cell so we 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 the link between the cyalic acid residue and the hemagglutinin and that'll basically allow for the virus to butt 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 uncoding 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 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 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 uncoding we have particular drugs that can actually inhibit this m2 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 will not allow for the release of the actual or the uncoding or the liberation of the viral rna out into the actual host cell cytoplasm and get utilized by the nuclear machinery to make more rna 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 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 is primarily only used in influenza a now the second step here is this part here where you have this endonuclease transfer the five 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 five prime cap onto the viral rna if we don't have the five 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 block severe so baloxaviras 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 and again just to recap it again you have here five prime cap on the actual host rna you're trying to transfer that five prime 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 biloxavir it inhibits this process the transfer of the viprime cap so you won't be able to cut this actual five prime cap off and then transfer it 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 an aramid ace is designed to be able to cut the actual hemagglutinin which is basically the part of the virus that's stuck to the cyalic 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 neuraminidase from cutting the connection between the cyalic acid and the hemoglobin will be able to release the virus allow for it to butt 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 osceltamivir and another one is called zenamovir 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 developed symptoms of influenza arb 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 they are 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 block severe oscillatomavirs and amavir 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 ataxia it can also cause libido 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 torsos to points so when again when it comes down to amantadine amantadine can actually cause ataxia it can lead to laveto reticularis and it can also prolong the qt interval increasing the risk of torsos to points all right now that we've talked about that let's move on to the next virus which is the hepatitis medications all right so now we're going to talk about the anti-hepatitis medication 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 tissue 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 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 i'm sorry the hepatitis b virus 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 n ctp protein if you really want to know that but basically what happens is once the hepatitis b virus is bind 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 it's what's called partially double stranded dna it then will get taken up into the actual host cells 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 we'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 it undergoes a transcription process it'll make lots of rna and it'll make two different types of rna one of the rnas 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 pre-genomic 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 pre-genomic rna the mrna will then go and utilize the host cells 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 etc and so what happens is these proteins are very very crucial because we're going to 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 into dna that's got 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 pre-genomic rna and convert it into dna it actually turns into something called negative sense dna and then then 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 onto 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 infect 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 i'm glad you asked 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 as 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 strain in this case to make a new dna strand but it needs nucleotides to make dna off of the rna template guess what these nrtis act like they act like nucleotides they're nucleoside reverse transcriptase numbers and usually they don't have a hydroxyl group on the end so what happens is you try to add them on 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 lamivudine and intakovir all right so lumidine and takavira the two big ones that i want you guys to remember now it's hard to uh 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 nrtis they just are a nucleotide they just again they have the kind of a similar function just to the nrdis 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 numbers these are nucleocide so this is a defever and tanoff of here do you notice a similarity between both of these they both have fover in them so we can remember these by the fover 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 particularly adephavir and tanofever 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 defever a death of here 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 you have what's called phosphaturia you excrete out a lot of glucose so you have glycosauria and you excrete out a lot of amino acids so you have amino acid urea so there's a lot of phosphates glucose and amino acids that are excreted into the urine 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 particularly amino acid abnormalities this can be seen with the defiver and alpha veer 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 immunology is 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 there is a virus in the 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 sick second messenger systems they work to be able to stimulate the host cells dna to make particular types of proteins so it'll 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'll actually act as antiviral 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 elephants do here's what i want you to remember there's three 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 say here is that if we were to kind of follow this it makes these particular proteins interferon 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 mhc-1 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 this 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 mhc-1 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 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 going to 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 interferons 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 so we'll talk about a little bit later but with interferon alpha what are the particular com complications adverse effects that you can see with this particular drug one of the things is this teratogenic so you want to 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 the 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 hepatitis b viruses when we talk about the drugs that are targeting it one is the reverse transcriptase inhibitors your nrtis which is the lemividine and your uh particularly in tacovir and again the other one is the ntrtis these are nucleotides transcriptase inhibitors and this would be a definition of their big thing to watch out for these is particularly a death evaporation of air 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 mhc-1 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 interference 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 hepatitis medication so with hepatitis c virus again same thing we know that you have the hepatitis c virus that's going to love to attack the liver cells so it's going to cause damage to the liver cause inflammation and again potentially increase the risk of a vital cell 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 srv1 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 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 see this is a rough endoplasmic reticulum and then on there they're going to have all these ribosomes studying all the on the edges of it this viral rna hepatitis c viral rna will then go 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 poly protein when it breaks down the polyprotein it breaks it into two components one is it breaks it into the different types of structural proteins so obviously these are the different like capsion burner proteins envelope proteins all of those things but it also breaks it into functional proteins so these are proteases and polymerases etc so we need both of these in order for the virus to be able to replicate 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 out the ns3 site and the ns4h site it's called a produce but we actually know what we call this dang thing we call this an ns3 for a protease i know it's ridiculous but that's what we call this little cube pink enzyme and what it does it'll actually work to be able to cut this poly protein particularly at the sites in 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 here is it's really really interesting is you take rna right so we have the rna that the virus is actually going to 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 is actually you know what the ns5b is it's actually 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 are going to target this ns5b and then we'll finish off talking about this last enzyme that 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 a protease inhibitors so these are protease inhibitors that actually are directly acting so it will inhibit this ns3 4a protease preventing the cleavage of this polyprotein in the different types of structural functional proteins and again it targets like right here at that site so if we utilize particular drugs such as cemeprovere peretoperia 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 preview go with that so if we have previer 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 and s5a ns5b it's working to cleave this actual protein at this particular ns34a site making your different types of structural proteins making your different types of functional proteins so if we can inhibit this actual protease will inhibit the actual cleavage and prevent the formation of structural functional proteins which are integral to making more virus so again protease inhibitors semeprovere pareto prevail glycoprevia just remember the previers 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 le dip severe vopatosphere to cladosphere 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 particularly hcv viruses all right you guys notice like a very interesting thing here between all of these la dip severe velpatosvir the cladosphere do you guys notice a common like root term between all of these you see there's as veer as vir as vir that's the way i would want you guys to remember the ns5 a inhibitors so remember previer at the end for proteus inhibitors as veer at the end for ns5a inhibitors the next drug if you just want to look here we'll actually hit this part two ns5b inhibitors we'll talk about what it does in just a second we already kind of have a good idea but remember how you look here so phosphavir de zabovir what do you notice as a kind of a common theme between both of these it's the beuver right so they both have buver at the end so again previer protease asvir ns5a buvir and s5b inhibitors now again here is going to be your ns3 ns4a and s5a 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 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 but we'll have a link down in the description box to that below and we'll also talk about in a case but i want you to remember there are 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 oftentimes is just super expensive is actually an ns5b and an ns5a inhibitor combination and that's usually so phosphavir and ledipsevere but again it depends upon the genotype and we'll have a little 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 rib of iron all right so the next one is ribavia ribavia is pretty interesting so this drug here it's primarily to be honest with you we only use this uh in refractory hepatitis c virus so really it's it's primarily only used in like your refractory refractory hcv all right and 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 rib of iron so would be three drugs rib of iron will be one of them the second one will be sophosphavir which was a buver that was an ns5b inhibitor so again we'll put ns5b inhibitor in this is going to be so phosphavir here we'll put down so fosbuver 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 remember what this one did increases antiviral peptides to inhibit protein synthesis inhibits the viral rna activity and also increases the expression of mhc-1 complexes for cytotoxic t-cells okay remember tradogenic and for adverse effects but either way when we talk about this actual triple combo we utilize riboviron in the triple combo now what does it do it inhibits a very particular type of enzyme this enzyme is called ionosine monophosphate dehydrogenase so this enzyme basically what it does it helps to be able to make uh 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 make more rna so it's a nucleotide you need this in order to be utilized by ns5a and ni5b 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 riboviron what ribovirin does is is it actually works to inhibit this ionoscene monophosphate adenosine 5-fall it's actually ionosine 5-phosphate ionosine 5-phosphate ionosine 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 going to be able to utilize these to make rna no can i make rna then no and i hit with the rna replication and formation thereby inhibiting the virus from being able to replicate and form so a rib of iron is particularly going to be utilized to inhibit this particular enzyme the ionosine 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 adverse effects of these drugs produce inhibitors ns5a inhibitors ns5b inhibitors they're actually relatively well tolerated not a ton of like toxic effects of these you got to be careful if a patient has like decompensated cirrhosis that you don't really want to give these drugs but for the most part riboviron is really the only one that can have some kind of nasty adverse effects and the big thing to remember here is it's terratogenic so you don't want to give this to a person who is pregnant and then the other thing here or someone who's you know again don't give us 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 rhyme of iron hemolytic anemia tyradogenic 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 antihepatitis medication so let's now move on to the last big category which is the anti-herpes medications so the anti-freeze 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 in your hsv could be one particular one so if we were talking about these hi hsv you get your varicella zoster virus 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 zosovirus 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 too so for example herpes labials with the herpes simplex 1 you can see the genital lesions with herpes simplex 2. for 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 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 cell's 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 vcv 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 uncoding 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 also release particular 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 going to 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 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 types of protein structural and subsequently functional proteins and these proteins that we're going to make are going to be needed to incorporate to make a new virus what will we do we'll send these to the golgi apparatus and then from the golgi apparatus will 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 fuses 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 where 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 formation of doing 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 we'll talk about some other interesting ones called guanosine analogues let's move on to those so now with 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've 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 sedophobia then the second one here is called phoscarnate now these drugs will inhibit this particular enzyme what the boards may try to test you on here is saddafi fair acts directly binds onto the actual dna polymerase and inhibits it but the phoscarnit 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 likely is it's a pyrophosphate 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 a little bit but cmv infections that maybe are resistant to something called gan cyclovir and this would be our infections like like cmv pneumonia cmv retinitis cmv esophagitis that ganciclovir wasn't able to actually treat so we would give sadafavir or phoscarnet the other one is we can use this in a cyclovir 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 n a 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 a cyclovir we can try things like sadofa verifoscarnet so that'll 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 sedophobia has been shown to be able to produce something called crystal induced nephropathy okay that might sound familiar remember one of the other drugs over there with the uh we talked about that a little bit ago with the hiv medications the indenavir 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 just it's just also just naturally nephrotoxic too so with this particular drug you want to be very very careful with saddafire now one of the things that we can actually do with saddafivir to reduce the crystal inducing property 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 phoscarnic so phosparnate 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 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 phoscarnit so phoscarnet i want you to remember seizures via electrolyte abnormalities sadofovir crystal induced nephropathy but again you can try to reduce that by giving lots of iv fluids and probenicid 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 getting your cyclovirs so for example you have something called a cyclovir and then there's another one called val acyclovir 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 pham ganciclovir but what happens is acyclovir valley cyclovir 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 going to be utilizing hsv infections that cause herpes labialis or some type of genital 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 valley cyclovir the gansiclovir 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 are caused by 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 acyclovir vicente valcyclovir 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 analogues so this is acyclovir valcycle very 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 really want to know thymidine kinase really acts on the top two val cyclovir acyclovir and then ul 97 kinase axon 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 valcyclovir 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 for particularly their rna and their dna so here we have something that looks like a nucleotide do you remember this enzyme here what's this enzyme this was the dna 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 analogue acyclovir valcyclovir ganciclovir if we phosphorylate them they almost look like a nucleotide and if we try 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 a cyclovir valcyclovir 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 fluid same thing with the sadofa beer you give it with iv fluids but also give prabenosid the other thing here is valley cyclovir and acyclovir have also been shown to be able to increase the risk of ttp the mechanism is not exactly like completely known but if a patient has ttp and they're on one of these drugs potentially go looking as it has a potential drug cause okay and then the last thing here is potentially pan cytopenia 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 all righty so big thing that i want you guys to remember for adverse effects here again never toxic acyclovir give it with iv fluids ttp thrombotic thrombocytopenia papura look for acyclovir and valcyclovir in the actual drug list and then again ganciclovir bone marrow suppression for these drugs acyclovir valcyclovir 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 like 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 got to put all this together and do some cases let's get to it now all right guys let's do some practice problems there's a lot of stuff that will be covered on the whiteboard so there's a lot of things that we have to be able to review and let's see if we can just test your 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 decides 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 blocked the cd4 gp41 interaction you say okay it's inferior tight i know that one and he says okay what's he used for in the heart therapy and you say it's not really part of the main regimen but you can say it's an adjunct it's an add-on and hiv-resistant strains to the nrtis so that would be the inferivite all right good we die done boom easy he says okay what are the drugs that block the ccr5 receptor and the gpu 120 interaction between hiv and the th2 cell and you say oh that's easy that's morava rock boom done because maravaroc prevents the docking right and then he says okay what kind of you know genotypes are you know 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 then 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 r or reverse transcriptase can't tell the difference it's what tries to incorporate into the growing dna strand so when it adds this end you can't add any other nucleotides beyond that point after that one so it terminates the actual dna formation and it's okay what are the name of the drugs and you say well you say zale's td and he's like what he says oh there that's the way i remember it zaidovudine a baccavir lemivoudine m tricidabean stavudine tenofovir and didannosine 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 well mitochondria toxicity is actually classified by lactic acidosis peripheral neuropathy myopathy and also hepatic steatosis as well as lactic acidosis i've already said that one uh and it's it's all of them that do that and he's like all right yeah you got that one and he said all right which one calls pancreatitis and you say oh that's a stabby dean and didenosine he says which one of the ones actually cause nephrotoxicity it's an off of her and he says okay which one is actually caused like a pansitopenia by trying to suppress the bone marrow you see the dovadeen he's alright guy i got you here you got a patient who potentially has a very specific type of haplotype that is positive for and if you give them this drug they can have 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 test a positive can you say a backup here 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 yeah i guess 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 you say oh that's the non-nucleoside reverse transcriptase inhibitors i always remember then by the veer that is in the center of the word f of irons right nevirapine uh urtravine and delavaridine and so again you always see the veer in the center this is the only one that has the veer in the center of the actual name he says okay good which of these nrt nrtis is actually specifically hepatotoxic and you would say oh well pretty much like you know generally f of irons is the biggest one and the european he says okay we're going to cause vivid dreams and hallucinations kind of like when you're sleeping and you say oh that's epivirus and which one's actually causing the teratogenic effect and you have irons and diloveridine so these are the big things to remember here for your inner rtis 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 cell's dna and that's the integrace inhibitors and i always remember them by the ending tegravir tegrovir so again if you go back the actual particularly the nrcis always has the veer in the center and then the integration arbiters always has the tegravir at the end it's important to remember this so dolutegravial radital or vigor 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 okay what kind of labs would i actually test for to see if they have that can you check the actual ck the serum ck as well as the urine myoglobin all right good next question what's the actual drugs that inhibit a particular enzyme that breaks down polyprotein specifically the gag pole 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 never so it was the ver in the center that was the nnrtis and then the integrase inhibitors is the tegravir at the end and then navir at the end is the protease inhibitors so you got that one down and he says okay what are the actual protease inhibitors actually associated with cyp450 inhibition right tonvir 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 then you say indentavir 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 nnnrtis the adjuncts that you can add on is infuriated if they're resistant to one of these regimens and then ravvarock if they're positive for the ccr5 receptor boom next case case study two you had an infectious disease attending again he's performing a war rounds 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 uncutting excuse me encoding inhibitors and primarily this is amantadine the next question he says is okay 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 you say ataxia you say a prolonged qt interval and levitoreticularis 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 five prime cap swapping and he says uh which one is it you say oh it's blocks of air it inhibits that particular enzyme and then biloxavir 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 cyalic acid from the hemoglobin and releasing the virus allowing for it to spread throughout the bloodstream and to affect other cells and these are called neuraminidase inhibitors this is osceltamivir xenamovir and the primarily the only use for this is influenza ap same thing like blocks very 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 in 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 these performing arounds and yeah and i wanted 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 when you say oh the nucleosides is lemiviudine or entechovir 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 strain it 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 a defever and the nucleosides would be lamivudine and in tachovir all right so then he says okay which are 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 a deference in alphavir and then which drugs actually form antiviral peptides that were to inhibit protein synthesis they work to inhibit rna synthesis and they actually form mhc-1 complexes that lead to the activation of cytotoxic t-cells to kill those virus-infected cells and this is called interferon alpha okay and off of the main adverse effects of watchful is don't give this and someone who's pregnant and it can actually suppress your bone marrow and cause panzoidopenia 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 polypro proteases that break down these big poly proteins into 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 ns34a protease which breaks down this polyprotein well it's a protease inhibitor yeah exactly and so the protease inhibitors will end in prover pervert for this group for the hepatitis c virus category it ends in prover okay 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 all right so that would be this particular category then he says okay which 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 maybe even involved in a virus assembly at the golgi apparatus well it's called ns5a inhibitors and ns5a inhibitors always end with azvar like ledipsiver uh velpatosphere the cladosphere 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 helping us to make more rna so it's important rna formation this is going to be ns5b inhibitors and we always remember these by buver like so phosphovir all right so we got prover for the protease inhibitors in this category we got asvare 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 ionosine 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 riboviron 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 rib of iron saucephosphavir and interferon alpha now you probably have the question is like i don't really know which one of these i actually utilize do you 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 rib of iron 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 and 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 phoscarnit and sidophofer and then he says okay which one of these is actually a pyrophosphate analog remember phos is phoscarnet right so that's going to be phos carnet 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 cyclovir resistance cmv infections like cmv pneumonia retinitis esophagitis where their ul 97 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 to seizures due to electrolyte abnormalities you would say phoscarnit and then which one obviously can cause crystal induced nephropathy and is naturally nephrotoxic sadophophir how do we have minimize this iv fluids and probenocid all right last part here is you have another group of drugs he says that actually act as guanosine and logs and what happens is they get taken up into the cell that's infected with the herpes virus and gets phosphorylated via these thymidine kinases or ul-97 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 valcyclovir there's even way more but these are the two most commonly utilized ones and then ganciclovir okay so the next question is what are the indications of acyclovir 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 acyclovir 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 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 [Music] you