DIP Episode 34 - Antivirals

Okay, welcome to episode 34 of the Divine Intervention Podcasts. My name is Divine. I guess I'm no longer an MS4. I guess I'm some kind of PGY1. Okay, so today we're going to be talking about all the antiviral medications and hopefully you find this high of for your exams. So let's begin. So obviously we have to talk about herpes, right? And there are many kinds of herpes, right? There's like herpes 1 through 8. You probably want to know what those are for your tests, right? So there's herpes 1. That's the one that could cause oral or genital herpes, but generally causes oral herpes. There's herpes 2, right? So HHV 2. That one could also cause oral or genital herpes, but it usually causes genital herpes. And then HSV3, right? You're thinking about VZV, Viracelo Zastrovirus for HHV4. You're thinking of EBV, the Epstein Bar Virus. Remember, you use this CD21 to get into B cells. And then for CMV, you're thinking of herpes 5, okay? HHV5 is CMV, Sato Megaloviar. Remember the monospot negative mononuclosis-like syndrome? For herpes 6, you're thinking about Rosiola. And for herpes 8, you're thinking about Carposis Sarcoma, right? That's a pretty classic in HIV. So how do you treat herpes? Right? So the gold standard drug in general that you'll see on exams all the time is acyclovere, okay? Acyclovere or an oral formulation, valley cyclover, okay? So acyclovere is used to actually treat HHV and VZV. And how does acyclovere work? Acyclovere is a guanosine analog, okay?

It's basically the nucleoside form. So because it's a nucleoside to be incorporated into DNA, it needs to be turned into a nucleotide, okay? So it's an analog of guanosine. There's a thymidine kinase that will add three phosphates to it. And once that acyclovere, that guanosine analog has been activated, it then basically inhibits DNA polymerase as it's incorporated into the DNA strand. Because the thing is, if you look at normal DNA, there's a hydroxy group on the three-prime position. Acyclovere does not have a hydroxy group on the three-prime position. So that phosphodiester bond will not form, right? So it's mechanism of action, basically, is that it's a chain term in need. That's how acyclovere works. And the good thing is the thymidine kinase is expressed specifically in the herpes virus. That's why acyclovere is generally a relatively clean drug. But the thing is acyclovere is actually clear, right? So you can actually, like, accumulate in a renal self, right? You can destroy them. That's why acyclovere is never toxic. Another thing is it could actually crystallize in the nephron, and it can cause, like, a crystalline nephropathy. And the thing that you can do is, you can actually do the same thing. And the thing that you can do is, like, you can actually do the same thing. And the thing that you can do is, like, you can actually do the same thing. And the thing that you can do is, like, you can actually do the same thing.

And the thing that you can do is, like, you can actually do the same thing. And the thing that you can do is, like, you can actually do the same thing. And the thing that you can do is, like, you can actually do the same thing. And the thing that you can do is, like, you can actually do the same thing. And the thing that you can do is, like, you can actually do the same thing. And the thing that you can actually do is, like, you can actually do the same thing. And the thing that you can do is, like, you can actually do the same thing. And the thing that you can do is, like, you can actually do the same thing. And the thing that you can actually do is, like, you can actually do the same thing. For your exam, think of these as the primary treatment for CMV. And basically, these drugs, so Gansai clover, is a Guano-Sent analog as well. The only thing is that it's not activated by a Thymidine kinase. It's actually activated by a different kind of kinase known as the UL97 kinase. The UL97 kinase has three phosphates. And then you have activated Gansai clover. And again, Gansai clover is the drug of choice in the treatment of CMV. Okay, remember, CMV is the one where a person has a mononuclosis-like presentation. But the monospot test is negative. And remember, CMV can cause a high-yout congenital cluster of thins that are tested on exams, especially with a peri-ventricular calcifications on imaging. And CMV is a pretty common infection in HIV patients, right?

So, for HIV patients, it has a CD4 count less than 50. You want to begin to think about diseases like CMV or MAC. Remember, MAC, that's what you'd prefer, that is the Z-thru micelle. And again, the mechanism of resistance is so similar to that for a cyclover. If you mutate that UL97 kinase, Gansai clover does not work anymore. And again, think of it in terms of competitive inhibition mechanics. If you're going along the mechalis menthen pathway. And the big side effect you want to know with Gansai clover is myelose suppression. I mean, yes, it's the UL97 kinase that activates it. So, there are other kinases in us that can activate Gansai clover. If those kinases activate Gansai clover, it can incorporate into like our own DNA. See, for example, the lymphocytes, and it can suppress the bone marrow. E-cyclover actually can cause bone marrow suppression as well. But, for exams, if they say bone marrow suppression antiviral, the first thing I want you to think about is Gansai clover. Val Gansai clover is just again the oral formulation of Gansai clover. And the next drug I'll talk about is FOSKA Rnet. FOSKA Rnet is actually a pretty broad spec drug. It can treat HSV, it can treat VZV, it can treat CMV. Basically, there's the list resistance of these bugs to FOSKA Rnet. And one good thing about FOSKA Rnet, there is less resistance because you don't need to FOSKA Rnet for a little to activate it. The other drugs you do need to FOSKA Rnet for is not so for FOSKA Rnet.

FOSKA Rnet is a pyrophosphate on a log. It actually inhibits DNA polymerase. So basically, binding the pyrophosphate pocket of DNA polymerase and the active side of DNA polymerase changes shape. So, no new nucleotide can bind to DNA polymerase. So, think of FOSKA Rnet as working with irreversible, non-competitive, inhibiting kinetics, if you may. So, basically, like your VMAX is going down with FOSKA Rnet, but there's no change to your KM. Contrast that with A-cyclover and Gansai clover. And it's never toxic, but they don't really test that. And basically, the only time you will ever use FOSKA Rnet on any exam for anything is if a person has like A-cyclover or Gansai clover resistant like HSV or CMV. Okay. So now let's talk about HIV and the HIV drug. So, we probably should talk about the life cycle of HIV. Don't forget HIV is an RNA virus, right? It has like GP41 on its surface that actually has the ability to bind to the CX-CR4 receptor on the surfaces of T cells, right? And with that happening, you can make the fusion of HIV with a T cell possible. And it's an RNA virus, but it needs to integrate into our genomes, right? So, it needs to be converted to DNA. And that's done by reverse transcripties. Remember, reverse transcripties depends on RNA as the template and it makes DNA as the product. So, it's an RNA-dependent DNA polymerase. And then once you've made that DNA, you integrate it into the genome with integrates, okay?

And then if you transcribe that DNA, you can make a HIV polypeptide. But a polypeptide is useless. The HIV polypeptide has to be broken down into individual proteins, by an enzyme known as proteins, okay? And then once you make those individual proteins, you make those variants, and then you package it out for disbursement to other parts of the body. Also, please note this, right? So, there's also the CCR5 receptor. You actually find it on the surface of white cells like macrophages. In fact, HIV in many cases, you use, tries to actually use the CCR5 receptor to get into a white cell, right? So, in fact, in general, if a person has a CCR5 mutation, they have like a relative resistance to HIV, because HIV in general loves to use CCR5 as its first point of contact to get entry to the immune system. Now, there are three high-yogins you want to know about in HIV, right? So, there's the pole, the pole gene POL, okay? Just remember RIP like resting piece for the products of the protein products of the pole gene, okay? You get the R for reverse transcriptase, the I for integrates, and the P for proteins. They all come from the pole gene. And then there's the ONF gene, the ONF gene quotes for GP 160. It's basically a polypeptide that's cleaved by protease into GP 41 and GP 120. And then there's the GAAG gene, the GAAG gene calls for P24. The P24, the higher thing you want to know about this is it's the antigen that's actually detected in the ELISA test that's useful HIV.

So, once you understand the life cycle of HIV, that's the thing I always tell people. If you're trying to learn, just try to organize information. Regardless of how nebulous a given body of knowledge is, if you can try to gain some understanding and try to put it in a very good schema, it's much easier to remember, much easier to memorize. So now you know the life cycle, the drugs should fall into place nicely, okay? So, the first drugs will start with other drugs that inhibit the entry of HIV into cells, right? So, the fusion inhibitors. So, they're drugs that bind to GP 41. The big one you want to know for your exam is Enfuvertide. Enfuvertide, it basically, it's a fusion inhibitor and it prevents the entry of the virus into host cells. And you want to know that Enfuvertide works only for HIV 1. Doesn't do anything for HIV 2, okay? Doesn't do anything for HIV 2. Now, the next drug I'll talk about is Maraviroc. Think of Maraviroc, the buzzword you're looking for in exams is Chimokine receptor blocker. The thing is, it binds to CCR5 and again, that prevents the HIV virus from fusing with our white cells and it prevents HIV from gaining entry into our white cells. And again, it only works for HIV. So, these special drugs like Enfuvertide and Maraviroc only work for HIV 1. They do not work for HIV 2. And then we go to the class of the reverse transcripties inhibitors, right? So, the reverse transcripties inhibitors, there's two kinds of reverse transcripties inhibitors, okay?

There are those that are competitive inhibitors, okay? So, basically, they increase KM, but they do nothing to VMAX. And then there are those that are non-competitive inhibitors. Those decrease KM, sorry, those decrease VMAX, but they do nothing to KM. And the competitive inhibitors are the drugs known as NRT Is, the nucleoside reverse transcripties inhibitors. And the high yield drug means you want to know here, drugs like STAVUDIN. That's a high yield one that shows up on exams. There is Didadocene. There is Intracidabin. Intracidabin is actually also used to treat head B. There is Lamyvudin. Lamyvudin also is used to treat head B. There is a Zalcidabin that one is Loreal. There is Zaidovudin. You definitely want to know Zaidovudin. That's the one that's commonly known on exams as AZT. It's actually used to prevent a vertical transmission. That's the classic issues of one exam. It's used to prevent vertical transmission for exposure-preferlaxis for six to 12 weeks in an infant. If you're like, oh, maybe this infant contracted HIV from mom. Tenoffovir is another NRTI. Another high yield thing you want to know about is it's also used for head B. So basically, to treat head B, just remember, that head B like head B and then an ELT, the effointracidabin, the L-Folamyvudin, and the T-Foltenovovir. And then another high yield NRTI you want to know about is a back-of-year. I'll talk about these drugs in a bit. And again, these drugs increase KM. They do not change VMAX.

Contrast that with the non-competitive inhibitors. These are the N-N-RT Is, the nucleoside, the non-nucleoside. Reverse transcripts these inhibitors. The big ones you want to know here, there's N-Virapin. That's probably what's used most commonly these days. And then there's a Favirans. And a Favirans, you don't want to give it to a pregnant woman. It's a terrarogen, and it's also neurotoxic. So you can cause like vivid dreams, because it actually has the ability to cross the blood-brain barrier. These drugs basically, they bind to a different site on reverse transcripts. That essentially prevents it from binding new nucleotide. So again, they decrease your VMAX, but they should be no change in KM. Now, here's the thing. There's tons and tons and tons of side effects you'll see in first aid with these drugs. But I will say in general, if you know these side effects I'm going to mention right now, you'll probably be able to answer any question within reason, related to the side effects of these HIV meds, especially these reverse transcripts these inhibitors. So I'll just mention like one side effect for each, but those are the ones that I've seen tested very commonly on exams. So the first group is Stavudin Dydanosine. So these are NRT Is. The big side effects you want to know here is pancreatitis. That's it. For Zaidouvudin, the big side effects you want to know is bone marrow suppression.

For a father, and I already mentioned it's a terrarogen, so don't give it to a pregnant woman. And it also causes vivid dreams, right? So it's neurotoxic. And then for a back-up ver, you want to know about the hypersensitivity reaction on HLAB57. In fact, they can give you an exam question and say, oh, prior to prescribing a back-up ver was the next best step in management. And the next step in management is to test for HLAB57, because there is been studies that showed like 8% of people could get like a life threatening hypersensitivity reaction to a back-up ver. So that's all I'm going to say about the RT Is. Now, the next drugs I'll jump into are the integrators. They are basically the cleanest HIV drugs. They have few if any side effects, and the all-ending gravere, right? So like L-vitegravere, or L-vitegravere, Dolotegravere, blah, blah, blah. Okay? That's essentially all I'm going to say about those. They don't really test any side effects with those drugs, but they are very clean. They have very few side effects. Now, the prudest inhibitors, basically the all-ending navir. Okay, so drugs like Atazanavere, Retonavir, Indinavere, Darunavere. I'll say of all these drugs, probably the highest yield wants to know about in terms of side effect profile, is Retonavir and Indinavere. Okay? The class side effects of all these medications is that they cause the metabolic syndrome. Okay?

People don't really know why, but they think that these drugs potentially mess with insulin signaling. Okay? So they tend to cause like fatter distribution, so like above a low hump around the neck. So that's not something that's unique to steroids. That's something that can happen with oolanzapine. The atypical anti-psychotic, it could happen with the prudest inhibitors, but it could also happen with the chronic use of cortical steroids. Now, in terms of specific side effects, the first one I'll talk about is Retonavir. Retonavir, the big thing you want to know here is that it's a very powerful inhibitor of SADROMP450. In fact, it's very good at boosting the levels of many other medications because it slows down their metabolism. That's why it's actually still used as a HIV med, because it makes it possible for you to give much lower doses of the other HIV drugs. And then in Retonavir, the big thing you want to know about in Retonavir is kidney stones. In Retonavir can cause nephrolithiasis. Don't forget that the anti-seizure med to pyramid can also cause nephrolithiasis. Those are very classic side effects. They love testing with these drugs. And again, in general, for HIV, you give twin RT Is plus some other kind of drug. You can give twin RT Is plus a prudest inhibitor, or twin RT Is plus an integrase inhibitor, or twin RT Is plus one of those fusion inhibitors. Remember, those fusion inhibitors work only for HIV-1. They do not work for HIV-2.

Now, for hepatitis, and HIV-1, if a numb is sticking, is more common in the US. HIV-2 is more common in African countries. Okay, now we are done with HIV. So let's jump to the hepatitis virus for HIV-1. In the way you can treat HIV, you can use an interferon alpha. So you can use those NRT Is I mentioned, remember, hep-B-L. So hep-B-L. So you can use emtricidabene, laminvidean, and tenofovir. Okay, for hep-B, you could also use ribovarine. Ribovarine has multiple mechanisms of action. One you probably want to know about is that it can work as a guanosine analog. So you can prevent the conversion of I-Nosin monofosphino-IMP to guanosimonophosphino-GMP. Okay, the enzyme that makes that conversion from I-N-P to GMP and XMP, like XMP monofosphite, is an enzyme known as I-Nosin monofosphidehydroginics. It so happens that ribovarine inhibits I-N-P dehydrogenies. But don't forget that I-N-P dehydrogenies can also be inhibited by the immunosuppressant microphenolite mofetil. Microphenolite mofetil also inhibits I-N-P dehydrogenies. And then ribovarine also inhibits RNA polymerase, right? And again, like I said, you can use ribovarine to treat hep-B. You can use the treat hep-C. This is a little more controversial, but you can actually use the treat R-S-V as well. Although I will see that that is, I have just never seen that done clinically. But you could use it for R-S-V on exams usually I see that more with treatment more with Palavizio-Map.

It's a monoclonal antibody against the virus. You can use it to prevent R-S-V because you essentially prevent it from getting in contact with epithelial cells, especially like in the lungs and the earway. Now for hep-C, hep-C, I think some background will make remembering these drugs a little easier on your brain. The thing is, hep-C is a virus, okay? And for hep-C to like spread to other cells of the body, just like HIV. We say that HIV has this polypeptide that's made. And then some kind of produce in HIV chops up those polypeptides to make proteins that can then be packaged into like variants, into viral particles. Same thing with hep-C. Okay? Hep-C has this magic polypeptide. And that magic polypeptide has to be broken down into individual hep-C proteins if you may. Okay? And it's a produce that makes that chopping up happen. And those produce is the buzzwords you want to remember, an NS3 A and NS5 A. NS3 A and NS5 A are the produces that chop up the hep-C polypeptide. Okay? Now, the thing is, if you chop up that hep-C polypeptide, there is a non-structural protein that can be made from that polypeptide. It's one of the subunits of that polypeptide if you may. That non-structural protein actually helps with hep-C viral replication. The buzzword you want to remember for that non-structural protein is NS5 B. So again, NS5 A and NS3 A are produces in hep-C. NS5 B is a non-structural protein derived from the hep-C polypeptide.

That's the schema I want you to take away from this podcast. It's derived from the hep-C polypeptide and it helps with viral replication. So now you'll have that background, right? So let's talk about the hep-C drugs. For hep-C, you can actually treat with a bosepravir. Bosepravir is an NS3 A5 A inhibitor. So basically, it's a bosepravir is a produce inhibitor. But in this case, the produce is its inhibited. NS3 A5 A, it essentially prevents the formation of the individual proteins that are necessary for hep-C to function. The next drug is so fosebovir. So if you watch TV at all, I know that's not a common pastime of medical students in this country. But if you watch TV, you've probably heard about Harvoni. It's a combination of so fosebovir and some other drug that's like loyal for step one, the deepest beer. So fosebovir is an NS5 B inhibitor. So it inhibits that non-structural protein derived from the hep-C polypeptide. So it basically interferes with hep-C viral replication because it's ticking that protein out of commission. Now, you could actually use interferon-alpha as well to treat hep-C. This is basically not the standard of care anymore in general, because it has many nasty side effects. So it's like you have a flu-like illness from months on end, pretty nasty. And depression is actually another well-known side effect of interferon-alpha. In fact, before a person is prescribed interferon, a relative contraindication is actually the history of depression.

Believe it or not, that's a very good NBM exam question. Interferon-alpha, you generally have to be screened for depression before you're prescribed interferon-alpha. So the history of depression is a relative contraindication to the administration of interferon-alpha. And I don't know if you know these interferon words around. Please, please, please. Do not confuse interferon-alpha that's used for hep-B and C. With interferon-beta that's used to treat MS. Interferon-beta is for multiple sclerosis. And don't confuse interferon-alpha again for the BC or interferon-beta for MS with interferon gamma. That's actually used for macrophage disorders like CGD. So like chronic relonomatoid disease, where a person has a deficiency in any deep-page oxidies. You use interferon gamma for treatment with that. Because remembering interferon gamma is made by T-helper oneself, if I remember correctly. And interferon gamma activates macrophages, right? And you want to basically use, I sort of think of interferon gamma as something that gives macrophages like six packs or whatever. And it makes them super-struck. That's done by interferon gamma. And interferon gamma is a very good drug for treating macrophage disorders. And an unusual exam question could also be a person that has brittle bone disease. So osteoportrosis. Remember osteoportrosis is a macrophage disorder. So that's where macrophages are. A kind of macrophage, if you may. The osteoclasts have a carbonic and hydrate to deficiency.

It cannot make acid to pump across that raw food water to resort bone. You also treat osteoportrosis with interferon gamma. So that's it with the hepatitis viruses. So let's jump to the last viruses I'll talk about. And I guess the last set of anti-virus. That's the influenza virus. The thing is, cells, right? Db's like an nitrophilus or macrophages, be formed like endosomes or I guess phagosomes around influenza virus. And then the endosythose that stuff. And then that phagosome fuses with a lysosome to form a phagolysosome. Now, the thing is, for a lysosome to do its job, it needs an acidic environment. But the thing is, the influenza virus actually loves that. Because I sort of think of the influenza virus and like strolling into your cells. And it's wearing like this jacket and it's like, oh man. This lysosome is a little too warm. Let me get rid of this jacket, right? So it's on coating. For that, on coating process to happen. It actually needs an acidic environment in the lysosome. Now, if you want to create an acidic environment, well, you need something like a proton pump. If you may. That proton pump is known as M2. It's the M2 proton pump that brings in hydrogen ions into the lysosome and makes the lysosome slum in acidic. So that the influenza virus can encode. So, once influenza virus has encoded, it replicates. And it wants to go from like one cell to the other, right? The thing is, there is like this feather.

So sort of think of like a boat being attached to like shore. There's this feather that holds the influenza virus to the cell it has just infected. That's the acidic acid. So if you want to go away from that cell and go infect someone new, it needs to chop up that feather. Okay? That feather is chopped up by an enzyme known as Neuromeneidase. If you if Neuromeneidase does its job, you chop up that feather and then he I mean the influenza virus can go around and infect some new cell you can sail off into the sunset or whatever. It's called these days and infect new cells. So, how do we treat influenza? Once you have the background, it's much easier to remember the drugs, right? So basically the drugs were influenza. You can divide them into two classes. Drugs that don't work. Okay? But I still tested mainly for pharmacologic interest. And then drugs that do work that actually like used in clinical practice. So the drugs that don't work, okay? But I still tested. That's where we have a mantidine and a mantidine. A mantidine basically inhibits that M2 proton pump. So you do not make a low pH in the lumen of the lysosome. So the influenza virus cannot encode. There is essentially a 100% resistance to a mantidine. So no one uses that stuff anymore. Remantidine is also a drug that works the same way. And again, these drugs actually worked only against influenza A. There are many kinds of influenza that is like influenza A and B. They only work for influenza A.

They do not work for influenza B. But again, 100% resistance they don't work. If you're a physician, you should never prescribe this for your patients. But it so happens that a mantidine actually increases the release of dopamine in the central nervous system. So it's actually used now to treat Parkinson's disease. So I guess good for the pharmaceutical company that discovered that use. Now, the drugs that actually do work, that's why we have the Neuromeneidase inhibitors. So drugs like Sanamivere or Selthamivere. Okay? Or Selthamivere. If you've ever had the flu before, you've ever heard of the drug Tamiflu. Tamiflu, I believe, is or Selthamivere. So these drugs are basically the inhibitor Neuromeneidase. So the influenza virus cannot go from one cell to the next. And you have to give these drugs within the first 48 hours of infection. After 48 hours, there is no proven benefit with these drugs. And the thing is, these drugs actually don't cure the influenza. They just reduce your symptomatology by like one to two days. But you definitely want to know that these drugs are effective against influenza A and influenza B. They work for influenza A and influenza B. Super high yield to nozzles. As against a mantidine, remantidine that work only for influenza A. So if I'm not mistaken, I believe those are all the high yield antiviral that you're responsible for. And step one or step two or step three, whatever.

I will make another podcast hopefully in the next few days about the antifongals. And with that, I guess maybe joining the antipyrosetics as well. But with that, we should be done with the antibiotics. I know it's a lot of stuff, but if you know the stuff I've talked about in this podcast, you should be good to go. So we show the best, have a wonderful evening. I really hope the Cleveland Cavaliers win their game too. Yesterday was pretty sad with them losing the game from the blunders with GR Smith. But hopefully things go better on Sunday. And I will see you guys in the next podcast. Have a wonderful weekend and God bless. Thank you.

Guanosine analogs (e.g., Ganciclovir).

Acyclovir.

Foscarnet (a pyrophosphate analog).

CCR5.

Protease Inhibitors.

History of depression.

HIV-1 only.

Ganciclovir.

Chain termination due to lack of a 3'-OH group on the sugar analog.

Myelosuppression (bone marrow suppression).

Oseltamivir/Zanamivir.

Entecavir, Lamivudine, or Tenofovir.

Acyclovir needs Thymidine Kinase; Ganciclovir needs UL97 kinase.

Foscarnet.

Ganciclovir.

Chain termination due to lack of a 3'-OH group on the sugar analog.

Myelosuppression (bone marrow suppression).

Oseltamivir/Zanamivir.

Entecavir, Lamivudine, or Tenofovir.

Acyclovir needs Thymidine Kinase; Ganciclovir needs UL97 kinase.

Foscarnet.