Antiviral drugs pharmacology part 3 -Drugs for HIV, antiretroviral drugs

Duration: 20:06 2807 transcript words EN summary

Video summary

This video provides a comprehensive overview of antiviral pharmacology specifically targeting retroviruses, with a primary focus on the human immunodeficiency virus (HIV). Before discussing the medications, the transcript explains the viral life cycle, detailing how HIV enters CD4 helper T cells by binding its glycoprotein to the CD4 receptor and coreceptors like CCR5 or CXCR4. Once inside, the virus utilizes the enzyme reverse transcriptase to convert its RNA into DNA, which is then integrated into the host cell's genome by viral integrase. The infected cell subsequently produces viral proteins from a polyprotein complex that must be cleaved by the protease enzyme to form new infectious viruses, a process that serves as the target for several drug classes. The main categories of antiretroviral drugs are introduced, including fusion inhibitors, reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors. The discussion delves deeply into reverse transcriptase inhibitors, which are further divided into nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). NRTIs act as chain terminators that get incorporated into the viral DNA, preventing its synthesis, while NNRTIs bind to a different site on the enzyme to inhibit it non-competitively. Specific examples like zidovudine, lamivudine, efavirenz, and nevirapine are highlighted, along with their unique naming conventions and specific uses against HIV-1 versus HIV-2. A significant portion of the summary is dedicated to the adverse effects and clinical considerations for these drugs. NRTIs are noted for causing bone marrow suppression, peripheral neuropathy, pancreatitis, and lipodystrophy, with abacavir specifically requiring HLA-B*5701 genetic testing due to the risk of hypersensitivity reactions. NNRTIs like efavirenz are associated with neurotoxicity and skin rashes, while protease inhibitors often cause metabolic abnormalities such as hyperglycemia and increased cholesterol levels, though atazanavir is an exception. The video also explains the concept of "boosting," where ritonavir or cobicistat are used to inhibit liver enzymes like CYP3A4, thereby increasing the plasma concentration and efficacy of other protease inhibitors to reduce pill burden. The final section covers integrase inhibitors and fusion inhibitors, which prevent the integration of viral DNA into host DNA and block viral entry, respectively. Integrase inhibitors such as raltegravir and dolutegravir are effective against both HIV-1 and HIV-2 but can cause myopathy and interact with calcium or magnesium supplements. Fusion inhibitors include enfuvirtide, which prevents membrane fusion, and maraviroc, a CCR5 antagonist that requires a tropism assay before administration. The video concludes by emphasizing that modern HIV treatment regimens typically combine drugs from these different classes to maximize efficacy and manage side effects, underscoring the complexity and importance of understanding each drug's mechanism and limitations.

Read the full video transcript

Hello everyone. In our previous two videos we have already discussed antiviral drugs for DNA viruses and for RNA viruses. Now in this video we will focus on the antiviral drugs for retrovirus, that is human immunodeficiency virus, that is HIV. So before we discuss the drugs, little bit we should know about how HIV virus enters into cells and replicates. Because if we know that, we will easily understand how various drugs act, that is the classes of drugs we will understand. So here this schematic diagram is showing a CD4 T cell, that is the helper T cell. Because these HIV viruses mainly attack the helper T cells. So this is the HIV virus and this on this basically there is a membrane protein, basically glycoprotein, and this glycoprotein combines with the CD4 receptor on the CD4 T cell. And there is a coreceptor along with that, that is the CCR5 or CXCR4 receptor. So these are chemokine receptors which are present on this helper T cells. And these are coreceptors along with the CD4 receptor. So this glycoprotein on HIV virus combines with this and then it is endocytosed and then the RNA of this HIV virus is released into the cytoplasm. Now this is a retrovirus, that means in this virus DNA is synthesized from RNA. Normally we always study that RNA synthesized from DNA, but here in this virus RNA is synthesized by DNA and for this there is an enzyme that is reverse transcriptase enzyme. Reverse transcriptase is basically an RNA-dependent DNA polymerase. Okay? So basically it is synthesizing DNA from the RNA. Okay, so that is reverse transcriptase and with this double-stranded DNA is synthesized. Now this DNA enters into the nucleus and integrates with the human cell DNA. Okay, so this is human cell DNA and we see that the viral DNA has integrated with this and for this another viral enzyme is required that is viral integrase. Right? Now once that happens, now from this integrated DNA, now transcription will take place that it will use the host machinery to synthesize viral RNA. So two types of viral RNA will be synthesized. One from which proteins will be synthesized. So this is viral mRNA from which the viral proteins will be synthesized and another is viral RNA that is the genetic material of the virus. Okay, so that is viral RNA that is a genomic RNA and then there is viral mRNA. So from this viral mRNA, a polyprotein complex will be synthesized. That's a complex which consists of many proteins and finally this polyprotein complex is broken down by a protease enzyme. Okay? And then we have the various proteins which are released and then the viral RNA along with these proteins which are released, they combine together, they assemble together and the assembled virus is released outside. Okay? So there are certain key things which are happening here. One, fusion of the viral proteins with the receptor on the cell. Then there is reverse transcriptase which is forming DNA from RNA. Then there is integration of this DNA with the human DNA. Then we have a viral mRNA formation and from this protein polyprotein complex is being synthesized and then the protease enzyme is breaking down this polyprotein complex. So this polyprotein complex we also discussed when we discussed about the hepatitis C virus. In that also we discussed about this. Because we will see later that there are certain proteas inhibitors, okay? So, if these proteas inhibitors act, then these proteins will not be released from the polyprotein complex and the functional the virus cannot be assembled again, right? So, this we studied in hepatitis C virus also and here also we will study that there are certain proteas inhibitors. So, what are the different classes of drugs for HIV? We have first is fusion inhibitors, which can inhibit the fusion of the virus with this here will be CD4 receptor and also CCR5 CXC R4 uh coreceptor, right? Then we have the reverse transcriptase inhibitors and in this reverse transcriptase inhibitors we have two subclasses, that is nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors, okay? Then we have the viral integrase inhibitors, right? Then we have the proteas inhibitors. So, four classes of drugs are main, fusion inhibitors, reverse transcriptase inhibitors, integrase inhibitors and proteas inhibitors. So, let us see what are these drugs. Now, first one which we are going to study is the reverse transcriptase inhibitors. So, in this reverse transcriptase inhibitors I told you before that there is nucleoside and non-nucleoside. So, when we are talking nucleoside reverse transcriptase inhibitors, actually there are two, nucleoside also and nucleotide reverse transcriptase inhibitors also. And if you have seen my previous video on antiviral drugs, you will understand that when I say any drug which is a nucleoside analog, then it is triple phosphorylated within the cell. And if it is a nucleotide analog, then it is uh two times within the cell because already there is one phosphorylation when we are talking about nucleotide. Okay, so this is a common concept which we have seen everywhere that any drug which is a nucleoside analog, like a thymidine analog, so that has to be phosphorylated within the cell. So, that will lead to activation of the drug. So, this is a common concept we have seen everywhere. Now, these nucleoside or nucleotide reverse transcriptase inhibitors, they inhibit the reverse transcriptase as the class of the drug suggests and they're also incorporated into the DNA which is being synthesized. So, suppose this is the mRNA, viral mRNA is there, and there will be a reverse transcriptase enzyme, and as it moves forward along this mRNA, the nucleotides are being added here, right? Now, when this drug is given, one thing it directly inhibits this enzyme, and they also get incorporated here. So, instead of our uh the nucleotide which needs to be incorporated, we will have this drug which will be incorporated instead of that nucleotide. So, there will be premature chain termination. Okay, so whole DNA will not be synthesized, right? So, in this class we have drugs like zidovudine, didanosine, stavudine, lamivudine. Okay, so these drugs mainly you are seeing that they are ending in -dine. Zidovudine, stavudine, lamivudine. Then there is also didanosine, emtricitabine. This drug we have also seen that it acts against hepatitis B virus. Okay, then we have zalcitabine. So, they are ending in -dine, -bine, and -cine, except abacavir. Abacavir. Okay, so that is why this abacavir is very commonly asked in MCQ that which of the following is some other class they will show and which of the following is not of this class then generally they will give a backer video you will get confused because the nucleoside reverse transcriptase inhibitors they end in this dean and bean except abacavir so important to remember for MCQ. Then we have the nucleotide reverse transcriptase inhibitor in that we have we have seen in previous antiviral videos where I talked about that nucleotide drugs they are ending in this term fovir okay so I would suggest you better watch those videos as well okay so that was a nucleoside and nucleotide reverse transcriptase inhibitors. Now they have certain common side effects what are these side effects? First one is bone marrow suppression which is common with zidovudine so when there will be bone marrow suppression you will see basically pancytopenia there will be anemia neutropenia platelets will also go down okay then there is peripheral neuropathy peripheral neuropathy is seen with stavudine and didanosine for stavudine it is dose limiting that means as you increase the dose you will see that with higher dose peripheral neuropathy will occur. Similarly pancreatitis pancreatitis is dose limiting side effect for didanosine okay so these two peripheral neuropathy PP you remember peripheral neuropathy pancreatitis are with stavudine and didanosine more commonly they are seen with others also but stavudine didanosine they are more common okay then we have a lipodystrophy again seen with zidovudine and stavudine. Then increased risk of MI very common MCQ it is there increased risk of MI is seen with abacavir okay so this abacavir is important to remember because this drug is commonly used in HIV regimes. Lamivudine also is a common drug which is used in the regimes, but abacavir also is commonly used. Depends on which age group are talking about, okay? So, abacavir there is increased risk of myocardial infarction and it can also cause hypersensitivity reaction. So, for this actually HLA-B 5701 genetic testing is required before administering abacavir, okay? Then another common MCQ asked is that all of these nucleoside and nucleotide reverse transcriptase inhibitors can cause hepatomegaly, steatosis, and lactic acidosis. So, all of them have high chances of causing this side effect, lactic acidosis, hepatomegaly, and steatosis. And among the nucleoside reverse transcriptase inhibitors, we have lamivudine and emtricitabine which are best tolerated, okay? So, next class of drugs we have is non-nucleoside reverse transcriptase inhibitor. And these drugs are also reverse transcriptase inhibitors as the name suggests. What is the difference? That they inhibit the reverse transcriptase non-competitively, okay? So, these drugs also do not require activation like we said in nucleoside and nucleotide drugs, they require activation, they require phosphorylation, but these non-nucleoside reverse transcriptase inhibitors do not require that phosphorylation and they inhibit reverse transcriptase enzyme non-competitively. And important for MCQ that they are used for HIV-1. There are two types of HIV viruses, HIV-1 and HIV-2. Non-nucleoside reverse transcriptase inhibitors are used for HIV-1. Now, in this we have drugs which are ending in -viridine, -virine, okay? So, we have this -virine non-nucleoside reverse transcriptase inhibitors. Another drug is efavirenz, efavirenz, and nevirapine. Okay, efavirenz and nevirapine. So, these drugs, basically efavirenz and nevirapine, these are basically cytochrome P450 enzyme inducers. Okay? So, that we need to know because this efavirenz, actually efavirenz was commonly used drug in the HIV regimens. See, HIV regimens involve multiple drugs which are given together. So, we have two nucleoside reverse transcriptase inhibitors combined with the non-nucleoside reverse transcriptase inhibitors or with protease inhibitors. So, we have different HIV regimens. And in this, efavirenz was commonly used before. Now, this rilpivirine is being used because it is better tolerated. So, it is a second-generation non-nucleoside reverse transcriptase inhibitor. Okay? What are the adverse effect? Well, all the non-nucleoside reverse transcriptase inhibitors, they can cause skin rash. And nevirapine can cause Stevens-Johnson syndrome and toxic epidermal necrolysis. And with efavirenz, with efavirenz, there are high chances of neurotoxicity. Again, it is important for MCQ because this efavirenz was commonly used. Okay? Then, we have the next class of drugs, that is the protease inhibitors. And these protease inhibitors, you remember that all of them actually are ending in the name navir. Okay? So, we have saquinavir, ritonavir, indinavir. You see, all of them are ending with navir. Right? So, these protease inhibitors are important drugs because again, they are common in HIV regimens. And important common things which you should remember about them is that all of these drugs inhibit cytochrome P450 enzyme, cytochrome P3A4 enzyme. All of them are metabolized by liver and all of them cause metabolic abnormalities except atazanavir. Okay? So, atazanavir does not has metabolic side effects, but others you will see they have metabolic abnormalities that is hyperglycemia. They will increase the triglycerides, they will increase the cholesterol. So, all of these protease inhibitors there are high chances of these metabolic abnormalities, okay? Then uh certain other uh side effects can occur for example with indinavir, crystalluria and kidney stones can form, okay? Now, these protease inhibitors generally have large tablet load. That means too many tablets are required to be taken per day. Now, to reduce that load, we combine these protease inhibitors with another protease inhibitor that is ritonavir. So, in this list you see there is ritonavir. So, when we combine these protease inhibitors which we are giving, we combine with ritonavir, so this ritonavir actually inhibits CYP3A4, okay? So, these enzymes are inhibited, as I told you all are inhibiting, but this ritonavir it has a main effect of inhibiting so that the clearance of other protease inhibitors is decreased, okay? So, it's like the other protease inhibitors are not being metabolized. Their first pass metabolism is decreased and this increases their plasma concentration. And because of that, the dose required of these protease inhibitors decreases, okay? In fact, whenever the protease inhibitors are added in the HIV regimens, they are always added as a boosted protease inhibitor. So, always you have to combine with ritonavir except nelfinavir. Nelfinavir, no boosting is required with ritonavir, right? For all other protease inhibitors, you need to use this ritonavir. And what will be the mechanism of action of these protease inhibitors? Sorry, I I forgot to tell. Maybe because we have already discussed before that polyprotein complex is broken down with this proteases. So, this protease inhibitors is inhibiting that poly protease enzyme so that the proteins of the virus cannot be released and then the assembly of the virus will be affected. Okay? So, that is ritonavir combined with all other proteases except the nelfinavir. Then we have another type of boosting which can be done, that is with cobicistat. Cobicistat is basically again, it inhibits the liver enzyme CYP3A4. So, that also can be used for protease inhibitor boosting. Okay? But this cobicistat, remember it is does not has any antiviral activity as such. It is just a CYP3A4 inhibitor. Then we have the next class of drug, that is the integrase inhibitors. Integrase inhibitors, so this viral integrase we saw it was required for incorporation of viral double-stranded DNA with the human cell DNA. So, these integrase inhibitors will prevent that integration. And integrase inhibitors are active against both HIV-1 and HIV-2, that is important. Okay? Integrase inhibitors active against both HIV-1 and HIV-2. And the common integrase inhibitors which are available, they include raltegravir and dolutegravir. Okay? So, they are ending in gravir. So, this is grace, no? So, they are ending in gra- that is inhibiting the integrase enzyme of the virus. Okay? So, raltegravir and dolutegravir and their side effects include one is myopathy. Both of them actually can cause myopathy and increase serum creatinine. And they also chelate the calcium, magnesium, basically the divalent ions they can chelate. They combine with them, remove them. So, they are best avoided with supplements because if you give this drug with the supplements, then they will combine together and even the drug these drugs also will not be absorbed and the HIV treatment may fail. Okay. So, those were the various classes. Last one is the fusion inhibitors. In fusion inhibitors, we have for enfuvirtide. Enfuvirtide binds with the viral protein that is GP41 which is present on the viral membrane. So, it prevents the fusion of the viral protein with the CD4 CCR5 receptor. Okay. This drug is given only subcutaneously and only for HIV-1. Okay. Important again, only for HIV-1 enfuvirtide is given. Integrase inhibitors, they are given for both HIV-1 and HIV-2. And since they are given only subcutaneously, adverse effect includes localized skin reaction. Then we have other drug, monoclonal antibodies are there, ibalizumab. Ibalizumab. So, these are CD4 binding inhibitors. So, here CD4 receptor is there. So, they bind to that, prevent the binding of the virus with the CD4 receptor. Then we have CCR5 receptor inhibitors, maraviroc. Maraviroc binds with CCR5 and again prevents the fusion of the virus with the coreceptor on the CD4 cell. Okay. So, these are the fusion inhibitors. They will prevent the entry of the virus into the cell. Now, this CCR5 you see, I told that either it is CCR5 or there is CXCR4 receptor. So, this maraviroc will only function if the receptor present with the CD4 cell is CCR5. So, the coreceptor along with CD4, if it is CCR5, then only this maraviroc will function. So, before giving this drug, it is always better to perform this coreceptor tropism assay. So, if this CCR5 is present, then this maraviroc is given. And this drug can be given orally, but only for HIV-1. And the adverse effects include hepatotoxicity and also rash. Okay. So, those were the various classes of drugs for HIV virus, which include the fusion inhibitors, reverse transcriptase inhibitors, integrase inhibitors, and we also saw the protease enzyme inhibitors. Okay. So, that was about the antiviral drugs for HIV. Thanks for watching the video. If you liked it, do press the like button. Do share the video with others, and don't forget to subscribe to the channel Physiology Open. Thank you.