Antiviral Drugs Pharmacology- part 1, Mechanism & Clinical Use- AntiHerpesvirus , Hep B drugs

Hello everyone. In this video we will talk about the antiviral drugs. Now before we start with the antiviral drugs you should know something about which are DNA viruses, RNA viruses and retroviruses because the drugs act with different mechanisms on these viruses. So I have a simple classification here that is DNA viruses include herpes vid which includes so many viruses. Then hepat that is there is hepatitis B in this classification. Then we have pox var papaloma ver adeno verid and polyoma verid. So these viruses we will discuss in this video. The antiviral drugs acting on RNA viruses and retroviruses we will discuss in other video. So talking about the DNA viruses first is herpes vid. So what are the anti- herpes virus drugs? See when we are talking about the DNA viruses little bit we should know about how they are multiplying. See viruses are obligate intracellular parasites. So they enter into the human cells and they use the host machinery for multiplication and synthesis of the proteins. So this is the uh simple herpes virus. Actually it enters into the cell and you see that this is the genome. This yellow one is the genome and this is the outer envelope. So as it enters there is a membrane surrounding the genome and then that genome is released which enters into the nucleus and in the nucleus that is this doublestranded DNA of the virus. In the nucleus there is uh this RNA polymerase that is the host RNA polymerase. It is using host RNA polymerase to synthesize the mRNA and then this mRNA is going into the cytoplasm and it is using the host ribosomes for the synthesis of the protein. So basically the transcription that is DNA to mRNA and mRNA to proteins that is the translation that is happening because they are using the host machinery but there is viral DNA polymerase okay which is being synthesized from this mRNA there is viral DNA polymerase which is responsible for DNA replication. So our drugs which will we will be talking that is the nucleotide and nucleotide analogs they are going to inhibit this viral DNA polymerase. See we don't want drugs to act against the host. So they should not target this host RNA polymerase though it will affect the synthesis of proteins of the virus but it is affecting the host isn't it? So that we don't want. We want the drugs to act at the virus level. So here we have the nucleotide analogs which target this viral DNA polymerase and prevent the DNA replication of the viruses. So we have this nucleotide analogs that is the guanosine analogs are there. The prototype drug in this is asyclloe. So this asyclloe enters into the cells in the virally infected cells and since it is getting activated by a viral enzyme only. Okay. So here we have asyclloe and this is the herpes simplex virus. So this asyclloe is phosphorilated you see ACV is phosphorilated with an enzyme of the herpes simplex virus that is the thyodine kynise. Okay. So this kynise whenever we say the term kynise that enzyme phospholates. Okay. So this kynise is phospholating the cyclloine and this is moving out and then within the cell the host cellular kinases. So this is the human cells cellular kinasis which will cause further phosphorilation of this asyclloease. So it gets triphosphilated a cyclloe triphosph triphosphate is formed and that is the active drug. Okay. So what does it do? So once that is formed this asyclloe triphosphate is inhibiting the viral DNA polymerase. So that is the first mechanism of action. Second mechanism of action is that it gets incorporated into the DNA because it competes with deoxy guanosine triphosphate. I told you see a cyclloe is the guanosine analog. So it will compete with the uh deoxy guanosine triphosphate to get inserted into the DNA. See this is the DNA and here your ATGC code is there. Okay. So instead of this G when the DNA is replicating instead of G this as cyclloh is getting incorporated into the DNA right. So that will halt the DNA replication and obviously by binding with the viral DNA polymerase there will be no further addition of nucleotides and this will also lead to chain termination. So that is the basic mechanism of action of asycllo B that is the nucleotide analog. Now we have different drugs in this category that is the nucleotide analogs. We have asyclloe, bellacycyclloe, jan cyclloe and we have some other drugs as well that is the pensy and others. We will see very soon. But here you see that asyclo we have discussed but this asyclloe is not able to act against all herpes virus. It is most active against herpes simplex virus one. And then next is herpes simplex virus 2. So these herpes virus cause different diseases. Herpes simplex virus one affects the mouth, face, skin, esophagus and brain. So it causes encphilitis as well. Herpes simplex virus 2 affects the genitals, rectum, meninjas, skin and hands. So this herpes simplex viruses have this enzyme thymodine kynise which we have seen here. You see that asyclloe is getting activated by this enzyme herpes simplex virus thyodine kynise. So this herpes simplex viruses have that enzyme which will lead to activation of this asyclloe. So that is why asycllov is a drug of choice for herpes simplex virus. It can also act against vicela zoster virus. It also has thyodine kindness. But for vicella zoster virus the dose of a cyclloe which is required is much higher. Right. Now the bioavailability of ascyclloe it is less that means when you give orally when you are giving orally the amount of drug which is absorbed into the blood it is very less that is known as bioavailability. So instead of asyclloe we give valacy. Balacy is the drug of choice for vascella zoster virus because it's a prod drug and as it is absorbed enters into the liver there it is converted to asyclloe and this asycllohir then acts. Okay. So the bioavailability of elicyclloe is much higher. So instead of using higher doses of asyclloir we prefer valycllovir for vicela zoster virus. Then next um virus in herpes ver is cytogallo virus. This cytogallo virus does not has thyodine kynise. So that means asylloid cannot be activated. A cycllo will not be active against CMV because it cannot be activated. In fact CMV has another enzyme that is ul7 kynise. So this drug can't be used as cyclloid can't be used for cm. In fact for CMV the drug of choice is janlovir and it is used for treatment as well as prophylaxis for CMV in imunompromised okay because this janloir is activated by this ul 97 kynise enzyme for epstein bar virus we don't have any drug available okay so that is the herpes vod then moving on to certain features and toxicity of these nucleioide analoges asyclloir is excreted unchanged by urine. So if it is excreted unchanged by urine that means if renal impairment is there its dose needs to be decreased. Okay. Second it has less bioavailability as already told and it has very low T half. So that is why multiple dosings are required for asyclloir. Okay. However this asycllopir has very less toxicity. Why? Because its activation requires viral enzyme. So anyways the cells which are not infected by this virus they will not activate asyclloid and asyclo will not be able to act against those cells. So only the virus infected cells will be affected. Okay so that is asyclloe toxicity can occur that is the nephro and neurotoxicity can occur. So these are the dose limiting side effects of a IV cyclloid. That means as we are increasing the dose then these toxicity can occur. Then we have the balyclloid. Balacyovir again it is excreted unchanged by urine but it is having increased bioavailability and it is having long tiha. Again rarely we can have nephro and neurotoxicity and as I told you balicyclloir is actually the pro drug pro drug for asyclloe because it is being converted to asycllo. Then we have pensylo and famylo. Fancy is the pro drug of pens. Again it is having more bioavailability compared to pensylo. Then we have jansylloid which I told you it is used against the cytogallo virus. It is activated by the enzyme present in the cytogallo virus. It is activated even in uninfected cells. That is important because if it is activated in uninfected cells that means it is having more toxicity and this important toxicity for janlo is bone marrow depression. It is important. Okay. I told you that asyclloe has less toxicity because it is not activated in non-infected cells. In normal cells it is not activated but in janlo is activated even in uninfected cells. Then we have val janloe which is the pro drug for jansy. Okay. So we have studied six drugs here. One drug is there and then another pro drug for that particular drug is there. So valacy is pro drug for escyclloe. Pamyclloe is a prod drug for pensylo and val jancyclloe is the pro drug for jansy. Okay. So obviously the pro drug is having more bioavailability. Then moving on to other anti-hpes virus drugs that is the nucleotide analogs that what we have discussed till now they were nucleotide analogs that means they needed three phosphate groups to attach to them. Nucleotide analogs means there is already one phosphate group which is attached to the drug. So it needs only two more phosphate groups to be attached. So we have seen before that this first phosphate group was actually attached by a viral enzyme. The next two were attached by the host cellular enzyme. So this nucleotide analogs that means these two phosphate groups will be attached just by the host cellular kinases. So what will be the problem? Yes, there will be more toxicity because any host cell will have the cellular kinases and these drugs the nucleotide analogs will be activated in even uninfected cells. If the viral enzyme is attaching the phosphate group that means the drug is activated preferably in the infected cell but here cedophob which is a nucleotide analog it is activated even in the uninfected cell. Okay. Mechanism of action is same once activated it inhibits the DNA polymerase but because it is activated in any cell actually it is one of the broad spectrum DNA antiviral drug and can be used against you see almost all the uh viruses the DNA viruses okay is not there but you see we have herpes virus adeno virus pox virus polyoma virus and papilloma virus in papilloma virus topical treatment is available then the uh herpes virus herpes simplex varicelazer and cytoalo virus which are resistant to asyclloe or janycylo then this cedopal drug can be used okay and adeninoirus that is used in transplant patient actually in mild infections we don't need the drug in serious infections we can need this uh drug in adinoirus okay so it is not used commonly remember why because it is very toxic and toxicity which happens is neprotoxicity. Why it is very toxic? Because it can be activated in any cell of the body since it needs only these two phosphate groups. Right? Then next drug we have is phoscarnate. Phoscarnate is a not a nucleic acid precursor but it inhibits the DNA polymerase. So what it does is see when the DNA is being synthesized this deoxy guanosine triphosphate or any nucleotide is being attached to the DNA as it is being synthesized. Now during this pyrophosphate group is removed from this nucleotide. Now this first carnate actually binds to this uh region of the DNA polymerase so that the pyrophosphate group cannot be released. So inhibits cleavage of the pyrohosphate group and that is why there is no further addition of this nucleotide in the DNA. So DNA cannot be synthesized further. Right? Again because it doesn't need any activation. It is not a nucleic acid precursor. Poscarbonate has high toxicity. Again same it is neprotoxic. Then another important toxicity which occurs it it chates the dalent cations. Dient kions include calcium, magnesium. Okay this is the two plus here that means it is a dalent kion. So it chiates that means it binds with these ions and removes them. So it leads to hypocalcemia decrease in the calcium concentration. Hypomagnesmia that is decrease in the magnesium concentration. Okay. So that is a special side effect of this phoscarnate. Nephrotoxicity we have seen in all the drugs till now zero co also we saw it is very nephrotoxic and then we also saw in the nucleotide analogs. So this was carcinate being so toxic it is act it is used as a rescue drug for asyclloe resistant preimplex virus and transylo resistant cytogallo virus. Right. Then we have one another drug that is fomyin fomibin. So where it acts actually this drug is complmentary to the mRNA. So this is the mRNA being synthesized using the host RNA polymerase I told you that is in the transcription DNA is converted to mRNA. Now if this is the mRNA 5-2 3- direction this fomverin is a anti-sense mRNA drug that means it like binds with this mRNA 3-2 5- direction so this is anti-sense that means in the opposite direction it will form a double stranded mRNA kind of thing this is not mRNA this is the drug okay so sorry this is not the mRNA yeah so for me will not allow the transcription of mRNA to proteins. So these proteins will not form. If proteins are not formed, this assembly of the virus is not going to take place. Okay? So it is not affecting the DNA replication. It is affecting the transcription. Right? So this fomverin is used for intramial injection in cytogalloirus retinitis. the infection if the infection is unresponsive to other drugs. Right? So that is fomibin. Then we have two more drugs which are used for herpes verine. They are used topically only that is doposenol and iodox urodine. Doenol and iodox uridine. Idox urodine again is an inhibitor of viral DNA polymerase used topically for a P simplex virus keratitis and doposenol it has a different mechanism of action. It prevents fusion of the virus envelope with the host cell membrane. So till now we were talking of all drugs which are acting at this level that is inhibiting virna polymerase and we also saw a drug fiin which is the anti-sense strand it forms with mRNA preventing the transcription. Ducosenol is the one which is preventing the fusion of the virus with the host cell membrane and hence prevents virus entry. Okay. Again it is used topically for herpes simplex diseases. Now moving on to another virus the DNA virus that is hepatitis B. So this hepatitis viruses are of different types. There are RNA viruses also and DNA viruses also. So hepatitis B is a DNA virus and that is why we are covering hepatitis B in this particular video. Right? So first drug which is used against hepatitis B is interferon alpha. Now this interprons are normally released by the body in response to virus infection and these affect the various steps in the viral replication and the protein synthesis. So these interferons are given medically as well. Right? So this interferon alpha when given it binds to its receptors and activates the jackat pathway. Okay. So when this is activated actually these tat proteins they are the transcription factors. What is transcription factor? Transcription factor is any protein which is increasing or decreasing the synthesis of certain proteins. So here this stat transcription factor is activated and it goes into the nucleus where it binds to its site and leads to synthesis of new proteins. Now these proteins inhibit the transcription main action is it inhibits the transcription of viral uh proteins. Okay. So no new proteins will be synthesized. It also causes the death of the infected cells. Death of infected cells. Right? So it just causing the cellular apoptosis. then it also causes the expression of the MSC1 complex on the cell. So this is a human cell right this is the human cell. So it causes the expression of more expression of MSC1 uh proteins on the cell. Now this MSC1 is recognized by our CD8 T cells CD8 positive T cells that is the cytotoxic T- cells and these cytotoxic T cells actually kill the virally infected cells. So basically by causing more expression of MSC1 protein on the surface of the cell. It is like the cell will be better identified by the cytotoxic T- cell and there is increased chances of destruction of the cell by the cytotoxic T- cells. Right. So increased action of cytotoxic tea cells is going to occur. So these interferons act by various mechanisms and they are given intramuscularly subcutaneously and there is now pegilated interferon alpha which is used which is given subcutaneously. So this is having lesser side effects remains in the circulation for longer time. So this is preferred. Okay. So to whom is interferon alpha given? It is given to patients with ongoing HBV DNA replication and patients with liver inflammation because hepatitis B we are talking hepatitis B virus which is causing liver injury. Okay, liver inflammation is going to occur. So that's what the patients with ongoing HPV DNA replication we give interferon alpha but it is contraindicated in advanced liver disease because it can precipitate liver failure as well. So advanced liver disease it is not given. What are the other drugs now for hepatitis B? So we have antavircavir again which is inhibiting the reverse transcriptise enzyme of hepatitis B virus. Now hepatitis B virus actually it is a DNA virus. It has a circular DNA and this is the circular DNA. as it enters into the cell, it uses host DNA repair enzymes. Actually, this is a partial DNA. Okay, one is the full circular DNA and this one is the partial DNA. So, this DNA is made full, right? This is the full. So, it needs host DNA repair enzymes and then using host RNA polymerase, this DNA under go transcription that is synthesis of mRNA is taking place. Now with the mRNA proteins will be synthesized and also there is synthesis of pregenomic RNA RNA pregenomic means that from this pregenomic RNA now DNA will be synthesized. So when we synthesize DNA from RNA we need a reverse transcriptise enzyme that we are going to see in HIV as well. Right? So till now we talk that RNA synthesized from DNA. RNA synthesized from DNA that is known as transcription but here we are telling DNA is synthesized from RNA. So for this we need reverse transcriptise enzyme and our uh this mRNA you see that from the DNA mRNA synthesize which is synthesizing proteins among these proteins this reverse transcriptise is a protein it is an enzyme right that is being synthesized and this reverse transcriptise enzyme is now being used for converting the RNA basically forming the DNA from the RNA right so that is DNA synthesis taking place So this enta be which again is a guanosine analog as cyclloir was guanosine analog. So you see this is also ending in v. So this enta vir is a guanosine analog which inhibits this reverse transcriptise enzyme. Then the DNA which is synthesized again a DNA polymerase is used and this DNA synthesis is completed. So this entire inhibits both DNA polymerase and reverse transcriptise. Simple you remember we have seen the guanosine analogs that is the asyclloe jyloe they are all inhibiting the DNA polymerase isn't it so here also we have another drug inte which is inhibiting DNA polymerase same thing also reverse transcriptise enzyme okay so activation for this is same asycllov same class of drug isn't it so activation is same we need the attachment of the phosphate groups right so this entabir has good oral bio availability and is taken an empty stomach and just like asycllobe it is excreted unchanged in urine. Okay. So that is entir. Then we have tenofir tenopir. Now this is a nucleotide analog like a cedophob. See similar name cedopir. So this we had seen in herpes virus cedophob right. This was a nucleotide analog. So same thing now we are telling in the tenophob but tenophob is used for hepatitis B it is a nucleotide analog and it is a given as a daisoproxylester product to increase the bioavailability mechanism of action same inhibits DNA polymerase inhibits reverse transcriptise and also gets inserted into DNA then similar we have another drug edifir so edifir has High toxicity side effect is nephrotoxicity. So anything which is ending in fau cedophob ed these are the nucleotide analoges but cedophobe is used for other viruses not hepatitis B virus. We have seen that it is a broadsp spectrum DNA virus drug. It is used for all other uh DNA viruses. Even resistant herpes virus for a cycllohylo resistant CMB virus we can use cedophob and for hepatitis B we have tenophob and adapov. Okay. Then we have other drugs for hepatitis B that is the lamiodine and telbodine. Now these are nucleioide analoges. They have similar mechanism like nucleioide analogs. That means what they will do? Inhibit the DNA polymerase but they are not preferred drugs because of they are being associated with high rates of viral resistance. So they are not the preferred drugs for hepatitis B that is lameodine and deli bodine. Then we have other DNA viruses one of which is virus. Now this box virus is different from other DNA viruses because it is replicating in cytoplasm. Yes, other DNA viruses replicate in nucleus. Box virus replicates in cytoplasm. Now in cytoplasm do we have RNA polymerase enzyme? No, host RNA polymerase enzyme is present in the nucleus. So how this box virus will form proteins? Well, in the virus itself we have the viral RNA polymerase. Okay. So we have viral RNA polymerase and viral DNA polymerase. Okay. So with the viral RNA polymerase mRNA synthesized and then ribosomes of the host itself are used for synthesis of protein. So enzyme the box virus itself is carrying there is viral RNA polymerase viral DNA polymerase. DNA polymerase will cause replication. RNA polymerase will lead to synthesis of mRNA from DNA and then there will be synthesis of protein from mRNA. So how any drug acts for this? Well there is a drug ticcoirimatic binds to envelope protein of this box virus. So this blue one you see that is the envelope. Then we have the genome. Okay. So tomat binds to envelope protein of BP37 and prevents the wrapping and assembly. DNA will be synthesized but the protein will not wrap the DNA. So the virus is not going to assemble. Okay. So that means it cannot be released from the cell. Okay. Now this drug is used against a pox virus. And what is the pox virus? It is a small pox and a small pox is eradicated. Then why do we have a drug? Well, it is a stockpiled in US to counter bioteterror attacks. Okay. So last one we have some viruses that is papilloma virus, adeninoid, polyoma virus. So that we have already seen cedophob is a broadsp spectrum DNA virus antiviral drug and it can be used against these as well. Then we have against HPV. We said can be used but we also have HPV vaccine for the prevention of HPV infection. Basically HPV can cause several types of cancer. very important is cervical cancer and HPV vaccine can prevent HPV infection and hence those cancers. There are other infections as well that is warts can occur by HPV infection. So we have different drugs there is podiline which causes the death of infected cells and we have imumo which stimulates cytoine from the cells their release of cytoines is there which acts against the viruses. Okay. So that was about the antiviral drugs which act against the DNA viruses. The next part, this part we will talk in the next video. 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.