Antivirals | HIV, Hepatitis, Influenza, Herpes Treatment

Introduction to Antivirals

In this video, the speaker discusses antiviral therapies and their use against various viruses. The speaker urges viewers to visit their website for additional resources.

Antiretroviral Therapies Against HIV

• HIV is a retrovirus that attacks T helper cells in the immune system.

• The virus uses specific proteins, such as gp41 and gp120, to bind with host cell receptors like CD4 and CCR5/CXCR4.

• Entry inhibitors like enfuvirtide prevent viral RNA from entering host cells by inhibiting fusion between gp41 and CD4.

• Maraviroc prevents the virus from docking onto host cells by inhibiting interaction between gp120 and CCR5.

Antivirals Against Other Viruses

• There are antivirals available for influenza, hepatitis, and herpes viruses.

• Oseltamivir is an antiviral used against influenza A/B that works by inhibiting neuraminidase activity.

• Acyclovir is an antiviral used against herpes simplex virus that works by inhibiting DNA synthesis.

• Sofosbuvir is an antiviral used against hepatitis C virus that works by inhibiting RNA polymerase activity.

Conclusion

Antiviral therapies can be effective in treating viral infections. Entry inhibitors like enfuvirtide and maraviroc are examples of drugs used to prevent viral entry into host cells. Other antivirals target specific aspects of viral replication such as neuraminidase or RNA polymerase activity.

Reverse Transcriptase and Reverse Transcriptase Inhibitors

In this section, the speaker explains what reverse transcriptases are and how they work. They also discuss the significance of reverse transcription in HIV replication and introduce the concept of reverse transcriptase inhibitors.

Reverse Transcriptases

• Reverse transcriptases are enzymes that can take RNA and make DNA.

• The speaker zooms in on a maroon dot to show an example of a reverse transcriptase enzyme.

• The viral DNA produced by reverse transcription can be incorporated into host cells' DNA, which is bad news for T helper cells.

• Drugs that inhibit reverse transcriptase can potentially stop this process.

Reverse Transcriptase Inhibitors

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• NRTIs are drugs that act as nucleotides to stop the formation of DNA from RNA templates during reverse transcription.

• The speaker explains how nucleotides are used to make DNA from RNA templates during normal transcription.

• NRTIs act like nucleotides but cannot be added onto growing DNA strands, stopping further DNA formation.

• Zales TD is a mnemonic device for remembering some examples of NRTIs: zidovudine, abacavir, lamivudine, emtricitabine, stavudine, tenofovir, and didanosine.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• NNRTIs bind directly to the reverse transcriptase enzyme to inhibit its activity.

• Unlike NRTIs, NNRTIs do not act as nucleotides or incorporate into growing DNA strands.

Other Types of Reverse Transcriptase Inhibitors

• Integrase inhibitors prevent integration of viral DNA into host cell's genome by inhibiting the integrase enzyme.

• Protease inhibitors prevent viral maturation by inhibiting the protease enzyme.

HIV Drug Categories

In this section, the speaker discusses the different drug categories used to treat HIV and how they work.

Fusion/Entry Inhibitors

• Drugs like Fuverytide and Maravarock inhibit the fusion and entry of HIV RNA into the host cell.

• These drugs bind to a specific site on the virus, preventing it from entering the cell.

Reverse Transcriptase Inhibitors

• Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) like Zidovudine act as nucleotides, terminating further DNA formation from RNA templates.

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) like Nevirapine bind to an allosteric site on the enzyme, inhibiting its function.

Integrase Inhibitors

• Integrase is an enzyme that incorporates viral DNA into host cell DNA during replication.

• Drugs like Dolutegravir, Raltegravir, and Elvitegravir inhibit integrase activity by binding to its active site.

• This prevents viral DNA from being incorporated into host cell DNA during replication.

Remembering Drug Categories

The speaker provides tips for remembering different drug categories used to treat HIV.

NNRTIs

• NNRTIs include drugs like Efavirenz, Etravirine, and Delavirdine.

• All NNRTI names contain "veer" in their center.

NRTIs

• NRTIs include drugs like Zidovudine and Stavudine.

• All NRTI names contain "veer" somewhere in their name's center.

Integrase Inhibitors

• Integrase inhibitors include drugs like Dolutegravir, Raltegravir, and Elvitegravir.

• All integrase inhibitor names end in "tegravir."

Understanding the Transcription and Translation Process

In this section, the speaker explains how the virus causes problems by utilizing the transcription and translation process to make viral RNA and proteins.

The Transcription Process

• The transcription process involves reading the viral DNA and transcribing it into viral RNA.

• Viral RNA is then produced, which goes out into the cytoplasm to find ribosomes for translation.

The Translation Process

• Translation is the process of making proteins from viral RNA.

• Proteins are made using polyproteins, which need to be cleaved by proteases to create different types of structural and functional proteins.

Importance of Proteases

• Proteases are essential in cleaving polyproteins into structural and functional proteins.

• Without proteases, it is impossible to make integral viral proteins such as reverse transcriptase or gp proteins on the surface.

Inhibiting Proteases with Drugs

• Using drugs that inhibit proteases can prevent cleavage of polyproteins, leading to a lack of structural and functional proteins necessary for creating new viruses.

• If proteases are inhibited, core proteins, capsimir proteins, enzymes inside the virus, and gp proteins on the surface cannot be made.

Understanding Drug Categories for HIV Treatment

In this section, the speaker discusses drug categories used in HIV treatment and how they work.

Protease Inhibitors

• Protease inhibitors end with "naveer" and work by inhibiting proteases from cleaving polyproteins into structural and functional proteins.

Integrase Inhibitors

• Integrase inhibitors end with "tegravir" and work by inhibiting the integrase enzyme from inserting viral DNA into host DNA.

Reverse Transcriptase Inhibitors

• Reverse transcriptase inhibitors (RTIs) come in two categories: nucleoside/nucleotide RTIs (NRTIs) and non-nucleoside RTIs (NNRTIs).

• NRTIs work by incorporating themselves into viral DNA, preventing further replication.

• NNRTIs bind to reverse transcriptase, preventing it from making viral DNA.

Understanding GagPol Polyproteins

In this section, the speaker explains how GagPol polyproteins act as proteases to cut polyproteins into different types of structural and functional proteins necessary for creating new viruses.

• GagPol polyproteins help act as a protease to cut polyproteins into different types of structural and functional proteins.

• This process is essential for creating new viruses.

HIV Treatment Regimen

In this section, the speaker discusses the highly active antiretroviral therapy regimen for treating HIV.

NRTIs

• The heart regimen is based on NRTIs.

• At least two NRTIs are needed to perform this process.

• Adverse effects and contraindications of some NRTIs may deter their use.

Additional Agents

• One of the other agents can be added to the heart regimen.

• Rava rocker and fever tide are adjuncts that can be added to the therapy in hiv-resistant strains.

• Moravirock is an add-on in hiv-resistant strains, especially to the nrtis, but they have to have a ccr5 positive receptor.

• Infuriating is an add-on as well particularly in hiv resistance very specifically to the nrtis.

Adverse Effects and Contraindications

• Mitochondrial toxicity is a common adverse effect seen with all categories of anti-HIV medications.

• It's important to consider medical history before prescribing medication.

Mitochondrial Toxicity and Adverse Effects of NRTIs

In this section, the speaker discusses the adverse effects of nucleoside reverse transcriptase inhibitors (NRTIs) due to mitochondrial toxicity. The speaker explains how mitochondrial toxicity can lead to various health issues such as fatty acid oxidation, steatosis, lactic acidosis, pancreatitis, nephrotoxicity, bone marrow suppression and hypersensitivity reactions.

Mitochondrial Toxicity

• NRTIs cause mitochondrial toxicity which affects fatty acid oxidation leading to fat buildup in tissues like liver causing steatosis.

• Pyruvate is converted into lactic acid when mitochondria are unable to convert it into acetyl coa due to toxic effect leading to lactic acidosis.

• Mitochondrial toxicity can lead to myopathy neuropathy and hepatocytosis.

Pancreatitis

• Stavudine and Didanosine are two NRTIs that may induce pancreatitis.

Nephrotoxicity

• Tenofovir is an NRTI that causes nephrotoxicity leading to acute kidney injury.

Bone Marrow Suppression

• Zidovudine causes bone marrow suppression leading to anemia and neutropenia.

Hypersensitivity Reaction

• Abacavir can cause a hypersensitivity reaction by interacting with mast cells leading to histamine response causing nausea, vomiting, diarrhea, rash fever and respiratory failure.

• Patients with HLA-B 5701 haplotypes are susceptible to hypersensitivity reactions when put on abacavir.

**** It is important to check for HLA-B 5701 haplotypes before prescribing abacavir.

Adverse Effects of Antiretroviral Drugs

In this section, the speaker discusses the adverse effects of antiretroviral drugs, specifically focusing on NRTIs, integrase inhibitors, and protease inhibitors.

Adverse Effects of NRTIs

• NRTIs end in "vir" and can cause hepatotoxicity and CNS toxicity.

• Foviraprevir and nevirapine are particularly associated with hepatotoxicity.

• Foviraprevir is also associated with CNS toxicity.

• Epivir is teratogenic and should not be given to pregnant patients.

• Delavirdine can cause adverse effects.

Adverse Effects of Integrase Inhibitors

• Integrase inhibitors end in "tegravir" and can cause rhabdomyolysis.

• Rhabdomyolysis can lead to an increase in CK levels and myoglobinuria.

Adverse Effects of Protease Inhibitors

• Protease inhibitors end in "navir" and can cause crystal-induced nephropathy.

• Indinavir is particularly associated with crystal-induced nephropathy.

• Protease inhibitors can also cause lipodystrophy, hyperglycemia, and Cushing-like effects.

HIV and Influenza Medications

This section discusses the mechanism of action, adverse effects, contraindications, and indications of HIV medications. It also covers the life cycle of influenza virus and how it infects host cells.

HIV Medications

• Ritanovir is a protease inhibitor that inhibits CYP450 enzymes, leading to higher drug concentration in the body.

• Higher drug concentration can increase the risk of adverse effects or contraindications.

Influenza Medications

• Influenza primarily spreads through respiratory droplets and infects the respiratory tract.

• The virus binds onto particular cells within the respiratory tract using hemagglutinin proteins and neuraminidases.

• Once inside a host cell, the virus needs to be uncoated so that its RNA can be released into the host cell nucleus.

• M2 proton ion channels are used to pump protons into the structure to allow for uncoding to occur.

Viral RNA Translation

In this section, we learn about the process of viral RNA translation and how it requires a specific structure called a five prime cap. We also learn about an enzyme called endonuclease that helps transfer the five prime cap from host cell mRNA to viral RNA.

Five Prime Cap Process

• The ribosome needs a specific structure called a five prime cap to interact with mRNA.

• Viral RNA lacks a five prime cap, making it unable to use ribosomes for protein synthesis.

• An endonuclease enzyme cuts off the five prime cap from host cell mRNA and transfers it onto viral RNA.

Utilizing Host Cell Ribosomes

• With the new five prime cap, viral RNA can now interact with host cell ribosomes for protein synthesis.

• Proteins synthesized include structural and functional proteins necessary for assembling new viruses.

Making More Viral RNA

• Viral RNA can make more copies of itself using particular RNA polymerases.

• The newly synthesized viral RNA is combined with structural and functional proteins in the Golgi apparatus to form new viruses.

Budding and Release of Virus

• The virus formed in the Golgi apparatus gets released through budding but gets stuck due to hemagglutinin protein being attached to sialic acid residue on epithelial cells.

• Neuraminidase protein cleaves the link between hemagglutinin and sialic acid residue allowing release of the virus from the host cell.

Influenza Treatment

This section discusses the drugs used to inhibit the process of viral RNA release and synthesis in influenza treatment.

Inhibiting Viral RNA Release

• Drugs can be utilized to inhibit the release of viral RNA into host cell cytoplasm.

• Amantadine is a drug primarily used in influenza A to inhibit this process.

Inhibiting Five Prime Cap Transfer

• Endonuclease enzyme transfers five prime cap from host mRNA to viral RNA for protein synthesis.

• Blocking endonuclease enzyme with Baloxavir inhibits transfer, preventing protein synthesis.

• Baloxavir must be administered within 48 hours of symptom onset.

Neuraminidase Inhibitors

• Neuraminidase inhibitors like Oseltamivir and Zanamivir prevent neuraminidase from cutting connection between sialic acid and hemagglutinin, allowing virus to infect other cells.

• These drugs are only used in influenza A and B, and must be administered within 48 hours of symptom onset.

Adverse Effects and Contraindications

• Amantadine can cause adverse effects, while Baloxavir, Oseltamivir, and Zanamivir are well-tolerated with few side effects.

Amantadine and Anti-Hepatitis Medications

In this section, the speaker discusses the side effects of amantadine and antiviral medications for hepatitis B and C.

Side Effects of Amantadine

• Amantadine can cause ataxia.

• It can lead to livedo reticularis.

• It can prolong the QT interval, increasing the risk of torsades de pointes.

Antiviral Medications for Hepatitis B

• Hepatitis B virus attacks hepatic tissue, specifically hepatocytes.

• Antivirals target specific parts of the virus's life cycle.

• The virus uses specific protein channels to enter hepatocytes and release partially double-stranded DNA.

• The DNA is converted into a completely circular double-stranded DNA (cccDNA).

• The cccDNA replicates itself and undergoes transcription to make viral mRNA and pre-genomic RNA.

• Viral mRNA utilizes host cell ribosomes to synthesize proteins that are structural or functional enzymes such as DNA polymerases, RNA polymerases, proteases etc.

• These proteins are moved towards the golgi apparatus where they are incorporated into new vesicles containing structural and functional proteins important to viral structure.

Antiviral Medications for Hepatitis C

The speaker does not discuss antiviral medications for hepatitis C in this section.

Reverse Transcriptase and Inhibitors

In this section, the speaker explains how reverse transcriptase works in converting pre-genomic RNA into DNA for viral replication. The goal is to convert it back into the DNA component that it was prior to infection so that more viruses can be made and passed on to other cells. The speaker also discusses the importance of inhibiting reverse transcriptase as a way of preventing viral replication.

Reverse Transcriptase Function

• Reverse transcriptase converts pre-genomic RNA into DNA.

• It turns into negative sense DNA and then positive sense DNA.

• Partially double-stranded DNA is eventually formed.

Viral Replication

• The goal is to replicate the virus and make more of it so that it can infect other hepatocytes.

• Structural and functional proteins are combined with the converted DNA in the golgi to make a new virus.

• The new virus is put into a vesicle from the golgi, fuses with the cell membrane, and exocytosed.

Inhibiting Reverse Transcriptase

• Inhibiting reverse transcriptase prevents viral replication formation infection of other types of hepatocytes.

• Reverse transcriptases are rate-limiting steps that need to be targeted by inhibitors.

• Nucleoside reverse transcriptase inhibitors (NRTIs) act like nucleotides but terminate further formation of DNA off an RNA template.

• Lamivudine and intakovir are two NRTIs used as inhibitors.

Adverse Effects of Antiviral Drugs

In this section, the speaker discusses the potential adverse effects of antiviral drugs, particularly adephavir and tanofever. The speaker highlights Fanconi syndrome as a rare but possible condition that may occur when taking these drugs.

Fanconi Syndrome

• Adephavir and tanofever can cause Fanconi syndrome.

• Fanconi syndrome is a condition where three things are excreted into the urine - phosphates, glucose, and amino acids.

• Watch out for electrolyte abnormalities, glucose abnormalities, and amino acid abnormalities when monitoring patients taking these drugs.

Interferon Alpha's Functions

In this section, the speaker explains how interferon alpha works in our body to fight viral infections. The speaker describes three particular functions of interferon alpha.

Three Functions of Interferon Alpha

• Interferons are released by infected cells to alert nearby healthy cells about the presence of a virus.

• Interferon alpha stimulates host cell DNA to produce specific proteins that act as antiviral peptides.

• The three functions of interferon alpha include inhibiting protein synthesis, preventing viral RNA formation, and increasing expression of MHC1 complexes.

Importance of MHC1 Complexes

In this section, the speaker explains why MHC1 complexes are important in fighting viral infections.

Role of MHC1 Complexes

• MHC1 complexes express a piece of the virus on infected cells.

• CD8 positive T cells recognize the viral antigen presented by MHC1 complexes and destroy the infected cell.

Antiviral Peptides

This section discusses the ways antiviral peptides work against viruses, particularly in inhibiting protein synthesis and viral RNA activity. It also explains how they increase the expression of MHC-1 complexes to attract cytotoxic T cells to kill virus-infected cells.

Ways Antiviral Peptides Work

• Inhibiting protein synthesis

• Inhibiting viral RNA activity

• Increasing the expression of MHC-1 complexes

Function of MHC-1 Complexes

• Attracting cytotoxic T cells to kill virus-infected cells

Interferons Alpha Against Hepatitis B and C Virus

This section discusses how interferons alpha can be used against hepatitis B and C viruses. It also highlights potential complications and adverse effects associated with this drug.

Use of Interferons Alpha

• Can be used against hepatitis B virus

• Can be utilized in refractory hepatitis C virus

Adverse Effects of Interferon Alpha

• Teratogenic effect

• Avoid use in pregnant women

• Pancytopenia

• Monitor CBC for any evidence of pancytopenia

• Avoid use in patients with anemia, thrombocytopenia or leukopenia

Antivirals Against Hepatitis B Virus

This section discusses two types of drugs that target hepatitis B virus: reverse transcriptase inhibitors (NRTIs), including lamivudine and entecavir, and nucleotides transcriptase inhibitors (NtRTIs). It also highlights a potential complication associated with NtRTIs.

Reverse Transcriptase Inhibitors (NRTIs)

• Includes lamivudine and entecavir

Nucleotides Transcriptase Inhibitors (NtRTIs)

• Definition of NtRTIs

• Potential complication: Fanconi syndrome caused by tenofovir

Antivirals Against Hepatitis C Virus

This section discusses how hepatitis C virus attacks liver cells, the receptors it uses to bind to hepatocytes, and the process of viral RNA translation. It also mentions antiviral drugs used against hepatitis C virus.

Hepatitis C Virus Attack on Liver Cells

• Causes damage to the liver

• Potentially increases risk of hepatocellular carcinoma

Receptors Used by Hepatitis C Virus

• Binds with a plethora of receptors, including LDL receptor and SRV1

Process of Viral RNA Translation

• Viral RNA is released into host cell cytoplasm

• Binds with ribosomes on rough endoplasmic reticulum

• Ribosomes utilize RNA to synthesize polyproteins via translation

Antiviral Drugs Against Hepatitis C Virus

• No specific drugs mentioned in this section

HCV Life Cycle

In this section, the speaker discusses the different proteins that make up the HCV polyprotein and how they are broken down. They also talk about the importance of certain enzymes in the replication process and how drugs can be used to target them.

Proteins that Make Up HCV Polyprotein

• The HCV polyprotein is made up of different types of structural and functional proteins, including ns3, ns4a, ns5a, and ns5b.

• The protease enzyme works to break down the polyprotein into these components.

Importance of Enzymes in Replication Process

• The protease enzyme is important for cleaving the polyprotein at specific sites, particularly at ns3 and ns4a. This allows for the formation of both structural and functional proteins needed for virus replication.

• Ns5a and ns5b are enzymes utilized to replicate RNA so they play a crucial role in virus replication.

• Drugs can be used to inhibit these enzymes such as protease inhibitors which prevent cleavage by inhibiting NS3 4A protease or NS5B inhibitors which inhibit RNA-dependent RNA polymerase activity of NS5B protein.

Packaging and Exocytosis

• Once all necessary components are formed, they are sent to the Golgi apparatus where they are packaged into new viruses before being exocytosed out to infect other cells.

NS5A Inhibitors

This section discusses the mechanism of action of NS5A inhibitors, including their role in RNA replication and viral assembly. It also covers common drugs in this category and how to remember them.

Mechanism of Action

• NS5A is an integral protein involved in RNA replication and viral assembly.

• NS5A inhibitors such as ledipasvir, velpatasvir, and pibrentasvir inhibit the protein from undergoing RNA replication and inhibit viral assembly.

Drug Categories

• Remember "asvir" at the end for NS5A inhibitors.

• Remember "buvir" at the end for NS5B inhibitors.

Genotype Specific Treatment

• The type of genotype determines which type of drug combination to use.

• Common combinations include protease inhibitor plus NS5A inhibitor or protease inhibitor plus NS5B inhibitor.

Ribavirin

This section discusses ribavirin, a drug primarily used in refractory hepatitis C virus cases as part of triple therapy.

Mechanism of Action

• No specific information provided.

Usage

• Ribavirin is primarily used in refractory hepatitis C virus cases as part of triple therapy.

Mechanism of Action for Hepatitis C Virus Drugs

In this section, the speaker discusses how interferon alpha can treat both hepatitis B and C viruses. They explain that ribavirin is used in a triple combo to inhibit ionosine monophosphate dehydrogenase, which inhibits guanine nucleotides formation and RNA replication.

Interferon Alpha Treatment

• Interferon alpha can treat both hepatitis B and C viruses.

• It increases antiviral peptides to inhibit protein synthesis, inhibits viral RNA activity, and increases the expression of MHC-1 complexes for cytotoxic T-cells.

Ribavirin Triple Combo

• Ribavirin is used in a triple combo to inhibit ionosine monophosphate dehydrogenase.

• Ionosine monophosphate dehydrogenase helps make guanine nucleotides needed for RNA replication.

• Ribavirin inhibits ionosine monophosphate adenosine 5-fall enzyme from making guanine nucleotides.

• Without guanine nucleotides, RNA replication is inhibited.

Adverse Effects

• Direct acting antivirals are relatively well-tolerated with few toxic effects.

• Ribavirin can cause hemolytic anemia and is teratogenic.

• Do not give these drugs to patients with decompensated cirrhosis.

Anti-Herpes Medications

In this section, the speaker discusses anti-herpes medications and the types of tissues that herpes simplex viruses and varicella zoster virus tend to attack.

Types of Tissues Attacked

• Herpes simplex viruses and varicella zoster virus tend to attack specific types of tissues.

• Herpes simplex viruses can cause mucocutaneous lesions on the skin, herpes labialis with HSV-1, genital lesions with HSV-2, and esophagitis.

Overall Summary

In this transcript, the speaker discusses the mechanism of action for hepatitis C virus drugs and anti-herpes medications. They explain how interferon alpha can treat both hepatitis B and C viruses by increasing antiviral peptides to inhibit protein synthesis, inhibiting viral RNA activity, and increasing the expression of MHC-1 complexes for cytotoxic T-cells. Ribavirin is used in a triple combo to inhibit ionosine monophosphate dehydrogenase which inhibits guanine nucleotides formation needed for RNA replication. The adverse effects are relatively well-tolerated except for ribavirin which can cause hemolytic anemia and is teratogenic. For anti-herpes medications, herpes simplex viruses tend to attack specific types of tissues such as mucocutaneous lesions on the skin or esophagitis.

Viral Replication

In this section, the speaker discusses how viruses such as varicella-zoster virus (VZV), cytomegalovirus (CMV), and herpes simplex virus (HSV) replicate within host cells.

Virus Binding and Entry

• VZV, CMV, and HSV bind to specific receptors on host cells.

• The viruses are taken into the cell via endocytosis.

• The viral DNA is released into the host cell.

Viral DNA Replication

• Once inside the nucleus, viral DNA utilizes enzymes to replicate.

• A viral DNA polymerase takes viral DNA and makes more of it.

• RNA polymerases can be used to make RNA from viral DNA.

Protein Synthesis and Assembly

• Messenger RNA is synthesized from viral mRNA in ribosomes.

• Ribosomes synthesize structural and functional proteins integral to making new viruses.

• Proteins combine with nucleic acid in the Golgi apparatus to create new viruses that are released via exocytosis.

Conclusion

The speaker explains how these viruses utilize host cells' machinery for replication. Understanding how these viruses replicate can help identify targets for preventing their replication or shedding.

Inhibiting Viral DNA Polymerase

In this section, the speaker discusses how inhibiting viral DNA polymerase can prevent the formation of new viruses. They also discuss two drugs that can be used to inhibit this enzyme.

Viral DNA Polymerase Inhibitor

• This category of drugs inhibits viral DNA polymerase, which prevents the formation of new viral DNA.

• The drugs Sadafavir and Phoscarnate are examples of viral DNA polymerase inhibitors.

• Sadafavir directly binds to the enzyme, while Phoscarnate acts as an analog that inhibits it.

Indications for Use

• These drugs are primarily used to treat herpes infections and CMV infections that are resistant to other treatments like Ganciclovir.

• They can also be used in cases where patients have acyclovir-resistant HSV infections.

Adverse Effects

• Sadafavir has been shown to produce crystal-induced nephropathy, which can lead to acute kidney injury. It is also naturally nephrotoxic.

• To reduce the risk of crystal-induced nephropathy, Sadafavir should be given with lots of IV fluids and probenicid.

Electrolyte Abnormalities and Antiviral Drugs

In this section, the speaker discusses electrolyte abnormalities that can be caused by certain drugs and how these abnormalities can lead to seizures. They also discuss antiviral drugs, specifically viral DNA polymerase inhibitors and guanosine analogs.

Electrolyte Abnormalities

• Certain drugs can cause imbalances in calcium, phosphate, potassium, and magnesium levels.

• These imbalances may potentially produce increased metabolic abnormalities that precipitate seizures.

• Phoscarnet is one drug that can cause seizures via electrolyte abnormalities.

• Sadofovir crystal-induced nephropathy can be reduced by giving lots of IV fluids and probenicid during drug administration.

Viral DNA Polymerase Inhibitors

• Viral DNA polymerase inhibitors are a type of antiviral drug.

• Acyclovir and valacyclovir are primarily indicated for HSV and VZV infections that cause herpes labialis or some type of genital infection, encephalitis, meningitis, or some type of HSV esophagitis.

• Ganciclovir is used to treat CMV infections that cause pneumonia, retinitis, or some type of CMV esophagitis.

Guanosine Analogs

• Guanosine analogs are another type of antiviral drug.

• Acyclovir, valacyclovir, and ganciclovir are all guanosine analogs.

• These drugs get taken up into the cell where they get phosphorylated by viral kinases to look like nucleotides.

• This allows them to terminate DNA formation or RNA formation because they act like nucleotides.

Adverse Effects of Antiviral Drugs

In this section, the speaker discusses the adverse effects of antiviral drugs and how to prevent them.

Nephrotoxicity

• Acyclovir can cause nephrotoxicity.

• Giving acyclovir with a good amount of IV fluid can help prevent acute kidney injury.

Thrombotic Thrombocytopenia Purpura (TTP)

• Acyclovir and valcyclovir have been shown to increase the risk of TTP.

• If a patient has TTP while on one of these drugs, it could be a potential drug cause.

Pan Cytopenia

• Acyclovir, valcyclovir, and ganciclovir can potentially cause bone marrow suppression.

• Ganciclovir may be responsible for pan cytopenia.

Mechanism of Action

• These drugs are guanosine analogs that directly inhibit viral DNA polymerase.

• They look like nucleotides and are phosphorylated by the host cell's enzymes.

• The viral DNA polymerase tries to add them to make more DNA but cannot add any more nucleotides after that point. This terminates the replication process.

Practice Problems: Antiretroviral Therapy

In this section, the speaker presents practice problems related to antiretroviral therapy.

Blocking CD4 gp41 Interaction

• Inferior tight blocks CD4 gp41 interaction.

• It is not part of the main regimen but can be used as an adjunct in HIV-resistant strains to NRTIs.

Blocking CCR5 Receptor and GPU 120 Interaction

• Maravaroc blocks the CCR5 receptor and GPU 120 interaction between HIV and TH2 cells.

• The TH cells must be CCR5 positive.

Blocking Reverse Transcriptase

• Two drugs that block reverse transcriptase are nucleoside analogs.

• They act like nucleotides, so the viral reverse transcriptase cannot tell the difference.

• When it adds one of these drugs to the growing DNA strand, it terminates DNA formation.

Drug Toxicity

In this section, the speaker discusses drug toxicity and its classification based on various symptoms.

Drugs causing mitochondrial toxicity

• Mitochondrial toxicity is classified by lactic acidosis, peripheral neuropathy, myopathy, and hepatic steatosis.

• All drugs cause mitochondrial toxicity.

Specific drug toxicities

• Stavudine and didanosine cause pancreatitis.

• Offavir causes nephrotoxicity.

• Abacavir can cause hypersensitivity reaction in patients with HLA-B5701 haplotype.

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to an allosteric site and prevent the enzyme from functioning to convert RNA to DNA. Examples include nevirapine, efavirenz, etravirine, and delavaridine.

• NNRTIs are generally hepatotoxic. Efavirenz can cause vivid dreams and hallucinations. Zidovudine and didanosine can cause teratogenic effects.

• Protease inhibitors (PIs) inhibit the 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. Examples include darunavir, ritonavir, indinavir.

• PIs are associated with CYP450 inhibition. Ritonavir causes hyperglycemia and lipodystrophy while indinavir causes crystal-induced nephropathy.

Antiretroviral therapy combinations

• Antiretroviral therapy consists of two nucleoside reverse transcriptase inhibitors (NRTIs) plus one of either integrase inhibitors (raltegravir), protease inhibitors (darunavir), or NNRTIs (efavirenz).

• If a patient is resistant to one of these regimens, enfuvirtide can be added as an adjunct.

• If a patient is positive for the CCR5 receptor, maraviroc can be added as an adjunct.

Influenza and Hepatitis B & C Treatment

This section covers the treatment of influenza and hepatitis B & C. It discusses the drugs used to inhibit reverse transcriptase, endonuclease, neuraminidase enzyme, NS3 4A polypro proteases, and NS5A.

Influenza Treatment

• Amantadine is an uncoating inhibitor that primarily covers influenza A.

• The primary adverse effects of amantadine are ataxia, prolonged QT interval, and levitoreticularis.

• Baloxavir is used for influenza A and B but must be taken within 48 hours of symptom onset.

• Neuraminidase inhibitors such as oseltamivir and xenamovir are used for influenza A and reduce the severity of symptoms. They can also potentially be prophylactic in adults and pediatrics greater than five years old.

Hepatitis B Treatment

• Nucleosides such as lamivudine or entecavir act like a nucleotide to inhibit reverse transcriptase.

• Nucleotides such as tenofovir and adefovir also act like a nucleotide to inhibit reverse transcriptase by terminating further formation of DNA.

• Interferon alpha forms antiviral peptides that inhibit protein synthesis. It can suppress bone marrow function and cause pancytopenia.

Hepatitis C Treatment

• Protease inhibitors ending in "prover" are used to inhibit NS3 4A polypro proteases in hepatitis C virus therapy.

• NS5A inhibitors such as ledipsiver, velpatosphere, and the cladosphere inhibit NS5A involved in RNA synthesis and virus assembly at the golgi apparatus.

Antiviral Drugs

In this section, the speaker discusses antiviral drugs used to treat hepatitis C and herpes.

Antiviral Drugs for Hepatitis C

• Protease inhibitors: Prover

• NS5A inhibitors: Asvare

• NS5B inhibitors (RNA-dependent RNA polymerase inhibitors): Buver

• Ionosine 5-phosphate dehydrogenase inhibitor: Riboviron. Used in HCV refractory therapy as part of a triple therapy with Riboviron, Sausphosphavir, and Interferon alpha.

Choosing the Right Drug Combo

• The choice of drug combo depends on the genotype of the virus.

Adverse Effects of Riboviron

• Teratogenic

• Can cause hemolytic anemia.

Antiviral Drugs for Herpes

Viral DNA Polymerases Inhibitors

• Phoscarnet and Sidophofer inhibit viral DNA polymerases responsible for making more herpes virus DNA.

• Phoscarnet is a pyrophosphate analog.

• Indications:

• HSV resistance to acyclovir

• Severe mucocutaneous lesion

• CMV infections like pneumonia, retinitis esophagitis where their ul 97 kinase is mutated in some particular way.

• Phoscarnet can cause seizures due to electrolyte abnormalities.

• Sadophophir can cause crystal-induced nephropathy and is naturally nephrotoxic. IV fluids and probenocid can minimize this effect.

Guanosine Analogs

• Guanosine analogs act as nucleotides and get phosphorylated via thymidine kinases or ul-97 kinases.

• They inhibit the viral DNA polymerase from adding them into the growing DNA.

• Indications: Treatment of herpes virus infections.

Adverse Effects of Antiviral Drugs

In this section, the speaker discusses the adverse effects of antiviral drugs.

Acyclovir

• Acyclovir is extremely nephrotoxic.

• It should be given with IV fluids to minimize the nephrotoxic effect.

• Acyclovir has been shown to potentially increase the risk of TTP (thrombotic thrombocytopenic purpura).

Valcyclovir and Acyclovir

• Both drugs have been shown to potentially increase the risk of TTP (thrombotic thrombocytopenic purpura).

Ganciclovir

• Ganciclovir is utilized in CMV infections such as retinitis, esophagitis, pneumonia, etc.

• One of its adverse effects is that it may cause bone marrow suppression leading to pancytopenia.

Conclusion

In this section, the speaker concludes their discussion on antiviral drugs.

The speaker thanks their audience for watching and hopes that they enjoyed and understood the content.