Antivirals Lecture Notes

Jul 10, 2024

Lecture on Antivirals

Introduction

  • Antivirals: similar to antibiotics, covering specific viruses (HIV, Influenza, Hepatitis, Herpes viruses).
  • Resources available online with illustrations and notes for better understanding.

Antiretroviral Therapies for HIV

  1. HIV Overview

    • HIV: a retrovirus that converts RNA to DNA.
    • Targets immune system, specifically CD4+ T helper cells.
    • Important proteins: gp41 and gp120 for virus entry.
    • Host cell receptors: CD4, CCR5, CXCR4.

  2. Fusion and Entry Inhibitors

    • Prevent viral RNA from entering host cells.
    • Drugs:
      • Infervetid: inhibits gp41 and CD4 binding, preventing RNA entry.
      • Maravaroc: prevents gp120 from binding with CCR5.

  3. Reverse Transcriptase Inhibitors

    • Inhibit the reverse transcriptase enzyme that converts HIV RNA to DNA.
    • NRTIs (Nucleoside Reverse Transcriptase Inhibitors):
      • Mimic nucleotides, causing premature termination of the DNA strand.
      • Drugs: Zales TD (Zidovudine, Abacavir, Lamivudine, Emtricitabine, Stavudine, Tenofovir, Didanosine).
    • NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors):
      • Bind to allosteric sites of reverse transcriptase, changing enzyme shape and preventing function.
      • Drugs: Efavirenz, Nevirapine, Delavirdine.

  4. Integrase Inhibitors

    • Prevent viral DNA from integrating into the host genome.
    • Drugs: Integrase inhibitors ending in "-tegravir" (Dolutegravir, Raltegravir, Elvitegravir).

  5. Protease Inhibitors

    • Inhibit protease, an enzyme important for making viral proteins.
    • Drugs: Protease inhibitors ending in "-navir" (Atazanavir, Darunavir, Saquinavir, Lopinavir).

  6. Combination Therapy (HAART)

    • Uses at least 2 NRTIs plus one of the following: NNRTI, Integrase inhibitor, or Protease inhibitor.

Adverse Effects and Contraindications (HIV Medications)

  • NRTIs: Mitochondrial toxicity (myopathy, neuropathy, hepatosteatosis, lactic acidosis), pancreatitis (Stavudine, Didanosine), nephrotoxicity (Tenofovir), bone marrow suppression (Zidovudine), hypersensitivity (Abacavir).
  • NNRTIs: Hepatotoxicity (Efavirenz, Nevirapine), CNS toxicity and vivid dreams (Efavirenz), teratogenic (Efavirenz, Delavirdine).
  • Integrase Inhibitors: Rhabdomyolysis (CK and myoglobin levels).
  • Protease Inhibitors: Crystal induced nephropathy (Indinavir), Lipodystrophy and hyperglycemia (all), CYP450 inhibition (Ritonavir).

Influenza Medications

  1. Lifecycle of Influenza Virus

    • Entry via respiratory tract, binding via hemagglutinin to sialic acid.
    • M2 ion channels for uncoating, releasing RNA.
    • RNA-dependent RNA polymerase activity and proteins' synthesis.
    • Budding and release by neuraminidase.

  2. Medications

    • M2 Ion Channel Inhibitors: Amantadine (Influenza A only).
    • Endonuclease Inhibitors: Baloxavir (Influenza A and B, <48 hours since symptom onset).
    • Neuraminidase Inhibitors: Oseltamivir, Zanamivir (Influenza A and B, <48 hours since symptom onset, prophylactic use possible).

  3. Adverse Effects

    • Amantadine: Ataxia, Libido reticularis, QT prolongation.
    • Other influenza drugs: Generally well tolerated.

Anti-Hepatitis Medications

  1. Hepatitis B Virus (HBV) Medications

    • Lifecycle involving host hepatocytes, integration via reverse transcriptase.
    • NRTIs: Lamivudine, Entecavir.
    • NtRTIs (Nucleotide Reverse Transcriptase Inhibitors): Adefovir, Tenofovir.
    • Interferon Alpha: Increases antiviral peptides, inhibits viral RNA, and enhances immune response.

  2. Adverse Effects

    • NRTIs: Fanconi syndrome (Adefovir, Tenofovir).
    • Interferon Alpha: Teratogenic, pancytopenia.

  3. Hepatitis C Virus (HCV) Medications

    • Lifecycle specific details involving RNA replication and polyprotein cleavage.
    • Protease Inhibitors (end in "-previr"): Simeprevir, Paritaprevir.
    • NS5A Inhibitors (end in "-asvir"): Ledipasvir, Velpatasvir.
    • NS5B Inhibitors (RNA-Dependent RNA Polymerase) (end in "-buvir"): Sofosbuvir, Dasabuvir.
    • Ribavirin: Inhibits inosine monophosphate dehydrogenase, used in refractory cases.

  4. Adverse Effects

    • Ribavirin: Teratogenic, hemolytic anemia.
    • Other antivirals: Generally well tolerated, avoid in decompensated cirrhosis.

Anti-Herpes Medications

  1. Types and Manifestations

    • HSV: Mucocutaneous lesions, encephalitis, meningitis, esophagitis.
    • VZV: Chickenpox, shingles.
    • CMV: Retinitis, pneumonia, esophagitis.

  2. Medications

    • Viral DNA Polymerase Inhibitors: Cidofovir, Foscarnet.
    • Guanosine Analogs: Acyclovir (HSV, VZV), Valacyclovir (HSV, VZV), Ganciclovir (CMV).

  3. Adverse Effects

    • Foscarnet: Seizures (electrolyte imbalances).
    • Cidofovir: Crystal-induced nephropathy (mitigated with IV fluids, probenecid).
    • Acyclovir: Nephrotoxicity, TTP.
    • Ganciclovir: Bone marrow suppression (pancytopenia).

Summary

  • Comprehensive steps to understanding and memorizing antivirals for different viruses.
  • Side effects and contraindications are crucial for effective treatment design.
  • Utilization of combinations for enhanced efficacy and reduced resistance in viruses.