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Antiviral Agents (Anti-Herpes Agents (3 levels of cellular selectivity…

- - - - Oral, IV, topical formulation
      - Fairly poor oral & topical absorption (15-30%)
      - Concentration in Zoster vesicles fluid = in that of plasma
      - Crosses placenta & enters breast milk (conc. 3x higher than maternal serum)
      - T1/2: 3-4hours
      - Excretion: Renal excretion (60-90% UNCHANGED)
  - - - Oral BA 20%
      - 10-20% sequestered in bone w/ gradual release
      - T1/2: 4-8 hours
      - Renal clearance (mostly UNCHANGED)
    - - Nephrotoxicity (25% Most common ADR, reversible)
      - Hypo-/hypercalcemia (chelates divalent cations)
      - Hypo-/Hyperphosphatemia
      - CNS toxicities (hallucinations, seizures, headache
  - - - Additionally phosphorylated to active metabolite, cidafovir diphosphate (CELLULAR ENZYMES) -> Diphosphate, inhibitor of viral DNA polymerase -> Intefere viral DNA synthesis
      - MOR
        
        Cidofovir does not rely on viral kinases for phosphorylation & development of resistance may be more difficult
        
        Mutation in viral DNA polymerase gene
    - - Poor oral BA -> IV
      - T1/2: 2.6 hours but active diphosphate intracellular T1/2: 17-65 hours
      - Renal excretion (Mostly UNCHANGED)
    - - Nephrotoxicity -> prehydrate
      - Uveitis/ iritis, rash
      - Neutropenia, GI intolerance
    - - nephrotoxic drugs = Higher nephrotoxicity
      - Synergism with ganciclovir & foscarnet against CMV
  - - - Inhibits viral DNA synthesis
        
        Triphosphate form compete with dGTP for viral DNA polymerase
        
        Chain termination
      - Viral DNA polymerase is much more SUSCEPTIBLE to its effects than cellular DNA (Drug more selective for thymidine kinase -> lower attack to human cells)
      - Polymerase monophosphorylation is catalyzed by a phosphotransferase in CMV & by thymidine kinase in HSV cells
    - - Lower activity of thymidine kinase
      - Alteration in viral thymidine kinase
      - Altered DNA/mutation in polymerase
      - Reduction in drug-phosphorylation
    - - N/V/GI disturbances (Aciclovir & Valganciclovir)
      - Rash, headache (Aciclovir & Valganciclovir)
      - Nephrotoxicity (rare & reversible with Aciclovir)
      - Myelosuppression (Ganciclovir & Valganciclovir) ; Leukopenia 40%; Thrombocytopenia 20%; Mainly IV
- - - - Inhibition of viral uncoating & assembly & release of virions at cell surface blocked
    - - Mode of administration: Oral, inhalation
      - Well absorbed orally, crosses BBB
      - Amantadine levels in nasal secretion & saliva = in plasma
      - Rimantadine levels in nasal mucous 50% > in plasma
      - T1/2 (half-life): Amantadine = 12-18 hours ; Rimantadine = 24-36 hours
      - Majority of Amantadine excreted in URINE (unchanged) ; Majority of RImantadine excreted in URINE (metabolites)
    - - Dizziness (Amantadine)
      - Nervousness, insomnia, slurred speech
      - Nausea, loss of appetite
      - CNS side effects, less with rimantadine inhalation
- - - - Active against influenza A & B (treatment & prevention)
    - - Inhibit neuraminidase (required for viral release)
    - - Natural resistance seems rare
      - Most oseltamivir-resistant viruses remain susceptible to zanamivir
        
        N/V/Abdominal discomfort
        
        Headache
        
        Food improves GI tolerance
    - - Oseltamivir
        
        Oral absorption rapid, bioavailability 80%
        
        Oral absorption NOT affected by food
        
        Metabolised by esterases in GI tract & liver
        
        T1/2: Oseltamivir carboxylate = 6-10 hours
        
        Excreted via kidney
      - Zanamivir
        
        Low oral bioavailability (~2%), given via NASAL route
        
        Not metabolized
        
        Excreted UNCHANGED via kidneys
- - - - Broad spectrum: against wide range of DNA & RNA viruses inc. influenza A & B, RSV (Respiratory syncytial virus), measles, mumps, Hepatitis C & HIV-1
    - - Multiple action sites
      - Inhibit viral mRNA synthesis
      - Undergoes triple phosphorylation by host cell enzymes
      - Monophosphate blocks GTP synthesis
      - Triphosphate inhibits GTP-dependent enzymes
    - - MOA: Oral, IV, inhalation
      - Oral BA 50-65% (fatty food higher absorption)
      - T1/2 varies (200-300 hours at steady state)
      - Extensively taken up by cells (RBC)
      - Metabolism by Liver & excretion renal
    - - Oral & IV: Dose-related & reversible hemolytic anemia
      - Aerosol: conjunctival irritation, rash, wheezing
    - - Inteferon alpha-2b = synergism against Hepatitis C
      - Inhibits activity of pyrimidine nucleoside HIV RT inhibitors (Zidovudine)
      - Higher activity of purine nucleoside HIV RT inhibitors (DDI)