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					                  Antiviral Agents




Jillian H. Davis
Dept. of Pharmacology
March 31, 2004
Viruses
 Obligate intracellular parasites
 Consist of a core genome in a protein
  shell and some are surrounded by a
  lipoprotein
 lack a cell wall and cell membrane
 do not carry out metabolic processes
 Replication depends on the host cell
  machinery
Viruses
   Steps for Viral Replication
     1)   adsorption and penetration into cell
     2)   uncoating of viral nucleic acid
     3)   synthesis of regulatory proteins
     4)   synthesis of RNA or DNA
     5)   synthesis of structural proteins
     6)   assembly of viral particles
     7)   release from host cell
Sites of Drug Action
Antiviral Agents
 Block viral entry into the cell or
  must work inside the cell
 Most agents are pyrimidine or purine
  nucleoside analogs
Sites of Drug Action
Antiherpes Agents

   Acyclovir- prototype
   Valacyclovir
   Famciclovir
   Penciclovir
   Trifluridine
   Vidarabine
Mechanism of Action
  Acyclovir
 an acyclic guanosine derivative
 Phosphorylated by viral thymidine
  kinase
 Di-and tri-phosphorylated by host
  cellular enzymes
 Inhibits viral DNA synthesis by:
     1) competing with dGTP for viral DNA
      polymerase
     2) chain termination
Mechanism of Resistance
  Acyclovir
   Alteration in viral thymidine kinase

   Alteration in viral DNA polymerase

   Cross-resistance with valacyclovir,
    famciclovir, and ganciclovir
Clinical Uses
    Acyclovir
 Oral, IV, and Topical formulations
 Cleared by glomerular filtration and
  tubular secretion
 Uses:
     Herpes Simplex Virus 1 and 2 (HSV)
     Varicella-zoster virus (VZV)

   Side Effects: nausea, diarrhea,
    headache, tremors, and delirium
Valacyclovir
 L-valyl ester of acyclovir
 Converted to acyclovir when ingested
 M.O.A.: same as acyclovir
 Uses:
     1) recurrent genital herpes
     2) herpes zoster infections

   Side Effects: nausea, diarrhea, and
    headache
Famciclovir
 Prodrug of penciclovir (a guanosine
  analog)
 M.O.A.: same as acyclovir
 does not cause chain termination
 Uses: HSV-1, HSV-2, VZV, EBV, and
  hepatitis B
 Side Effects: nausea, diarrhea, and
  headache
    Trifluridine

   Trifluridine- fluorinated pyrimidine
     inhibits viral DNA synthesis same as
      acyclovir
     incorporates into viral and cellular DNA

     Uses: HSV-1 and HSV-2 (topically)
Vidarabine
 An adenosine analog
 inhibits viral DNA polymerase
 incorporated into viral and cellular
  DNA
 metabolized to hypoxanthine
  arabinoside
 Side Effects: GI intolerance and
  myelosuppression
Anti-Cytomegalovirus
Agents

   Gancyclovir
   Valgancyclovir
   Cidofovir
   Foscarnet
   Fomivirsen
Ganciclovir
 An acyclic guanosine analog
 requires triphosphorylation for
  activation
 monophosphorylation is catalyzed by a
  phosphotransferase in CMV and by
  thymidine kinase in HSV cells
 M.O.A.: same as acyclovir
 Uses: CMV*, HSV, VZV,and EBV
 Side Effect: myelosuppression
    Valgancyclovir
 Monovalyl ester prodrug of gancyclovir
 Metabolized by intestinal and hepatic
  esterases when administered orally

 M.O.A.: same as gancyclovir
 Uses: CMV*
 Side Effect: myelosuppression
    Cidofovir
 A cytosine analog
 phosphorylation not dependent on
  viral enzymes
 Uses: CMV*, HSV-1, HSV-2, VZV,
  EBV, HHV-6, adenovirus, and human
  papillomavirus
 Side Effects: nephrotoxicity
  (prevented by admin. of probenecid)
 Resistance: mutation in DNA
  polymerase gene
    Foscarnet
   An inorganic pyrophosphate
   inhibits viral DNA polymerase, RNA
    polymerase, and HIV reverse transcriptase
   does not have to be phosphorylated
   Uses: HSV, VZV, CMV, EBV, HHV-6, HBV,
    and HIV
   Resistance due to mutations in DNA
    polymerase gene
   Side Effects: hypo- or hypercalcemia and
    phosphotemia
Fomivirsen
 An oligonucleotide
 M.O.A.: binds to mRNA and inhibits
  protein synthesis and viral
  replication
 Uses: CMV retinitis
 Side effects: iritis and increased
  intraocular pressure
Antiretroviral Agents
1) Nucleoside Reverse Transcriptase
 Inhibitors (NRTIs)

2) Nonnucleoside Reverse
 Transcriptase Inhibitors (NNRTIs)

3)Protease inhibitors
    Reverse Transcriptase
    Inhibitors
 Zidovudine (AZT)
 Didanosine- causes pancreatitis*
 Lamivudine- causes pancreatitis
 Zalcitabine- causes peripheral neuropathy*
 Stavudine- causes peripheral neuropathy*
 Abacavir
Mechanism of Action
  Zidovudine (AZT)
 A deoxythymidine analog
 enters the cell via passive diffusion
 must be converted to the
  triphosphate form by mammalian
  thymidine kinase
 competitively inhibits
  deoxythymidine triphosphate for the
  reverse transcriptase enzyme
 causes chain termination
Mechanism of Resistance
   Zidovudine

   Due to mutations in the reverse
    transcriptase gene

   more frequent after prolong therapy
    and in persons with HIV
Clinical Uses
    Zidovudine
 Available in IV and oral formulations
 activity against HIV-1, HIV-2, and
  human T cell lymphotropic viruses
 mainly used for treatment of HIV,
  decreases rate of progression and
  prolongs survival
 prevents mother to newborn
  transmission of HIV
Side Effects
   Zidovudine
   Myelosuppression, including anemia
    and neutropenia

   GI intolerance, headaches, and
    insomnia
Other NRTIs
   Didanosine- synthetic deoxy-
    adenosine analog; causes pancreatitis*
 Lamivudine- cytosine analog
 Zalcitabine- cytosine analog; causes
    peripheral neuropathy*
   Stavudine- thymidine analog;causes
    peripheral neuropathy*
   Abacavir- guanosine analog; more
    effective than the other agents; fatal
    hypersensitivity reactions can occur
Nucleotide Inhibitors
 Tenofovir
 Adefovir
Tenofovir
 An acyclic nucleoside phosphonate
  analog of adenosine
 M.O.A.- competively inhibits HIV
  reverse transcriptase and causes
  chain termination after incorporation
  into DNA
 Uses – in combination with other
  antiretrovirals for HIV-1 suppression
Adefovir
 An analog of adenosine
  monophosphate
 Phosphorylated by cellular kinases
 M.O.A. - Competitively inhibits HBV
  DNA polymerase and results in chain
  termination after incorporation into
  viral DNA
 Uses - Hepatitis B
 Side effects - nephrotoxicity
Nonnucleoside Reverse
Transcriptase Inhibitors
(NNRTIs)

 Nevirapine
 Delavirdine
 Efavirenz
Mechanism of Action
  NNRTIs
 Bind to site on viral reverse
  transcriptase, different from NRTIs
 results in blockade of RNA and DNA
  dependent DNA polymerase activity
 do not compete with nucleoside
  triphosphates
 do not require phosphorylation
 these drugs can not be given alone
 substrates and inhibitors of CYP3A4
Nonnucleoside Reverse
Transcriptase Inhibitors
(NNRTIs)
 Nevirapine- prevents transmission
  of HIV from mother to newborn
  when given at onset of labor and to
  the neonate at delivery
 Delavirdine- teratogenic, therefore
  can not be given during pregnancy
 Efavirenz- teratogenic, therefore
  can not be given during pregnancy
Protease Inhibitors
 Indinavir
 Ritonavir
 Saquinavir
 Nelfinavir
 Amprenavir
Protease Inhibitors
 The protease enzyme cleaves
  precursor molecules to produce
  mature, infectious virions
 these agents inhibit protease and
  prevent the spread of infection
 These agents cause a syndrome of
  altered body fat distribution, insulin
  resistance, and hyperlipidemia
    Indinavir and Ritonavir
 M.O.A.: Specific inhibitors of the HIV-1
  protease enzyme
 M.O.R.: mediated by expression of
  multiple and variable protease amino
  acid substitutions
 Side Effects:hyperbilirubinemia
 Contraindications:inhibitor/substrate
  for CPY3A4, do not give with antifungal
  azoles
Saquinavir
   A synthetic peptide-like substrate
    analog

   inhibits HIV-1 protease

   prevents cleavage of viral
    polyproteins
Nelfinavir and
Amprenavir
   M.O.A.: Specific inhibitors of the HIV-1
    protease enzyme
   M.O.R.: mediated by expression of
    multiple and variable protease amino acid
    substitutions
   Less cross-resistance with Amprenavir
   Side Effects: diarrhea and flatulence
   Amprenavir can cause Stevens-Johnson
    syndrome
   Contraindications:inhibitor/substrate
    for CPY3A4
Fusion Inhibitors
   Enfuvirtide (T-20)- binds to the gp41
    subunit of the viral envelope glycoprotein,
    preventing the conformational changes
    required for fusion of the viral and cellular
    membranes
   By blocking fusion (entry into cell),
    FUZEON prevents HIV from infecting CD4
    cells
Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor
(NNRTI) and protease inhibitor (PI) classes prevent the replication of HIV by working inside CD4
cells after they have been infected with HIV. The drugs in these three classes then target specific
steps in the replication process to prevent the creation of new HIV particles.

Fusion inhibitors differ from these drugs because they work on the outside of the cell to prevent
HIV from fusing with, and infecting the CD4 cells in the first place.




                                                                             from
                                                                             Fuzeon.com
Anti-Hepatitis Agents
   Lamivudine -Nucleoside Reverse
    Transcriptase Inhibitor (NRTI)
 Adefovir -Nucleotide Inhibitor
 Interferon Alfa
 Pegylated Interferon Alfa
 Ribavirin
Interferons
   Interferon Alfa

   Endogenous proteins

   induce host cell enzymes that inhibit viral
    RNA translation and cause degradation of
    viral mRNA and tRNA
   Bind to membrane receptors on cell
    surface
   May also inhibit viral penetration,
    uncoating, mRNA synthesis, and
    translation, and virion assembly and
    release
Interferons
 Pegylated interferon Alfa
 A linear or branced polyethylene
  gylcol (PEG) moiety is attached to
  covalently to interferon
 Increased half-life and steady drug
  concentrations
 Less frequent dosing
 Tx chronic hepatitis C in combination
  with ribavirin
Ribavirin
 A guanosine analog
 phosphorylated intracellularly by
  host enzymes
 inhibits capping of viral messenger
  RNA
 inhibits the viral RNA-dependent
  RNA polymerase
 inhibits replication of DNA and RNA
  viruses
Anti-Influenza Agents

 Amantadine
 Rimantadine
 Zanamivir
Amantadine and
Rimantadine
  cyclic amines
  inhibit the uncoating of viral RNA
   therefore inhibiting replication
  resistance due to mutations in the
   RNA sequence coding for the
   structural M2 protein
  used in the prevention and
   treatment of Influenza A
Zanamivir and
Oseltamivir

 Inhibits the enzyme neuraminidase
 inhibit the replication of influenza A
  and Influenza B
 treats uncomplicated influenza
  infections
 administered intranasally
Antifungal Agents
Fungal Infections
   Develop due to a loss of mechanical
    barriers (i.e. burns,major surgery) or
    immunodeficiency (chemotherapy,organ
    transplant, AIDS)
   fungal infections may be superficial or
    systemic
   Fungi possess different ribosomes, cell
    wall components, and discrete nuclear
    membrane
Systemic Antifungals
 Amphotericin B
 Flucytosine
 Azoles
     Ketoconazole
     Itraconazole

     Fluconazole
Amphotericin B
 An amphoteric polyene macrolide
 Broad spectrum of activity
 Binds to ergosterol and alters the
  permeability of the cell by forming
  pores in the membrane leading to
  cell death
 Resistance occurs when ergosterol
  binding is impaired
Amphotericin B
   2 categories of toxicity

       Infusion-related: fever, chills, muscle
        spasm, and hypotension

       Slower toxicity: renal damage
Flucytosine
 A pyrimidine analog
 related to fluorouracil (5-FU)
 spectrum of activity narrower than
  amphotericin B
 used in combination with
  amphotericin B
    Flucytosine
 Enters the cell via a cytosine-specific
  permease
 converted to 5-FU via cytosine
  deaminase
 5-FU is converted to 5-FdUMP which
  inhibits thymidylate synthase 
  inhibiting DNA synthesis
 metabolized to 5-FUTP which is
  incorporated into fungal RNA, inhibiting
  nucleic acid and protein synthesis
Flucytosine
 Decreased levels of any of the
  enzymes can lead to resistance
 toxic effects may be related to the
  formation of 5-FU including, anemia,
  leukopenia, and thrombocytopenia
 hepatic dysfunction may occur
    Azoles
 Prototype- Ketaconazole
 interact with C-14 -demethylase
  (P450 enzyme) to block the
  demethylation of lanosterol to
  ergosterol, thereby disrupting
  membrane function and increasing
  permeability
 Ketaconazole has additive effect with
  flucytosine and antagonizes
  amphotericin B
Differences in Azoles


•Refer to Katzung table 48-1
Mucocutaneous Antifungals
   Griseofulvin
     enters fungal cells by an energy-
      dependent process
     interacts with the microtubules within
      the fungus to disrupt the mitotic
      spindle and inhibit mitosis
     resistance due to lack of energy-
      dependent uptake system
     toxicities include allergic syndrome and
      hepatitis
Topical Antifungals
   Nystatin
     polyene macrolide
     M.O.A. same as amphotericin B

     due to toxicity it is only used topically

				
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