Drug Mech: Antivirals

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Drug Mech: Antivirals
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2011-03-01 20:18:23
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Drug Mech Antivirals
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Drug Mech: Spring 2011 Antivirals
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  1. What is a virus and how does it replicate?
    Viruses are obligate intracellular parasites (meaning they cannot survive on their own); their replication depends primarily on synthetic processes of the host cell.
  2. How must antivirals work in order to be effective against viruses?
    • To be effective in treating viral infections, antiviral
    • agents must either:
    • 1) block viral entry into or viral exit from the host cell
    • 2) inhibit viral replication inside the host cell
  3. What are the three stages of human viral infection?
    Human viral infection involves three stages:

    • 1) Viral Entry: the virus has to get inside the cell
    • 2) Viral Replication: the virus must replicate its genome
    • 3) Viral Exit: the mature viral particles exit the cell to infect other cells

    The antiviral drugs on the market target these three areas!
  4. What are the steps of viral replication?
    Viral replication consists of the following steps:

    • 1) Adsorption to and penetration into susceptible host cells
    • 2) Uncoating of viral nucleic acid
    • 3) Synthesis of early regulatory proteins (e.g., nucleic acid polymerases)
    • 4) Synthesis of RNA or DNA
    • 5) Synthesis of late structural proteins
    • 6) Assembly (maturation) of viral particles
    • 7) Release from the cell

  5. What are the three enzymes involved in viral replication?
    • There are three enzymes involved in viral replication:
    • 1) Reverse Transcriptase
    • 2) Integrase
    • 3) Protease

    • Note that Reverse Transcriptase has two catalytic (active) binding sites on it:
    • 1) DNA polymerase catalytic site
    • 2) RNase H catalytic site

    • The steps involved in viral replication are as follows:
    • 1) DNA polymerase catalytic site on Reverse Transcriptase enzyme: Build RNA/DNA double helix.
    • 2) RNase H catalytic site on Reverse Transcriptase enzyme: cleave off RNA, therefore you have a single stranded DNA.
    • 3) DNA polymerase catalytic site (again) on the Reverse Transcriptase enzyme: single-stranded. DNA is converted to double-stranded DNA
    • 4) Integrase enzyme: clips 3' end and moves into nucleus with DNA and allows integration into host DNA.
    • 5) Protease enzyme: clips pro-viral proteins from pro-viral mRNA, therefore uses clipped proteins to make the viral capsid, which then allows a mature viral DNA particle to go and infect other host cells.
  6. Antivirals for the treatment of Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) Infections
    • Acyclovir
    • Valacyclovir
    • Famciclovir
    • Penciclovir
    • Trifluridine
    • Docosanol
  7. Antivirals for the treatment of Cytomalovirus (CMV) Infections
    • Ganciclovir
    • Valganciclovir
    • Cidofovir
    • Foscarnet
  8. Antiretroviral Agents (HIV): Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
    • Zidovudine
    • Didanosine
    • Lamivudine
    • Zalcitabine
    • Stavudine
    • Abacavir
    • Emtricitabine
  9. Antiretroviral Agents (HIV): Nucleotide Reverse Transcriptase Inhibitors
    Tenofovir
  10. Antiretroviral Agents (HIV): Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
    • Nevirapine
    • Delavirdine
    • Efavirenz
    • Etravirine
  11. Antiretroviral Agents (HIV): Protease Inhibitors
    • Saquinavir
    • Ritonavir
    • Lopinavir
    • Indinavir
    • Nelfinavir
    • Amprenavir
    • Tipranavir
    • Fosamprenavir
    • Darunavir
    • Atazanavir
  12. Antiretroviral Agents (HIV): Fusion Inhibitors
    Enfuvirtide
  13. Antiretroviral Agents (HIV): CCR5 Antagonists
    Maraviroc
  14. Antiretroviral Agents (HIV): Integrase Strand Transfer Inhibitors (InSTIs)
    Raltegravir
  15. Anti-Hepatitis Agents
    • Lamivudine
    • Adefovir
    • Interferon Alfa
    • Pegylated Interferon Alfa
    • Ribavirin
    • Entecavir
    • Telbivudine
    • Tenofovir
    • Emtricitabine
  16. Anti-Influenza Agents
    • Amantadine & Rimantadine
    • Zanamivir & Oseltamivir
  17. Antivirals for the treatment of Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) Infections
    • Acyclovir
    • Valacyclovir
    • Famciclovir
    • Penciclovir
    • Trifluridine
    • Docosanol
  18. What is the difference between a nucleoside and a nucleotide?
    A nucleoside (with an s) consists of a nitrogenous base covalently attached to a (ribose or deoxyribose) sugar but without the phosphate group.

    A nucleotide (with a t) consists of a nitrogenous base, a sugar, and a phosphate group. So, a nucleotide is a "nucleoside mono-phosphate."

    The only difference between a nucleoside and a nucleotide is that the nucleotide contains one or more phosphates.
  19. What is the only anti-HSV agent available for IV use?
    Acyclovir
  20. What is Acyclovir?
    Acyclovir is an acyclic guanosine derivative.

    Recall guanosine is a nucleotide. Therefore acyclovir competes with guanosine triphosphate.

  21. What is required for acyclovir activation?
    Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by viral thymidine kinase, and then to the diphosphate and triphosphate derivatives by the host’s cellular enzymes (human cell kinases).
  22. What is the mechanism of action of acyclovir?
    1) Acyclovir first needs to be bioactivated via phosphorylation. The guanosine is added and then phosphorylated (a phosphate group is added). The first phosphorylation is by a viral kinase. The other two phosphorylations are by human kinases.

    2) Acyclovir competes with guanosine triphosphate.

    3) Acyclovir inhibits viral DNA synthesis.
  23. What phosphorylates?
    Kinases phosphorylate
  24. What is a polymerase?
    A polymerase is an enzyme whose central function is associated with polymers of nucleic acids, such as RNA and DNA.

    The primary function of a polymerase is the polymerization of new DNA or RNA against an existing DNA or RNA template in the processes of replication and transcription.
  25. Why is acyclovir selective in its actions?
    Because viral kinase is required for its initial phosphorylation, acyclovir is selectively activated and accumulates only in infected cells.
  26. What is the active form of acyclovir called?
    acyclovir triphosphate
  27. How does acyclovir inhibit viral DNA synthesis?
    Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms:

    • 1) Competitive inhibition with deoxyGTP (Guanosine Triphosphate) for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex.
    • 2) Chain termination following incorporation into the viral DNA.

  28. What are mechanisms of resistance to acyclovir?
    Resistance to acyclovir can develop in HSV or VZV through alteration (mutations) in either the viral thymidine kinase or the DNA polymerase.
  29. Which medications work against very resistant strains of viruses?
    Agents such as:

    • foscarnet (antiviral for CMV)
    • cidofovir (antiviral for CMV)
    • trifluridine (antiviral for HSV & VZV)

    do not require activation by viral thymidine kinase. As a result, they are active against the most prevalent acyclovir-resistant strains.
  30. Are there any adverse effects or toxicities of acyclovir?
    Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported.
  31. How is acyclovir selective?
    Acyclovir is highly selective for infected human cells where the first enzyme for bioactivation can be found because it is provided by the virus (which is inside the cell, thus making the human cell "infected"). This is good because it lowers the toxicity of the drug.
  32. Antivirals for the treatment of Cytomalovirus (CMV) Infections
    • Ganciclovir
    • Valganciclovir
    • Cidofovir
    • Foscarnet
  33. What is ganciclovir?
    Ganciclovir is an acyclic guanosine analog.

  34. How does ganciclovir compare to acyclovir?
    Its activity against CMV is up to 100 times greater than that of acyclovir.

    The mechanisms of action are very similar, though.
  35. How does ganciclovir inhibit the viral DNA polymerase?
    Ganciclovir requires triphosphorylation for activation prior to inhibiting the viral DNA polymerase.

    Initial phosphorylation is catalyzed by the viral protein kinase phosphotransferase UL97 in CMV-infected cells.

    The other two phosphorylations are catalyzed by human cell kinases.

    Ganciclovir triphosphate (the active form of the drug) competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation.
  36. What is the mechanism of action for ganciclovir?
    1) Ganciclovir first needs to be bioactivated via triphosphorylation. The guanosine is added and then phosphorylated (a phosphate group is added). The first phosphorylation is by a viral kinase. The other two phosphorylations are by human kinases.

    2) Ganciclovir competes with the natural substrate to inhibit the viral DNA polymerase.

    3) Ganciclovir inhibits viral DNA synthesis.
  37. What are the mechanisms of resistance to ganciclovir?
    1) Altered Viral Kinase: Mutations in UL97, resulting in decreased levels of the active triphosphorylated form of ganciclovir. Isolates with these mutations are not cross-resistant to cidofovir or foscarnet. In other words, cidofovir and foscarnet will still work, even when ganciclovir does not.

    2) Altered DNA Polymerase: Mutations in UL54, resulting in a mutant DNA polymerase; these mutations occur less frequently.
  38. Is there cross resistance with ganciclovir and cidofovir or foscarnet?
    Mutations in UL97, resulting in decreased levels of the active triphosphorylated form of ganciclovir. Isolates with these mutations are not cross-resistant to cidofovir or foscarnet. In other words, cidofovir and foscarnet will still work, even when ganciclovir does not.
  39. What toxicities are associated with ganciclovir?
    Myelosuppression, particularly neutropenia (more common with IV than with oral administration)

    Retinal detachment (in patients with CMV retinitis)
  40. Antivirals for the treatment of Cytomalovirus (CMV) Infections
    • Ganciclovir
    • Valganciclovir
    • Cidofovir
    • Foscarnet
  41. What is cidofovir?
    Cidofovir is a cytosine nucleotide analog.

  42. Is cidofovir associated with guanosine or cytosine?
    Cidofovir is a cytosine analog.
  43. Is cidofovir a nucleoside or a nucleotide?
    Cidofovir is a nucleotide because it already has the phosphate group on it...it just needs two more phosphates to convert the drug to its active form.
  44. What is the mechanism of action for cidofovir?
    Following phosphorylation, cidofovir acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain.
  45. How does cidofovir compare to ganciclovir?
    In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes.
  46. What toxicities are present with cidofovir?
    • Dose-dependent nephrotoxicity
    • Decreased intraocular pressure
  47. Which toxicity of cidofovir is dose dependent?
    nephrotoxicity is dose dependent
  48. Antivirals for the treatment of Cytomalovirus (CMV) Infections
    • Ganciclovir
    • Valganciclovir
    • Cidofovir
    • Foscarnet
  49. What is foscarnet?
    • Foscarnet (phosphonoformic acid) is an inorganic
    • pyrophosphate analog.

  50. Is foscarnet a nucleoside or a nucleotide?
    No...foscarnet is neither a nucleoside nor a nucleotide. Rather, it is just a phosphate.
  51. What is the mechanism of action for foscarnet?
    Foscarnet inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly, without requiring activation by phosphorylation.
  52. What three things does foscarnet inhibit?
    • DNA polymerase
    • RNA polymerase
    • HIV reverse transcriptase
  53. Does foscarnet work by competition?
    No...foscarnet will not compete with the natural substrate. Foscarnet does not compete. Rather, it is an inhibitor, not a competitor.
  54. Does foscarnet require phosphorylation for activation?
    No...foscarnet does not require phosphorylation for activation.
  55. What mechanisms of resistance are associated with foscarnet?
    Resistance to foscarnet in HSV and CMV is due to point mutations in the DNA polymerase gene and is associated with prolonged or repeated exposure to the drug. Mutations in the HIV-1 reverse transcriptase gene have also been reported.

    In other words, Target Modification is taking place in resistance that alters where the drugs can bind.
  56. What is resistance in foscarnet associated with?
    Point mutations, which is the mechanism of resistance seen with foscarnet, are associated with prolonged or repeated exposure to the drug.
  57. What toxicities are there with foscarnet?
    • Nephrotoxicity
    • Anemia
    • CNS toxicity (headache, hallucinations, seizures)
  58. What is therapy for the HIV-1 virus called?
    Antiretroviral therapy
  59. What is the difference between a regular virus and a retrovirus?
    • regular virus: makes DNA from RNA (like human cells do)
    • retrovirus: makes RNA from DNA (exact opposite of a regular virus)
  60. Are there any pharmacologic treatments available for HIV-1 infection?
    A large number of antiretroviral drugs are available for the treatment of HIV-1 infection.
  61. Should antiretrovial therapy be used in combination or not?
    Monotherapy with any one agent should be avoided because of the need for maximal potency to inhibit viral replication and to avoid premature development of resistance.
  62. What is HAART and why is it important?
    A combination of drugs (Highly Active Antiretroviral Therapy; HAART) is usually effective in reducing plasma HIV RNA levels and in gradually increasing CD4 cell counts, particularly in antiretroviral-naive patients.

    Optimization of adherence, tolerability, and convenience is also important in selecting the antiretroviral drugs for therapy.
  63. How many drugs does HAART therapy consist of?
    HAART therapy consists of at least three antiviral drugs.
  64. Why is monitoring therapy important in HAART therapy?
    Given that many patients will experience at least one treatment failure, close monitoring of viral load and CD4 cell counts and the use of drug resistance testing are critical to trigger appropriate changes in therapy.
  65. What are three things to monitor in HIV patients?
    • viral load
    • CD4 cell count
    • drug resistance testing
  66. Antiretroviral Agents (HIV): Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
    • Zidovudine
    • Didanosine
    • Lamivudine
    • Zalcitabine
    • Stavudine
    • Abacavir
    • Emtricitabine

  67. Are the NRTIs nucleosides?
    Yes...nucleosides compete for the catalytic site and then inhibit. NRTIs fall into this category, and are therefore nucleosides.
  68. Do NRTIs need to be bioactivated?
    Yes...NRTIs are considered prodrugs because they need to be bioactivated. Each one of the NRTIs requires intracytoplasmic activation by phosphorylation to the triphosphate form. Phosphorylation of the NRTIs is catalyzed by human cell kinases.
  69. What is the NRTIs mechanism of action?
    • The reverse transcriptase enzyme has two active (catalytic) sites:
    • 1) The RNase H (RNA-cleaving) active site
    • 2) The DNA polymerase (DNA-synthesizing) active site

    Both activities (RNA-cleaving and DNA-synthesizing) are needed to reverse-transcribe HIV’s RNA-based genomic material into DNA.

    NRTIs bind to the DNA polymerase catalytic site of the reverse transcriptase enzyme. As a result, they competitively inhibit the DNA polymerase activity of the enzyme and can also be incorporated into the growing viral DNA chain to cause termination.
  70. Are both transcription and translation needed to replicate HIV DNA?
    Yes...both activities (RNA-cleaving and DNA-synthesizing) are needed to reverse-transcribe HIV’s RNA-based genomic material into DNA.
  71. Where do NRTIs bind?
    NRTIs bind to the DNA polymerase catalytic site of the reverse transcriptase enzyme.
  72. Do NRTIs compete for the active site?
    Yes...NRTIs bind to the DNA polymerase catalytic site of the reverse transcriptase enzyme. As a result, they competitively inhibit the DNA polymerase activity of the enzyme and can also be incorporated into the growing viral DNA chain to cause termination.
  73. Must the NRTIs be phosphorylated for activation?
    Each one of the NRTIs requires intracytoplasmic activation by phosphorylation to the triphosphate form. Phosphorylation of the NRTIs is catalyzed by human cell kinases.
  74. Do the NRTIs need a viral enzyme for activation?
    No...NRTIs are catalyzed by human cell kinases.
  75. Are there any mechanisms of resistance present in the NRTIs?
    Resistance to the NRTIs is caused by viral mutations.
  76. Is there cross resistance among the NRTIs?
    Cross-resistance between the NRTIs has been demonstrated. Recall that a mutation in the DNA polymerase will cause resistance. Because all the NRTIs bind to the same site on the DNA polymerase, there is 100% cross resistance because if one can't bind, none can bind....all because they have the same binding site.
  77. What are toxicities of NRTIs?
    Lactic acidemia and severe hepatomegaly have been reported with the use of the NRTIs, alone or in combination with other antiretroviral drugs.
  78. What was the first antiviral drug to be approved by the FDA?
    Zidovudine (Azidothymidine; AZT)
  79. What is zidovudine?
    Zidovudine is a deoxythymidine analog.
  80. Why is zidovudine used in antiretrovirus therapy?
    It has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals.
  81. Should zidovudine be used during pregnancy?
    When administered during pregnancy, during labor, and to the neonate, zidovudine has also been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV.
  82. What is vertical transmission of HIV?
    Vertical transmission is when an HIV-positive mother passes the virus onto the newborn.
  83. If AZT therapy is given for the prevention of transmission to a neonate, what are the chances of preventing transmission?
    There is a 30% decrease of preventing transmission from the HIV transmission from mom to the neonate. It's not a lot, but it's better than nothing.
  84. What types of resistance are found among AZT?
    As with other NRTIs, viral resistance to AZT may limit its clinical efficacy.

    High-level resistance to AZT is generally seen in strains with three or more mutations.

    Withdrawal of AZT exposure may permit the reversion of AZT-resistant HIV-1 isolates to the susceptible wild-type phenotype.
  85. Can resistance to AZT be reversed?
    Withdrawal of AZT exposure may permit the reversion of AZT-resistant HIV-1 isolates to the susceptible wild-type phenotype.
  86. What are toxicities associated with AZT?
    Myelosuppression (resulting in anemia or neutropenia) is the most common adverse effect of AZT.
  87. Antiretroviral Agents (HIV): Nucleotide Reverse Transcriptase Inhibitors
    Tenofovir
  88. What is tenofovir?
    Tenofovir is an acyclic nucleoside phosphonate (nucleotide) analog of adenosine.
  89. Does tenofovir require phosphorylation for activation?
    It requires activation by phosphorylation to the triphosphate form. Phosphorylation of tenofovir is catalyzed by human cell kinases.
  90. Does tenofovir need a viral kinase for activation?
    No. Phosphorylation of tenofovir is catalyzed by human cell kinases.
  91. Does tenofovir compete for the active site?
    Like the NRTIs, tenofovir competitively inhibits the DNA polymerase activity of the HIV reverse transcriptase enzyme and causes chain termination following its incorporation into viral DNA.
  92. Is there cross resistance with tenofovir?
    Cross-resistance between tenofovir (Nucleotide Reverse Transcriptase Inhibitor) and the NRTIs (Nucleoside Reverse Transcriptase Inhibitors) have been reported. Recall they have the same active site.
  93. What are toxicities associated with tenofovir?
    GI upset is the most common side effect of tenofovir. As with the NRTIs, lactic acidosis and hepatomegaly may occur.
  94. Antiretroviral Agents (HIV): Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
    • Nevirapine
    • Delavirdine
    • Efavirenz
    • Etravirine
  95. What does NNRTI stand for?
    Non-nucleoside Reverse Transcriptase Inhibitor
  96. How do NNRTIs inhibit viral activity?
    The NNRTIs bind directly to sites on the HIV-1 reverse transcriptase, resulting in inhibition of RNA- and DNA-dependent DNA polymerase activities.
  97. How do NNRTIs compare to NRTIs?
    Although both NNRTIs and NRTIs inhibit the same enzyme, they work differently.

    • NNRTIs
    • - bind directly to the reverse transcriptase enzyme
    • - don't require phosphorylation for activation
    • - don't compete with natural substrates

    • NRTIs
    • - don't bind directly to reverse transcriptase enzyme
    • - require phosphorylation for activation
    • - compete with the natural substrate
  98. Do the NNRTIs have the same binding site as the NRTIs?
    The binding sites for the NNRTIs are near to but distinct from the binding site for the NRTIs (i.e., they are near to the DNA polymerase catalytic site of the enzyme). Binding of the NNRTIs blocks the DNA polymerase activity by disrupting the DNA polymerase catalytic site of the enzyme.
  99. What exactly do NNRTIs do?
    Binding of the NNRTIs blocks the DNA polymerase activity by disrupting the DNA polymerase catalytic site of the enzyme.
  100. Do NNRTIs require phosphorylation to be active?
    Unlike the NRTIs, the NNRTIs do not compete with nucleoside triphosphates and do not require phosphorylation to be active.
  101. Do NNRTIs compete for the catalytic site?
    Unlike the NRTIs, the NNRTIs do not compete with nucleoside triphosphates and do not require phosphorylation to be active.
  102. Should NNRTIs be used in combination or not?
    Resistance to a NNRTI is rapid with monotherapy, so combination therapy is suggested.
  103. Which mechanisms of resistance are found in NNRTIs?
    Resistance to a NNRTI is rapid with monotherapy and is associated with specific viral mutations.
  104. Is there any cross resistance with NRTIs?
    There is no cross-resistance between the NNRTIs and the NRTIs or the protease inhibitors.
  105. Is Nevirapine normally used in combination?
    Nevirapine, a NNRTI, is used mainly as a component of a combination antiretroviral regimen.
  106. What enzymes in the liver does nevirapine affect?
    Nevirapine is extensively metabolized by CYP3A4 in the liver (ie, it is a substrate for CYP3A4).

    • It is also an inducer of CYP3A metabolism (drug
    • interactions).
  107. What are toxicities associated with nevirapine?
    • Severe and life-threatening skin rashes, including toxic epidermal necrolysis, have occurred during nevirapine therapy; in such cases,
    • nevirapine therapy should be discontinued.

    • Fulminant (sudden and severe enough to be life threatening) hepatitis may occur within the
    • first 6 weeks of initiation of therapy; serial monitoring of liver function tests is recommended.
  108. Antiretroviral Agents (HIV): Protease Inhibitors
    • Saquinavir
    • Ritonavir
    • Lopinavir
    • Indinavir
    • Nelfinavir
    • Amprenavir
    • Tipranavir
    • Fosamprenavir
    • Darunavir
    • Atazanavir
  109. What is the protease enzyme responsible for in the HIV infection?
    During the later stages of the HIV growth cycle, the Gag and Gag-Pol gene products are translated into polyproteins and then become immature budding particles.

    The protease enzyme is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core.

  110. What do protease inhibitors do?
    Recall that the protease enzyme is like the scissors....it cuts off the virus when mature so it can go infect other cells. In other words, the protease enzyme converts non-infectious immature viral particles into mature viral particles by cleaving polyproteins (which the virus needs to mature) into smaller functional proteins.

    Protease inhibitors inhibit this protease enzyme, which inhibits the mature virus.

  111. What do Protease inhibitors inhibit?
    The protease inhibitors prevent cleavage of the Gag-Pol polyprotein by inhibiting the protease enzyme.

    Inhibition of the protease enzyme results in the production of immature, noninfectious viral particles.
  112. Are protease inhibitors used in combination?
    • Specific genotypic mutations that confer viral
    • resistance to the protease inhibitors are common.

    As a result, monotherapy is contraindicated. (In other words, protease inhibitors are always used in combination).
  113. Does cross resistance appear among the protease inhibitors?
    Cross-resistance among the protease inhibitors exists and appears to require a minimum of four substitutions in the gene.
  114. What are toxicities associated with protease inhibitors?
    • A syndrome called lipodystrophy is characterized by redistribution and accumulation of body fat that includes:
    • central obesity
    • dorsocervical fat enlargement
    • breast enlargement

    • Other toxicities include:
    • increases in triglyceride levels
    • increase in LDL levels
    • glucose intolerance
    • insulin resistance

    These abnormalities appear to be particularly associated with the use of the protease inhibitors; the cause is not yet known.
  115. What are the two types of lipodystrophy?
    • Recall lipodystrophy is the redistribution of fat on the body. There are two types:
    • 1) lipohypertrophy (accumulation of fat)
    • 2) lipoatrophy (loss of fat)
  116. The cause to lipodystrophy is currently unknown. What are the three theories proposed for an explanation?
    • 1) lipodystrophy is caused just by protease inhibitors
    • 2) lipodystrophy is caused by protease inhibitors and HAART combination
    • 3) lipodystrophy is caused by protease inhibitors, HAART combination and the HIV infection itself
  117. Is there any FDA approved treatment for lipodystrophy?
    Tesamorelin (Egrifta®), a growth hormone-releasing factor administered as a once-daily injection, was approved by the FDA for the treatment of lipodystrophy in patients receiving antiretroviral therapy.
  118. Do protease inhibitors cause changes in lipid and carbohydrate metabolism?
    Yes. Recall protease inhibitors will cause diabetes-like symptoms, such as glucose intolerance and insulin resistance. Therefore, protease inhibitors cause changes in lipid and carbohydrate metabolism.
  119. What is a substrate?
    A molecule on which an enzyme acts.
  120. Which enzyme are protease inhibitors substrates for?
    All protease inhibitors are substrates for CYP3A4 in the liver (ie, they are metabolized by CYP3A4 in the liver). As a result, there is a great potential for drug-drug interactions.
  121. Which enzyme do protease inhibitors inhibit?
    In addition, protease inhibitors are CYP3A4 inhibitors as well. Consequently, these agents can cause decreased clearance and increased plasma levels of other substrate drugs. Protease inhibitors should not be administered concurrently with agents that are extensively metabolized by CYP3A4.
  122. What is the most potent CYP3A4 inhibitor of the protease inhibitors?
    Ritonavir
  123. Antiretroviral Agents (HIV): Protease Inhibitors
    • Saquinavir
    • Ritonavir
    • Lopinavir
    • Indinavir
    • Nelfinavir
    • Amprenavir
    • Tipranavir
    • Fosamprenavir
    • Darunavir
    • Atazanavir
  124. What is Ritonavir?
    Ritonavir is an inhibitor of HIV-1 and HIV-2 proteases.
  125. Why would Ritanovir be given concurrently with other protease inhibitors?
    Since ritonavir is an inhibitor of CYP3A4, concurrent administration of ritonavir with other protease inhibitors results in increased plasma levels of these agents because it decreases the rate of metabolism of these drugs (there will be no enzyme to degrade them with ritonavir inhibiting the CYP3A4 enzyme).

    • These pharmacokinetic interactions between ritonavir and other protease inhibitors have been exploited to permit:
    • more convenient dosing (ie, improve patient compliance)
    • improve tolerability
    • enhance efficacy
  126. What is an example of ritanovir concurrent therapy?
    • For example, administration of saquinavir
    • in combination with a low (subtherapeutic) dose of ritonavir has allowed clinicians to decrease the frequency of saquinavir dosing and resulted in improved antiviral efficacy of saquinavir and decreased GI side effects that are typically associated with saquinavir therapy.

    In this combination, the subtherapeutic dose of ritonavir inhibits the CYP3A4-mediated metabolism of saquinavir, thereby resulting in increased exposure (blood levels) to saquinavir.

    The high saquinavir plasma levels that are produced by this combination maintain potent viral suppression as well as provide a pharmacologic barrier to the emergence of resistance.
  127. Besides the saquinavir-ritonavir combination, what are other examples?
    Other examples of the use of ritonavir in a combination with another protease inhibitor are the lopinavir/ritonavir and the tipranavir/ritonavir combinations.
  128. What is the most potent CYP3A4 inhibitor?
    Ritonavir is the most potent CYP3A4 inhibitor.
  129. What is "PI Boosting"?
    PI boosting, which stands for "Protease Inhibitor Boosting" is a unique trick used by practitioners in fighting the HIV virus. Rather than directly inhibit the protease enzymes, CYP3A4 inhibitors, like Ritonavir can be used to boost plasma levels of other protease inhibitors, which in essence, makes the effect of protease inhibitors stronger.

    Blocking the liver enzyme that metabolizes drugs (CYP3A4) would enhance the protease inhibitors plasma levels because the protease inhibitors won't be degraded as quickly by the CYP3A4 enzyme.
  130. Antiretroviral Agents (HIV): Fusion Inhibitors
    Enfuvirtide (T-20)
  131. What is fusion?
    In terms of viral replication, fusion is a pre-requisite for viral entry.

    Fusion is when the viral envelope melts into the cell membrane. It begins with binding of glycoproteins gp 41 located in the viral envelope.
  132. What is Enfuviritide?
    Enfuvirtide is a synthetic 36-amino-acid peptide.

    Of interest, this drug was developed in North Carolina.
  133. How is Enfuviritide administered?
    Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.
  134. Is Enfuvirtide administered in combination or not?
    Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.
  135. In what type of HIV-1 is Enfuvirtide administered?
    Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.
  136. What is the mechanism of action for Enfuviritide?
    Enfuvirtide is a fusion inhibitor that blocks entry of the virus into the cell. It binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.
  137. Is there viral resistance present with Enfuvirtide?
    Viral resistance to enfuvirtide can occur and it is being investigated.
  138. Is there any cross resistance between enfuvirtide and other drugs?
    There is no cross-resistance between enfuvirtide and the other currently available antiretroviral drug classes.
  139. What are toxicities associated with enfuvirtide?
    The most common side effects of enfuvirtide therapy are local injection site reactions. Hypersensitivity reactions of varying severity may occur and recur on rechallenge.
  140. Antiretroviral Agents (HIV): CCR5 Antagonists
    Maraviroc
  141. What is CCR5?
    CCR5 are co-receptors on CD4 lymphocytes (the cells that HIV attacks) that the virus needs to enter the cell.

    If the infection uses only CCR5, we call it a "tropic" infection. For example, a strain that uses only CCR5 would be called: CCR5-tropic HIV-1 detectable disease.

    In other words, HIV uses one of two co-receptors known as Chemokine Receptor 5 (CCR5) and Chemokine Receptor 4 (CXCR4) to enter human CD4 cells of the immune system and infect them.

    In general, viruses that use CCR5 predominate in early disease; as CD4 cell counts decline in more advanced disease, patients begin to harbor viruses that use CXCR4 for cell entry.

    Patients with HIV that preferentially uses CCR5 are classified as having CCR5-tropic disease.
  142. What would an infection be called if it uses more than CCR5?
    An HIV infection that uses more than CCR5 would be called a "dual" or "mixed tropism" infection. For instance, some strains use both CCR5 and CXCR4.
  143. What is Maraviroc (Selzentry®)?
    Maraviroc is a new anti-HIV drug approved by the FDA in August 2007.

    It is indicated for use in combination with other antiretroviral drugs to treat adults with CCR5-tropic HIV-1-detectable disease.
  144. Should Maraviroc be used in combination?
    It is indicated for use in combination with other antiretroviral drugs to treat adults with CCR5-tropic HIV-1-detectable disease.
  145. Can Maraviroc be used in children with HIV?
    No. Maraviroc has been approved for adult use only.
  146. What is the target for Maraviroc?
    Unlike other antiretroviral drugs that inhibit viral proteins, maraviroc targets host CD4 T cells.
  147. What is the mechanism of action for Maraviroc?
    Maraviroc binds to and blocks CCR5 on CD4 cells. As a result, it is able to block the entry of HIV into CD4 cells and prevent the infection.
  148. What type of infection must an HIV patient have in order for Maraviroc to be effective?
    Maraviroc is effective only in patients with CCR5-tropic disease; it is ineffective against HIV that uses both receptors (dual/mixed tropism) or that preferentially uses CXCR4 for cell entry (CXCR4-tropic disease).
  149. How can a clinician determine the tropism of an HIV patient?
    Patients must undergo a screening test to determine the tropism of their HIV infection (CCR5, CXCR4, or dual-tropic) before initiating treatment with maraviroc.

    However, the test (Trofile®) may fail to detect the presence of small numbers (<0.3%) of the CXCR4-tropic virus, which would proliferate and cause maraviroc to fail. The Trofile test will work 100% of the time as long as the CXCR-4 virus affects at least 0.3% of the viral population.
  150. What toxicities are associated with Maraviroc?
    Treatment with maraviroc has been associated with an increased incidence of hepatotoxicity (it has a boxed warning for potential hepatotoxicity). Symptoms of a systemic allergic reaction may occur before hepatotoxicity develops.

    Treatment with maraviroc has also been associated with cardiovascular events such as myocardial ischemia and infarction and postural hypotension. It should be used with caution in patients with increased risk of cardiovascular disease.

    • Treatment with maraviroc may increase a patient’s
    • risk of developing infections and malignancy.
  151. What symptom may precede hepatotoxicity when taking Maraviroc?
    Treatment with maraviroc has been associated with an increased incidence of hepatotoxicity (it has a boxed warning for potential hepatotoxicity). Symptoms of a systemic allergic reaction may occur before hepatotoxicity develops.
  152. Which cardiovascular events are increased with Maraviroc?
    • Treatment with maraviroc has been associated with
    • cardiovascular events such as myocardial ischemia and infarction and postural hypotension.

    It should be used with caution in patients with increased risk of cardiovascular disease.
  153. Will taking Maraviroc increase the risk of cancer and infection?
    Yes. Treatment with maraviroc may increase a patient’s risk of developing infections and malignancy.
  154. Antiretroviral Agents (HIV): Integrase Strand Transfer Inhibitors (InSTIs)
    Raltegravir
  155. What is Raltegravir?
    Raltegravir is the first in a new class of oral HIV drugs called HIV-1 integrase strand transfer inhibitors (InSTIs).
  156. How is Raltegravir administered?
    orally
  157. Should Raltegravir be used in combination?
    It is approved for use in combination therapy for treatment-experienced adults infected with HIV-1 strains that are resistant to multiple antiretroviral agents.
  158. Is Raltegravir first line?
    No. It is approved for use in combination therapy for treatment-experienced adults infected with HIV-1 strains that are resistant to multiple antiretroviral agents.
  159. Should Raltegravir be used with children?
    No. Raltegravir has only been approved for adult use only.
  160. What type of viral strains is Raltegravir active against?
    Raltegravir is active against HIV strains that are resistant to other antiretroviral drugs.
  161. What is the mechanism of action for Raltegravir?
    In essence, Raltegravir attacks the enzyme that integrates viral DNA into the cell DNA:

    HIV-1 integrase
    catalyzes an important step in the process of inserting viral DNA into the host cell genome.

    Raltegravir inhibits the integrase enzyme, preventing viral DNA from integrating with cellular DNA.
  162. Is there viral resistance associated with Raltegravir?
    Target Modification Viral resistance to raltegravir has occurred due to mutations in the integrase enzyme.
  163. Is there any cross resistance associated with Raltegravir?
    Raltegravir has different target than other drugs, so there is no cross resistance with NRTIs, Tonofovir and other drugs. That is why Raltegravir is used in resistant strains of HIV.
  164. What toxicities are associated with Raltegravir?
    Think muscle malfunctions with Raltegravir toxicities!

    • Increases in the following have occurred in raltegravir’s clinical trials, but cause and effect are not clear:
    • 1) serum creatine kinase (Clinically, creatine kinase is assayed in blood tests as a marker of myocardial infarction (heart attack), rhabdomyolysis (severe muscle breakdown), muscular dystrophy, the autoimmune myositides and in acute renal failure),
    • 2) myopathy (muscle fibers do not function right)
    • 3) rhabdomyolysis (Rhabdomyolysis is the breakdown of muscle fibers resulting in the release of muscle fiber contents (myoglobin) into the bloodstream)
  165. Anti-Hepatitis Therapy
    • Lamivudine
    • Adefovir
    • Interferon Alfa
    • Pegylated Interferon Alfa
    • Ribavirin
    • Entecavir
    • Telbivudine
    • Tenofovir
    • Emtricitabine
  166. How prevalent are Hepatitis infections?
    • The prevalence of infections caused by hepatitis B
    • virus (HBV) and hepatitis C virus (HCV) is very high worldwide.

    The morbidity (the rate of incidence of disease) and mortality (the rate of deaths associated with the disease) associated with these infections reflect a great and critical need for improved anti-hepatitis therapies.
  167. Will anti-hepatitis therapy cure infection?
    Similar to the antiretroviral therapy, available anti-hepatitis therapy is suppressive rather than curative.
  168. What is Adefovir?
    Like tenofovir, adefovir is a nucleotide analog of adenosine monophosphate.
  169. What type of infection is Adefovir used for?
    Adefovir has been approved for the treatment of HBV infection.
  170. How long must Adefovir be administered?
    • Studies have shown that adefovir therapy results in significant suppression of HBV replication
    • and improvement in liver histology and fibrosis.

    However, serum HBV DNA reappeared following cessation of therapy.
  171. What is the mechanism of action for Adefovir?
    1) Adefovir is phosphorylated by cellular kinases to the active diphosphate metabolite.

    2) Following activation, it competitively inhibits HBV DNA polymerase

    3) Adefovir then inserts itself via incorporation into the viral DNA

    4) This inhibition results in chain termination
  172. Does Adefovir need to be phosphorylated to be active?
    Yes. Adefovir is similar to tenofavir...it must be phosphorylated to become activated.
  173. Does Adefovir need viral kinases to be activated?
    No. Adefovir is phosphorylated by cellular kinases (not viral kinases) to the active phosphorylated form with two phosphate groups.
  174. Does Adefovir compete for the active site?
    Yes. Adefovir competitively inhibits HBV DNA polymerase.
  175. What is the final consequence of Adefovir?
    Once Adefovir has incorporated itself into viral DNA, it causes chain termination which will inhibit the virus.
  176. What toxicities are associated with Adefovir?
    Adefovir therapy is associated with a dose dependent nephrotoxicity. The risk of nephrotoxicity may rise in patients with preexisting renal dysfunction or in those treated for longer durations.

    • As with the antiretroviral nucleoside analogs (NRTIs) the following can occur:
    • 1) lactic acidosis (Lactic acidosis is when lactic acid builds ups in the bloodstream faster than it can be removed. Lactic acid is produced when oxygen levels in the body drop.)
    • 2) severe hepatomegaly may occur. (An enlarged liver).
  177. What are two risk factors that may increase the chances of nephrotoxicity when taking Adefovir?
    Adefovir therapy is associated with a dose dependent nephrotoxicity.

    The risk of nephrotoxicity may rise in patients with preexisting renal dysfunction or in those treated for longer durations.
  178. What other class of drugs share toxicities with Adefovir?
    As with the antiretroviral nucleoside analogs (NRTIs) the following can occur:

    • 1) lactic acidosis (Lactic acidosis is when lactic acid builds ups in the bloodstream faster than it can be removed. Lactic acid is produced when oxygen levels in the body drop.)
    • 2) severe hepatomegaly may occur. (An enlarged liver).
  179. What is Interferon Alfa (IFN-a)?
    Interferons (IFNs) are a group of cytokines. They are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving the synthesis of both RNA and protein.
  180. What type of infection does Interferon Alfa treat and how is it administered?
    Interferon alfa preparations are available for the treatment of both HBV and HCV infections; they are administered SC or IM.
  181. What signal transduction pathway do cytokines work on?
    • Recall that cytokines:
    • 1) bind to a cytokine receptor
    • 2) activate JAK-STAT signal transduction pathway which produces anti-viral proteins like cytokines
    • 3) cytokines can then inhibit different steps in the viral mechanism of action
  182. Does Interferon alfa need to be used in combination?
    Interferon alfa can be used alone for HBV and HCV, or it is also used in combination with Ribaviron.
  183. What type of variation of interferon drugs are available?
    Pegylated interferon alfa preparations (where a linear or branched polyethylene glycol (PEG) moiety is attached to the interferon molecule by a covalent bond) are available.
  184. Is there any advantage to using pegylated interferon alfa preparations?
    • In comparison with the nonpegylated interferon alfa preparations, the pegylated products have:
    • 1) substantially longer half-lives
    • 2) slower clearance
    • 3) steadier serum concentrations

    All of these things allow for less frequent dosing.
  185. What is the mechanism of action for Interferons (IFNs)?
    Interferons (IFNs) are a group of cytokines. They are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving the synthesis of both RNA and protein.

    They bind to specific membrane receptors (cytokine receptors) on the cell surface and initiate a series of intracellular events that include enzyme induction, suppression of cell proliferation, immunomodulatory activities, and inhibition of viral replication.

    Following binding to specific cellular receptors (cytokine receptors), IFNs activate the JAK-STAT signal-transduction pathway and lead to the nuclear translocation of a cellular protein complex that binds to genes containing an IFN-specific response element. This leads to the synthesis of over 24 antiviral proteins that contribute to viral resistance mediated at different stages of viral penetration.

    A major effect of IFN-induced antiviral proteins is inhibition of viral protein synthesis for many viruses. A given virus may be inhibited at several steps, and the principal inhibitory effect differs among virus families.

    Remember the general idea of the picture below: interferon alfa will lead to anti-viral proteins expressed which will inhibit several steps in the viral mechanism of action. The predominant effect varies from one virus to another, but in most viruses, the anti-viral proteins inhibit step #2 below, which is translation.

  186. Is there viral resistance associated with interferons (IFNs)?
    Certain viruses are able to resist the antiviral effects of IFNs by blocking production or activity of selected IFN-inducible antiviral proteins.

    For example, resistance to IFN therapy in HCV infections is attributed to a number of mechanisms including inhibition of the IFN-induced protein kinase.
  187. Do Interferons have any other effects (either good or bad) besides the direct antiviral effects?
    Yes. In addition to their direct antiviral effects, IFNs are also able to modify the immune response to viral infections.

    The GOOD: For example, IFN-induced expression of MHC antigens (major histocompatibility antigens) may contribute to the antiviral actions of IFNs by enhancing the lytic effects of cytotoxic T-lymphocytes.

    The BAD: Conversely, IFNs may mediate some of the systemic symptoms associated with viral infections and contribute to immunologically mediated tissue damage in certain viral diseases.
  188. Are there any toxicities associated with Interferons (IFNs)?
    • Common side effects include a flu-like syndrome within 6 hours after dosing that tends to resolve
    • upon continued administration.

    Other potential adverse effects include: thrombocytopenia, hypotension, and severe neuropsychiatric side effects.
  189. How does one deal with a common side effect of flu-like symptoms that happens with Interferons?
    Common side effects include a flu-like syndrome within 6 hours after dosing that tends to resolveupon continued administration. Therefore, just continue on with therapy.
  190. What are some contraindications with Interferons (IFNs)?
    • There are many contraindications to interferon
    • therapy, including:
    • psychosis
    • severe depression
    • symptomatic heart disease
    • uncontrolled seizures
  191. Can alfa interferons be used during pregnancy?
    Alfa interferons are abortifacient in primates and should not be administered during pregnancy.
  192. What is Ribavirin?
    It is a guanosine analog that requires intracellular activation. It is phosphorylated by host cell enzymes to the active triphosphate.
  193. Must Ribavirin be phosphorylated to become activated?
    Yes. Ribavirin must be phosphorylated by the host cell enzymes to the active triphosphate form.
  194. Ribavirin is used in combination with what drug?
    Ribavirin is used in combination with interferon alfa for the treatment of HCV infection.
  195. When is Ribavirin used?
    Because Ribavirin is used in combination with interferon alfa for the treatment of HCV, they won't put you on Ribavirin combination unless the single therapy doesn't work.
  196. What is the mechanism of action for Ribavirin?
    Its mechanism of action has not been fully elucidated. However, it appears to be involved in the following:

    • 1) It interferes with the synthesis of guanosine triphosphate.
    • 2) It inhibits capping of viral mRNA.
    • 3) It inhibits viral RNA-dependent RNA polymerase.
  197. What are the three anti-viral effects of Ribavirin?
    • 1) It interferes with the synthesis of guanosine triphosphate.
    • 2) It inhibits capping of viral mRNA.
    • 3) It inhibits viral RNA-dependent RNA polymerase.
  198. What are the toxicities associated with Ribavirin?
    Dose-dependent hemolytic anemia and depression.
  199. Are the toxicities of Ribavirin dose dependent?
    Dose-dependent hemolytic anemia and depression.
  200. Can Ribavirin be used during pregnancy?
    It is contraindicated during pregnancy (it is teratogenic in animals and mutagenic in mammalian cells).
  201. Anti-Influenza Agents
    • Amantadine & Rimantadine
    • Zanamivir & Oseltamivir
  202. What are the Adamantanes?
    Amantadine & Rimantadine
  203. What are Amantadine & Rimantadine?
    Amantadine (Symmetrel®) and its derivative rimantadine (Flumadine®) are cyclic amines.
  204. Between Amantadine & Rimantadine, which is more active?
    • Rimantadine is four to ten times more active than
    • amantadine in vitro.

    Recall in vitro means not in a living organism, but in a controlled environment, like a test tube.
  205. What do Amantadine & Rimantadine treat?
    Influenza type A. However, resistance of influenza A virus to both agents has increased substantially in recent years.
  206. What is the mechanism of action of amantadine and rimantadine?
    Amantadine and rimantadine inhibit the uncoating of the viral RNA of influenza A virus within infected host cells, thus preventing its replication. For some influenza A strains, they also inhibit viral assembly.

    The primary target for both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane).

    By binding to and inhibiting the function of the M2 protein (an ion channel), these drugs are able to inhibit the acid-mediated dissociation of the viral ribonucleoprotein complex early in viral replication (i.e., inhibiting viral uncoating) and alter hemagglutinin processing (by inducing conformational changes in hemagglutinin during its intracellular transport) later in replication (i.e., inhibiting viral assembly).

    Remember, the virus cannot replicate unless the coat is removed in the genome. That is why inhibiting viral uncoating will block the virus from replicating.
  207. What is the primary target for both Amantadine and Rimantadine?
    The primary target for both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane).
  208. What are the two main things that Amantadine and Rimantadine inhibit?
    • inhibit viral uncoating
    • inhibit viral assembly (in some selected strains)
  209. Are Amantadine and Rimantadine considered specific?
    Yes. The primary target for both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane).
  210. Why is Amantadine & Rimantadine currently not recommended for use?
    Resistance of influenza A virus to both agents has increased substantially in recent years, to the point that this combination is currently not recommended for use.
  211. Can the resistant Hepatits A virus be transferred from patient to patient?
    Yes. Resistance, caused by mutation, rapidly develops in treated patients. Transmission of resistant virus to household contacts has been reported.
  212. Is there cross resistance with Amantadine and Rimantadine?
    Yes. These drugs share cross resistance.
  213. Do Amantadine and Rimantadine share cross resistance with the other combination anti-influenza drugs?
    No. Cross-resistance to zanamivir and oseltamivir does not occur.
  214. Do Amantadine and Rimantadine share cross-susceptibility?
    Yes. Both drugs share cross-susceptibility?
  215. What is the difference between cross-susceptibility and cross-resistance?
    • cross-susceptibility is when the virus can be either susceptible or resistant to drugs that work the same way. In the case of Amantadine and Ramantidine, then, influenza A would be either susceptible to both or resistant to both because they both work on the same M2 protein.
    • cross-resistance is when the virus figures out how to change its mechanism of action to get around one drug, other drugs that work the same way won't work either. For example, in the case of Amantadine and Rimantadine, when the virus changes the M2 protein to avoid Amantadine, then Rimantadine won't work either.
  216. Cross Susceptibility vs. Cross Resistance
    • Cross-susceptibility means that if rimantadine is effective against a particular viral strain, then amantadine is also effective against the same strain.
    • Cross-resistance means that if a viral strain is resistant to rimantadine, it is also going to be resistant to amantadine.
  217. What are toxicities associated with Amantadine & Rimantadine?
    CNS toxicity (e.g., nervousness, lightheadedness, difficulty in concentrating). The CNS side effects are more frequent with amantadine.

    • Serious neurotoxic reactions, occasionally fatal,
    • may be associated with high amantadine plasma levels (1-5 mg/mL).
  218. What dose of amantadine is considered high enough to cause serious neurotoxic reactions?
    Serious neurotoxic reactions, occasionally fatal, may be associated with high amantadine plasma levels (1-5 mg/mL).
  219. Which drug is more toxic: Amantadine or Rimantadine?
    Amantadine is more toxic than Rimantadine because the CNS side effects more frequent with amantadine. Also because serious neurotoxic reactions, occasionally fatal, may be associated with high amantadine plasma levels (1-5 mg/mL).
  220. Can Amantadine & Rimantadine be used during pregnancy?
    Amantadine is teratogenic in rodents; birth defects have been reported after exposure during pregnancy.
  221. What are Neuraminidase Inhibitors?
    Zanamivir & Oseltamivir
  222. What is neuraminidase?
    Neuraminidase is an essential viral glycoprotein for viral release.
  223. What type of infection do zanamivir and oseltamivir treat?
    Zanamivir (Relenza®) and oseltamivir (Tamiflu®) are active against both influenza A and influenza B.

    Both agents have been approved for prophylaxis (prevention) or treatment of acute uncomplicated influenza infection.
  224. When should zanamivir and/or oseltamivir be administered?
    When administered for a 5-day course within 36-48 hours after the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults.

    The earlier they are started, the more effective they are in treating influenza.
  225. Besides shortening the severity and duration of the flu virus, what other symptom can zanamivir and oseltamivir decrease?
    Administration may decrease the incidence of respiratory complications in children and adults
  226. How do zanamivir and oseltamivir differ from amantadine and rimantadine?
    Unlike amantadine and rimantadine (which just treat influenza A), zanamivir (Relenza®) and oseltamivir (Tamiflu®) are active against both influenza A and influenza B.

    Also, unlike amantadine and rimantadine (which are not recommended for treatment because of resistance), zanamivir (Relenza®) and oseltamivir (Tamiflu®) are the current recommended drugs for treatment or prophylaxis of influenza.
  227. How are zanamivir and oseltamivir administered?
    Zanamivir is administered via oral inhalation; oseltamivir is an orally administered prodrug that is activated in the gut and liver. Both drugs are also available in IV formulations.
  228. Which drug, zanamivir or oseltamivir, must be bio-activated in the gut and the liver?
    Oseltamivir is an orally administered prodrug that is activated in the gut and liver.
  229. Are zanamivir and oseltamivir useful in the hospital setting? Are they used to prevent or treat nosocomial infections?
    In hospitalized patients with the flu, both drugs have been shown to reduce the duration of hospitalization and the risk of death. They may also decrease viral shedding and the risk of spread to contacts even when started more than 48 hours after the onset of illness.
  230. How effective, percantage-wise, are zanamivir and oseltamivir for prophylaxis?
    Both drugs are about 70%-90% effective for prophylaxis after exposure to influenza A or B.
  231. If prophylactically treating a patient, when should zanamivir or oseltamivir be administered?
    They should be given within 48 hours after a household exposure or other close contact with an influenza virus-infected person.
  232. Is there any viral resistance to zanamivir or oseltamivir?
    Yes. Viral resistance to this class of drugs has been reported in both A and B strains of the influenza virus.

    Viral resistance, mainly to oseltamivir, is associated with a mutation in the viral neuraminidase (target modification).
  233. Is there any cross resistance between zanamivir and oseltamivir and any other previous drug class?
    No. There is no cross resistance between these and any other previous drug class.
  234. Can someone receive zanamivir and oseltamivir with the flu vaccine?
    Inactivated flu vaccines are not affected by antiviral drug therapy.

    However, antivirals may interfere with the efficacy of the live-attenuated intranasal flu vaccine (FluMist®); they should be stopped at least 48 hours before and should not be started for at least 2 weeks after FluMist administration.
  235. What is the mechanism of action for zanamivir and oseltamivir?
    Zanamivir and oseltamivir are inhibitors of the viral neuraminidase enzyme.

    Neuraminidase is an essential viral glycoprotein for viral release, therefore, these drugs inhibit viral release.
  236. What are toxicities associated with zanamivir?
    Zanamivir can cause cough, nasal and throat irritation; bronchospasm in patients with reactive airway disease has also been reported. It is generally not recommended for use in patients with asthma or COPD.
  237. Zanamivir is contraindicated for patients with what condition?
    Zanamivir is generally not recommended for use in patients with asthma or COPD.
  238. What toxicities are associated with oseltamivir?
    Potential side effects of oseltamivir include headache, nausea and vomiting. Taking the drug with food may reduce the incidence of GI effects.
  239. What might be a good patient education counseling point with oseltamivir and why?
    Potential side effects of oseltamivir include headache, nausea and vomiting. Taking the drug with food may reduce the incidence of GI effects.
  240. Is there any association with oseltamivir and neuropsychiatric effects in children or adolescents?
    Neuropsychiatric events, including self-injury, delirium, and hallucinations, have occurred in some children and adolescents treated with oseltamivir, but causation has not been established (i.e., the data increasingly points to the influenza infection, not oseltamivir, as the cause of these events).
  241. What is the only emergency use anti-flu drug available?
    In 2009, the FDA issued an ‘emergency use authorization’ for the neuraminidase inhibitor peramivir.

    This was around the same time as H1N1 epidemic.
  242. Why is Peramivir only authorized under emergency use?
    Peramivir (given IV) is an investigational drug that inhibits viral neuraminidase.
  243. How is Peramivir administered?
    Peramivir is administered via IV route.
  244. What are the requirements for use of peramivir?
    The FDA authorized the use of peramivir in hospitalized adults or children with confirmed or suspected pandemic 2009 H1N1 influenza infection who cannot take or are not responding to treatment with oseltamivir or zanamivir.
  245. Can peramivir be used in children?
    Yes. The FDA authorized the use of peramivir in hospitalized adults or children with confirmed or suspected pandemic 2009 H1N1 influenza infection who cannot take or are not respondingto treatment with oseltamivir or zanamivir.
  246. If there is resistance to peramivir, there might also be resistance to what drug?
    Many clinical isolates resistant to oseltamivir have, however, also been resistant to peramivir.
  247. Is there viral resistance with peramivir?
    Yes. Many clinical isolates resistant to oseltamivir have, however, also been resistant to peramivir.
  248. How do we know which viral strains in the US are actually susceptible and not susceptible to drugs we have available?
    Susceptibility of the circulating influenza strains to antiviral drug therapy varies from one strain to another and from one flu season to another.

    In recent years, however, susceptibility of circulating influenza strains has evolved rapidly and treatment recommendations have changed during the same flu season.

    The CDC influenza website (www.cdc.gov/flu) provides frequently updated information on viral resistance/susceptibility to available anti-influenza drugs.
  249. Which website should all healthcare professionals (and the public) visit for the latest information on influenza (the flu)?
    The CDC influenza website (www.cdc.gov/flu) provides frequently updated information on viral resistance/susceptibility to available anti-influenza drugs.

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