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Block G -- Infection > Dr. Papenburg -- Antiviral Agents > Flashcards

Dr. Papenburg -- Antiviral Agents Flashcards

1
Q

4 virus-specific events that antiviral agents must ideally inhibit

A
  • Block viral entry into the cell
  • Block viral exit from the cell
  • Be active inside the host cell
  • Exert some sort of immunomodulatory effect
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2
Q

How a therpeutic agent’s antiviral effect is measured

A

By its ability to *inhibit *viral replication (50% Inhibitory Concentration)

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3
Q

6 stages of viral replication

A
  1. Attachment
  2. Entry
  3. Uncoating
  4. Synthesis
    1. Early proteins
    2. Nucleic acids
    3. Late proteins
  5. Assemply
  6. Release
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4
Q

2 classes of antivirals against influenza

A
  • Adamantanes (M2 ion channel inhibitors)
  • Neuraminidase inhibitors
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5
Q

2 adamantanes

A
  • Amantadine
  • Rimantidine
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6
Q

2 neuraminidase inhibitors

A
  • Oseltamivir (Tamiflu)
  • Zanamivir (Relenza)
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7
Q

Amantadine function

A

Disable M2 protein –> prevent viral uncoating –> virus rendered inert

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8
Q

Neuraminidase inhibitor function

A

Inhibit release of virions and promote clumping

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9
Q

Target stage of Adamantanes

A

Uncoating

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10
Q

Target stage of neuraminidase inhibitors

A

Release

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11
Q

Flu type covered by adamantanes

A

Influenza A

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12
Q

Flu types covered by NAIs

A

A and B

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13
Q

Administration of adamantanes

A

Oral

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14
Q

Administration of NAIs

A

Zanamivir = Inhaled

Oseltamivir = Oral

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15
Q

Age range for adamantanes

A

> 1 year old

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16
Q

Age range for NAIs

A

Zanamivir = > or = 7 yo

Oseltamivir = all ages

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17
Q

4 side effects of adamantanes

A
  • Nausea
  • Dizziness
  • Insomnia
  • Anxiety
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18
Q

Side effects of NAIs

A

Zanamivir = Bronchospasm

Oseltamivir = GI

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19
Q

Signs of resistance against treatment with adamantanes

A

Persistent or recurrent fever in children

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20
Q

Type of mutation involved in resistance to adamantanes

A

Single point mutation of the M2 protein

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21
Q

Effect of mutation for adamantane resistance on viral replication, transmission and virulence

A

No impairment

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22
Q

Effect of mutations for NI resistance on replication, infectivity and virulence

A

Decreased

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23
Q

Major problem with adamantanes

A

Rapid emergence of resistance during treatment

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24
Q

5 benefits of oseltamivir therapy

A

Reduction of:

  1. Duration of illness in adults and children
  2. Viral shedding and viral load
  3. Antibiotic use
  4. Length of hospitalization
  5. Mortality in hospital
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25
Q

4 types of people to treat for influenza

A

Prompt empiric treatment recommended for persons with suspected or confirmed influenza AND:

  • Illness requiring hospitalization
  • Progressive, severe, or complicated illness
  • At risk for severe disease
  • Essential healthcare workers
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26
Q

7 types of patients who are an increased risk for complications

A
  1. Chronic medical conditions
  2. Living in a nursing home or long-term care center
  3. Age 65 years and over
  4. Pregnant women, especially in T2 and T3
    • Also post-partum 2 - 4 weeks
  5. Healthy children <24 months
    • If severe or progressive disease
  6. Neurological/nerudevelopmental disorders
  7. Severe obesity = BMI >40
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27
Q

4 alternatives to oseltamivir

A
  • Zanamivir (if tolerated)
  • IV zanamivir (special access)
  • IV peramivir (investigational; only in emergency)
  • Combination Tamiflu + Amantidine
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28
Q

How many types of herpesviruses are there? Name most of them

A

8 types:

  1. HSV-1
  2. HSV-2
  3. VZV
  4. CMV
  5. EBV
  6. HHV-6
  7. HHV-8
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29
Q

Acyclovir activity for herpesvirus

A
  • HSV
  • VZV (lower affinity)
  • Very poor activity against others
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30
Q

Acyclovir bioavailability po

A

15 - 30%

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31
Q

Metabolism of acycolvir (ACV)

A
  1. Phosphorylated to monophosphate form by viral thymidine kinase (TK)
  2. Di- and tri-phosphrylated by host cellular enzymes
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32
Q

Antivirally active form of ACV

A

Triphosphate form

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33
Q

Triphosphate ACV function

A

Inhibit viral DNA synthesis by:

  1. Competing with dGTP for viral DNA polymerase
  2. Chain termination
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34
Q

Most common reason for ACV resistance in HSV

A

Virus deficient in TK

NOTE: rarely due to altered TK or DNA pool; rare in immunocompetent

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35
Q

Most common reason for ACV resistance in VZV

A

Altered TK (lower affinity for ACV)

36
Q

3 PO uses of ACV

A
  1. Genital herpes
    • Primary infection
    • Suppression of recurrences
  2. Oro-labial herpes
    • Primary
    • ± Recurrence
  3. Primary VZV
37
Q

Topical ACV use

A

Keratoconjunctivitis

38
Q

5 IV uses of ACV

A
  1. HSV encephalitis
  2. Neonatal HSV
  3. HSV in immunocompromised
  4. VZV (primary or reactivation) in immunocompromised
  5. Prophylaxis post bone marrow transplant
39
Q

2 potential side effects of ACV

A

Generall well tolerated, but may have:

  1. Nephrotoxicity when given IV
  2. Neurotoxicity in renal failure
40
Q

Define valacyclovir

A

Pro-drug of acyclovir

41
Q

Method of administration of valacyclovir and its bioavailability

A

PO –> 70%

42
Q

Describe the resistance profile of penciclovir/famciclovir

A
  • Able to overcome some resistance to acyclovir
  • TK deficient mutants remain resistant
  • Rare in immunocompetent
43
Q

3 clinical indications for famciclovir

A
  1. Genital herpes
    • Primary
    • Recurrence
    • Suppression
  2. Oro-labial HSV
  3. VZV
    • Primary
    • Zoster
44
Q

Gancyclovir activity

A

In vitro = all herpesviruses

NOTE: 100x more active against CMV than ACV

45
Q

Method of administration of gancyclovir

A

IV via central venous line

46
Q

Gancyclovir mechanism in CMV infected cells

A
  1. Virally-encoded UL97 phosphotransferase performs first phosphorylation
  2. After di and tri-phosphorylation cellular enzymes), GCV inhibits viral DNA pol
47
Q

Most common cause of GCV resistance in CMV

A

Mutations in the UL97 gene

NOTE: DNA pol (UL54) mutations are rare. DOuble mutants (UL97 AND UL54) = most resistant

48
Q

Cross-resistance of GCV in event of UL54 mutation

A

Cidofovir and foscarnet

49
Q

4 clinical indications for GCV

A
  1. CMV retinitis
  2. CMV pneumonitis
  3. Prophylactic or pre-emptive
    • Bone marrow transplant (D-/R+)
    • Solid organ transplant (D+/R-)
  4. Congenital CMV
50
Q

Combo treatment for CMV pneumonitis

A

GCV + anti-CMV immunoglobulin

51
Q

4 GCV side effects

A
  1. Requirement of central line
  2. Bone marrow toxicity
    • Neutropenia (40%)
    • Thrombocytopenia (15 - 20%)
  3. CNS manifestations (5%)
  4. Teratogenic
52
Q

Define valgancyclovir

A

Oral pro-drug of gancyclovir with 60% bioavailability

53
Q

2 indications for valgancyclovir

A
  1. Treat and suppress CMV retinitis
  2. CMV prophylaxis in solid organ transplant
54
Q

In vitro activity of cidofovir (4)

A
  1. Herpesviruses
  2. Adenoviruses
  3. Papillomaviruses
  4. Polyomaviruses
55
Q

In vivo activity of cidofovir (2)

A
  • CMV resistant to GCV (UL97)
  • TK-deficient HASV/VZV
56
Q

Antiviral that does not depend on viral enzymes for phosphorylation

A

Cidofovir

57
Q

Clinical indications for cidofovir

A

CMV disease in

  • Immunosuppressed patients who do not tolerate FCV and foscarnet
  • Whose virus is suspected to be resistant to GCV and foscarnet
58
Q

3 side effects of cidofovir

A
  1. Dose-dependent nephrotoxicity
  2. Neutropenia
  3. Potentially carcinogenic and teratogenic
59
Q

Foscarnet activity

A
  • All herpesviruses
  • CMV resistant to GCV (UL97)
  • TK deficient HSV/VZV
60
Q

Admniistration of foscarnet

A

IV

61
Q

Antiviral that does not require any phosphorylation

A

Foscarnet (direct inhibition of DNA pol)

62
Q

Clinical indication of foscarnet

A

CMV disease in immunosuppressed patients who do not tolerate GCV or whose virus is suspected to be resistant to GCV

63
Q

2 side effects of foscarnet

A
  • Nephrotoxicity
  • Electrolyte abnormalities (calcium, phosphate, potassium)
64
Q

3 types of anti-hepatitis agents

A
  1. Interferon-alpha
  2. Ribavirin
  3. Nucleoside/nucleotide analogues
65
Q

Type of hepatitis covered by IFN-alpha

A
  • HBV
  • HCV
66
Q

Type of hepatitis covered by ribavirin

A

HCV

67
Q

Type of hepatitis covered by nucleoside/nucleotide analogues

A

HBV

68
Q

5 nucleoside/nucleotide analogues to treat hepatitis

A
  1. Lamivudine
  2. Adefovir
  3. Telbivudine
  4. Tenofovir
  5. Entecavir
69
Q

Mechanism of action of IFN-alpha

A

No direct antiviral effect, but antiviral activity occurs via activation of host cells to produce a series of antiviral proteins

70
Q

Method of admnistration of IFN-alpha

A

IM or subcutaneous injection

71
Q

What allows once weekly dosing of IFN-alpha

A

Attachment of large, inert polyethylene glycol (PEG) molecules

72
Q

5 side effects of IFN -alpha

A
  1. Flu-like syndrome
  2. Myelosuppression
  3. Neurotoxicity
  4. Autoimmune disorders (thyroiditis)
  5. Cardiovascular effects
73
Q

3 clinical indications of IFN-alpha

A
  1. Chronic HBV
  2. Acute and chronic HCV
  3. Refractory codylomata accuminata (intralesional)
74
Q

Mechanism of action of ribavirin

A
  1. Phosphorylation by host cell enzymes
  2. Mono and tri-phosphorylated forms inhibit synthesis of GTP
75
Q

3 clinical indications of ribavirin

A
  1. Chronic HCV (po)
  2. RSV, parainfluenza virus (inhaled + or - IV)
    • In severely immunocompromised
  3. Arenavirus hemorrhagic fevers
76
Q

2 side effects of ribavirin

A
  1. Dose-related reversible anemia
  2. Teratogenic
77
Q

Administration of nucleoside/nucleotide inhibitors in chronic Hep B infection

A

Oral

78
Q

Mechanism of nucleoside/nucleotide inhibitors in chronic Hep B infection

A
  1. Require phosphorylation
  2. Inhibit HBV DNA-pol / reverse transcriptase
79
Q

2 viruses with emergent resistance towards nucleoside/nucleotide inhibitors

A

HBV and HIV

80
Q

Indication for nucleotide/nucleoside inhibitors

A

Chronic HBV

81
Q

Antiviral that is a general purine nucleoside analog

A

Ribavirin

82
Q

Pyrophosphate analog

A

Foscarnet

83
Q

Cytidine analog

A

Cidofovir

84
Q

3 guanosine analogs

A
  1. Acyclovir
  2. Penciclovir
  3. Gancyclovir
85
Q

3 antivirals that are prodrugs and the active drug with which they are associated

A
  1. Vancyclovir (acyclovir)
  2. Famiciclovir (penciclovir)
  3. Valgancyclovir (gancyclovir)

Block G -- Infection (23 decks)

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