Dr. Papenburg -- Antiviral Agents Flashcards Preview

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

Flashcards in Dr. Papenburg -- Antiviral Agents Deck (85)
1

4 virus-specific events that antiviral agents must ideally inhibit

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

2

How a therpeutic agent's antiviral effect is measured

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

3

6 stages of viral replication

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

4

2 classes of antivirals against influenza

  • Adamantanes (M2 ion channel inhibitors)
  • Neuraminidase inhibitors

5

2 adamantanes

  • Amantadine
  • Rimantidine

6

2 neuraminidase inhibitors

  • Oseltamivir (Tamiflu)
  • Zanamivir (Relenza)

7

Amantadine function

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

8

Neuraminidase inhibitor function

Inhibit release of virions and promote clumping

9

Target stage of Adamantanes

Uncoating

10

Target stage of neuraminidase inhibitors

Release

11

Flu type covered by adamantanes

Influenza A

12

Flu types covered by NAIs

A and B

13

Administration of adamantanes

Oral

14

Administration of NAIs

Zanamivir = Inhaled

Oseltamivir = Oral

15

Age range for adamantanes

> 1 year old

16

Age range for NAIs

Zanamivir = > or = 7 yo

Oseltamivir = all ages

17

4 side effects of adamantanes

  • Nausea
  • Dizziness
  • Insomnia
  • Anxiety

18

Side effects of NAIs

Zanamivir = Bronchospasm

Oseltamivir = GI

19

Signs of resistance against treatment with adamantanes 

Persistent or recurrent fever in children

20

Type of mutation involved in resistance to adamantanes

Single point mutation of the M2 protein

21

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

No impairment

22

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

Decreased

23

Major problem with adamantanes

Rapid emergence of resistance during treatment

24

5 benefits of oseltamivir therapy

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

25

4 types of people to treat for influenza

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

26

7 types of patients who are an increased risk for complications

  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

27

4 alternatives to oseltamivir

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

28

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

8 types:

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

29

Acyclovir activity for herpesvirus

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

30

Acyclovir bioavailability po

15 - 30%

31

Metabolism of acycolvir (ACV)

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

32

Antivirally active form of ACV

Triphosphate form

33

Triphosphate ACV function

Inhibit viral DNA synthesis by:

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

34

Most common reason for ACV resistance in HSV

Virus deficient in TK

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

35

Most common reason for ACV resistance in VZV

Altered TK (lower affinity for ACV)

36

3 PO uses of ACV

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

37

Topical ACV use

Keratoconjunctivitis

38

5 IV uses of ACV

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

39

2 potential side effects of ACV

Generall well tolerated, but may have:

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

40

Define valacyclovir

Pro-drug of acyclovir

41

Method of administration of valacyclovir and its bioavailability

PO --> 70%

42

Describe the resistance profile of penciclovir/famciclovir

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

43

3 clinical indications for famciclovir

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

44

Gancyclovir activity

In vitro = all herpesviruses

NOTE: 100x more active against CMV than ACV

45

Method of administration of gancyclovir

IV via central venous line

46

Gancyclovir mechanism in CMV infected cells

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

47

Most common cause of GCV resistance in CMV

Mutations in the UL97 gene

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

48

Cross-resistance of GCV in event of UL54 mutation

Cidofovir and foscarnet

49

4 clinical indications for GCV

  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

Combo treatment for CMV pneumonitis

GCV + anti-CMV immunoglobulin

51

4 GCV side effects

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

52

Define valgancyclovir

Oral pro-drug of gancyclovir with 60% bioavailability

53

2 indications for valgancyclovir

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

54

In vitro activity of cidofovir (4)

  1. Herpesviruses
  2. Adenoviruses
  3. Papillomaviruses
  4. Polyomaviruses

55

In vivo activity of cidofovir (2)

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

56

Antiviral that does not depend on viral enzymes for phosphorylation

Cidofovir

57

Clinical indications for cidofovir

CMV disease in

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

58

3 side effects of cidofovir

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

59

Foscarnet activity

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

60

Admniistration of foscarnet

IV

61

Antiviral that does not require any phosphorylation

Foscarnet (direct inhibition of DNA pol)

62

Clinical indication of foscarnet

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

63

2 side effects of foscarnet

  • Nephrotoxicity
  • Electrolyte abnormalities (calcium, phosphate, potassium)

64

3 types of anti-hepatitis agents

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

65

Type of hepatitis covered by IFN-alpha

  • HBV
  • HCV

66

Type of hepatitis covered by ribavirin

HCV

67

Type of hepatitis covered by nucleoside/nucleotide analogues

HBV

68

5 nucleoside/nucleotide analogues to treat hepatitis

  1. Lamivudine
  2. Adefovir
  3. Telbivudine
  4. Tenofovir
  5. Entecavir

69

Mechanism of action of IFN-alpha

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

70

Method of admnistration of IFN-alpha

IM or subcutaneous injection

71

What allows once weekly dosing of IFN-alpha

Attachment of large, inert polyethylene glycol (PEG) molecules

72

5 side effects of IFN -alpha

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

73

3 clinical indications of IFN-alpha

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

74

Mechanism of action of ribavirin

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

75

3 clinical indications of ribavirin

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

76

2 side effects of ribavirin

  1. Dose-related reversible anemia
  2. Teratogenic

77

Administration of nucleoside/nucleotide inhibitors in chronic Hep B infection

Oral

78

Mechanism of nucleoside/nucleotide inhibitors in chronic Hep B infection

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

79

2 viruses with emergent resistance towards nucleoside/nucleotide inhibitors

HBV and HIV

80

Indication for nucleotide/nucleoside inhibitors

Chronic HBV

81

Antiviral that is a general purine nucleoside analog

Ribavirin

82

Pyrophosphate analog

Foscarnet

83

Cytidine analog

Cidofovir

84

3 guanosine analogs

  1. Acyclovir
  2. Penciclovir
  3. Gancyclovir

85

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

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