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Bloc G - Infection > Apr26 M2-Antiviral Agents > Flashcards

Apr26 M2-Antiviral Agents Flashcards

1
Q

viruses targeted by antivirals

A
  • influenza
  • herpes viruses (HSV, CMV, EBV, VZV, HHV8, etc.)
  • hepB and hepC
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2
Q

virus-specific events that antiviral agents inhibit or things they have to do

A
  • viral entry into cell
  • viral exit from cell
  • viral being active in host cell
  • antivirals also exert some immunomodulatory effect
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3
Q

what antivirals do to viruses (end result) and how we measure that

A
  • inhibit viral replication (don’t kill them)

- measure the 50% inhibitory concentration = IC50 (minimum conc to inhibit 50% of the pathogen)

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4
Q

6 steps of viral replication

A
  1. attachment
  2. entry
  3. uncoating
  4. synthesis (1. early proteins 2. nucleic acids 3. late proteins)
  5. assembly
  6. release
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5
Q

premature babies or babies with cardiac congenital anomaly are at risk for what virus + tx for that

A

RSV infection
-give palivizumab (monoclonal Ab binding F surface protein for fusion, which is the antigenic determinant, the epitope that the immune system sees)

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6
Q

most common cause of hospitalization of children in winter time

A

RSV

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7
Q

current state of tx knowledge for RSV

A
  • no vaccine
  • no antiviral
  • only have palivizumab
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8
Q

cornerstone of influenza therapy

A

immunization

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9
Q

limitation of influenza immunization

A

don’t know about effectiveness of vaccine every year. less effective when there’s a drift

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10
Q

antivirals when vaccination didn’t work: why are they particularly useful

A
  • for patients with severe influenza, hospitalized

- for patients at risk of severe disease (have COPD, diabetes, renal failure)

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11
Q

2 classes of influenza antivirals and what they do

A
  1. adamantanes (not used anymore) (amantadine and rimantidine): inhibit the M2 ion channel
  2. neuraminidase inhibitors (oseltamivir =Tamiflu and Zanamivir = Relenza): inhibit the viral neuraminidase
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12
Q

which influenzas have M2 ion channel (adamantanes susceptibility)

A

influenza A only (note: that’s not the H and the N)

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13
Q

2 surface proteins of influenza + main one and its role

A
  • neuraminidases
  • hemagglutinins** (major antigenic determinant = epitope for influenza. role = attachment to epithelial cells of the respiratory tree)
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14
Q

function of hemagglutinin in influenza (note: no drugs act on hemagglutinin)

A
  • binds to receptt beau n sialic acid on cell surfaces for the virus to attach
  • also binds the cell membrane when the virus is about to bud out
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15
Q

function of neuraminidases in influenza

A

cleave the bond formed by hemagglutinins and sialic acid before a virus buds out of a cell so that it can be released

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16
Q

step of viral replication that M2 channel inhibitors block

A

viral internaliation uncoating (adamantanes block that)

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17
Q

step of viral replication that NAi block do

A

release and budding of the virus

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18
Q

influenzas that NAi act on

A

influenzas A and B

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19
Q

why no antiviral resistance developed against NAi

A

the same conserved active site pocket is in all neuraminidases, it’s so important that the viruses can’t mutate that

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20
Q

adamantanes administration, SE and resistance

A
  • po
  • nausea, dizziness, insomnia, anxiety
  • 30% resist in children, 80% in adults
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21
Q

NAi administration, SE and resistance

A
  • zanamivir = inhaled (rarely IV) and SE = bronchospasm
  • oseltamivir (Tamiflu) = po and SE = GI effects
  • very small resistance*
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22
Q

how resistance to adamantanes developed

A
  • point mutation in M2 channel protein

- this point mutation doesn’t impair viral replication, transmission and virulence

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23
Q

are adamantanes still used

A

no, because of resistance

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24
Q

how resistance to oseltamivir (Tamiflu) developed

A
  • oseltamivir binds the viral NA (N) to stop hemagglutinin from binding sialic acid on host cell surface.
  • this binding requires a conformational change of viral NA to accept oseltamivir
  • mutation made viral NA unable to make the conformational change
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25
Q

is a virus that resists oseltamivir also resistant to zanamivir

A

no, zanamivir can bind viral NA without a need for a conformational change

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26
Q

what influenza strains resist and are susceptible to adamantanes and NAi nowadays

A
  • all susceptible to NAi

- all resistant to adamantanes

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27
Q

advantages of oseltamivir therapy for someone with influenza (knowing that influenza usually self-resolves)

A

reduces

  • duration of illness
  • viral shedding
  • Abx use (bacterial complication)
  • duration of hospitalization
  • mortality in hospital
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28
Q

how symptoms in influenza evolve after someone gets infected

A
  • symptoms start 12-24 hrs after infection
  • then they get fever
  • then they present to medical care
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29
Q

time of peak viral replication of influenza in its host and what that means

A
  • peak viral replication (max viral titer in the nasopharynx before treatment) at 2-3 days
  • this corresponds with time time of presentation to medical care, or before that
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30
Q

knowing that you reach max viral replication at 2-3 days after infection and people present at that time, what are the goals of anti-influenza therapy (2)

A
  • treat people early

- treat people with comorbidities

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31
Q

how much is it better to treat influenza earlier (with oseltamivir)

A
  • less symptoms duration

- less chance of ending up in ICU when tx hospitalized pt with influenza

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32
Q

who should be treated with oseltamivir (prompt empiric treatment)

A

suspected or confirmed influenza with

  • illness requiring hospitalizatio
  • progressive, severe or complicated illness
  • at risk for severe disease
  • essential healthcare workers
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33
Q

who are the patients at increased risk for complications and who need oseltamivir for influenza

A
  • chronic medical condition
  • nursing home or long-term care
  • aged 65+
  • healthy and under 2 with severe or progressive disease
  • neuro disorder
  • BMI>40
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34
Q

how prophylaxis with oseltamivir is done

A
  • have an at-risk person in the family of a person who is sick with influenza
  • give the at-risk person oseltamivir 1 dose per day for 10 days
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35
Q

who benefits from late treatment (>48 hrs after infection) of influenza

A

ONLY severe disease, immunocompromised pts

36
Q

list of herpesviruses

A
  • HSV-1 and HSV-2
  • VZV
  • CMV
  • EBV
  • HHV-6
  • HHV-8
37
Q

specific charact of herpesviruses

A

stays with you for life if catch it once (viral DNA)

38
Q

how antivirals for herpesvirus work (what events do they target)

A
  • competitive inhibition of viral DNA polymerase (inhibitation of viral DNA synthesis)
  • incorporation into viral DNA (chain termination)
39
Q

acyclovir (ACV) used for what herpesviruses + what it is exactly

A

HSV mostly
VZV (lower affinity, higher IC50)
acyclovir is a guanosine analog

40
Q

other type of virus ACV (and similar drugs) are used for

A

HIV

41
Q

what happens to ACV in the HSV infected cell

A
  • VIRAL thymidine kinase makes it monophosphorylated
  • HOST cellular enzymes make it di- and tri- phosphorylated ACV.
  • the triphosphorylated form blocks DNA polymerase (chain ending non functional nucleotide)
42
Q

2 ways triphosphate form of ACV inhibits viral DNA synthesis

A
  • competes with dGTP for viral DNA polymerase

- chain termination

43
Q

how HSV gets resistant

A

in prolonged viral replication in immunocompromised pt

-HSV becomes deficient in thymidine kinase

44
Q

how VZV acquires resistant to acyclovir

A

altered TK (lower affinity to acyclovir)

45
Q

when do we use ACV po (backed by evidence or not)

A
  • genital herpes (primary infection or recurrences)
  • oro-labial (labial = lips) herpes (primary or recurrence)
  • primary VZV
46
Q

when do we use ACV IV

A
  • HSV encephalitis
  • neonatal HSV
  • HSV in immunocompromised
  • VZV in immunocompromised
  • prophylaxis after BM transplant
47
Q

ACV side effects

A
  • usually well tolerated
  • neutropenia if prolonged
  • IV = nephrotoxicity
  • if pt has renal failure, NEUROtoxicity
48
Q

pro-drug of ACV that is given and its advantages

A

valacyclovir

  • 70% bioavailability
  • po only
  • becomes ACV on first pass metabolism
49
Q

famciclovir charact

A
  • is the pro-drug of penciclovir
  • guanosine analog and acts like ACV. (is an HSV and VZV drug)
  • 70% bioavailability
50
Q

resistance to famciclovir (penciclovir): how it compares to ACV

A
  • overcomes some of the resistance to acyclovir

- can still find cross resistance to acyclovir and penciclovir

51
Q

3 drugs used for CMV and mechanism of action

A
  • ganciclovir: mono, di and tri phosphorylated, and then blocks viral DNA polymerase
  • cidofovir: di and tri phosph then blocks viral DNA polymerase
  • foscarnet: inhibits DNA polymerase directly
52
Q

gancyclovir type of molecule

A

guanosine analog

53
Q

what molecule performs the first phosphorylation event of gancyclovir in CMV infected cells and what does the 2nd and 3rd phosph

A
  • 1st = viral UL97 phosphotransferase

- 2nd and 3rd = cellular enzymes

54
Q

how gancyclovir is administered

A

central venous line

55
Q

how CMV develops resistance to gancyclovir

A
  • mutations of UL97 gene

- (rarely) if mutates UL54 (DNA pol gene), get also resistant to cidofovir and foscarnet

56
Q

what is the consequence of a longer duration of therapy with gancyclovir

A

a higher chance of developing resistance

57
Q

when is gancyclovir used specifically (when indicated)

A
  • CMV retinitis
  • CMV pneumonitis (with anti-CMV Ig)
  • prophylactic or pre-emptive before HSCT or SOT
  • for congenital CMV
58
Q

GCV SE and problems

A
  • requires central line
  • BM toxicity (neutropenia in 40%, thrombocytopenia in 15-20%)
  • CNS (5%)
  • teratogenic
59
Q

what’s valgancyclovir

A
  • the oral pro-drug of gancyclovir (60% availability). (if don’t want or have central venous line)
  • 60% bioavailability
  • also for CMV retinitis and CMV prophylaxis after SOT
60
Q

cidofovir type of molecule

A

cytidine analog

61
Q

how cidofovir works

A
  • phosphorylated by host enzymes only (di and tri) ***

- inhibits viral DNA polymerase (competitive inhibitor, bc binds it instead of the normal C binding it)

62
Q

ORGANISMS cidofovir is good for (remember was in CMV drugs category) (2 main 1 rare)

A
  • CMV and CMV resistant to GCV (UL97 mutated)
  • TK-deficient (resistant) HSV and VZV
  • (rare) CMV that’s DNA polymerase mutated
63
Q

CLINICAL CONDITIONS cidofovir is good for

A
  • CMV in immunosuppressed who don’t tolerate GCV and foscarnet
  • CMV resistant to GCV and foscarnet
64
Q

SE of cidofovir

A
  • very nephrotoxic (dose-dependent)
  • neutropenia
  • potentially carcinogenic and teratogenic
65
Q

foscarnet type of molecule

A

pyrophosphate analog

66
Q

foscarnet viruses that it targets (remember is in CMV drugs category)

A

ALL herpesviruses (so CMV included). so EBV, VZV, HSV, etc.

67
Q

foscarnet mech of action

A

inhibits DNA pol directly

68
Q

resistant viruses that foscarnet can target

A

like cidofovir:

  • CMV and CMV resistant to GCV (UL97 mutated)
  • TK-deficient (resistant) HSV and VZV
  • (rare) CMV that’s DNA polymerase mutated
69
Q

foscarnet route of administration

A

IV

70
Q

when is foscarnet indicated (used as a drug)

A

CMV in immunosuppressed who don’t tolerate GCV or who have resistant CMV

71
Q

side effects of foscarnet

A
  • nephrotoxicity

- electrolyte abnormalities (Ca, PO4, K)

72
Q

drugs for HCV (done with herpesviruses, hepB and hepC now)

A
  • IFN-a (not used anymore)
  • ribavirin (not used anymore)
  • new drugs targeting site of viral replication
73
Q

drugs for hepB (HBV)

A
  • IFN-a

- nucleoside or nucleotide analogis (end in vir or udine: lamivudine, adefovir, etc.)

74
Q

how IFN-a acts + type of molecule it is

A
  • large glycoprotein

- anti-viral, immunomodulatory, anti-prolif cytokine that activates host cells to produce antiviral proteins

75
Q

how IFN-a given

A

IM or subcu

76
Q

SE of IFN-a

A
  • flu-like syndrome
  • BM suppression
  • neurotoxicity
  • autoimmune disorders like thyroiditis
  • CV effects
77
Q

when is IFN-a indicated

A
  • chronic HBV
  • acute and chronic HCV
  • refractory condolymata accuminata (intralesional) = genital wart from HPV
78
Q

ribavirin mechanism of action and type of molecule

A
  • purine (adenosine and guanosine) nucleoside analog
  • mono, di and tri phosph. the mono and tri phosph forms inhibit SYNTHESIS OF GTP
  • inhibits a lot of DNA and RNA viruses
79
Q

nucleoside and nucleotide inhibitors (analogs) used in what conditions

A
  • chronic hepB infection, following the criteria of a persistent infection
  • HIV
80
Q

how nucleoside and nucleotide inhibitors used in chronic hepB

A

-oral
-analog is phosph in cell
-inhibits the hepB (a DNA virus) DNA polymerase which is a reverse transcriptase
(resistance of hepB and HIV to it exists)

81
Q

end result of hepatitis

A
  • HCC

- cirrhosis

82
Q

side effects of nucleoside nucleotide inhibitors

A

well tolerated

83
Q

some IC events that the new hepatitis C drugs (other than IFN-a and ribovirin) target

A
  • protease inhibitors target proteases that cleave viral prots to make them functional
  • NS5A replication complex inhibitors
  • polymerase (viral RNA synthesis) inhibitors
84
Q

drugs used in HCV now

A
  • NOT ribovarin and IFN-a

- drugs targeting site of viral replication

85
Q

course of hepC drugs now

A

12 weeks (used to be 1 year)

86
Q

who’s at risk for HCV infection

A

marginalized individuals

  • doing IV drugs
  • bloodborne transmission
87
Q

who HCV tx are changing with time

A

becoming more tolerable and have more efficacy

Bloc G - Infection (39 decks)

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