Apr26 M2-Antiviral Agents Flashcards
(87 cards)
1
Q
viruses targeted by antivirals
A
- influenza
- herpes viruses (HSV, CMV, EBV, VZV, HHV8, etc.)
- hepB and hepC
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
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)
4
Q
6 steps of viral replication
A
- attachment
- entry
- uncoating
- synthesis (1. early proteins 2. nucleic acids 3. late proteins)
- assembly
- release
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)
6
Q
most common cause of hospitalization of children in winter time
A
RSV
7
Q
current state of tx knowledge for RSV
A
- no vaccine
- no antiviral
- only have palivizumab
8
Q
cornerstone of influenza therapy
A
immunization
9
Q
limitation of influenza immunization
A
don’t know about effectiveness of vaccine every year. less effective when there’s a drift
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)
11
Q
2 classes of influenza antivirals and what they do
A
- adamantanes (not used anymore) (amantadine and rimantidine): inhibit the M2 ion channel
- neuraminidase inhibitors (oseltamivir =Tamiflu and Zanamivir = Relenza): inhibit the viral neuraminidase
12
Q
which influenzas have M2 ion channel (adamantanes susceptibility)
A
influenza A only (note: that’s not the H and the N)
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)
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
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
16
Q
step of viral replication that M2 channel inhibitors block
A
viral internaliation uncoating (adamantanes block that)
17
Q
step of viral replication that NAi block do
A
release and budding of the virus
18
Q
influenzas that NAi act on
A
influenzas A and B
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
20
Q
adamantanes administration, SE and resistance
A
- po
- nausea, dizziness, insomnia, anxiety
- 30% resist in children, 80% in adults
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*
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
23
Q
are adamantanes still used
A
no, because of resistance
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
25
is a virus that resists oseltamivir also resistant to zanamivir
no, zanamivir can bind viral NA without a need for a conformational change
26
what influenza strains resist and are susceptible to adamantanes and NAi nowadays
- all susceptible to NAi
| - all resistant to adamantanes
27
advantages of oseltamivir therapy for someone with influenza (knowing that influenza usually self-resolves)
reduces
- duration of illness
- viral shedding
- Abx use (bacterial complication)
- duration of hospitalization
- mortality in hospital
28
how symptoms in influenza evolve after someone gets infected
- symptoms start 12-24 hrs after infection
- then they get fever
- then they present to medical care
29
time of peak viral replication of influenza in its host and what that means
- 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
30
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)
- treat people early
| - treat people with comorbidities
31
how much is it better to treat influenza earlier (with oseltamivir)
- less symptoms duration
| - less chance of ending up in ICU when tx hospitalized pt with influenza
32
who should be treated with oseltamivir (prompt empiric treatment)
suspected or confirmed influenza with
- illness requiring hospitalizatio
- progressive, severe or complicated illness
- at risk for severe disease
- essential healthcare workers
33
who are the patients at increased risk for complications and who need oseltamivir for influenza
- chronic medical condition
- nursing home or long-term care
- aged 65+
- healthy and under 2 with severe or progressive disease
- neuro disorder
- BMI>40
34
how prophylaxis with oseltamivir is done
- 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
35
who benefits from late treatment (>48 hrs after infection) of influenza
ONLY severe disease, immunocompromised pts
36
list of herpesviruses
- HSV-1 and HSV-2
- VZV
- CMV
- EBV
- HHV-6
- HHV-8
37
specific charact of herpesviruses
stays with you for life if catch it once (viral DNA)
38
how antivirals for herpesvirus work (what events do they target)
- competitive inhibition of viral DNA polymerase (inhibitation of viral DNA synthesis)
- incorporation into viral DNA (chain termination)
39
acyclovir (ACV) used for what herpesviruses + what it is exactly
HSV mostly
VZV (lower affinity, higher IC50)
*acyclovir is a guanosine analog*
40
other type of virus ACV (and similar drugs) are used for
HIV
41
what happens to ACV in the HSV infected cell
- 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
2 ways triphosphate form of ACV inhibits viral DNA synthesis
- competes with dGTP for viral DNA polymerase
| - chain termination
43
how HSV gets resistant
in prolonged viral replication in immunocompromised pt
| -HSV becomes deficient in thymidine kinase
44
how VZV acquires resistant to acyclovir
altered TK (lower affinity to acyclovir)
45
when do we use ACV po (backed by evidence or not)
- genital herpes (primary infection or recurrences)
- oro-labial (labial = lips) herpes (primary or recurrence)
- primary VZV
46
when do we use ACV IV
- HSV encephalitis
- neonatal HSV
- HSV in immunocompromised
- VZV in immunocompromised
- prophylaxis after BM transplant
47
ACV side effects
- usually well tolerated
- neutropenia if prolonged
- IV = nephrotoxicity
- if pt has renal failure, NEUROtoxicity
48
pro-drug of ACV that is given and its advantages
valacyclovir
- 70% bioavailability
- po only
- becomes ACV on first pass metabolism
49
famciclovir charact
- is the pro-drug of penciclovir
- guanosine analog and acts like ACV. (is an HSV and VZV drug)
- 70% bioavailability
50
resistance to famciclovir (penciclovir): how it compares to ACV
- overcomes some of the resistance to acyclovir
| - can still find cross resistance to acyclovir and penciclovir
51
3 drugs used for CMV and mechanism of action
- 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
gancyclovir type of molecule
guanosine analog
53
what molecule performs the first phosphorylation event of gancyclovir in CMV infected cells and what does the 2nd and 3rd phosph
- 1st = viral UL97 phosphotransferase
| - 2nd and 3rd = cellular enzymes
54
how gancyclovir is administered
central venous line
55
how CMV develops resistance to gancyclovir
- mutations of UL97 gene
| - (rarely) if mutates UL54 (DNA pol gene), get also resistant to cidofovir and foscarnet
56
what is the consequence of a longer duration of therapy with gancyclovir
a higher chance of developing resistance
57
when is gancyclovir used specifically (when indicated)
- CMV retinitis
- CMV pneumonitis (with anti-CMV Ig)
- prophylactic or pre-emptive before HSCT or SOT
- for congenital CMV
58
GCV SE and problems
- requires central line
- BM toxicity (neutropenia in 40%, thrombocytopenia in 15-20%)
- CNS (5%)
- teratogenic
59
what's valgancyclovir
- 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
cidofovir type of molecule
cytidine analog
61
how cidofovir works
- 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
ORGANISMS cidofovir is good for (remember was in CMV drugs category) (2 main 1 rare)
- CMV and CMV resistant to GCV (UL97 mutated)
- TK-deficient (resistant) HSV and VZV
- (rare) CMV that's DNA polymerase mutated
63
CLINICAL CONDITIONS cidofovir is good for
- CMV in immunosuppressed who don't tolerate GCV and foscarnet
- CMV resistant to GCV and foscarnet
64
SE of cidofovir
- very nephrotoxic (dose-dependent)
- neutropenia
- potentially carcinogenic and teratogenic
65
foscarnet type of molecule
pyrophosphate analog
66
foscarnet viruses that it targets (remember is in CMV drugs category)
ALL herpesviruses (so CMV included). so EBV, VZV, HSV, etc.
67
foscarnet mech of action
inhibits DNA pol directly
68
resistant viruses that foscarnet can target
like cidofovir:
- CMV and CMV resistant to GCV (UL97 mutated)
- TK-deficient (resistant) HSV and VZV
- (rare) CMV that's DNA polymerase mutated
69
foscarnet route of administration
IV
70
when is foscarnet indicated (used as a drug)
CMV in immunosuppressed who don't tolerate GCV or who have resistant CMV
71
side effects of foscarnet
- nephrotoxicity
| - electrolyte abnormalities (Ca, PO4, K)
72
drugs for HCV (done with herpesviruses, hepB and hepC now)
- IFN-a (not used anymore)
- ribavirin (not used anymore)
- new drugs targeting site of viral replication
73
drugs for hepB (HBV)
- IFN-a
| - nucleoside or nucleotide analogis (end in vir or udine: lamivudine, adefovir, etc.)
74
how IFN-a acts + type of molecule it is
- large glycoprotein
| - anti-viral, immunomodulatory, anti-prolif cytokine that activates host cells to produce antiviral proteins
75
how IFN-a given
IM or subcu
76
SE of IFN-a
- flu-like syndrome
- BM suppression
- neurotoxicity
- autoimmune disorders like thyroiditis
- CV effects
77
when is IFN-a indicated
- chronic HBV
- acute and chronic HCV
- refractory condolymata accuminata (intralesional) = genital wart from HPV
78
ribavirin mechanism of action and type of molecule
- 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
nucleoside and nucleotide inhibitors (analogs) used in what conditions
- chronic hepB infection, following the criteria of a persistent infection
- HIV
80
how nucleoside and nucleotide inhibitors used in chronic hepB
-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
end result of hepatitis
- HCC
| - cirrhosis
82
side effects of nucleoside nucleotide inhibitors
well tolerated
83
some IC events that the new hepatitis C drugs (other than IFN-a and ribovirin) target
- protease inhibitors target proteases that cleave viral prots to make them functional
- NS5A replication complex inhibitors
- polymerase (viral RNA synthesis) inhibitors
84
drugs used in HCV now
- NOT ribovarin and IFN-a
| - drugs targeting site of viral replication
85
course of hepC drugs now
12 weeks (used to be 1 year)
86
who's at risk for HCV infection
marginalized individuals
- doing IV drugs
- bloodborne transmission
87
who HCV tx are changing with time
becoming more tolerable and have more efficacy
