Apr26 M2-Antiviral Agents Flashcards
viruses targeted by antivirals
- influenza
- herpes viruses (HSV, CMV, EBV, VZV, HHV8, etc.)
- hepB and hepC
virus-specific events that antiviral agents inhibit or things they have to do
- viral entry into cell
- viral exit from cell
- viral being active in host cell
- antivirals also exert some immunomodulatory effect
what antivirals do to viruses (end result) and how we measure that
- inhibit viral replication (don’t kill them)
- measure the 50% inhibitory concentration = IC50 (minimum conc to inhibit 50% of the pathogen)
6 steps of viral replication
- attachment
- entry
- uncoating
- synthesis (1. early proteins 2. nucleic acids 3. late proteins)
- assembly
- release
premature babies or babies with cardiac congenital anomaly are at risk for what virus + tx for that
RSV infection
-give palivizumab (monoclonal Ab binding F surface protein for fusion, which is the antigenic determinant, the epitope that the immune system sees)
most common cause of hospitalization of children in winter time
RSV
current state of tx knowledge for RSV
- no vaccine
- no antiviral
- only have palivizumab
cornerstone of influenza therapy
immunization
limitation of influenza immunization
don’t know about effectiveness of vaccine every year. less effective when there’s a drift
antivirals when vaccination didn’t work: why are they particularly useful
- for patients with severe influenza, hospitalized
- for patients at risk of severe disease (have COPD, diabetes, renal failure)
2 classes of influenza antivirals and what they do
- adamantanes (not used anymore) (amantadine and rimantidine): inhibit the M2 ion channel
- neuraminidase inhibitors (oseltamivir =Tamiflu and Zanamivir = Relenza): inhibit the viral neuraminidase
which influenzas have M2 ion channel (adamantanes susceptibility)
influenza A only (note: that’s not the H and the N)
2 surface proteins of influenza + main one and its role
- neuraminidases
- hemagglutinins** (major antigenic determinant = epitope for influenza. role = attachment to epithelial cells of the respiratory tree)
function of hemagglutinin in influenza (note: no drugs act on hemagglutinin)
- 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
function of neuraminidases in influenza
cleave the bond formed by hemagglutinins and sialic acid before a virus buds out of a cell so that it can be released
step of viral replication that M2 channel inhibitors block
viral internaliation uncoating (adamantanes block that)
step of viral replication that NAi block do
release and budding of the virus
influenzas that NAi act on
influenzas A and B
why no antiviral resistance developed against NAi
the same conserved active site pocket is in all neuraminidases, it’s so important that the viruses can’t mutate that
adamantanes administration, SE and resistance
- po
- nausea, dizziness, insomnia, anxiety
- 30% resist in children, 80% in adults
NAi administration, SE and resistance
- zanamivir = inhaled (rarely IV) and SE = bronchospasm
- oseltamivir (Tamiflu) = po and SE = GI effects
- very small resistance*
how resistance to adamantanes developed
- point mutation in M2 channel protein
- this point mutation doesn’t impair viral replication, transmission and virulence
are adamantanes still used
no, because of resistance
how resistance to oseltamivir (Tamiflu) developed
- 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
is a virus that resists oseltamivir also resistant to zanamivir
no, zanamivir can bind viral NA without a need for a conformational change
what influenza strains resist and are susceptible to adamantanes and NAi nowadays
- all susceptible to NAi
- all resistant to adamantanes
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
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
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
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
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
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
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
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
who benefits from late treatment (>48 hrs after infection) of influenza
ONLY severe disease, immunocompromised pts
list of herpesviruses
- HSV-1 and HSV-2
- VZV
- CMV
- EBV
- HHV-6
- HHV-8
specific charact of herpesviruses
stays with you for life if catch it once (viral DNA)
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)
acyclovir (ACV) used for what herpesviruses + what it is exactly
HSV mostly
VZV (lower affinity, higher IC50)
acyclovir is a guanosine analog
other type of virus ACV (and similar drugs) are used for
HIV
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)
2 ways triphosphate form of ACV inhibits viral DNA synthesis
- competes with dGTP for viral DNA polymerase
- chain termination
how HSV gets resistant
in prolonged viral replication in immunocompromised pt
-HSV becomes deficient in thymidine kinase
how VZV acquires resistant to acyclovir
altered TK (lower affinity to acyclovir)
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
when do we use ACV IV
- HSV encephalitis
- neonatal HSV
- HSV in immunocompromised
- VZV in immunocompromised
- prophylaxis after BM transplant
ACV side effects
- usually well tolerated
- neutropenia if prolonged
- IV = nephrotoxicity
- if pt has renal failure, NEUROtoxicity
pro-drug of ACV that is given and its advantages
valacyclovir
- 70% bioavailability
- po only
- becomes ACV on first pass metabolism
famciclovir charact
- is the pro-drug of penciclovir
- guanosine analog and acts like ACV. (is an HSV and VZV drug)
- 70% bioavailability
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
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
gancyclovir type of molecule
guanosine analog
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
how gancyclovir is administered
central venous line
how CMV develops resistance to gancyclovir
- mutations of UL97 gene
- (rarely) if mutates UL54 (DNA pol gene), get also resistant to cidofovir and foscarnet
what is the consequence of a longer duration of therapy with gancyclovir
a higher chance of developing resistance
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
GCV SE and problems
- requires central line
- BM toxicity (neutropenia in 40%, thrombocytopenia in 15-20%)
- CNS (5%)
- teratogenic
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
cidofovir type of molecule
cytidine analog
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)
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
CLINICAL CONDITIONS cidofovir is good for
- CMV in immunosuppressed who don’t tolerate GCV and foscarnet
- CMV resistant to GCV and foscarnet
SE of cidofovir
- very nephrotoxic (dose-dependent)
- neutropenia
- potentially carcinogenic and teratogenic
foscarnet type of molecule
pyrophosphate analog
foscarnet viruses that it targets (remember is in CMV drugs category)
ALL herpesviruses (so CMV included). so EBV, VZV, HSV, etc.
foscarnet mech of action
inhibits DNA pol directly
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
foscarnet route of administration
IV
when is foscarnet indicated (used as a drug)
CMV in immunosuppressed who don’t tolerate GCV or who have resistant CMV
side effects of foscarnet
- nephrotoxicity
- electrolyte abnormalities (Ca, PO4, K)
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
drugs for hepB (HBV)
- IFN-a
- nucleoside or nucleotide analogis (end in vir or udine: lamivudine, adefovir, etc.)
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
how IFN-a given
IM or subcu
SE of IFN-a
- flu-like syndrome
- BM suppression
- neurotoxicity
- autoimmune disorders like thyroiditis
- CV effects
when is IFN-a indicated
- chronic HBV
- acute and chronic HCV
- refractory condolymata accuminata (intralesional) = genital wart from HPV
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
nucleoside and nucleotide inhibitors (analogs) used in what conditions
- chronic hepB infection, following the criteria of a persistent infection
- HIV
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)
end result of hepatitis
- HCC
- cirrhosis
side effects of nucleoside nucleotide inhibitors
well tolerated
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
drugs used in HCV now
- NOT ribovarin and IFN-a
- drugs targeting site of viral replication
course of hepC drugs now
12 weeks (used to be 1 year)
who’s at risk for HCV infection
marginalized individuals
- doing IV drugs
- bloodborne transmission
who HCV tx are changing with time
becoming more tolerable and have more efficacy
