Pharm - Antiviral Drugs Part 2 Flashcards
another name for viral thymidine kinase
viral UL97
ganciclovir is a ___ ___ analog
acyclic guanosine
does ganiciclovir need the viral enzyme?
yes
needed for the initial monophosphorylation
ganciclovir has 100x greater affinity for ___ than acyclovir
CMV
2 resistance mechanisms for ganciclovir
- mutation in UL97 kinase
- mutation in UL54 (viral DNA polymerase)
3 main AE of ganciclovir
which 2 are rare
rare - CNS and hepatotoxicity
MYELOSUPPRESSION - dose-dependent toxicity
true or false
UL54 mutation gives cross resistance with other drugs
TRUE
this affects the viral DNA polymerase
prodrug of ganciclovir
valgancyclovir
true or false
foscarnet is a nucleotide
FALSE
does not have a base, but DOES have phosphate and bypasses first step with viral thymidine kinase
chemically, foscarnet is…..
phosphonoformic acid
structurally, what does foscarnet mimic
inorganic pyrophosphate
which viruses can foscarnet inhibit and how
BOTH HSV and HIV!!!!
-inhibits herpes DNA and RNA polymerase
-inhibits HIV reverse transcriptase
does so by BLOCKING THE PYROPHOSPHATE BINDING SITE ON THE VIRAL DNA POLYMERASE
true or false
foscarnet is a prodrug
true
how is foscarnet administered and why
ONLY IV
it is small, but too polar for oral use - not good bioavailability
where is foscarnet deposited?
does it distribute well in CSF?
deposits in bones and distributed well in the CSF
name 2 things that foscarnet can be used for
-end organ CMV that is ganciclovir resistant
-HSV and VZV when acyclovir resistant
bc both ganciclovir and acyclovir need the 1st step and it’s mutated, but foscarnet does not!!!
resistance mechanism for foscarnet
point mutations in viral DNA polymerase
(happens with chronic administration)
if HIV - mutations in reverse transcriptase
true or false
resistance to acyclovir also means resistance to foscarnet, but not vice versa
FALSE - other way around
foscarnet CAN be used for acyclovir resistance bc it bypasses 1st step
however, if there is resistance to foscarnet that means there is mutations in DNA polymerase and acyclovir cannot work either
2 AE of foscarnet
nephrotoxicity
Ca2+ and K+ alterations
foscarnet is contraindicated with what drugs and why
other nephrotixic drugs like amphotericin B and aminoglycosides
too much nephrotoxicity
Cidofovir is a ____ analog
cytosine
does cidofovir need viral thymidine kinase?
NO
cidoFOvir
has a phosphate group already
true or false
cidofovir IS active against thymidine kinase mutants
TRUE
does not need 1st step - already a monophosphate
true or false
cidovofir has broad activity against a lot of viruses
true
AE cidoofovir
nephrotoxic
major treatment in which cidofovir is used
CMV retinitis
when an antiviral is converted into triphosphate, what does this allow the drug to do
competitively inhibit viral DNA polymerase and stop viral DNA synthesis OR incorporate into viral DNA chain and cause chain termination
another name for spanish flu
avian flu
in flu viruses, where do the periodic mutations occur?
in neuraminidase and hemagglutin
ie - H1N1 for spanish flu
pandemic vs epidemic vs endemic
endemic - restricted to particular region
epidemic - new cases appear in a given population during a given period, at a rate that exceeds what is “expected” based on epidemiology
pandemic - outbreak of infectious disease that has spread throughout a very large region or even globally
influenza is what kind of virus
orthomyxovirus
RNA (negative sense)
single strand
helical and enveloped
the core proteins for influenza can be…..
A B or C
what 2 species can influenza be
swine or avian
how many H and N subtypes for influenza
16 H
9N
2009 swine flu pandemic had what surface proteins
H1N1 (similar to 1918 spanish flu
explain antigenic drift for influenza virus
the antibodies to hemagglutinin bind to it and block the virus from binding to the host cell
HOWEVER, antigenic drift occurs when mutations ALTER hemagglutinin and the neutralizing antibody can no longer bind to it
virus can now bind the host cell and infect it
explain anitgenic SHIFT
when an avian and human virus come together, they undergo recombination to produce NEW GENETIC SEGMENTS
leads to new viruses and potential pandemic
do avian viruses directly infect humans
NO - very rare
avians have a2-3 subtypes and humans have a2-6
only swines can infect humans ( havea2-6)
what is the function of M2
ion channel that is required for uncoating – open the envelope and allow the nucleic acid to go into the nucleus of the host cell
function HA (hemagglutinin)
allows for viral attachment to host cell membranes and membrane fusion
function NA (neuraminidase)
cleaves sialic acid on the surface of host cells, allowing for new viruses to be released
prevents aggregation of the new viruses
what is PA and what is proposed function
acidic polymerase
function is unknown
just by looking at the name, how can you tell if something is a neuraminidase inhibitor
“mivir”
name 3 neuraminidase inhibitors
oseltamivir
zanamivir
peramivir
all 3 NA inhibitors are analogs of what?
sialic acid
explain how viruses are able to leave the host cell and reinfect others (without an NA inhibitor)
mucin forms a barrier for microbes in the respiratory tract. however, mucin is rich in sialic acid, and viral neuraminidase REMOVES THIS SIALIC ACID which helps the virus to penetrate the mucin and leave the cell to reinfect others
“the snipper”
neuraminidase – removes sialic acid
true or false
oseltamivir is a sialic acid analog
true
what does oseltamivir inhibit
neuraminidase
HOW does oseltamivir inhibit neuraminidase (ie - irreversible/reversible competitive/noncompetitive)
reversible and competitive
(structurally mimics sialic acid)
as mentioned, oseltamivir is an NA inhibitor
how does this prevent new viral release?
the virus will be trapped on the membrane, and all the new viruses will aggregate and can’t get released from the infected cell and reinfect others
oseltamivir resistance
mutations in hemagglutinin or neuraminidase
true or false
oseltamivir is only active vs influenza A
FALSE
influenza a and b
oseltamivir is active against _____ resistant influenza
amantadine
WHEN must oseltamivir be administered and why
within 48 hours of onset
will not work if you give too late because the new viruses have already been released and are infecting other cells
how long is oseltamivir given and why?
how is it good vs the flu
5 days - want to make sure cover the entire viral cycle
decreases influenza symptoms, shedding, transmission, and complications
**interaction between oseltamivir and probenecid
probenecid will increase the plasma half life of oseltamivir
counseling point for oseltamivir
take with food to decrease unwanted GI side effecys
any side effects oseltamavir?
not really significant
NVD, fatique
in japan neuropsych events were reported
zanamivir mechanism and route of administration
inhalation
same MOA as oseltamavir - NA inhibitor
of the 3 NA inhibitors, which is considered the “best” route of administration for treating the flu?
inhalation (zanamivir) because it’s a respiratory virus
zanamivir has 1000x IC50 values for NA
also, gives fast onset and avoids 1st pass
what is peramivir and how is it administered
a neuraminidase inhibitor for flu
given by IV infusion for min of 15 minutes
explain what type of patient would be indicated to receive peramivir
18 years and older who have acute uncomplicated influenza who have been symptomatic for NO MORE THAN 2 days (same as other NA inhibitors)
amantadine and rimantidine mechanism
binds and blocks viral M2 channel (which normally is open to allow the influx of H ions into the vesicle with the virus). this prevents the uncoating of the virus. and release from the endosome and into the extracellular matrix to infect other cells
true or false
amantadine/rimantadine are ONLY active against influenza A
true
which is more active - rimantadine or amantadine
rimantadine
compare the t1/2 of amantadine/rimantadine with other anti influenza drugs
a lot longer than others
like 12-36 hours
some major disadvantages of amantadine/rimantadine (not really used anymore)
VERY HIGH RESISTANCE PROFILE
lot of AE like GI effects, CNS effects (bc small molecules - nervousness, insomnia, affects dopamine system, deliruym, seizure, etc)
also CONTRAINDICATED IN PREGNANT WOMEN
true or false
amantadine cannot be given to a pregnant person
true
name of the anti influenza drug that is not an NA inhibitor or M2 channel blocker
baloxavir
true or false
baloxavir is not a prodrug
FALSE - it is
baloxavir marboxil is converted by hydrolysis to baloxavir
how is baloxavir administered and what is its mechanism??
SINGLE DOSE TREATMENT
it inhibits the endonuclease activity of the polymerase acidic protein, which is an enzyme that’s part of viral RNA polymerase.
thus, inhibits viral gene transcription and hence inhibits the replication of new influenza virus
baloxavir resistance
amino acid substitutions in the PA (polymerase acidic) protein
counseling point for baloxavir
DO NOT GIVE WITH MILK OR ANTACIDS!! absorption prevented bc of diketo acid
also, metabolized by CYP3A4 so potentil DDI
dosage form baloxavir and what age is it indicated for
oral tablets
12 years or older
