Pharm - HIV pharmacotherapy part 2 Flashcards
true or false
Efavirenz is an NNRTI that can be used in pregnancy
FALSE
it is an NNRTI but cannot be used in pregnancy
efavirenz is a potent ___ agent
HIV-1
name some AE of efavirenz
CNS psychiatric events (depression, mania, disturbing dreams, insomnia)
hepatotoxicity (increased liver enzymes)
increased cholesterol
rare - SJS
true or false
nevirapine is an NNRTI that can be used in pregnancy
true
AE of nevirapine
rash (if becomes severe, discontinue - can be life threatening)
hepatotoxicity
true or false
nevirapine as an excellent oral PK profile and is also effective in preventing transmission of HIV
true
name a second gen NNRTI
what is an advantage?
etravirine
has better resistance profile
counseling point for etravirine
take with food! better absorption
AE etravirine
serious rash and allergy, elevated triglyceride and cholesterol, IRIS
also DDI because substrate and inducer of CYP3A4 and CYP2C9 AND 2C19 inhibitor
rilpivirine is an NNRTI ONLY for which patients?
treatment naive, 12 and older, greater than 100,000 virus copies/mL
important counseling point for rilpivirine
take with meals, but NOT with antacids, H2 antagonists, or PPIS
AE rilpivirine
rash, depression, hepatotoxicity, fat redistribution, QT prolongation
name an NNRTI that is CONTRAINDICATED with CYP3A4 inducers
doravirine
what is an advantage of doravirine over other NNRTIs
It is less hepatotoxic and has a better lipid profile than the others
which 3 NNRTIS are considered 2nd generation
etravirine
rilipivirine
doravirine
name 3 protease inhibitors
atazanavir
darunavir
ritonavir
explain the MOA of protease inhibitors
prevent the breakdown of polyprotein into smaller proteins which come together to form a new virus
inhibits aspartyl protease.
normally, protease breaks the peptide bond between phenylalanine and proline. but when protease is blocked it can;t do this and protein maturation is affected
protease inhibitors mimic what structure
peptide
true or false
protease inhibitors for HIV have much less affinity for human proteases
TRUE - this is good - prevent side effects
true or false
protease inhibitors are administered alone
FALSE
bc of mutations and resistance - need multiple drugs
some AE of protease inhibitors
dyslipidemia (cushingoid appearance)
cardiac conduction issues (WT prolongation)
hepatotoxicity
DDI concern with protease inhibitors
they are metabolized by CYP3A4 and are substrates of P-gp efflux pump
only PI contraindicated in pregnancy
fosamprenavir + ritonavir
atazanavir counseling point
take with meals. acidic medium is good for absorption
true or false
atazanavir is recommended in pregnancy
TRUE
only one that isnt is the oral solution of fosamprenavir + ritonavir
how is the AE of atazanavir unlike other protease inhibitors?
NO dyslipidemia!!
also hyperbilirubinemia is a concern (jaundice)
darunavir is a protease inhibitor that must be coadministered with ______
ritonavir
AE concern with darunavir
has sulfa group!!!! watch out for hypersensitivity
true or false
darunavir has less frequent dyslipidemia than other protease inhibitors
true
fosamprenavir is a prodrug of _______
amprenavir
what is fosamprenavir administered with
low dose ritonavir
which 2 protease inhibitors have a hypersensitivity concern due to their sulfa group
darunavir
fosamprenavir
WHY is fosamprenavir + low dose ritonavir not given in young children and in pregnancy?
the oral solution has propylene glycol
true or false
ritonavir is recommended in pregnancy
TRUE
alone, it’s fine
which 2 drug levels should be monitored with ritonavir and why
theophylline and digoxin - have narrow TIs and their levels may increase
ritonavir is not given with -___ due to _____
saquinavir
QT prolongation
name an entry inhibitor
maraviroc
name a fusion inhibitor
enfuvirtide
enFU (fusion)
“tide” - peptide
explain the MOA of maraviroc
it’s an entry inhibitor
binds CCR5, preventing it from binding to gp120, which thus prevents fusion and entry of the virus
Just the cd4 receptor attachment is not enough to get in!!!
true or false
maraviroc is an ALLOSTERIC CCR5 receptor antagonist
true
maraviroc can only be given in what type of HIV?
HIV1 and CCR5+
and in combo with other drug(s)
maraviroc should be given with caution in what patients
hepatic compromised and CV issues
2 mechanisms of maraviroc resistance
-mutation in the v3 loop of the gp120 protein
-virus changing to the CXCR4 tropism. maraviroc only works against ccr5
AE of maraviroc
cough, upper resp tract infections, hepatotoxicity, allergic rxns
explain the mechanism of enfuvirtide
fusion inhibitor. it’s a 36 amino acid peptide that blocks the interaction between the gp41 glycoprotein. does this by binding to a hydrophobic groove
this prevents the formation of a 6-HELIX BUNDLE, which is CRITICAL for membrane fusion and viral entry
name 3 clinical-like effects of enfuvirtide
-inhibits infection of cd4 cells
-inhibits cell to cell transmission of hiv
-retains activity against viruses that have become resistant to other classes!!!!
enfuvirtide is mainly given to what patients/
treatment experienced in combo with other retroviral
even if other classes are resistant, this drug isn’t!!!
how is enfuvirtide administered and what is an advantage and disadvantage
SUBQ
advantage - absorbed slowly so dont need to inject a lot (it’s a chronic condition)
disadvantage - more painful. also, if poor circulation, there will be poor absorption
resistance mechanism to enfuvirtide
any cross ressitance?
mutations in gp41
NO cross resistance with other agents
true or false
enfuvirtide is administered orally
FALSE
subq
cannot give oral – it’s a 36 amino acid peptide and we have peptidase in our GI
name an attachment inhibitor
fostemsavir
name a post attachment inhibitor
ibalizumab
true or false
fostemsavir is an attachment inhibitor and is a prodrug
TRUE
prodrug of temsavir
fostemsavir is a _______ attachment inhibitor
gp120-directed
explain the MOA of fostemsavir
metabolized to temsavir in vitro, which directly binds the gp120 subunit in the HIV-1 envelope which inhibits the interaction between the virus and the CD4 receptors, thus preventing ATTACHMENT to the host cell
3 AE fostemsavir
hepatotoxicity
QT prolongation
IRIS
explain MOA ibalizumab
CD4-directed POST-attachment HIV-1 inhibitor
binds CD4 domain 2
prevents binding to CCR5/CXCR4 (coreceptors)
how is ibalizumab administered
IV once every 2 weeks
for treatment experienced pts with MDR HIV-1
AE ibalizumab
rash, IRIS
what does INSTI stand for
integrase strand transfer inhibitors
name 3 INSTIS
dolutegravir
raltegravir
biictegravir
true or false
INSTIS are active against both HIV 1 and HIV 2
true
AE of INSTIS
generally well tolerated - do not affect lipid metabolism
however, rare events of hypersensitivity reactions and rhabdomyolysis
MOA of integrase inhibitors (INSTIs)
normally, integrase would cut host DNA and integrate viral DNA
however, INSTIS bind to HIV integrase and prevent the DNA strand transfer and the viral DNA cannot be integrated and viral protein cannot be produced to make more HIV virus
counseling points dolutegravir
no antacids, laxatives, Fe or Ca supplements - chelation and decreased absorption
which INSTI is NOT affected by CYP3A4
raltegravir
all of the INSTIS have what metabolism
glucuronide formation by UGT1A1
raltegravir should be given with caution with ____
antacids - polyvalent cations can bind them
raltegravir AE
srs hypersensitivity like SJS
same AE as other INSTIS - fat redistribution, etc
AE bictegravir
IRIS, lactic acidosis/hepatomegaly with steatosis, SJS, nephrotoxicity
name a capsid inhibitor
lenaCAPavir
explain MOA lenacapavir
selective inhibitor of HIV-1 capsid function
directly binds between capsid protein (p24) subunits in hexamers
this affects capsid functions such as:
-nuclear uptake of HIV proviral DNA
-virus assembly and release
-capsid core formation
what is cobicistat
a pharmacokinetic enhancer - potent inhibitor of CYP3A4
cobicistat is only used with what class of antiretrovirals for HIV? specifically which 2?
protease inhibitors
atazanavir
darunavir
to increase the systemic exposure of them
which of the following drugs is an INSTI
tenofovir
lopinavir
raltegravir
zidovudine
raltegravir
tenofovir = NRTI
lopinavir = protease inhibitor
zidovudine = NRTI
which of the following is an NRTI
zidovudine
darunavir
raltegravir
maraviroc
zidovudine
darunavir = protease inhibitor
raltegravir = INSTI
maraviroc = attachment/entry inhibitor
fusion inhibitors prevent…
the virus from fusing with the host cell membrane
NNRTIs block reverse transcriptase by…..
DIRECTLY BINDING to reverse transcriptase - causing a structural change
NOT at the enzymatic site - at an allosteric site that induces conformational change
which is a protease inhibitor
efavirenz
ritonavir
tenofovir
enfuvirtide
ritonavir
efavirenz = NNRTI
tenofovir = NRTI
enfuvirtide = fusion inhibitor
which HIV drug is an entry inhibitor that blocks CCR5 co receptor, preventing HIV from entering the hose cell
MARAVIROC
how do protease inhibitors work in treating HIV infection
inhibit the enzyme that cuts viral protein into functional units
which is NOT a prodrug
tenofovir
zidovudine
emtricitabine
efavirenz
efavirenz - an NNRTI
all the others are NRTIS
name a prodrug that needs TWO additional phosphorylation steps
tenofovir
what is a nucleoside analog
a nucleotide without phosphate groups
drug has no direct antiviral effect but increases plasma levels of protease inhibitors by inhibiting CYP3A4. also reduces the daily pill burden
what drug is this
cobicistat
