B3.071 - HIV Antivirals Flashcards
what are HIV life cycle drug targets for intervention
Binding and fusion
Reverse transcriptase
Integrase
HIV protease
what does integrase do
clips host cell DNA strand and inserts viral genome
what do early stage targets do
prevent infection of new cells
what is a limitation of early stage targets
they are “one time” targets
what do late target drugs do
prevent production of mature infectious virus, spread of infection in pt and transmission
what drug inhibits binding
maraviroc
what drug inhibits fusion
Enfuvirtide
what drugs inhibit integrase
Raltegravir
Dolutegravir
Elvitegravir
what drugs are nucleoside RT inhibitors
Zidovudine (AZT) Abacavir Tenofovir disoproxil Tenofovir alafenamide Lamivudine Emtricitabine
what are the NNRTIs
Nevirapine Efavirenz Rilpivirine Etravirine Delavirdine
what are metabolism inhbititors
Cobicistat
Ritonavir (also a PI, not clinically used alone)
what are the protease inhibitors
Darunavir Atazanavir Lopinavir Nelfinavir Fosamprenavir Tipranivir Indinavir Saquinavir
what does maraviroc do
chemokine receptor CCR5 antagonist, prevents CCR5:gp120 interaction
what is a tropism assay
test to see if virus uses CCR5 or CXCR4, need to know before giving drug
how is maraviroc given and how is it metabolized
oral;CYP3A4 and MDR1 (pgp) substrate
AEs of maraviroc
cough, muscle pain, diarrhea
Possible severe hepatotoxicity may be preceded by systemic allergic response (black box warning)
what is Enfuvirtide and what does it do
Fusion Inhibitor
Binds to gp41 of HIV-1 envelope, prevents fusion of viral and host cell membranes
what are AEs of Enfuvirtide
most have injection site rxns, nodules and cysts are really common >80%
how is Enfuvirtide given and what is the half life
Subcutaneous, 4 hours
How does Zidovudine work
Thymidine analog that is a competitive substrate for/inhibitor of IHV reverse trancriptase
Inhibits initial replicaiton, stable infection of new cells
Zidovudine pharmacokinetics
well absorbed from GI, widely distributed including CNS (~60% of serum level), rapidly metabolized and excreted
half life of zidovudine
1-3 hours in plasma, intracellularly 3-7 hours
what is zidovudine used for
reduce mother to newborn transmission
Fixed dose combination with lamivudine
how does resistance to zidovudine arise
mutations in RT
what are AEs of zidovudine
common
Bone marrow depression
CNS - headaches, agitation, insomnia
Toxicity enhanced by drugs that compete for glucuronidation
what does abacavir do
Guanosine analog and chain terminator
resistance to abacavir
develops slowly, requires 2-3 concomitant mutations
how is abacavir metabolized
alcohol dehydrogenase
AEs of abacavir
skin rash, hypersensitivity, can be fatal
what do you need to do before administering abacavir and why
HLA testing
HLA*B5701 allele is predictive marker, but ~50% do no react
tenofovir disoproxil and alafenamide what is it and how does it work
after absorption its hydrolized to Acyclic nucleoside phosphonate, a chain terminator. NRTI
What is the difference between tenofovir disoproxil and alafenamide
alafenamide has less renal toxicity and bone density loss compared to disoproxil
describe the dosing of tenofovir
once daily, renal excretion
what are AEs of tenofovir in disoproxil/alafenamide
GI effects - nausea, vomiting, diarrhea
Disoproxil - acute/cumulateive renal toxicity
what is tenofovir often combined with
emtricitabine
what can be used as HIV prophylaxis
tenofovir
what does lamivudine do
cytosine analog, inhibits HIV RT and HBV DNA polymerase
how is lamivudine administered/excreted
oral, excreted unchanged in urine
half life of lamivudine
serum - 2.5 hr
cellular - 10-15 hr
what is the recommended use fo lamivudine (3TC)
pregnant women
what is emtricitabine (FTC)
fluorinated analog of lamivudine
how is embtricitabine administered
fixed dose combo with tenovir, once daily dosing
AEs of emtricitabine
headaches, nausea, rash
what does nevirapine do
first generation oral NNRTI
non competitive RT inhibitors, binds near but not in active site
what is nevirapine used for
rapid resistance so only approved for combination with nucleoside analogs
what is the exception for nevirapine being used only in combination
one dose to mother and neonate
what are AEs of nevirapine
skin rash, can be severe
hepatotoxicity
excellent substrate for CYP3A
what does efavirenz do
non competitive RT inhibitors, binds near but not in active site
describe the half life of efavirenz
40-60 hr half life; once daily dosing
Bioavailability 45%
how should patients take efavirenz
on a empty stomach bc while bioavailability is increased by fat it may increase toxicity
AEs of efavirenz
inducer and inhibitor of CYP3A4 so drug drug interactions
CNS effects, dizziness, drowsiness, headache, nightmares
why is efavirenz bumped to second line for use
CNS effects can be severe
what is raltegravir
INSTI
how is raltegravir taken
orally, not with cations or buffered drugs, twice daily
how is raltegravir metabolized
by UGT1A1
adverse effects of raltegravir
diarrhea, nausea, headache, dizziness, metabolic effects
how is dolutegravir administered
oral, not with cations or buffered drugs
how does dolutegravir work
integrase inhibitor
half life of dolutegravir and how its eliminated
14 hour half life by glucuronidation (UGT1A1)
AEs of dolutegravir
insomnia, headache, hypersensitivity
how do protease inhibitors work
HIV proteins must be translated as polyproteins, they have to be cleaved to yield active individual proteins. These drugs prevent mature viral particle production
HIV protease is what type of protease
aspartyl protease
AEs of protease inhibitors
diarrhea, nausea, lipodystrophy, insulin resistance
saquinovir downsides
first HIV protease inhibitor
Extensive first pass effect and many drug drug interactions (CYP3A4)
indinavir is metabolized by
CYP3A4
AEs of indinavir
hyperbilirubinemia, nephrolthiasis* (crystallizes in urine)
ritonavir metabolized by what
CYP3A4 and some 2D6
what are AEs of Ritonavir
potent CYP3A4 inhibitor
initial nausea, vomiting, diarrhea, GI, parathesias, headache
darunavir is often combined with what
Ritonavir
what does the ritonavir do in the darunavir combo
blocks CYP3A protecting darunavir and allowing its effect to persist longer
AEs of darunavir
GI, headache, rash
what other drug may be combined with darunavir
cobicistat
what does atazanavir do
protease inhibitor
how is atazanavir dosed and metabolized
once daily dosing, enters CNS, biliary excretion
what enzymes does Atazanavir inbibit
UGT1A1, CYP3A4, CYP2C9
AEs of atazanavir
diarrhea, nausea, vomiting, headache
hyerbilirubinemia
what is atazanavir not associated with AEwise that is important
No dyslipidemia, fat redistribution, metabolic syndrome
cobicistat is used for
not an antiviral, used in fixed combinations for boosting of accompanied antiviral drug
what does cobicistat inhibit and what does that do
CYP3A, decreases first pass clearance of protease inhibitors, integrase inhibitors
when should you not use cobicistat
if creatinine clearance <30
what does ART stand for
Anti-retroviral therapy
why do all ART regimens include RTIs
to prevent resistance, preventing mutations from sloppy reverse transcriptase
which drugs are substrates for CYP3A4
delavirdine, efavirenz, nevirapine, all protease inbhibitors
what drugs are inducers of CYP3A4 in other tissues
efavirenz, nevirapine, amprenavir
what drugs are inhibitors of CYP3A4
delavirdine, efavirenz, all protease inhibitors especially ritanovir
