EXAM 4 antivirals 2 HIV Flashcards
What are the activities of reverse transcriptase
RNA dependent DNA polymerase: Copies plus-strand RNA to produce minus-strand DNA
Ribonuclease H: Degrades RNA template from RNA-DNA hybrid
DNA dependent DNA polymerase: Synthesizes plus-strand DNA from minus-strand DNA
what is the MOA of Nucleoside Reverse Transcriptase Inhibitors (NRTI)?
Competitive inhibitor of reverse transcriptase by competing with endogenous
dATP, dCTP, dGTP, and dTTP
Higher afinity for HIV RT compared to cellular RT
what must be triphosphorylated?
CELLULAR KINASES
on NRTIs
Nucleoside Reverse Transcriptase Inhibitors (NRTI) drugs
Tenofovir
Tenofovir alafenamide
Emtricitabine
Lamivudine
Abacavir
what are the side effects of NRTIs
mitochondrial toxicity
- anemia, myopathy, pancreatitis, lactic acidosis, lipoatrophy
abacavir hypersenstivity reaction (BBW)
D/C immediately
highly assoicated with HLA-B*5701 allele
Testing for allele is needed before treatment
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI)
MOA?
Bind directly to site on reverse transcriptase at the hydrophobic pocket that
alters the flexibility of the enzyme to inhibit RNA & DNA-dependent
polymerase activities
blocks polymerization
do NOT compete with nucleotides
what are the first gen NNRTIs?
nevirapine
efavirenz
delavirdine
potentially teratogenic
what are the second gen NNRTIs?
Etravirine
Rilpivirine
NNRTIs side effects
All: rash and drug-drug interactions
Nevirapine: hepatotoxicity, SJS
Efavirenz: neuropsychiatric, teratogenic
NNRTIs drug-drug interactions
Metabolized by CYP3A4
Nevirapine, efavirenz, etravirine = inducers
Efavirenz, delavirdine = inhibitors
Etravirine = CYP2C9 & CYP2C19 inhibitor
NNRTIs resistance
1 mutation in binding site can lead to resistance
integrase inhibitors MOA
Inhibits insertion of HIV DNA into the human genome
Integrase inhibitors contain a metal-chelating pahramacophore than binds to the active site of the enzyme
Normal:
3’ processing
Strand transfer –> integrase inhibitors inhibit this
3 amino acids in active site chelates both metal ions and
stabilizes complex
Integrase inhibitor agents
Elvitegravir
Dolutegravir
Bictegravir
Elvitegravir clinical pearls
currently formulated with cobicistat (COBI) to inhibit CYP
Bictegravir clinical pearls
can be started without HLA-B*5701 testing
HIV protease inhibitors MOA
mimics protease substrate
causes conformational change in protease to close (non-cleavable linkages)
normal protease function
peptide bond cleavage is a hydrolysis reaction
protease catalyzes the addition of water to the amide
all protease inhibitors (except tipranavir) are peptidomimetics
Amide bond is replaced by non-cleavable linkage
what are protease inhibitor agents?
ritonavir
atazanavir
darunavir
tipranavir
rotinavir clinical pearls
Low doses inhibitor CYP3A4 to block metabolism of other PIs and increase serum concentrations
darunavir clinical pearls
makes extensive hydrogen bonds with protease backbone
inhibits HIV protease dimerization
tipranzavir clinical pearls
non-peptidic PI
can be used if resistant to other PI
CYP 3A4 substrate and inducer
resistance to protease inhibitors
PI bind tighter to protease than natural substrates
Resistance mutation has greater efect on PI than natural
Multiple mutations needed to confer resistance
