HIV drugs (NRTIs) Flashcards
Nucleoside reverse transcriptase inhibitors (drugs)
NRTIs
Abacavir (ABC) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir Disoproxil (TDF) Tenofovir Alafenamide (TAF) Zidovudine (AZT, ZDV)
Nucleoside reverse transcriptase inhibitors (MOA)
NRTIs
all NRTIs share the same mechanism of action:
inhibition of viral reverse transcriptase (viral DNA polymerase)
incorporation of NRTI 3P into viral DNA terminated any further DNA strand elongation
Nucleoside reverse transcriptase inhibitors (profile)
NRTIs
NRTIs are pro-drugs. they require host cell purine and pyrimidine kinase enzymes to convert nucleosides into nucleotides
nucleotides are the active form
Zidovudine (AZT, ZDV) (MOA problems)
thymidylate kinase doesn’t convert AZT-MP into AZT-DP fast enough, causing build up of AZT-MP. this leads to toxicity (hematological toxicity).
also high amounts of AZT-MP inhibits thymidylate kinase
what is rate limiting step for AZT-MP conversion
thymidylate kinase
which is more toxic?
AZT-MP or AMT
AMT
it is 5-7 times more toxic than AZT-MP
what causes build up of AMT?
AZT-MP
it inhibits the enzyme thymidylate kinase, forcing it into the AMT pathway
which NRTI drug is the only one active as a diphosphate?
Tenofovir DF
has a phosphate in the parent molecule, nucleotide
Nucleoside reverse transcriptase inhibitors (adverse effects)
(NRTIs)
the hallmark toxicity of NRTIs is mitochondrial toxicity
causes deficit of proteins encoded by mitoch which leads to impaired oxidative phosphorylation
for NRTIs, which typically experience the mitochondrial toxicity
(older or newer)?
mostly with older agents (not seen in newer ones as much)
how is mitochondrial toxicity (caused by NRTIs) presented
peripheral neuropathy
pancreatitis
lipoatrophy
hepatic steatosis
what does impaired oxidative phosphorylation lead to?
lactate acidemia/acidosis
caused by pyruvate unable to go thru mitochondria
what kind of warning do all NRTIs have?
Black box warning
b/c of lactic acidosis syndrome, which is potentially fatal
what NRTI causes pigmentation of soles and palms?
Emtricitabine
what NRTI causes pancreatitis?
Didanosine
NRTI treatment should be _____ in the setting of rapidly rising aminotransferase levels
suspended
Tenofovir (adverse effects)
Nephrotoxicity
Bone mineral density changes
(seen worse in Disoproxil as opposed to Alafenamide)
As a class, NRTIS have ____ clinically significant drug-drug interactions
FEW
they are not substrates of cyto P450 pathway, eliminated renally
NNRTIs and PIs have _____ drug interactions
significant number (due to their interaction with cyto P450 system)
NRTI combinations to avoid:
Zidovudine and Stavudine
antagonize each other (use same pathway and enzymes)
if given together, pathway will favor Stavudine (d4T) which will cause the toxic build up AZT is known for.
NRTI combinations to avoid:
Lamivudine and emtricitabine
nearly identical drugs with same primary resistance mutation
NRTI combinations to avoid:
Didanosine and Tenofovir
both are adenosines
high rates of virologic failure and rapid selection of resistant mutants
NRTI combinations to avoid:
Triple nucleoside analog combination
(notes)
you run the risk of pathways competing with each other using too many NRTIs.
what NRTIs drug is the only guanosine nucleotide analog?
Abacavir (ABC)
