HIV drugs (NRTIs)

Question 1

Nucleoside reverse transcriptase inhibitors (drugs)

NRTIs

Answer 1

Abacavir (ABC)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)
Tenofovir Disoproxil (TDF)
Tenofovir Alafenamide (TAF)
Zidovudine (AZT, ZDV)

Question 2

Nucleoside reverse transcriptase inhibitors (MOA)

NRTIs

Answer 2

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

Question 3

Nucleoside reverse transcriptase inhibitors (profile)

NRTIs

Answer 3

NRTIs are pro-drugs. they require host cell purine and pyrimidine kinase enzymes to convert nucleosides into nucleotides
nucleotides are the active form

Question 4

Zidovudine (AZT, ZDV) (MOA problems)

Answer 4

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

Question 5

what is rate limiting step for AZT-MP conversion

Answer 5

thymidylate kinase

Question 6

which is more toxic?

AZT-MP or AMT

Answer 6

AMT

it is 5-7 times more toxic than AZT-MP

Question 7

what causes build up of AMT?

Answer 7

AZT-MP

it inhibits the enzyme thymidylate kinase, forcing it into the AMT pathway

Question 8

which NRTI drug is the only one active as a diphosphate?

Answer 8

Tenofovir DF

has a phosphate in the parent molecule, nucleotide

Question 9

Nucleoside reverse transcriptase inhibitors (adverse effects)
(NRTIs)

Answer 9

the hallmark toxicity of NRTIs is mitochondrial toxicity

causes deficit of proteins encoded by mitoch which leads to impaired oxidative phosphorylation

Question 10

for NRTIs, which typically experience the mitochondrial toxicity
(older or newer)?

Answer 10

mostly with older agents (not seen in newer ones as much)

Question 11

how is mitochondrial toxicity (caused by NRTIs) presented

Answer 11

peripheral neuropathy
pancreatitis
lipoatrophy
hepatic steatosis

Question 12

what does impaired oxidative phosphorylation lead to?

Answer 12

lactate acidemia/acidosis

caused by pyruvate unable to go thru mitochondria

Question 13

what kind of warning do all NRTIs have?

Answer 13

Black box warning

b/c of lactic acidosis syndrome, which is potentially fatal

Question 14

what NRTI causes pigmentation of soles and palms?

Answer 14

Emtricitabine

Question 15

what NRTI causes pancreatitis?

Answer 15

Didanosine

Question 16

NRTI treatment should be _____ in the setting of rapidly rising aminotransferase levels

Answer 16

suspended

Question 17

Tenofovir (adverse effects)

Answer 17

Nephrotoxicity
Bone mineral density changes
(seen worse in Disoproxil as opposed to Alafenamide)

Question 18

As a class, NRTIS have ____ clinically significant drug-drug interactions

Answer 18

FEW

they are not substrates of cyto P450 pathway, eliminated renally

Question 19

NNRTIs and PIs have _____ drug interactions

Answer 19

significant number
(due to their interaction with cyto P450 system)

Question 20

NRTI combinations to avoid:

Zidovudine and Stavudine

Answer 20

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.

Question 21

NRTI combinations to avoid:

Lamivudine and emtricitabine

Answer 21

nearly identical drugs with same primary resistance mutation

Question 22

NRTI combinations to avoid:

Didanosine and Tenofovir

Answer 22

both are adenosines

high rates of virologic failure and rapid selection of resistant mutants

Question 23

NRTI combinations to avoid:
Triple nucleoside analog combination
(notes)

Answer 23

you run the risk of pathways competing with each other using too many NRTIs.

Question 24

what NRTIs drug is the only guanosine nucleotide analog?

Answer 24

Abacavir (ABC)

Question 25

Abacavir (ABC) (adverse effects)

Answer 25

cardiovascular toxicity (lowers HDL, raises LDL)

Question 26

what does it mean if a patient is positive for HLA-B*5701?

Answer 26

they will be allergic to abacavir

not IgE mediated but can result in patient death

Question 27

Abacavir (ABC) (major issue)

Answer 27

the worse thing that can be done to a patient taking this drug is to stop and then start again.
will be much worse when restarted. (life threatening hypotension)

if pt experiencing “flu-like” symptoms, they need to seek medical help before they stop taking this

Question 28

NRTIs drugs preferred in preganacy?

Answer 28

Zidovudine and Lamivudine