All Lectures: NRTIs

Su, Shah, and Horace (this is single drugs only not combo therapy)

name the nucleoside RT inhibitors

zidovudine

lamivudine

emtricitabine

stavudine

didanosine

abacavir

tenofovir

zidovudine acronyms

ZDV and AZT

zidovudine brand names

retrovir

retrovis

zidovudine is an analog of ____ with an ___ subbed at the C3’ position

thymidine; azido

what drug is this

zidovudine

zidovudine is converted into ___

5’ mono, di, or tri phosphates

Zidovudine is converted into 5’-mono-, di-, and tri- phosphates by which enzyme?

thymidine kinase

phosphorylated zidovudine incorporates into DNA of the virus to…

stop the synthesis of DNA and replication of virus

zidovudine is also called

azidothymidine (AZT, ZDV)

ADE of zidovudine

myelosuppression

what is the only HIV drug that shows reduction in perinatal HIV transmission?

zidovudine

you cannot use zidovudine with which other NRTI due to pharmacodynamic interactions?

stavudine

zidovudine + stavudine leads to…

pharmacodynamic interactions

avoid use of zidovudine with ______ due to decreased levels of zidovudine

tipranavir

zidovudine + tipranavir leads to…

decreased levels of ZDV

what was the first approved treatment for HIV

zidovudine

didanosine is also called

Dideoxynucleotides or ddNTPs

Didanosine are nucleotides that lack…

C-3’ hydroxyl group on the deoxyribose sugar

brand name of Didanosine

videx

Didanosine is a ____ dideoxynucleotide

purine

Didanosine is an analog of ____

inosine/purines

why is Didanosine is typically given orally

to avoid acid instability

didanosine causes less ____ than AZT

myelosuppression

Didanosine causes less myelosuppression than ____

AZT

toxic effects of Didanosine

hyperuricemia

pancreatitis

myelosupression

t or f: Didanosine is a prodrug

T

Didanosine is bioactivated by metabolism to ____ by cellular enzymes, inhibiting RT

2’,3’-dideoxyadenosine 5’-triphosphate

the ____ form of Didanosine is the competitive inhibitor of viral RT

triphosphate

Didanosine is incorporated into the developing viral DNA which leads to

chain termination and viral replication inhibition

if ddI is used with tenofovir it can lead to…

increased conc of ddI

ddI + tenofovir will lead to a(n) ________ conc of ddI and higher rates of virologic failure

increased

dosage change for tenofovir + ddI

decrease ddI dose to 250 mg qd

didanosine + stavudine have ____ interactions

pharmacodynamic

didanosine + ______ have pharmacodynamic interactions and additive toxicities

stavudine

what drug is this

lamivudine

lamivudine has pharmacodynamic interactions with…

ETC (emtrictabine)

what drug is this

zalcitabine

lamivudine is also called

3TC, (-) 2’3’ didexy-3’thiacytidine

lamivudine is a nucleoside analog that is related to ____ with the replacement of ____

zalcitabine;

one CH2 with S

lamivudine is synergistic with ___ against HIV1 and HBV

AZT (zidovudine)

which enantiomer of lamivudine is more active and less toxic

negative

Cellular 3’,5’-exonuclease cleave terminal ____-lamivudine monophosphate (MP) incorporation into viral DNA 6-fold faster than ____-lamivudine MP from the viral terminus.

+; -

Mutation that causes resistance to lamivudine will make the virus more susceptible to which drug?

AZT

combo of lamivudine and AZT in HIV pts causes an increase in ____

CD4 cells

addition of sulfur to zalcitabine to make lamivudine is dope asf bc it leads to…

slower metabolism, better bioavail, and less toxic

dosing options for lamivudine

150 mg BID or 300 mg QD

lamivudine ADE

Headache, fatigue, peripheral neuropathy, neutropenia

emtricitabine is a ___ nucleoside analogue

pyrimidine

ETC is also active against

HBV (hepatitis B)

why is addition of the F on emtricitabine dope asf

less likely to be metabolized and it increases bioavail and activity

what drug is this

emtricitabine

all NRTIs are…

prodrugs

ETC has pharmacodynamic interactions with…

3TC (lamivudine)

ETC + 3TC leads to ________ interactions

pharmacodynamic

ETC does not inhibit…

CYP450 enzymes

dose of ETC

200 mg qd

emtricitabine ADE

rash, HA, dizzy, insomnia, diarrhea, nausea, weakness, cough abnormal dreams, hyperpigmentation of palms and soles of feet

what two reactions lead to ETC’s metabolism?

oxidation and cojugation

ETC oxidation metabolism

oxidation of thiol (S) to form C-3’ sulfoxide

ETC conjugation metabolism

conjugation with glucuronic acid to form 5’-O-glucuronide

stavudine is also called

D4T

what is the important characteristic of stavudine’s structure

double bond ∆2’,3’ position on the deoxyribose ring

which form of Stavudine is active? and whats its % bioavail?

Triphosphate form

85%

which form of stavudine is active?

triphosphate

MOA of stavudine

phosphorylated triphosphate form is active and competes with deoxythymidine triphosphate for incorporation into viral DNA to stop replication

ADE of stavudine

neuropathic effects

stavudine + ____ or _____ leads to pharmacodynamic interactions

ddI or AZT

stavudine + ddI + AZT leads to…

pharmacodynamic interactions

abacavir is also called

ABC

abacavir is extensively metabolized to ___

5’ triphosphates

what is dope about abacavir structure?

has a cyclopropane which makes it less likely to be metabolized

which drug is this

stavudine

which drug is this

abacavir

dosing options of ABC

300 mg BID or 600 mg qd

abacavir leads to which ADE

depression, dizzy, anxiety, thrombocytopenia, increased transamidases, allergic reactions (anaphylaxis, rash, fever, etc)

ABC is a ____ analog

purine

ABC has an oxygen that is replaced with a carbon which leads to…

more stability and increases duration of effects

avoid use of ABC with ____ due to decreases in ABC conc

tipranavir

avoid use of ABC + tipranavir due to…

decreases in ABC conc

does ABC require renal adjustments?

no

which drug is this

tenofovir diphosphate

what drug is this

tenofovir alafenamide

what is the active form of tenofovir

tenofovir diphosphate

why is tenofovir diphosphate the active form of tenofovir

higher bioavail due to added phosphates, also higher water solubility

tenofovir disoproxil ADE

nephrotoxicity, bone toxicity, rash, diarrhea, HA, depression, nausea, fanconi syndrome

indication of tenofovir

HIV and HBV

HIV prophylaxisis

renal adjustments of tenofovir disoproxil are needed if CrCl is…

< 50

TDF is converted to the active form in the ____

blood

TAF is converted to active form in the ___

lymphocytes and macrophages

TAF cannot be used in pts with CrCl of ____

< 30

TAF can be used if CrCl is < 15 if…

pt is on dialysis

what is the only metabolite of lamivudine

trans-sulfoxide

which enzyme metabolizes lamivudine into trans-sulfoxide?

sulfotransferases

what are the metabolites of emtricitabine

C-3’ sulfoxide and 5’-O-glucuronide

how is emtricitabine metabolized into C-3′-sulfoxide epimers

oxidation of the thiol moiety

how is emtricitabine metabolized into 5′-O-glucuronide

conjugation with glucuronic acid

to make Emtricitabine’s Sulfur a chiral center it would have to have…

an oxygen, a lone pair e-, two C’s

which two enzymes are responsible for metabolizing abacavir

alcohol dehydrogenase and glucuronosyltransferase

alcohol dehydrogenase metabolizes abacavir into

5′ carboxylic acid metabolite

glucuronosyltransferase metabolizes abacavir into

5′-glucuronide metabolite