Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

SBL > HIV Pharmacology > Flashcards

HIV Pharmacology Flashcards

1
Q

achieving viral suppression currently requires the use of combination ARV regimens that generally include…

A

3 active drugs from 2+ drug classes

usually 2 NRTIs + INSTI

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

ART typically begins with what as the backbone of therapy?

A

2 NRTIs (nucleoside reverse transcriptase inhibitor)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what must occur for NRTIs to provide substrate for enzymes?

A

NRTI must enter the cells and become phosphorylated

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

how do NRTIs exert their effects?

A
  1. inhibiting incorporation of native nucleotides

2. terminating elongation of nascent proviral DNA (lacks 3’-OH group)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what human polymerase is inhibited by some NRTIs?

A

human mitochondrial DNA polymerase (“y”)

human DNA polymerase a and B have low affinity for these drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what four NRTIs have lower affinity for human mitochondrial DNA polymerase y?

A
  1. emtricitabine
  2. lamivudine
  3. abacavir
  4. tenofovir

these are the most commonly used NRTIs now

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

where does the NRTI bind to terminate production?

A

to the DNA chain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what is the black box warning on all NRTIs?

A

lactic acidosis syndrome

d/t mitochondrial toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what are the toxicities of NRTIs?

A
  1. black box - lactic acidosis syndrome
  2. peripheral neuropathy
  3. pancreatitis
  4. anemia
  5. myopathy

1-3 d/t mitochondrial toxicity, 4 d/t granulocytopenia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

NRTI - interferes w/ thymidine incorporation

S-phase specific (why?)

only NRTI available IV; t1/2 is 3-4 hours

loss of limb fat, bone marrow suppression, skeletal muscle myopathy, hepatic steatosis (among others)

A

zidovudine / AZT

s-phase specific b/c thymidine kinase is specific to that phase of the cell cycle

inhibits HIV-1, HIV-2, HTLV-1 and HTLV-2; approved for inhibiting transmission from mom to baby

other common complaints: [malaise, myalgia, anorexia, insomnia]

fever, HA, nausea

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

NRTI - interferes w/ thymidine incorporation

S-phase specific (why?)

excreted in urine; t1/2 3.5 hours; absorbed well, penetrates well (CSF)

most common serious toxicity is peripheral neuropathy, NRTI most strongly associated with lipodystrophy/fat wasting; lactic acidosis and hepatic steatosis associated

A

stavudine / d4T

s-phase specific b/c thymidine kinase is specific to that phase of the cell cycle

inhibits HIV-1 and HIV-2 only (AZT is in the same class, inhibits HTLV as well)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

NRTI - interferes w/ cytosine incorporation

low barrier to resistance if monotherapy; active against HBV; co-formulation w/ tenofovir provides superior combination

t1/2 39 hours; excreted in urine

one of the least toxic agents; prolonged used can lead to hyperpigmentation (palms and soles) in AAs

A

emtricitabine / FTC

approved for HIV-1 and HIV-2

common SE: [cough]

fever, infection, HA, N/D, rash, nasal symptoms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

NRTI - interferes w/ cytidine incorporation

low barrier to resistance if monotherapy; active against HBV; co-formulated w/ tenofovir

t1/2 12-18 hours; excreted in urine; rapid and extensive absorption

one of the least toxic agents

A

lamivudine / 3TC

lamivudine + dolutegravir is approved for treatment of naive patients w/ low HIV copy numbers in plasma

common SE: [neutropenia, infections of ENT, MSK pain]

fever, HA, fatigue, N/D, rash, nasal symptoms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

NRTI - the only guanosine analog

should not be given to patient w/ HLA-B*5701 genotype d/t toxicity (potentially fatal hypersensitivity syndrome)

t1/2 21 hours; not a CYP substrate, renal elimination; rapid and extensive absorption

avoid in pts w/ CAD

A

abacavir / ABC

not effective against HBV

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

lamivudine + what drug?

is approved for treatment of naive patients w/ low HIV copy numbers in plasma

A

dolutegravir

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what patients should not receive abacavir, and why?

describe the presentation of a patient w/ the unique toxicity

A

HLA-B*5701 genotype – potentially fatal hypersensitivity syndrome

w/in 6 days - 6 weeks…

  • fever
  • abdominal pain/GI distress
  • mild maculopapular rash
  • malaise, fatigue
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

which NRTIs are nucleoTIDE reverse transcriptase inhibitors?

A

tenofovir disproxil fumarate / TDF

tenofovir alafendamide / TAF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

NtideRTI - adenosine analog; selectively toxic

approved for HBV; co-formulated w/ emtricitabine – superior combination to other NRTIs

resistance to drug d/t single substitution in RT (K65R) - seldom

t1/2 10-50 hours; excreted in urine

nephrotoxicity w/ ATN –> Fanconi (what GFR is ideal?)
decreased bone mineral density; GI upset

A

tenofovir disoproxil fumarate / TDF

GFR <60

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what NRTI is associated w/ Fanconi syndrome?

A

tenofovir disoproxil fumarate / TDF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

a patient w/ RT K65R mutation will develop resistance to what NRTIs?

A

tenofovir disproxil fumarate / TDF

tenofovir alafenamide / TAF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

NRTI - adenosine analog

active against HIV-1, HIV-2, and HTLV-1 but supplanted by less toxic drugs d/t peripheral neuropathy pancreatitis, and hepatic steatosis

A

didanosine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

NtideRTI - adenosine analog; selectively toxic

approved for HBV; co-formulated w/ emtricitabine – superior combination to NRTIs

resistance to drug d/t single substitution in RT (K65R) - seldom

t1/2 10-50 hours; excreted in urine; lower doses administered (compared to other adenosine analog) leading to lower plasma concentrations but higher intracellular concentrations

less renal and bone toxicity than other adenosine analog

A

tenofovir alafenamide / TAF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

what drug class is the primary +1 active agent for treatment of HIV patients?

A

INSTIs

integrase strand transfer inhibitors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

what is the “-gravir” suffix for?

A

INSTIs

25
Q

INSTI - prevents strand transfer (formation of covalent bonds b/w viral and host DNA)

resistance develops d/t mutations in integrase

t1/2 9 hours; excreted in urine and feces

immune reconstitution syndrome; severe skin hypersensitivity; myopathy/rhabdomyolysis

A

raltegravir

26
Q

INSTI - prevents strand transfer (formation of covalent bonds b/w viral and host DNA)

resistance develops d/t mutations in integrase, but has high genetic barrier to resistance

t1/2 14 hours; primary metabolism is glucuronidation by UGT1A1 before renal excretion

immune reconstitution syndrome; severe skin hypersensitivity; increase in liver enzymes; avoid in pregnancy (NT defects)

A

dolutegravir

  • *combination w/ abacavir and lamivudine – Triumeq
  • *combination w/ rilpivirine – Juluca

((CYP3A4 metabolism after UGT1A1 like other INSTIs..??))

27
Q

what drug class is preferred for treatment of naive patients?

A

INSTIs

28
Q

INSTI - metabolized by CYP3A4 and needs to be boosted

A

elvitegravir

cobicistat + emtricitabine + [tenofovir alafendamide] – Genvoya

cobicistat + emtricitabine + [tenofovir disproxil fumarate] – Stribild

29
Q

INSTI - prevents strand transfer (formation of covalent bonds b/w viral and host DNA)

resistance develops d/t mutations in integrase, but has high genetic barrier to resistance

t1/2 16-23 hours; more readily absorbed than other INSTIs; glucuronidation by UGT1A1 and metabolized by CYP3A4, fewer DDIs b/c only affected by potent dual inhibitors of both enzymes; 1/3 excreted in urine, 2/3 excreted in feces

only available as fixed dose single tablet regimen

A

bictegravir

regimen: bictegravir + emtricitabine + tenofovir alafenamide – Biktarvy

SE: HA, D, insomnia

30
Q

what are the frequent second-line +1 active agents?

A

protease inhibitors (PIs)

31
Q

PIs are peptide-like chemicals that [non/competitively?] inhibit activity of…?

A

PIs competitively inhibit activity of virus aspartyl protease (homodimer)

*human aspartyl proteases are monomers – renin, pepsin, cathepsin D, etc – not inhibited by PIs

32
Q

PIs prevent proteolytic cleavage of HIV…

A

gag and pol precursor peptides

needed to generate RT, protease, and integrase; and various structural polypeptides of capsid

33
Q

do PIs penetrate the CSF well?

A

no – they are highly protein-bound (in the plasma)

34
Q

PI - first one, high pill burdern

t1/2 1-2 hours, poor bioavailability

A

saquinavir

HIV-1 and HIV-2

SE: NVD; lipodystrophy (long-term)

35
Q

PI - early

t1/2 1.8 hours w/

SE: crystaluria/renal stones

A

indinavir

for HIV-1 and HIV-2

no longer recommended, frequent exam question b/c of SE

36
Q

PI - non-peptidic PI

used off-label of post-exposure prophylaxis, current first-line choice when boosted

t1/2 15 hours when boosted; 80% fecal excretion w/ 40% unchanged

SE: sulfa drug so some rash, hypersensitivity; increases trigs and cholesterol, fat redistribution syndrome, immune reconstitution syndrome

A

darunavir

HIV-1 > HIV-2

metabolized by CYP3A4 (like the entire class..?)

37
Q

PI - current first-choice when boosted (w/ ritonavir, cobicistat)

used in treatment of naive patients; use in treatment-experienced patients guided by PI resistance substitutions

t1/2 7-9 hours but doubles when boosted; mostly excreted in feces w/ 20% unchanged

SE: elevated bili, unconjugated hyperbilirubinemia not associated w/ hepatitis; fat redistribution, hypersensitivity, immune reconstitution syndrome, increased serum cholesterol, NVD, fever, cough

A

atazanavir

HIV-1 and HIV-2

38
Q

PI - only available in boosted form (w/ ritonavir)

often works after failure of other PI-containing regimens

t1/2 5-6 hours

A

lopinavir (boosted = Lop/r)

*no longer go-to drug, supplanted by darunavir and azatanavir

39
Q

what are the two PI CYP3A4 inhibitors?

A

ritonavir and cobicistat

*not interchangeable

40
Q

PI - only used to inhibit CYP3A4 / booster

t1/2 3-5 hours

SE: flushing, rash, GI upset

A

ritonavir

41
Q

CYP3A4 inhibitor / booster – not a PI

t1/2 3-5 hours; primarily excreted in feces

A

cobicistat

42
Q

is cobicistat a PI?

A

no, just a CYP3A4 inhibitor

43
Q

which CYP3A4 inhibitor is excreted in feces?

A

cobicistat

44
Q

what is the third line +1 active agent?

A

NNRTIs

non-nucleoside reverse transcriptase inhibitors

45
Q

NNTRI binds to and causes denaturation of…

A

reverse transcriptase

46
Q

where do NNRTIs bind?

A

hydrophobic pocket in p6 subunit of HIV RT

47
Q

are NNRTIs competitive or non-competitive antagonists?

A

non-competitive

binding in hydrophobic pocket of HIV RT p66 subunit causes a conformational change in the enzyme

48
Q

do NNRTIs require phosphorylation for activation?

A

no

49
Q

are NNRTIs active against HIV-1, HIV-2, or both?

A

HIV-1; HIV-2 is intrinsically resistant to NNRTIs

50
Q

single exposure to this NNRTI in the absence of other drugs causes resistance in 1/3 of HIV-infected people

A

nevirapine

single substitution (K103N) in hydrophobic pocket of HIV RT p66 subunit confers resistance

51
Q

NNRTI

can be used in children (combination)

t1/2 25-30 hours

induces CYP3A4, reduces levels of OCP

SE: rash, itching

A

nevirapine

K103N renders ineffective; needs to be used in combination otherwise 1/3 patients develop resistance

52
Q

NNRTI

should not be added to failing regimen; co-formulation w/ emtricitabine and tenofovir helps maintain this as early selection in class; can be used in children (combination)

t1/2 40-50 hours (first NNRTI for 1x/daily dosing)

induces CYP3A4; reduces levels OCP

SE: CNS toxicity/psychiatric; questions about teratogenicity

A

efavirenz

other SE: dizziness, impaired concentration, vivid dreams but subside w/in a few weeks; rash, but also resolves

K103N mutation renders infeffective

53
Q

NNRTI

approved for treatment-naive patients; less resistant to mutation than other NNRTIs

t1/2 50 hours, metabolized by CYP3A4; 85% excreted in feces w/ 25% unchanged

SE (children, adolescents > adults): CNS depression, HA, drowsiness; nausea; decreased cortisol; fat redistribution, immune reconstitution syndrome

A

rilpivirine

**not susceptible to K103N mutation like nevirapine and efavirenz

54
Q

NNRTI – newest and best in class, but still in 3rd line class of +1 treatment options

treatment-naive patients; switching patients on stable effective regimen to this drug

novel resistance mutations

t1/2 15 hours, metabolized by CYP3A4, less drug interactions than other NNRTIs; available individually or co-formulated w/ lamivudine and tenofovir

A

doravirine

works when resistance to efavirenz or rilpivirine
if pt resistant to doravirine, efavirenz or rilpivirine will work

SE: low incidence of CV, CNS, GI, skin adverse effects – better than other NNRTIs; potential for immune reconstitution syndrome

55
Q

which entry blocker drug targets HIV fusion inhibitor?

A

enfuvirtide / T-20

T-20 peptides prevent conformational change –> prevent hairpin structure –> fusion prevented and entry blocked

56
Q

entry blocker - 36 aa peptide from viral gp41 part that fuses w/ cell membrane

inhibits formation of 6-helix bundle (critical for membrane fusion); inhibits infection of CD4+ by free virus particle; inhibits cell-cell transmission

only treatment-experienced patients w/ viral replication

expensive, administered parenterally

A

enfuvirtide / T-20

not active against HIV-2, only HIV-1

unique mechanism – retains retains activity against viruses resistant to other drug classes; only resistant w/ gp41 mutation

only HIV drug administered parenterally and happens 2x/daily

57
Q

which entry blocker drug targets CCR5?

A

maraviroc

gp120 anchors HIV to target cell via CD4; CCR5 stabilizes the complex, allowing gp41-mediated fusion of virus membrane w/ host membrane

maraviroc binds to CCR5 to prevent gp120 binding, fusion, and entry

58
Q

entry blocker - chemokine receptor antagonist, blocks binding of gp120 to CCR5 co-receptor

essential, but expensive, phenotypic test required to determine tropism

t1/2 10.6 hours; CYP3A4 substrate; renal elimination

SE: cold-like symptoms, dizziness, GI upset

seldom used

A

maraviroc

approved for use in ART combinations for HIV caused by CCR5 (R5) trophic virus; not active against CXCR4 (X4) or mixed trophic viruses

resistance d/t: shift from CCR5 to CXCR4 tropism or mutation in V3 loop of gp120

retains activity against viruses that have become resistant to other classes d/t unique MOA

SBL (4 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions