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SBL Exam 2 > 6. HIV Pharm > Flashcards

6. HIV Pharm Flashcards

1
Q

what are the clinical applications, pharmacokinetics and toxicities of efavirenz

A

application: HIV-1 infxn in adults & children;

co-formulate w/ emtricitabine & tenofovir to help maintain early NNRTI selected in class

pharmacokinetics: half life = 40-50; 1st NNRTI approved for 1x/day; induce CYP34 (reduce oral contraceptive levels - change pt’s form of BC)
toxicities: most significant = CNA toxicity/psychiatric side effects; rash is common; was considerd a teratogenic

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2
Q

how does HIV virion mature

A
  1. HIV viron bind (CD4 & chemokine receptor) to host, fuse and enter cell
  2. uncoat –> ssHIV RNA –> DNA by reverse transcriptase
  3. DNA insert into host genome–> take control of transcription –> make viral proteins and immature noninfectious virons
  4. mature into fully infectious mature HIV ​after proteolytic cleavage
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3
Q

what are the MOA, effects of raltegravir and dolutegravir

& bictegravir

A

MOA: prevent formation of covalent bonds btn viral & host DNA (=strand transfer)

effects: block strand transfer (characteristic of retrovirus) viral DNA remain in host for prolonged period of inactivity

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4
Q

What is the general function of ART

A

decrease inflam and immune activation

(so prevent contribution higher rates of CV and other end organ damage)

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5
Q

what are the pharmacokinetics & toxicities of bictegravir?

A

pharmacokinetics:

  • half-life = 16-23 hrs (1x/day dose);
  • more soluble and readily abs-ed compared to INSTI
  • glucuronidated by UGT1A1 & metabolized by CYP3A4 - BUT affected by potent dual inhibitors only==> few drug-drug interactions
  • eliminated 1/3 via urine and 2/3 via feces
  • only available as fixed-dose single tablet regimen

toxicity: well tolerated - maybe HA, diarrhea, insomnia

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6
Q

what are the predictors of virologic success

A

low baseline viremia

high potency of ARV regimen

tolerability

convenience

excellent adherence to regimen

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7
Q

compare and contrast zidovudine (AZT) to stavudine (d4T)

A

similar: MOA, effects, application (HIV-1,2), pharmacokinetic (abs well but…1/2-life = 3.5

toxicity = both= hepatic steatosis

& difference =

d4T = SEVERE toxiciy is peripheral neuropathy , lactic acidosis

NRTI associated w/ lipodystrophy/fat wasting (seen in AZT)

(rmr AZT used for prophylaxis, prevent vertical transmission & toxiciity = bone marrow suppression, sk. m myopathy)

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8
Q

What are common side effects seen with protease inhibitors

how do they build resistance?

A

nausea, vomit, diarrhea (better in several wks)

Speed of resistance btn NNRTI (fast) & NRTI (slow) - took 3-4 months in early trials & require mutation in 4-5 codons

short/long term toxicities including insulin resistance & lipdystrophy

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9
Q

What are the general pharmacokinetics for NNRTI

how can you build resistance?

A

eliminated by hepatic metabolism

single AA subsitution can cause resistance

*single exposure to Nevirapine in absence of other drugs –> resistance in 1/3 HIV-infected pts*

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10
Q

what are the MOA and pharmacokinetics of emtricitabine (FTC)

A

MOA: NRTI interfere w/ cytosine addition

rapid, extensive abs & long intracell half-life = 39 hr, excreted unchanged primarily in urine

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11
Q

how do NRTIs have selective toxicity

A

inhibit HIV RT w/o inhibiting host cell DNA polymerase ( DNA pol-alpha & beta have low affinity to these drugs)

BUT- mitochondrial DNA pol (gamma) are inhibited by some NRTI (emtricitabine, lamivudine, abacavir, tenofovir)

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12
Q

what are integrase strand transfer inhibitors

A

= primary (+1) active agents now recommended for treatment naive HIV pt

-end w/ “-gravir”

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13
Q

What are the clincal applications, pharmacokinetics and toxicities of nevirapine

A

application: HIV-1 infxn in adults & children
pharmacokinetics: half life = 25-30, induce CYP3A4 reduces level of oral contraceptive (change pts BC)
toxicities: rash/itching

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14
Q

Compare the pharmocokinetics of raltegravir and dolutegravir

A

Raltegravir: terminal half-life 9 hrs; eliminated in urine and feces as unchanged drug

Dolutegravir: terminal half life - 14 hrs ; 1x/day; metabolized by UGR1A1 glucuronidation before renal excretion

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15
Q

What are CCR5-blockers (ex. maraviroc)

A

MOA: chemokine receptor antagonist; block binding of gp120 to CCR5 (co-receptor)

block entry of CCR5-trophic HIV into cells

resistance developed by shift from CCR5 to CXCR4 tropism or mutation in V3 loop of GP120

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16
Q

what are the MOA and pharmacokinetics of atazanavir

A

MOA: protease inhibitor *1st choice PI when boosted*

pharmacokinetics: similar to darunavir (metabolized as CYP3A4 & excreted mostly in feces)

half life = 7-9 hrs

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17
Q

what is the mechanism of NRTIs

A

enter cell –> become phosphorylated –> bind DNA chain (inhibit incorporation of new NT) and terminate elongation (lack 3’OH group)

*these prevent infxn of susceptible cells but DO NOT eradicate the virus*

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18
Q

What are 3 considerations to keep in mind for ART

A

use combo therapy to prevent emergent resistant virus

tolerance and convience in addition to efficacy

realization that therapy must be life long

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19
Q

What are clinical applications and toxicities of saquinavir?

A

application : (-) HIV-1,2

no longer widely used in developed world due to pill burden

toxicities = GI distress, nausea, vomiting, diarrhea & long term = lipodystrophy

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20
Q

what are the clinical applications and toxicites of tenofovir disoproxil fumarate (TDF)

A

Applications; HIV w/ combo of drugs; HBV

resistance due to single substitution in RT (K65R) - but rare cause of tx failure

Toxicity:

generally well tolerate BUT possible nephrotoxicity w/ acute tubular necorsis –> Fanconi syndrome (so avoid is eGFR < 60ml/min/1.75 (m^2))

decreased bone mineral density but stabilizes w/ continued use

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21
Q

what are the MOA and pharmacokinetics of tenofovir disoproxil fumarate (TDF)

A

MOA: NRTI but nucleoTIDE- , ad__enosine analog ; poor bioavailability so use disoproxil fumarate prodrug formula

intracell half life = 10-50 hrs, 1x/day dose, excreted unchanged in urine

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22
Q

What are HIV fusion inhibitors (ex:enfuvirtide aka T20)

A

prvent the confirmation change and prevent the hairpin structure –> prevent fusion

MOA = 36 AA peptide derived from viral gp41 that fuses w/ cell mem

–> inhibit formation of 6-helix bundle critical for membrane fusion, inhibit infxn CD4 by free virus particles, also inhibit cell-to-cell transmission in vitro

(resistance developed by mutation in gp41)

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23
Q

What are the clinical application, pharmacokinetics and toxicites of doravirine

A

application: HIV-1 naive pt; for switching pt on stable regimen, novel resistance mutations

half-life = 15 hrs, metabolized by CYP3A4; available individually or co-formulated w/ lamivudine and tenofovir

toxicity: low incidence of CV, CNA, GI and skin adverse effects; potential immune reconstituion syndrome

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24
Q

What are protease inhibitors & what is its mechanism

A

=freq 2nd line (+1) active agent

inhibit protease –> prevent cleavage of polypeptide & maturation of virion

=peptide-like chemical- competitively inhibit activity of virus aspartyl protease

=prevent proteolytic cleavage of HIV gag & pol precursor peptides (which are needed to generate reverse transcriptase, proteast, integrase and more)

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25
Q

what are the consequences of treatment interruption

A

rebound virema

worsening of immune fxn

and increase morbidity/mortality

26
Q

what are the 6 targets for HIV therapy

A
  1. nuceloside reverse transcriptase (RT) inhibitor (NRTI)
  2. protease inhibitor
  3. non-NT RT inhibitor
  4. HIV fusion inhibitor
  5. CCR5 blocker (co-receptor to enter cell)
  6. integrase stand transfer inhibitor
27
Q

what are clinical applications and toxicities of lopinavir

A

application : (-) HIV-1,2; often works after failure of other PI containing regimen

toxicities: GI distress, nausea, vomiting, diarrhea, increase triglycerides & cholesterol

28
Q

What is the MOA, effects and clincal application of bictegravir

how does it build resistance

A

MOA and effect = ISTI - block strand transfer (same as dolutegravir & raltegravir)

application -niave HIV pt (same as dolutegravir)

resistance: mutation of integrase BUT high genetic barrier resistance (same as dolutegravir)

29
Q

what are the clinical applications and toxities for raltegravir and dolutegravir

A

application: HIV- naive pt

resistance due to mutations in integrase (dolutegravir has high genetic barrier to resistance)

toxicities:

  • rarely potentially severe skin/hypersensitivity rxn
  • see “immune reconstitution syndrome”

raltegravir : myopathy/rhadomyolysis

dolutegravir: avoid in pregnancy

30
Q

what are toxicities that present in darunavir

A

GI distress, nausea, vomit, diarrhea (like other PI) & immune reconstitution syndrome (like INSTI)

increased triglycerides & cholesterol & fat redistribution syndrome

sulfa drug - hypersensitivity (some rash)

31
Q

What are the clinical applications and toxicities for zidovudine (AZT)

A

application: (-) HIV-1, 2 & HTLV-1,2

adults and children, prevent mom-child transmission & post exposure prophyaxis in health care workers

toxicity:

  1. loss of limb fat,
  2. bone marrow suppression,
  3. skeletal M. myopathy &
  4. hepathic steatosis
32
Q

what are the cllinical applications, pharmacokinetics and toxicities for rilpivirine

A

application: HIV-1 naive pt; not susceptible to common mutation BUT affected by other mutations so less resistant than etravirine
pharmacokinetics: half life - 50 hrs, metabolized by CYP3A4; 85% excreted in feces and 25% uncharged drug
toxicites: MOST COMMON IN KIDS & TEENS- CNS, decreased cortisol, nausea, fat restribution, immune reconsitution syndrome

33
Q

what are the clinical application and toxicities of atazanavir

A

application: (-) HIV 1, 2; Tx naive pts; use in tx-experienced pts guided by PI resistance substitutions

toxicities =

  1. GI distress, nausea, vomiting, diarrhea, cough and fever (like other PI)
  2. increase serum cholesterol
  3. elevated bilirubin - unconjugated hyperbilirubinemia not assocaited w/ hepatitis
  4. fat redistribution, hypersensitivity rxn
  5. immune reconstitution syndrome
34
Q

What are the steps taken to achieve treatment goals

A
  1. baseline pt characteristic & drug resistance guide regimen
  2. give initial treatment to suppress HIV
  3. if not achieved/maintained –> new regimen w/ >= 2 active drugs (increase in drugs make viral suppression below detectable limits)
  4. after effective ART achieved, viral load reduction to below limits of assay detection occurs w/i first 12-24 wks
35
Q

compare and contrast TDF and TAF (tenofovir alafenamide)

A

similar: MOA, effects, clinical application
pharmacokinetics: like TDF but TAF transported differently - lower doses administed –> low [plasma] but higher intracel [tenofovir-diphosphate]
toxicities: TAF fewer side effects than TDF (= bloating, diarrhea, flatulence)

36
Q

what is didanosine

A

adenosine analog against HIV 1, 2,and HTLV-1

replaced by less toxic drugs (causes peripheral nephropaty, pancreatitis &/or hepatic steatosis)

37
Q

what is the MOA and pharmacokinetics of darunavir

A

MOA - non-peptidic protease inhibitor

pharmacokinetics - same as atazanavir (metabolized by CYP3A4 and mostly excreted in feces)

half life = 15 hrs

38
Q

What is cobicistat?

A

MOA: CYP3A4 inhibitor

effect/application: Boost level of other PIs (azatanavir & darunavir)

half life - 3-5 hr; excreted in feces

toxicity= misc.

39
Q

what are clincal applications, pharmacokinetics and toxicities of maraviroc?

A

application: combo for HIV caused by CCR5 trophic virus; not active agaisnt CXCR4 or mixed trophic viruses

retain activity against virus that become resistant

half-life 10.6 hr, CYP3A4 substrate; renal elimination

toxicities: generally well tolerated - cold like symptoms, dizziness, GI upset

40
Q

Compare and contrast

pharmacokinetics, MOA, effects, application and toxicities of

lamivudine (3TC) and emticitabine (FTC)

A

3TC - interfere w/ cytodine & FTC - interfere w/ cytosine

clincial application of 3TC all that FTC is used for PLUS dual agent combination of 3TC and doltegravir for naive pt w/ low HIV copy

Toxicities: same BUT ONLY FTC cause hyperpigmentation in AA pts

effects, pharmacokinetics are the same (long intracell half life & excreted unchanged in urine)

41
Q

what are the clinical applications and toxicities for abacavir (ABC)

A

applications:

  1. HIV in combo w/ other drugs;
  2. should NOT be used in pt w/ HLA-B*5701 genotype (bc toxicity- potentially fatal hypersensitivity) ;
  3. NOT effective against HBV

toxicities:

  1. potentially fatal hypersensitivity bc of HLA-B*5701 locus - fever, abd pain/GI distress, maculopapular rash, etc 6 day-6 wks –> death if continued use w/ adverse rxn
  2. AVOID in pt w/ coronary A disease bc may cause hyperlipidemia and CV events
42
Q

what is the protocol to prevent sexual tranmission

A

maintain plasma HIV RNA <200

use other form of prevention (condoms, pre-exposure prophylaxis for HIV (-) partner, abstinence) for >= 6 months of treatment

maintian high levels of adherence (esp is relying on ART for prevention)

43
Q

What are the toxicities associated w/ NRTIs

A

black box warning b/c possibility of lactic acidosis syndrome

peripheral neuropathy

pancreatitis

anemia

myopathy

44
Q

what is the MOA and pharmacokinetics of zidovudine (AZT)

(first anti-retroviral drug discovered)

A

NRTI - interfere w/ thymidine incorporation

most potent in active cells bc thymidine kinase is S-phase specific

well-abs, extensive first pass; 1/2-life = 3-4

excrete in urine as metabolite (some unchanged)

45
Q

what is the purpose of initiating ART immediately after HIV diagnosis

A

to increase uptake of ART & linkage to care

decrease time to viral supression

improve rate of virologic suppression

*imp to educate pt about benefits and strategies to optomize care*

46
Q

what is action of virus aspartyl protease

A

enzyme = homodimer w/ Asp essential for catalysis

cleaves N-terminal side of Pro-residues

human aspartyl proteases (renin, pepsin, etc) = MONOMERS so NOT inhibited by protease inhibitors

47
Q

What is the MOA and pharmacokinetics of saquinavir

A

MOA = 1st protease inhibitor

poor bioavailability (half-life 1-2 hr)

rmr- pill burden!

48
Q

how are protease inhibitors cleared from body

A

mainly by hepatic clearance (oxidation)

metabolized by CYP3A4, all inhibit metabolism of other drugs

all = substrates for P-glycoprotein (MDR1) so infleunce(d) by other drug transport

49
Q

what is imp to consider for child-bearing potential or pregnant pts

A

consider: pharmacokinetic interaxn w/ hormonal contraceptives –> change contraceptive method/switch ART

*pregnancy test before initiating ART*

-increased risk of n_eural tube defect_ if mother was taking dolutegravir

during pregnancy - goal of ART = maintain viral load below limit of detection thru-out pregnancy to decrease risk of transmission to fetus/newborn

50
Q

what is ritonavir

A

MOA: PI only to block CYP3A4

effects/application: boosts levels of other more potent PI

half life = 3-5 hr , potent CYP3A4 inhibitor

toxicities: flush rash, GI upset

51
Q

what are the MOA and pharmacokinetics of abacavir (ABC)

A

MOA: NRTI for guanosine analog (only one!)

rapid/extensive abs; intra cell half life = 21 hrs, not a CYP substrate (but metabolized by dehydrogenase and conjugated fro renal elimination)

52
Q

what should you include when reasoning why virologic failure occured

A

adherence

drug-drug and drug-food interaxn

tolerability

HIV RNA level & CD4 cell count trends

ART history

drug-resistance

*new regimen should include atleast 2, preferably 3, fully active agents*

53
Q

which NRTI/drug combinations are superior to other combos?

& which should not be combined?

A

FTC and tenofovir- commonly used & better than other combos

3TC w/ INSTI (dolutegravir) recommended in naive HIV pts

DONT combine -

emtricitabine & lamivudine (bc bot cytosine analogs)

TDF and TAF (bc both prodrug formulations of same active agent

54
Q

what is elvitegravir combined with to form a 1x/day dose

A

cobicistat, emtricitabine & either TAF or TDF

(INSTIs metabolized by CYP3A4 & needs to be boosted)

55
Q

Indinavir is a early protease inhibitor that inhibits HIV 1 & 2, what is it’s pharmacokinetics & toxicity

A

short half life - 1.8 hrs –> 3x/day

Toxicity ****** unique crystaluria/renal stones *****

56
Q

once you initiate ART, you should continue therapy.. with what treatment goals to keep in mind?

A
  1. maximally and durably suppress plasma HIV RNA
  2. restore & preserve (CD4 count) immune fxn
  3. decrease HIV-assocaited morbidity
  4. increase survival
  5. prevent transmision
57
Q

What are the clinical application and toxicities for emtricitabine (FTC)

A

applications - HIV-1, 2 in adults, HBV

low barrier to resistance if monotherapy

& co-formulated w/ tenofovir

toxicities:

*one of least toxic antiretrovirals - cause HA, nausea, diarrhea, rash, cough, infxn, fever in >10%

prolonged use –> hyperpigmentation of skin (ESP palm & soles) > in African Amercians

58
Q

What are Non-nucleoside reverse transcriptase inhibitors (NNRTI)

A

inhibitor binds to RT and denature it; enzyme cant produce viral DNA from viral RNA

-bind to hydrophobic pocket in p66 subunit of HIV RT –> induce confirmational change (non-competitive antagonist)

ONLY active against HIV-1 (2 is intrinsically resistant)

59
Q

what are the clinical applications, pharmacokinetics and toxicities of enfuvirtide (T20)

A

application: Tx-experienced adults w/ viral replication despite therapy; not active against HIV-2; retain activity against viruses resistant to other drug classes

MUST administered paraentrally (2x/day)

toxicity: injection site rxn

(not used often)

60
Q

What are clinical applications, pharmacokinetics and toxicities of etravirine

A

application: HIV-1 adult & childen; unique bc still works after mutation that disrupts other NNRTIs

pharmacokinetics - half life = 41 hrs (1x/day), induce CYP3A4

toxicities: fat redistribution, immune reconstitution syndrome, rash, Steven-Johnson syndrome possible

61
Q

what are the MOA and pharmakinetics in lopinavir

A

MOA: PI (only available in form boosted w/ ritonavir)

half life = 5-6

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