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SBL 2 > HIV Pharmacology > Flashcards

HIV Pharmacology Flashcards

1
Q

In general, how is viral suppression achieved?

A

By using a combo of ARV regiments that includes three active drugs from at least two drug classes

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2
Q

What does ART begin with for the backbone of therapy typically?

A

2 NRTI’s

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3
Q

How do NRTI’s work?

A

Inhibit incorporation of native nucleotides and terminate elongation of proviral DNA, they do NOT eradicate the virus

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4
Q

What human DNA polymerase is inhibited by some NRTI’s and what four NRTI’s have lower affinity for it?

A

Mitochondrial DNA polymerase (y)

  • Emtricitabine
  • Lamivudine.
  • Abacavir
  • Tenofovir
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5
Q

what are the AE’s associated with NRTI?

A
  • Lactic acidosis syndrome due to mitochondrial toxicity
  • Peripheral neuropathy due to mitochondrial toxicity
  • Pancreatitis due to mito toxicity
  • Anemia
  • Myopathy
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6
Q

Zidovudine (AZT):

  • MOA:
  • Use:
  • Toxicities:
A

NRTI

  • Interferes with thymidine incorporation, it was the first ARV discovered
  • Used in resource poor settings
  • bone marrow suppression, skeletal mm myopathy, hepatic steatosis
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7
Q

Stavudine (d4T)

  • MOA:
  • Use:
  • Toxicities:
A

NRTI

  • Interferes with thymidine incorporation
  • Inhibits HIV 1 and 2
  • Most common serious AE is peripheral neuropathy
    • associated most strongly with lipodystrophy
    • assoc. with lactic acidosis and hepatic steatosis

Rarely used bc of toxicities now

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8
Q

Emtricitabine (FTC)

  • MOA:
  • Use:
  • Toxicities:
  • Pharmacokinetics
A

NRTI

  • Interferes with cytosine incorporation and terminates elongation of provrial DNA
  • Tx for HIV1 and 2
    • low barrier to resistance if a monotherapy
    • active agaisnt HepB and if discontinued resistance can occur and rebound of HepB so should not be used for HepB unless TAF pr TDF also given
    • Co formulated with Tenofovir
  • Least toxic agens but still HA, N/V, rash, cough infection
    • long use leads to hyperpigmentation palms and soles
  • Long intracellualr half life, excreted unchanged in the urine
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9
Q

Lamivudine (3TC)

  • MOA
  • Use
  • Pharmokinetics
  • Toxicities
A

NRTI

  • intereferes with cytidine incorporation inhibiting native nucleotides and terminating elongation
  • HIV1/2 tx, with a low barrier to monotherapy
    • active against HBV and stopping causes rebound and resistance
    • Dual combo with lamivudine and dolutegravir is approved for tx naive patients
  • long intracellular half life, sorbitol interferes with absorption
    • unchanged excretion in the urine
  • Least toxic ARV no significant AE’s
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10
Q

Abacavir (ABC)

  • MOA
  • Use:
  • Pharmacokintics:
  • Toxicities:
A

NRTI

  • Guanosine analog
  • NOT given to patient with HLA-B 5701 genotype and NOT effective against HBV
  • NOT a CYP substrate, 21 hr half life
  • Unique fatal hypersensitivity syndrome:
    • fevr abdominal pain, maculopapular rash, fatiguge around 6 days to 6 weeks, but does not resolve and worsens
  • avoide in patients with CAD and hyperlipidemia and absolutely HLA-B5701 genotype
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11
Q

Tenofovir disoproxil fumarate (TDF):

  • MOA:
  • Use:
  • Pharmacokinetics:
  • Toxicities:
A

NRTI

  • Nucleotide reverse transcriptase, it is the only nucleotide used and has poor bioavailabiltiy and that is where the D and F come in
    • broad spectrum activity against viral DNA pol and low affinity for human DNA pol
  • HBV active against, resistance is due to single sub in K65R but rarely cause of tx failure
  • 10-50 hr half life, unchanged excretion in urinve
  • well tolerated few AE besides upset GI
    • nephrotoxicity with acute tublar necrosis leading to fanconi syndrome, avoid if GFR less than 60
    • Decreased bone mineral density but stablizes over time
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12
Q

Tenofovir alaenamide

  • MOA:
  • Use:
  • Pharmacokinetics:
  • Toxicities:
A

NRTI

  • Nucleotide adenosine analog parent compound has poor bioavailabilty so used with allafenamide prodrug, broad activity against viral DNA pol not human
  • causes weight gain the most among NRTI, but less than INSTI, less renal and bone toxicities than TDF

Use and pharmacokinetics same as TDF

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13
Q

What combo of NRTI is “superior” to other combos?

A

Emtricitabine and tenofovir

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14
Q

What two drugs are recommended for treatment naive patients, unless their viral load is high?

A
  • Lamivudine (NRTI) by itself in combo with the INSTI dolutegravir
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15
Q

What drugs end with “_gravir”?

A

INSTI

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16
Q

Raltegravir?

MOA:

Use:

Pharmacokinetics:

Toxicities:

A

INSTI

  • prevents formation of covalent bonds btw viral and host DNA (strand transfer)
    • lowers plasma viral RNA faster than NNRTI efavirenz
  • ART combos in HIV adults preferred for tx naive patients, resistance can develop due to mutations in integrase
  • eliminated in urine and feces as unchanged and undergoes glucuronidation
    • first drug in this class, not availabe in single tablet
  • Well tolerated but can see hypersensitivity rxn, immune reconstitution syndrome, myopathy, excellent target since human DNA doesn’t undergot excision/reintergration
17
Q

Dolutegravir?

MOA:

Use:

Pharmacokinetics:

Toxicities:

A

INSTI

  • prevents strand transfer process, blocks chromosomal integration of viral DNA
  • Resistance develops with mutations to inetegrase but has high genetic brarier to resistance
  • half life 14 hrs, metabolizedby UGR1A1 glucuronidation before renal excretion
    • DTG/3TC is first choice for tx naive patients
  • Well tolerated but significant weight gain and avoid in pregnancy
18
Q

Bictegravir?

MOA:

Use:

Pharmacokinetics:

Toxicities:

A

INSTI

  • prevent strand transfer, blocks chromoslam integration of viral DNA
  • approved for HIV adults and tx naive patients, resistance develops with intergrase mutation, but has haigh barrier to resistance
  • more soluble and readily absorbed than other INSTI’s
    • metabolized by CYP3A4 few drug drug interactions
  • well tolerated causes weight gain
19
Q

How do protease inhibitors work?

A
  • competitively inhibit virus aspartly protease, cleaves the N terminal side of pro residues
  • prevents proteolytic cleavage of hiv gag and pol precursor peptides
20
Q

How are protease inhibitors cleared?

A

Hepatic clearance and metabolized by CYP3A4

21
Q

Saquinavir?

MOA:

Use:

Pharmacokinetics:

Toxicities:

A

Protease Inhibitor

  • first one discovered
  • no longer used due to pill burden
  • GI distress N/V diarrhea Lipodystrophy
22
Q

Indinavir significance?

A
  • Protease inhibitor that has a unique AE of crystalluria and renal stones
23
Q

Darunavir (DRV)

MOA

Use

Toxicities

A
  • non peptidic protease inhibitor that prevents maturation of capsid and other proteins that budd off
  • First choice PI when boosted
  • Sulfa drug so rash and hypersensitivity rxn possible
    *
24
Q

Atazanavir (ATV)

MOA

Use

Pharmacokinetics

Toxicities

A

protease inhibitor

  • prevents maturation of capsid and other proteins that budd off
  • Inbibits HIV1 and 2 used in tx naive patients and experienced
  • higher barrier to resistance thtan NNRTI and INSTI
  • Jaundice unconjugated hyperbilirubinemia
25
Q

Lopinavir?

A
  • prevents maturation of HIV particle that budds off
  • Often works after failure of other PI containnig regiments
26
Q

What are the two CYP3A4 inhibitors?

A
  • Ritonavir and Cobicistat
  • both are used to boost levels of protease inhibitors
27
Q

What form of HIV is intrinsically resistant to NNRTI’s?

A

HIV2

28
Q

Nevirapine?

MOA

Use

Pharmacokinetics

Toxicities

A

NNRTI

  • prevents generation of DNA from viral RNA in host cells
  • reduces level of oral contraceptives
  • rash and itching common AE’s
29
Q

Efavvirenz (EFV)?

A

NNRTI

  • prevents DNA from viral RNA entry in host cells
  • Should not be added to failing regimen
  • First NNRTI approved for once daily
  • CNS toxicity/ psychiatric side effects
  • was considered teratogenic
30
Q

Etravirine?

A
  • NNRTI
  • used for tx experienced HIV1
  • still works after mutations that disrupt activity of other NNRTI
31
Q

Rilpivirine use and how to take?

A
  • NNRTI
  • Tx naive patient, not susceptible to common mutation that renders efavirenz and nevirapine innefective but affected by other mutations
  • Nees to be taken with a meal
32
Q

Doravirine?

A
  • novel resistance mutations
  • can be taken with or withoyt food
  • metabolzied by CYP3A4 but no drug drug interactions
  • low incidence of CV, CNS, GI skin AEs, better than other NNRTI’s
33
Q

What is a very expensive last resort entry blocker drug that has a 36 aa peptide from the gp41 component?

A

Enfuviritide (T-20)

  • unique MOA retains its activity agaisnt viruses resistat to other classes
34
Q

What is Maraviroc?

A
  • CCR5 entry blocker
  • binds GP120 to CCR5 co receptor
  • resistance develops y shifting from CCR5 to CXCR4 troposim

Essential and expensive tropism test required before use

SBL 2 (9 decks)

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