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SBL (Skin, Blood, Lymph) Exam 1 and 2 > Lecture 21: HIV Pharmacology (Exam 2) > Flashcards

Lecture 21: HIV Pharmacology (Exam 2) Flashcards

1
Q

What are 4 common drugs used as NTRIs? (E, L, A, T)

A

emtricitabine, lamivudine, abacavir, tenofovir

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2
Q

What are 3 common drugs used as INSTIs? (R, D, B)

A

raltegravir, doltegravir, bictelgravir

  • all end with “-gravir”
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3
Q

What are 2 common drugs used as Protease Inhibitors? (A and D)

A

azatanavir /c and darunavir /c

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4
Q

What are 5 common drugs used as NNRTIs? (N, E, E, R, D)

A

nevirapine, efavirenz, etravirine, rilpivirine, doravirine

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5
Q

What is the normal drug combination for achieving viral suppression via ART?

A
  • generally 3 active drugs are given from 2+ drug classes (usually 2 NRTIs as therapy BACKBONE)
  • viral load reduction below limits of assay detection usually occurs in first 12-24 weeks of therapy
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6
Q

What are 5 predictors of virologic ART success?

A
  • low baseline viremia, high potency of ARV regime, tolerability, convenience, and excellent adherence to regime
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7
Q

What is the MOA of NRTIs? (Nucleoside Reverse Transcriptase Inhibitors)

What can NTRIs potentially inhibit in human cells that is NOT viral related?

A
  • binds to the viral DNA chain being synthesized, competes for base pair addition, and causes termination of the product
  • terminate elongation because they LACK 3’-OH group (must be PHOSPHORYLATED to work)
  • some mitochondrial DNA polymerases are inhibited by NTRIs, but most human ones have low affinity
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8
Q

What nucleotide does each NRTI mimic? (6)

Thymidine
Cytidine
Guanosine
Adenosine

A

T: Zidovudine (AZT) –> first NRTI used
- and stavudine

C - emtricitabine/lamivudine

G - abacavir

A - tenofovir

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9
Q

What are 3 toxicities commonly associated with NRTIs? (LAS, PN, P)

A

Lactic Acidosis Syndrome, Peripheral Neuropathy, Pancreatitis

  • all due to mitochondrial toxicity
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10
Q

Zidovudine and Stavudine:

Clinical Applications and Toxicities

A
  • NRTIs (S-PHASE specific; thymidine mimic)

T: inhibits HIV-1/2 and HTLV-1/2 (only IV NRTI avail.)
- bone supp, skeletal muscle myopathy, heap. steat

S: inhibits HIV-1/2

  • Peripheral neuropathy, fat wasting (why we no use)
  • also lactic acidosis/hepatic steatosis
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11
Q

Emtricitabine and Lamivudine:

What are they, what are their clinical applications, and what are their toxicities?

What other drug are they normally given with?

A
  • NRTIs (cytidine mimic) that are coformulated with Tenofovir; low barriers to resistance if monotherapy and long half-lives; excreted unchanged in urine

CA: used to treat HIV-1/2 and HBV

T: not very toxic, though prolonged Emtricitabine use causes hyperpigmentation in the palms and soles of African Americans

  • lamivudine and doltegravir are given to treat naive pts.
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12
Q

Abacavir:

What is it, what is its clinical application, and what are its toxicities?

Who should it NOT be given to? (2)

A
  • NTRI (guanosine mimic) that should NOT given to HLA-B*5701 genotype pts. or pts with coronary artery disease

CA: treats HIV but does NOT treat HBV

T: potentially fatal hypersensitivity syndrome (HLA) and causes hyperlipidemia/cardiovascular events (CAD)

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13
Q

Tenofovir Disoproxil Fumarate and Alafenamide:

What are they, what are their clinical applications, and what are their toxicities?

A

NRTI (adenosine mimic) with POOR bioavailability; long half-lives and excreted unchanged in urine

CA: HIV and HBV

T: TDF has higher chance of nephrotoxicity w/acute tubular necrosis (Fanconi Syndrome) and dec. bone mineral density than TAF (due to lower plasma conc.)

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14
Q

What is the MOA of INSTIs? (Integrase Strand Transfer Inhibitors)

How are they incorporated into the ARV regime?

A
  • prevent formation of covalent bonds between viral and host DNA (“Strand Transfer” blockage)
  • are primary “+1” active agent recommended for treatment of NAIVE HIV patients
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15
Q

Raltegravir

What is it, what is its clinical application, and what are its toxicities?

A

INSTI that blocks strand transfer; eliminated in urine unchanged

CA: HIV and Naive pt. treatments
- resistance due to integrase mutations

T: little clinical toxicity but can cause Immune Reconstitution Syndrome

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16
Q

Dolutegravir and Bictegravir:

What are they, what are their clinical applications, and what are their toxicities?

A

INSTIs that block strand transfer and viral DNA integration into human DNA

CA: HIV and Naive pt. treatments

  • resistance due to integrase mutations
  • has HIGH GENETIC BARRIER to resistance though

T: D - (immune reconstitution syndrome; avoid in pregnancy) and B - generally well tolerated but only available as fixed-dose single tablet regimen

17
Q

Which INSTI is metabolized by CYP3A4 and needs to be boosted if given? What is it normally given with?

A

ELVITEGRAVIR

  • given with cobicistat, emtiricitabine, and TDF/TAF
18
Q

What is the MOA of Protease Inhibitors?

A
  • frequently second-line “+1” active agents
  • peptide-like chemicals that competitively inhibit activity of viral ASPARTYL PROTEASE by cleaving N-terminal side of Pro residues
  • prevents proteolytic cleavage of HIV gag and pol precursor peptides needed to generate reverse transcriptase, protease, and integrase
19
Q

How are Protease Inhibitors cleared by body and how do they interact with other drugs metabolism?

A
  • highly protein bound in plasma and mainly cleared by hepatic clearance
  • metabolized by CYP3A4 –> all inhibit metabolism of other drugs (RITONAVIR is most potent inhibitor with a low dose able to BOOST other agents)
  • all are substances for P-glycoproteins (MDR1)
20
Q

Saquinavir and Indinavir:

What are they, what are their clinical applications, and what are their toxicities?

A

Saquinavir (first protease inhibitor) and Indinavir are protease inhibitors with poor bioavailability

CA: inhibits HIV-1/2 (Saquinavir - not widely used anymore due to pill burden)

T: S (lipodystrophy - long term) and I (crystaluria and renal stones)

21
Q

Darunavir:

What is it, what are its clinical applications, and what are its toxicities?

A
  • non-peptide protease inhibitor (first choice PI when boosted)

CA: inhibits HIV-1/2 (mainly HIV-1 treatment)

T: rash and hypersensitivity (its a sulfa drug), immune reconstitution syndrome, fat redistribution syndrome

22
Q

Atazanavir:

What is it, what are its clinical applications, and what are its toxicities?

A
  • protease inhibitors (first choice PI when boosted)

CA: inhibits HIV-1/2 (also for naive patients)

T: unconjugated hyperbilirubinemia NOT associated with hepatitis, immune reconstitution syndrome, fat redistribution, hypersensitivity

23
Q

Iopinavir:

What is it, what are its clinical applications, and what are its toxicities?

A
  • protease inhibitor only available in form boosted with ritonavir

CA: inhibits HIV-1/2 (often works when other PI regimes fail, also for naive patients)

T: increases triglycerides and cholesterol

24
Q

Ritonavir and Cobicistat:

What are they, what are their clinical applications, and what are their toxicities?

A

both are used to BLOCK CYP3A4 (Ritonavir is a protease inhibitor though) used to boost levels of protease inhibitors

CA: boost plasma drug levels (cobicistat for Azatanavir and Darunavir)

T: flushing, rash, GI, CYP3A4 effects on other drugs

25
Q

What is the MOA of NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)?

When are they used and what are they NOT good for?

A
  • inhibitor that binds to REVERSE TRANSCRIPTASE and denatures it so that the enzyme cannot produce viral DNA (binds in p66 subunit hydrophobic pocket)
  • act as NON-COMPETITIVE ANTAGONISTS
  • now THIRD-line “+1” active agents
  • only active against HIV-1 because HIV-2 has instrinsic resistance to NNRTI
26
Q

What can cause resistance to NNRTIs?

A
  • single amino acid substitution in binding pocket

ex: single exposure to nevirapine in absence of other drugs causes resistance in 1/3 of HIV infected peoples

27
Q

Nevirapine:

What is it, what are its clinical applications, and what are its toxicities?

What is a special consideration women should be aware of when taking it?

A
  • NNRTI preventing viral DNA generation; induces CYP3A4 (use alternative forms of birth control)

CA: HIV-1 infection in adults and children

T: rash and itching

28
Q

Efavirenz:

What is it, what are its clinical applications, and what are its toxicities?

What is a special consideration women should be aware of when taking it?

A
  • NNRTI preventing viral DNA generation (first NNRTI approved); induces CYP3A4 (use alternate birth control)

CA: HIV-1 infection in adults and children

  • do NOT add to failing regimen
  • co-formulated w/emtricitabine/tenofovir

T: CNS toxicity and psychiatric side effect (few discontinue)
- WAS considered teratogenic (not anymore)

29
Q

Etravirine:

What is it, what are its clinical applications, and what are its toxicities?

A
  • NNRTI used to prevent viral DNA generation; induces CYP3A4

CA: HIV-1; works after mutations that disrupt other NNRTI activity

T: fat redistribution, immune reconstitution syndrome, Stevens-Johnson Syndrome

30
Q

Rilpivirine and Doravirine:

What are they, what are their clinical applications, and what are their toxicities?

A
  • NNRTIs that prevent viral DNA generation; both metabolized by CYP3A4 (Doravirine not impacted by ACID-REDUCING agents)

CA: naive patients with HIV-1 infection

T: R (fat redistribution, CNS, Endo in kids) and D (low incidence of typical problems, immune reconstitution syndrome)

31
Q

Which NNRTI is considered that new “best in class”?

A

Doravirine

  • still 3rd choice among +1 treatments
32
Q

Enfuvirtide (T-20):

What is it, what are its clinical applications, and what is its major toxicity?

How must it be administered?

A
  • HIV fusion inhibitor derived from gp41 part of HIV; inhibits CD4 infection as well as cell-cell transmission

CA: only for TREATMENT-EXPERIENCED adults

  • NOT active against HIV-2
  • very expensive; LAST RESORT drug

T: injection site reactions (MUST BE ADMINISTERED PARENTERALLY)

33
Q

Maraviroc:

What is it, what are its clinical applications, and what is its toxicity?

When is it used?

A
  • chemokine receptor antagonist that blocks GP120 binding to CCR5 co-receptor (blocks CCR5-trophic HIV entry into cells)

CA: for ART combos against HIV that likes CCR5, but NOT active against CXCR4 or mixed tropic HIV viruses
- expensive phenotypic test required to see tropism

T: generally well tolerated, though it is ORALLY active and a CYP3A4 substrate; also adjust renal dose due to renal elimination

used seldomly and is not recommended as initial therapy

34
Q

ART and Preventing Sexual Transmission

A
  • maintaining plasma HIV RNA levels of < 200 copies/mL prevents sexual transmission
  • use alternate prevention for first 6 months of treatment and until levels are < 200 copies/mL
  • MUST MAINTAIN HIGH LEVELS OF ART ADHERENCE; are still vulnerable to other STIs
35
Q

ART and Treatment Failure

A
  • drug-resistance testing while patient is taking failing regimen or < 4 weeks after discontinuation
  • new regimen should include at least 2, if not 3, fully active agents

DO NOT ADD SINGLE antiretroviral agent to failing regimen

36
Q

ART and Child-Bearing Potential/Pregnancy

What drug has been shown to cause neural tube defects in infants born to mothers on ART?

A
  • pregnancy test should be performed for those of childbearing age PRIOR to ART initiation
  • inc. risk of neural tube defects in infants born to mothers taking DOLUTEGRAVIR
  • focus to maintain viral load below limit of detection to reduce risk of transmission to fetus/newborn

SBL (Skin, Blood, Lymph) Exam 1 and 2 (22 decks)

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