Anti-HIV drugs Flashcards
Anti-HIV drug categories (4)
-Fusion inhibitors (now less used- either gp41 targeting or CCR5)
-Reverse Transcriptase inhibitors (nucleoside or non-nucleoside)
-Integrase inhibitors
-Protease inhibitors
plus coformatulations of these drugs for combo therapy
Gp41
viral surface protein protected by gp120. CCR5/CD4 peel back gp120, allowing gp41 to bind and pull surfaces together. Inhibited by fusion inhibitors (enfuvirtide, maraviroc (inhibits CCR5))
Enfuvirtide (class, mechanism, side effects)
fusion inhibitor- prevents unfolded gp41 from refolding to bring cell–>virus and allow fusion
- only works vs HIV1
- side effects: skin reactions (from IM injection), incidence of pneumonia
Maraviroc (class, mechanism, metabolism, side effects)
-Fusion inhibitor
-Binds CCR5, preventing HIV binding and entering CD4
-only works vs. HIV isolates that use CCR5 (not CXCR4).
-CYP metabolism
Side effects: hepatotoxicity, drug interactions (CYP), cough, URT, abdominal pain, rash. Rare MI
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) (mechanism, major side effect, drugs (2))
Chain terminators- resemble nucleosides but missing 3’ OH, so cant elongate DNA once incorporated
- preferential viral since human DNApol distinguishes better, but mitochondrial not, so mitochondrial defects/lactic acidosis
- Zidovudine (AZT), many others. We need to know Emtricitabine and Tenofovir
- prodrugs, phosphates added once in cells to make active
Emtricitabine (class, combo)
Newer NRTI (improved lamivudine), one-a-day pill -Truvada = Emtricitabine + Tenofovir
Tenofovir (class, side effects, combos, improved combo)
NRTI (contains phosphate, so nucleoTIDE RTI)
- side effects: nephrotoxicity, decreased bone mineral density
- Truvada = emtricitabine + tenofovir
- Tenofovir alafenamide fumarate- improved tenofovir, only deprotects once in lymphocytes
- Descovy = emtricitabine + tenofovir AF
non-NRTIs (mechanism, administration, metabolism, drugs (1))
RT inhibitors, but by allosteric RT binding to prevent polymerization activity
- only work vs HIV1
- oral administration, always in combination
- CYP metabolism, watch out for drug interactions
- side effects: rash, elevated liver enzymes
- Etravirine
Etravirine (class, mechanism, special use)
non-NRTI
- “strategic flexibility” prevents resistance
- used as second line drug for NNRTI resistance
Integrase inhibitors (mechanism, drugs (3))
prevent action of integrase (integrate viral DNA into human genome)
-include raltegravir, elvitegravir, dolutegravir (-tegravirs = inTEGRAse)
Raltegravir (class, mechanism)
integrase inhibitor (ISTI, integrase strand transfer inhibitor)
- binds Mg2+ of enzyme, kicking out 3’OH, preventing elongation
- low toxicity, so good adherence/first line drug
Elvitegravir (class, mechanism, combo pill)
integrase inhibitor (ISTI), same as raltegravir
- given as combo pill STRIBILD together with cobicistat (inhibit p450, increasing half life), descovy (emtricitabine + tenofovir - NRTIs)
- watch out for CYP drug interactions
Dolutegravir
Integrase inhibitor (ISTI) -combo pill is Triumeq- dolutegravir, abacavir + lamivudine (NRTIs)
Fusion inhibitors (mechanisms, drugs)
Enfuvirtide, maraviroc
-prevent gp41 refolding to to bring surfaces together for fusion, or bind CCR5 to prevent gp41 binding
Protease Inhibitors (mechanism, side effects, metabolism, drugs(2))
- inhibit HIV proteases, needed to cleave polypeptide into gag/pol/env proteins
- mimic transition state of protease substrate (2x 3º OH)
- CYP3A4 metabolism, so drug interactions (KCM, rifampin)
- side effects: changes in body fat, hyperlipidemia, diabetes
- Atazanavir, Darunavir (-navir - sounds like nazir, prevents cutting)
