Antiretroviral Agents Flashcards
Integrase inhibitors: MOA, example
- e.g.: raltegravir
- Inhibits viral integrase activity
Classes of antiretrovirals
- Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
- Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
- Protease Inhibitors
- Entry Inhibitors
- Fusion Inhibitors
- Integrase Inhibitors
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): MOA
- Nucleoside analogues that are activated (phosphorylated) by host cell kinases to active form that inhibits VIRAL reverse transcriptase.
- Gets incorporated and into DNA and causes chain termination.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): examples
- Abacavir
- Didanosine
- Emtricitabine
- Lamivudine
- Stavudine
- Zidovudine (ZDV)
NNRTIs: MOA, examples
- Bind to noncatalytic site to inhibit reverse transcriptase
- E.g.:
- Delavirdine
- Efavirenz
- Etravine
Protease Inhibitors: MOA, e.g.
- Inhibits Viral protease critical for posttranslational protein processing
- E.g. (“-avir”):
- Atazanavir
- Darunavir
- Ritonavir
- Saquinavir, Indinavir, Nefinavir, Amprenavir
Entry inhibitors: MOA, e.g.
- Block of CCR5-trophic HIV 1 into CD4 cells by antagonizing CCR5 receptor.
- E.g.: Maraviroc
Fusion inhibitors: MOA, e.g.
- 36 AA peptide that prevents HIV fusion with gp41 and cell entry
- E.g.: Enfuviratide aka T20
Clinical significance of NRTI delivery as prodrug
- mechanism used by NRTIs to inhibit reverse transcriptase is highly reminiscent of that employed by their counterparts to inactivate Herpes, CMV, or Hepatitis viral DNA polymerases inhibitors.
- NRTIs are prodrugs that enter cells and are then phosphorylated by cellular kinases to their triphosphorylated and fully active forms.
NRTI: mechanism of resistance
- Cross resistance across NTRI family members associated with point mutations in reverse transcriptase
NNRTI: mechanism of resistance
- Mutations in single AA’s target hydrophobic binding pocket of agents.
- Resistance to one confers cross resistance to others
Protease inhibitor: mechanism of resistance
- Single amino acid substitutions, usually PI specific.
- Much higher barrier to resistance
Entry inhibitors: mechanism of resistance
- X4 strains
- mutations in gp120
Fusion inhibitors: mechanism of resistance
- Mutation to binding region on gp41
Integrase inhibitors: mechanism of resistance
- Point mutation.
- Emergence in pts not taking other fully active drugs
NRTIs: administration, elimination
- Route: Oral. Bioavailability ranges from 40-85%, +/- food effect. Intracellular t 1/2 > plasma t 1/2
- Elimination
- Primarily, Renal
- Abacavir, Zidovudine: Hepatic glucouronidation
NNRTIs: administration, elimination
- Oral. Good bioavailability.
- Hepatic, CYP450
Protease inhibitors: administration, elimination
- Oral
- Hepatic: CYP 450 & CYP3A4
Entry inhibitors: administration, elimination
- Oral, 30% bioavailability
- Hepatic (P3A4) / Fecal + Renal
Fusion inhibitors: administration, elimination
- SQ injection twice daily (bid)
- Liver + Kidney / Proteolytic Hydrolysis
Integrase inhibitors: administration, elimination
- Oral, separate dosing from antacids
- Hepatic Glucouronidation.
- rifampin induces this pathway.
NRTIs: adverse rxns/drug interactions
- Class adverse reactions include rare mitochondrial toxicity, myopathy, neuropathy, via inhibition of DNA polymerase gamma, lactic acidosis, and hepatic steatosis, bone marrow suppression, rash, megaloblastic anemia
NNRTIs: adverse rxns/drug interactions
- Class adverse reactions include GI disturbances and skin rashes
- Interactions @ CYP450
Protease inhibitors: adverse rxns/drug interactions
- Class adverse reactions include GI upset, fat redistribution, hyperglycemia, insulin resistance, hyperlipidemia, increased risk of CAD.
- All inhibit CYP3A4
Entry inhibitors: adverse rxns/drug interactions
- Mild, GI, HA, URI, insomnia, rash
- DDI with inducers and inhibitors of CYP3A4 (eg -navir)
Fusion inhibitors: adverse rxns/drug interactions
Injection site inflammation
Integrase inhibitors: adverse rxns/drug interactions
- Well tolerated. N/D/HA.
- Incidences of myopathy, rhabdomyolysis reported.
- Hypercholesterolemia.
