Antiretroviral Agents Flashcards Preview

Infectious Disease: Unit 2 > Antiretroviral Agents > Flashcards

Flashcards in Antiretroviral Agents Deck (27):
1

Integrase inhibitors: MOA, example

  • e.g.: raltegravir
  • Inhibits viral integrase activity

2

Classes of antiretrovirals

  • Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
  • Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
  • Protease Inhibitors
  • Entry Inhibitors
  • Fusion Inhibitors
  • Integrase Inhibitors

3

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.

4

Nucleoside Reverse Transcriptase Inhibitors (NRTIs): examples

  • Abacavir
  • Didanosine
  • Emtricitabine
  • Lamivudine
  • Stavudine
  • Zidovudine (ZDV)

5

NNRTIs: MOA, examples

  • Bind to noncatalytic site to inhibit reverse transcriptase
  • E.g.:
    • Delavirdine
    • Efavirenz
    • Etravine

6

Protease Inhibitors: MOA, e.g.

  • Inhibits Viral protease critical for posttranslational protein processing
  • E.g. ("-avir"):
    • Atazanavir
    • Darunavir
    • Ritonavir
    • Saquinavir, Indinavir, Nefinavir, Amprenavir

7

Entry inhibitors: MOA, e.g.

  • Block of CCR5-trophic HIV 1 into CD4 cells by antagonizing CCR5 receptor.
  • E.g.: Maraviroc

8

Fusion inhibitors: MOA, e.g.

  • 36 AA peptide that prevents HIV fusion with gp41 and cell entry
  • E.g.: Enfuviratide aka T20

9

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.

10

NRTI: mechanism of resistance

  • Cross resistance across NTRI family members associated with point mutations in reverse transcriptase
     

11

NNRTI: mechanism of resistance

  • Mutations in single AA's target hydrophobic binding pocket of agents.
  • Resistance to one confers cross resistance to others
     

12

Protease inhibitor: mechanism of resistance

  • Single amino acid substitutions, usually PI specific.
  • Much higher barrier to resistance
     

13

Entry inhibitors: mechanism of resistance

  • X4 strains
  • mutations in gp120

14

Fusion inhibitors: mechanism of resistance

  • Mutation to binding region on gp41

15

Integrase inhibitors: mechanism of resistance

  • Point mutation.
  • Emergence in pts not taking other fully active drugs

16

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

17

NNRTIs: administration, elimination

  • Oral. Good bioavailability.
  • Hepatic, CYP450
     

18

Protease inhibitors: administration, elimination

  • Oral
  • Hepatic: CYP 450 & CYP3A4

19

Entry inhibitors: administration, elimination

  • Oral, 30% bioavailability
  • Hepatic (P3A4) / Fecal + Renal

20

Fusion inhibitors: administration, elimination

  • SQ injection twice daily (bid)
  • Liver + Kidney / Proteolytic Hydrolysis

21

Integrase inhibitors: administration, elimination

  • Oral, separate dosing from antacids
  • Hepatic Glucouronidation.
    • rifampin induces this pathway.

22

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
     

23

NNRTIs: adverse rxns/drug interactions

  • Class adverse reactions include GI disturbances and skin rashes
  • Interactions @ CYP450

24

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
     

25

Entry inhibitors: adverse rxns/drug interactions

  • Mild, GI, HA, URI, insomnia, rash
  • DDI with inducers and inhibitors of CYP3A4 (eg -navir)

26

Fusion inhibitors: adverse rxns/drug interactions

Injection site inflammation

27

Integrase inhibitors: adverse rxns/drug interactions

  • Well tolerated. N/D/HA.
  • Incidences of myopathy, rhabdomyolysis reported.
  • Hypercholesterolemia.