Antiretroviral Agents

Question 1

Integrase inhibitors: MOA, example

Answer 1

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

Question 2

Classes of antiretrovirals

Answer 2

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

Question 3

Nucleoside Reverse Transcriptase Inhibitors (NRTIs): MOA

Answer 3

• 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.

Question 4

Nucleoside Reverse Transcriptase Inhibitors (NRTIs): examples

Answer 4

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

Question 5

NNRTIs: MOA, examples

Answer 5

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

Question 6

Protease Inhibitors: MOA, e.g.

Answer 6

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

Question 7

Entry inhibitors: MOA, e.g.

Answer 7

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

Question 8

Fusion inhibitors: MOA, e.g.

Answer 8

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

Question 9

Clinical significance of NRTI delivery as prodrug

Answer 9

• 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.

Question 10

NRTI: mechanism of resistance

Answer 10

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

Question 11

NNRTI: mechanism of resistance

Answer 11

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

Question 12

Protease inhibitor: mechanism of resistance

Answer 12

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

Question 13

Entry inhibitors: mechanism of resistance

Answer 13

• X4 strains
• mutations in gp120

Question 14

Fusion inhibitors: mechanism of resistance

Answer 14

• Mutation to binding region on gp41

Question 15

Integrase inhibitors: mechanism of resistance

Answer 15

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

Question 16

NRTIs: administration, elimination

Answer 16

• Route: Oral. Bioavailability ranges from 40-85%, +/- food effect. Intracellular t 1/2 > plasma t 1/2
• Elimination
  
  • Primarily, Renal
  • Abacavir, Zidovudine: Hepatic glucouronidation

Question 17

NNRTIs: administration, elimination

Answer 17

• Oral. Good bioavailability.
• Hepatic, CYP450

Question 18

Protease inhibitors: administration, elimination

Answer 18

• Oral
• Hepatic: CYP 450 & CYP3A4

Question 19

Entry inhibitors: administration, elimination

Answer 19

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

Question 20

Fusion inhibitors: administration, elimination

Answer 20

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

Question 21

Integrase inhibitors: administration, elimination

Answer 21

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

Question 22

NRTIs: adverse rxns/drug interactions

Answer 22

• 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

Question 23

NNRTIs: adverse rxns/drug interactions

Answer 23

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

Question 24

Protease inhibitors: adverse rxns/drug interactions

Answer 24

• Class adverse reactions include GI upset, fat redistribution, hyperglycemia, insulin resistance, hyperlipidemia, increased risk of CAD.
• All inhibit CYP3A4

Question 25

Entry inhibitors: adverse rxns/drug interactions

Answer 25

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

Question 26

Fusion inhibitors: adverse rxns/drug interactions

Answer 26

Injection site inflammation

Question 27

Integrase inhibitors: adverse rxns/drug interactions

Answer 27

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