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Flashcards in antiretroviral pharm Deck (40):
1

HIV life cycle

binding to CCR5 or CXCR4 receptors > fusion and uncoating > reverse transcription > integration > transcription > translation > virion assembly > budding and maturation

2

Maximally suppressive antiretroviral therapy requires how many drugs

at least 3

3

goals of anti-HIV therapy

Durable suppression of HIV viral load (< 50 copies/ml). Restoration of immune function (CD4 cell count). Prevent HIV transmission, prevent drug resistance, improve QOL

4

Describe the general HIV treatment regimen

“Backbone” – typically 2 NRTIs. Tenofovir and emtricitabine preferred. “Base” – NNRTI (Efavirenz),OR protease inhibitor (Atazanavir or Darunavir), OR integrase strand transfer inhibitor (Raltegravir), OR CCR5 antagonist (Maraviroc)

5

drugs used to prevent perinatal transmission of HIV

Ritonavir-Lopinavir-rLPV plus Zidovudine-ZDV and Lamivudine-3TC

6

HLA screening for antiretrovirals

HLA 5701 can cause hypersensitivity to abacavir (NRTI)

7

Which antiretroviral is contraindicated in pregnancy

efavirenz (NNRTI)

8

List the NRTIs

Emtricitabine, Tenofovir disoproxil fumarate and abacavir, azidothymidine (AZT)

9

NRTIs MOA and resistance

Nucleoside reverse transcriptase inhibitor. Prevents genome replication and establishment of provirus. prodrug- Activated by intracellular kinases to active triphosphate which competitively inhibits viral RT and causes chain termination. Resistance can arise via mutations on RT and cross resistance within class is common so certain NRTI combos are avoided

10

NRTIs absorption, elimination, considerations

Oral. Intracellular half lives are longer than plasma half lives due to trapping inside cells. Abacavir undergoes hepatic metabolism. Emtricitabine and tenofovir undergo renal excretion (no DDIs) so once daily dosing

11

NRTIs adverse rxns

Inhbition of mitochondrial DNA polymerase gamma can cause anemia, myopathy, neuropathy. Lactic acidosis and hepatic steatosis possible

12

Best tolerated NRTIs

lamivudine and emtricitabine (least toxic): both are also active against HBV. and tenofovir

13

disadvantages of dual NRTIs

Lactic acidosis and hepatic steatosis: lower risk with tenofovir and emtricitabine. Also lipodystrophy possible

14

List the NNRTIs

Efavirenz (plus nevirapine, etravirine)

15

NNRTIs MOA

Non-nucleoside RT inhibitors.•Prevents genome replication - establishment of provirus. Do NOT require activation by intracellular kinases. Bind to non-catalytic hydrophobic region > non-competitively inhibit HIV Reverse Transcriptase

16

NNRTIs resistance

Single AA substitutions on RT. Cross resistance across multiple NNRTIs possible. Etravirine has high barrier to resistance

17

NNRTIs absorption, DDIs

Oral. Nevirapine crosses placenta. Efavirenz induces CYP3A4 (decreases methadone levels)

18

Efavirenz adverse rxns

Severe CNS effects possible. Pregnancy category D. Rash, dizziness, headahce, insomnia

19

Nevirapine adverse rxns

Greater potential for toxicity than efavirenz including hepatic necrosis and serious cutaneous reactions

20

Etravirine adverse rxns

•Generally well tolerated. Rash (less than nevirapine, but can be severe), nausea, hypertension, peripheral neuropathy

21

Disadvantages of NNRTIs in initial therapy

Low genetic barrier to resistance - single mutation, Cross resistance among most NNRTIs, Rash, hepatotoxicity (esp. nevirapine), Potential CYP450 drug interactions, Transmitted resistance to NNRTIs more common than resistance to Pis.

22

Advantages of NNRTIs in initial therapy

long half lives, less metabolic toxicity than Pis, Pis and INSTIs preserved for future use.

23

List the protease inhibitors

Atazanavir, Darunavir

24

Protease inhibitors MOA

•Noncleavable peptidomimetic agents that selectively target retroviral aspartyl proteases (not host proteases) HIV proteases cleaves and processes HIV gag and pol proteins necessary for survival and replication. Thus PIs prevents viral maturation.

25

Protease inhibitors resistance

Requires multiple mutations. High barrier to resistance

26

Protease inhibitors absorption, DDIs

oral. Metabolized by CYP3A4 so Ddis can occur if other drugs (like rotonavir) inhibit CYP3A4.

27

Pis adverse rxns

GI upset, hyperglycemia, hyperlipidemia, risk of CAD, central fat accumulation. Darunavir can cause severe rash (Stevens Johnson syndrome)

28

Pis advantages and disadvantages in intial therapy

advantages: high genetic barrier to resistance. Disadvantages: metabolic complications, GI intolerance, CYP450 drug interactions

29

List the INSTIs

Raltegravir

30

INSTIs MOA

Integrase Strand Transfer Inhibitors - Viral integrase catalyzes direct insertion of viral DNA into host cell DNA. INSTIs inhibit integrase activity preventing HIV-1 replication. No effect on human DNA polymerases

31

INSTIs advantages and disadvantages in initial therapy

advantages: few adverse events, does NOT have DDIs via CYP3A4 interactions. Disadvantages: twice daily dosing, higher risk of resistance than Pis, myopathy, rhabdomyolysis and skin reactions possible

32

HIV mechanisms of entry and when they occur

•HIV-1 virions using CCR5 called “R5 tropic”, present during initial and chronic phases. HIV-1 virions using CXCR4 called “X4 tropic”, associated with later stages and disease progression

33

List the steps of HIV-1 entry

CD4 binding > gp120 conformational change and co-receptor binding > gp41 conformation change/fusion

34

List the HIV entry inhibitors

Maraviroc

35

Maraviroc MOA

antagonist of CCR5 receptor that inhibits its interaction with viral gp120. Indicated for treatment experienced adults with R5-tropic virus

36

Maraviroc resistant

Most common when X4 strains are also present. Mutations in viral gp 120

37

Maraviroc disadvantages

requires tropism testing before use (CCR5 vs CXCR4).

38

Enfuvirtide MOA

Inhibits fusion of HIV-1 with host cell. Enfuvirtide is a synthetic peptidomimetic of the viral gp41 HR2 sequences . prevention of viral entry into cell and infection.

39

Enfuvirtide absorption

•As peptide, must be administered subcutaneously

40

Enfuvirtide adverse rxns

injection site reaction, eosinophilia, bacterial pneumonia, hypersensitivity rxns