antiretroviral pharm Flashcards
HIV life cycle
binding to CCR5 or CXCR4 receptors > fusion and uncoating > reverse transcription > integration > transcription > translation > virion assembly > budding and maturation
Maximally suppressive antiretroviral therapy requires how many drugs
at least 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
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)
drugs used to prevent perinatal transmission of HIV
Ritonavir-Lopinavir-rLPV plus Zidovudine-ZDV and Lamivudine-3TC
HLA screening for antiretrovirals
HLA 5701 can cause hypersensitivity to abacavir (NRTI)
Which antiretroviral is contraindicated in pregnancy
efavirenz (NNRTI)
List the NRTIs
Emtricitabine, Tenofovir disoproxil fumarate and abacavir, azidothymidine (AZT)
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
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
NRTIs adverse rxns
Inhbition of mitochondrial DNA polymerase gamma can cause anemia, myopathy, neuropathy. Lactic acidosis and hepatic steatosis possible
Best tolerated NRTIs
lamivudine and emtricitabine (least toxic): both are also active against HBV. and tenofovir
disadvantages of dual NRTIs
Lactic acidosis and hepatic steatosis: lower risk with tenofovir and emtricitabine. Also lipodystrophy possible
List the NNRTIs
Efavirenz (plus nevirapine, etravirine)
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
NNRTIs resistance
Single AA substitutions on RT. Cross resistance across multiple NNRTIs possible. Etravirine has high barrier to resistance
NNRTIs absorption, DDIs
Oral. Nevirapine crosses placenta. Efavirenz induces CYP3A4 (decreases methadone levels)
Efavirenz adverse rxns
Severe CNS effects possible. Pregnancy category D. Rash, dizziness, headahce, insomnia
Nevirapine adverse rxns
Greater potential for toxicity than efavirenz including hepatic necrosis and serious cutaneous reactions
Etravirine adverse rxns
•Generally well tolerated. Rash (less than nevirapine, but can be severe), nausea, hypertension, peripheral neuropathy
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.
Advantages of NNRTIs in initial therapy
long half lives, less metabolic toxicity than Pis, Pis and INSTIs preserved for future use.
List the protease inhibitors
Atazanavir, Darunavir
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.
Protease inhibitors resistance
Requires multiple mutations. High barrier to resistance
Protease inhibitors absorption, DDIs
oral. Metabolized by CYP3A4 so Ddis can occur if other drugs (like rotonavir) inhibit CYP3A4.
Pis adverse rxns
GI upset, hyperglycemia, hyperlipidemia, risk of CAD, central fat accumulation. Darunavir can cause severe rash (Stevens Johnson syndrome)
Pis advantages and disadvantages in intial therapy
advantages: high genetic barrier to resistance. Disadvantages: metabolic complications, GI intolerance, CYP450 drug interactions
List the INSTIs
Raltegravir
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
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
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
List the steps of HIV-1 entry
CD4 binding > gp120 conformational change and co-receptor binding > gp41 conformation change/fusion
List the HIV entry inhibitors
Maraviroc
Maraviroc MOA
antagonist of CCR5 receptor that inhibits its interaction with viral gp120. Indicated for treatment experienced adults with R5-tropic virus
Maraviroc resistant
Most common when X4 strains are also present. Mutations in viral gp 120
Maraviroc disadvantages
requires tropism testing before use (CCR5 vs CXCR4).
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.
Enfuvirtide absorption
•As peptide, must be administered subcutaneously
Enfuvirtide adverse rxns
injection site reaction, eosinophilia, bacterial pneumonia, hypersensitivity rxns
