HIV drugs Flashcards
Fusion inhibitor: Enfuvirtide: 36 amino acid peptide which binds to 1) inhibiting 2) of HIV with the target cell
1) gp41 2)fusion
active against HBV, patients co-infected with HIV and HBV should be closely monitored if treatment with either of these drugs is interrupted or discontinued, because of the likelihood of hepatitis flare
NRTIs (Emtricitabine, Lamivudine, Tenofovir):
36 amino acid peptide which binds to gp41 inhibiting fusion of HIV with the target cell
Fusion inhibitor: Enfuvirtide
a/e Metabolic changes including increased lipids, insulin insensitivity, and central fat accumulation
Protease inhibitors: Atazanavir, Darunavir, Ritonavir
binds to CD4
gp120
Binds specifically and selectively to CCR5
Penetration blocker: Maraviroc
Penetration blocker: Maraviroc resistance
develop due to mutations in gp120
Adverse effects i. Rash which could progress to Stevens-Johnson syndrome ii. Fetal abnormalities (neural tube defects)
Nonnucleoside: Efavirenz
Long-term complications of ART include 1). The statins are used to lower lipids but their metabolism is inhibited by 2). This can increase the blood levels of the statin and increase the risk of 3)
1) hyperlipidemia 2) Protease Inhibitorss 3) rhabdomyolysis
used to “boost” the levels of other protease inhibitors when given in combination, thus acting as a pharmacokinetic enhancer rather than an antiretroviral agent
Ritonavir boost
nucleoside analog of cytosine
Lamivudine
Life cycle of HIV:Reverse transcription HIV is equipped with 1)
1) RNA-dependent DNA polymerase (reverse transcriptase);
These drugs do not compete with nucleoside triphosphates nor require phosphorylation to be active
Nonnucleoside: Efavirenz
(nucleotide analog of adenosine
Tenofovir
All newborns born to HIV-infected mothers should receive 1) for 6 weeks; Infants born to mothers with no antiretroviral therapy should receive 6 weeks of 2) during the first week of life
1) zidovudine 2) zidovudine and three doses of nevirapine (an NNRTI)
gp120 and gp41 is made from cleavage of 1); functions of each?
gp160 gp120–> binds to CD4 gp41–> membrane fusion
prevent post-translational cleavage of the Gag-Pol polyprotein resulting in the production of immature, noninfectious viral particle
Protease inhibitors: Atazanavir, Darunavir, Ritonavir
bind directly to reverse transcriptase resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase
Nonnucleoside: Efavirenz
integrase strand transfer inhibitor (INSTI)
Integrase inhibitor: raltegravir
Life cycle of HIV: Penetration Viral gp120 binding to CD4 is enhanced by further binding to chemokine receptors, 1)
1) CCR5 and CXCR4.
Incorporation into the growing viral DNA chain results in premature chain termination due to inhibition of binding with the incoming nucleotide
NRTIs (Emtricitabine, Lamivudine, Tenofovir):
Protease Inhibitor therapy in pregnant women a/e
Hyperglycemia Premature birth
increases drug exposure, thereby prolonging the drug’s half-life and allowing reduction in frequency; in addition, the genetic barrier to resistance is raised
Ritonavir boosting
what is protease? cleaves the large precursor 1) into functional proteins which produce a complete virus; Without this step, 2)
1) polypeptide, known as gag-pol, 2) the virion is immature and unable to infect other cells.
1) catalyzes the process that results in viral DNA insertion into the host genome. 2) block the enzyme’s activity, preventing viral DNA from integrating with cellular DNA.
1) HIV-1 integrase 2) Integrase strand transfer (InST) inhibitors
Prophylaxis of HIV infection: Pre-exposure: oral fixed-dose combination of 1); resistance to 1) if pt infected with HIV so follow-up HIV antibody testing to ensure early diagnosis
1) emtricitabine and tenofovir
T/F–>The binding site of NNRTIs is distinct from that of NRTIs
True
NRTIs therapy in pregnant women a/e
Mitochondrial dysfunction in uninfected children with perinatal exposure to NRTIs
T/F–>there is no cross-resistance between the NRTIs and the NNRTIs
TRUE
A/E Peripheral neuropathy, pancreatitis, lipoatrophy, myopathy, anemia, increased transaminases
NRTIs (Emtricitabine, Lamivudine, Tenofovir):
fluorinated analog of lamivudine
Emtricitabine
HIV treatment during labor: Women who are already in labor and have had no antiretroviral therapy should receive 1) as a continuous infusion to decrease the risk of HIV transmission to the fetus
1) IV zidovudine
NRTIs (Emtricitabine, Lamivudine, Tenofovir) are prodrugs which require 1) to be active
1) phosphoylation to the 5’-triphosphate moiety
Hepatotoxicity
Penetration blocker: Maraviroc
Adverse effects Well-tolerated: diarrhea, nausea, dizziness, and headache
Integrase inhibitor: raltegravir
membrane fusion
gp41
a/e local injection site reactions with mild or moderate pain, erythema, induration, nodules and cysts
Fusion inhibitor: Enfuvirtide:
Life cycle of HIV: Assembly and release a. HIV proteins coalesce under the host cell lipid bilayer b. The nucleocapsid subsequently is formed with 1) and other components packaged inside. c. The virion then 2) d. 3), another enzyme unique to HIV, begins cleaving the large precursor polypeptide, gag-pol, into functional proteins which produce a complete virus. Without this step, the virion is immature and unable to infect other cells
1) viral ssRNA 2) buds through the plasma membrane and maturation begins 3) Protease
Drug interactions: Protease inhibitors can inhibit metabolism of drugs as well, in particular, the 1)
1) statins (e.g., atorvastatin, lovastatin, and others).
Life cycle of HIV: Integration The dsDNA migrates into the 1) and is integrated into the host chromosome by 2) another enzyme unique to HIV
1) nucleus 2) integrase,
Integrase inhibitor: raltegravir resistance
Mutation in integrase
Reverse transcription: i. A cDNA is first synthesized using 1) as a template ii. The RNA portion of the cDNA-RNA hybrid is removed by 2) iii. 3) then completes the synthesis of doublestranded DNA
1) viral RNA 2) ribonuclease H (RNase H) 3) Reverse transcriptase
Fusion inhibitor: Enfuvirtide resistance
due tospecific mutations in the enfuvirtide-binding domain of gp41
Adverse effects i. Cough, pyrexia, upper respiratory tract infection, rash, musculoskeletal symptoms, abdominal pain and postural dizziness
Penetration blocker: Maraviroc
T/F–.Most clinicians believe that the benefit of a potent antiretroviral regimen taken during pregnancy greatly outweighs the risk.
True
Ketoconazole drug interaction with Maraviroc
Inhibitors of P450 (and P-glycoprotein) (e.g., ketoconazole, macrolide antibiotics) increase the effects of maraviroc; may need to decrease dose
Life cycle of HIV: Uncoating After internalization, the viral protein shell surrounding the 1) is uncoated in preparation for replication.
1) nucleic acid (capsid)
Life cycle of HIV: Penetration CD4 and coreceptor binding (i.e., binding to CCR5 or CXCR4) promotes membrane fusion which is mediated by 1)
1) gp41
Pregnancy HIV treatment: In treatment-naive women, 1) and lamivudine plus either lopinavir/ritonavir or atazanavir/ritonavir
1) zidovudine (an NRTI)
NRTIs (Emtricitabine, Lamivudine, Tenofovir): -triphosphate moiety inhibits 1) by competing with endogenous deoxynucleotides for the catalytic site of the enzyme
1) reverse transcriptase
Hepatotoxicity (more common in patients who are co-infected with HBV or HCV
Protease inhibitors: Atazanavir, Darunavir, Ritonavir
Life cycle of HIV: Penetration The outer glycoprotein, gp160, on the surface of HIV is composed of two subunits 1). The 2) subunit is responsible for CD4 binding
1) gp120 and gp41 2) gp120
Life cycle of HIV:Reverse transcription The genetic material of HIV is 1) (5’ to 3’) 2) The virus must transcribe this RNA into DNA
1) positive-sense 2) single-stranded RNA
Adverse effects i. Mitochondrial toxicity due to inhibition of mitochondrial DNA polymerase-γ
NRTIs (Emtricitabine, Lamivudine, Tenofovir):
