C.6. Antiretroviral agents Flashcards
what do NRTI’s stand for?
Nucleoside/Nucleotide reverse transcriptase inhibitors
what is the mechanism of action of NRTI’s?
competitively inhibit the binding of natural nucleotides to reverse transcriptase (RNA- dependent DNA polymerase enzyme)
act as a DNA chain terminator, binding with no 3’ OH group
What are NRTI’s?
prodrugs, converted by host cell kinases to triphosphates
when does Resistance happen when giving NRTI’s or NNRTI’s?
when using a single agent, via mutations in the Pol Gene
side effects of NRTI’s
GI distress headache, fatigue hepatotoxicity lactic acidosis mitochondrial toxicity
list the NRTI’S
Abacavir (ABC) Emtricitabine (FTC) Lamivudine (3TC) Zidovudine (ZDV) *have you dined (vudine) with my nuclear (nucleosides) family Tenofovir (TDF)
which NRTI is a nucleotide?
Tenofovir
all the others are nucleosides, require more phosphorylation steps for activation
which NRTI’s are used for hepatitis B infection?
Lamivudine
Tenofovir
which NRTI’s is a Guanosine analogue?
Abacavir
which NRTI is used during pregnancy and lactation?
Zidovudine
what are the contraindications for giving Emtricitabine?
pregnancy, children, renal or hepatic dysfunction
which NRTI is the least potent and least toxic agent?
Lamivudine
which NRTI is the most toxic?
zidovudine
bone marrow suppression–> may need blood transfusions
which metabolism does Zidovudine have?
hepatic+ renal elimination
which NRTI is a more potent agent of Lamivudine?
Emtricitabine
which type of toxicity does Tenofovir cause?
Nephrotoxicity
what are the SE’s of Abacavir treatment?
allergy
associated with HLA-B *57:01 allele
what is the SE of Emtricitabine?
GI distress
what does Lamivudine cause?
peripheral neuropathy (mild)
what are NNRTI’s
Non- nucleoside reverse transcriptase inhibitors
NNRTI’s are not active against..?
HIV-2 strains
what is the mechanism of NNRTI’s?
bind to a site on reverse transcriptase different from the binding site of NRTI’s
a synergistic effect is achieved when NNRTI’s is used with..
NRTI’s and/or PI’s
is there cross-resistance of NNRTI’s with NRTI’s?
no
what is Etravirine?
the newest NNRTI approved for HIV treatment (2nd gen’)
maybe effective against strains resistant to other NNRTI’s
side effects of Etravirine
rash, nausea, diarrhea
is Etravirine an inducer or inhibitor of CYP450 enzymes
both
extensive drug-drug interactions
what is Elvitegravir?
Integrase inhibitor
what is the mechanism of action of Elvitegravir (tegra)
pyrimidine derivative that binds integrase
inhibits the integration of transcribed viral DNA into host cell chromosomes
is Elvitegravir safe during pregnancy?
yes
how do we give Elvitegravir?
orally
what are the SE of Elvitegravir
↑ CK, myopathy, rhabdomyolysis
nausea, headache, dizziness
list the protease inhibitors
Ritonavir
Darunavir
Lopinavir
“Navir (Never) tease a protease”
which proton inhibitor is the most commonly used?
Ritonavir
which PI is used in combination with Ritonavir in patients resistant to other PI’s?
Darunavir
mechanism of action of Protease inhibitors
inhibits Aspartate protease (encoded by Pol gene)
what is the mechanism of resistance of PI’s?
specific point mutations in the Pol gene
are all the PI’s substrates and inhibitors of cytochrome P450 enzymes?
yes,
extensive drug-drug interactions
the fact the PI’s inhibits lipid-regulating proteins has led to the development of..
metabolic disorder
which PI is used in combination with subtherapeutic dose of Ritonavir?
Lopinavir
ritonavir inhibits lopinavir metabolism –> enhances it’s activity
which PI is the most potent inhibitor of P450 enzymes?
ritonavir
boost other drug concentrations
what are the SE of ritonavir
Gi distress, bitter taste
hepatotoxicity
what are the SE of Darunavir
GI distress, skin rash
sulfonamide hypersensitivity reaction
what is Maraviroc?
CCR5 receptor inhibitor –> prevent interaction between viral gp120 and CD4 on the target cell
is Maraviroc given with other antiretroviral agents?
yes
how is Maraviroc given?
oral
what are the SE of Maraviroc
cough
diarrhea
muscle and joint pain
↑ liver enzymes
what is the approach for HAART? give examples
initiation of 3 antiretroviral drugs (‘2+1 role’), before symptoms appear (if possible)
Tenofovir+Emtricatbine+ Etravirine (NNRTI)
Tenofovir+Emtricatbine+ Ritonavir (PO)
Tenofovir+Emtricatbine+ Elvitegravir (Integrase inhibitor)
what is PrEP?
pre-exposure prophylaxis
Tenofovir +Emtricitabine
what is PEP?
post-exposure prophylaxis
Tenofovir +Emtricitabine +/- Reltegravir
what do we give for pregnancy antiretroviral prophylaxis?
2+1 regimen +zidovudine
prevent vertical transmission
