HIV Anti-viral Pharmacology (Fitz) Flashcards
Abacavir, Emtracitabine, Lamivudine, Tenofovir, and Zidovudine (prototype) are this class of drugs for HIV infx:
NRTIs –> these are 1st line
Efavirenz (avoid in pregnancy) is first line preferred and Nevirapine and Etravirine are first line alternatives for this drug class in tx of HIV:
NNRTI’s
Atazanavir and Darunavir (1st line), Ritonavir (adjunct), Lopinavir and Tipranavir and Fosamprenevir (alternate) are part of this class of drugs to tx HIV
PI’s
Raltegravir is this type of drug to tx HIV
HIV integrase strand transfer inhibitor
Maraviroc is this type of drug to tx HIV
CCR5 antagonist, Viral fusion/entry inhibitor
Enfuvirtide is this type of drug to tx HIV
GP41 antagonist, viral fusion/entry inhibitor
__ is the major factor contributing to tx failure in HIV
Drug resistance
What is the MOA of NRTI’s?
Inhibition of HIV reverse transcriptase. Incorporate into viral DNA and terminate viral DNA synthesis
To thwart HIV replication host cell purine and pyrimidine kinase enzymes must convert NRTI’s into nucleotide triphosphates of HIV infected CD4 cells
NRTI-TPs terminate viral DNA synthesis because they lack a __
3’-OH group
What is the black box warning of all NRTIs?
Possibility of Lactic Acidosis syndrome, which is potentially fatal –> NRTI inhibits DNA polymerase gamma of mitochondria and impairs ox pho which leads to mt deficiency in proteins for ox pho
Also, features of hepatic dysfunction
When should NRTI tx be suspended?
In setting of:
- rapidly rising aminotransferase levels
- progressive hepatomegaly
- metabolic acidosis of unknown cause
What is a potential toxicity of Tenofovir? What should it be replaced with?
Risk of nephrotoxicity in pts w/ renal insufficiency
Abacavir is preferred since it is not associated with renal toxicity
What is the HLA genotype that, if tested positive for, you should avoid Abacavir?
HLA-B*5701 –> ~6% pts are positive for genotype and want to avoid d/t hypersensitivity
How are NRTIs eliminated?
Regally –> few clinically significant drug-drug interactions
__ are the “backbone” in all regimens to control and treat HIV:
NRTIs
AVOID 3 NRTI COMBOS D/T ADDITIVE TOXICITY
What is the DHHS recommendation for dual-NRTI pairs to tx the naive pt because of its overall potency, favorable toxicity profile, and convenient dosing?
Tenofovir/emtricitabine (TDF/FTC)
This NRTI pair is preferred in pregnancy:
Zidovudine/Lamivudine
KNOW THIS!!!!!
When is Efavirenz not the preferred NNRTI?
Not preferred in 1st trimester of pregnancy
This NNRTI is for drug-resistant HIV strains
Etravirine
What is the MOA of NNRTIs?
Bind and distort reverse transcriptase. Inhibited reverse transcriptase cannot make viral DNA
What is a toxicity of NNRTIs?
All NNRTIs have been associated with rash and hypersensitivity-including Stevens Johnson syndrome (worse with Nevirapine)
Hepatotoxicity may be severe and life-threatening
In regards to NNRTI resistance, most experts do not continue NNRTI meds in teh setting of __ mutation
K103N
What is the current clinical use of NNRTIs?
In combo therapy together with 2 NRTIs
TDF/FTC/EFV (Aritripla)
What are PIs used with for a “boosting” effect?
Ritonovir
Boosts bioavailability and PK of other protease inhibitors
What is the MOA of PIs?
Mimic peptide bond betwen Phenylalanine and Proline at positions 167 and 168 of gag-pol polyprotein, which is the target of HIV aspartyl protease
How are PIs metabolized?
Extensive hepatic metabolism –> poor bioavailability
What does Ritonavir inhibit to boost levels of other PIs (ATV or LPV)?
CYP3A
Darunavir, fosamprenavir, and tipranavir provoke this hypersensitivity:
Sulfonamide
What are acute/short term adverse effects of PIs? Long-term?
Acute/short term: Hepatotoxic, Drug-drug interactions
Long: hyperlipidemia (increased visceral fat), lipodystrophy, insulin resistance
What are current clinical use of PIs?
In combo therapy together with 2 NRTIs
Preferred: TDF/FTC PLUS ATV/Ritonavir or DRV/Ritonavir
Describe what you should do for HIV post-exposure prophylaxis:
4 week tx with 2-3 drug regimen. Must be started ASAP-always within 3 days of a possible exposure
2 drug option: Tenofovir + Emtricitabine, once daily
3 drug option: The 2 above with the addition of Raltegravir
What is the overall preferred regimen in HIV+ pregnant women?
2 NRTIs-Zidovudine/Lamivudine PLUS PIs-Lopinavir/ritonavir
What is the MOA of Raltegravir?
HIV integrase inhibitor
Excellent tolerance and lack of impact on lipids
What is the MOA of Maraviroc?
Blocks binding of HIV outer envelope protein gp120 to CCR5 chemokine receptor –> prevents downstream events
What is the MOA of Enfuvirtide?
Inhibits gp41 fusion and entry
What are adverse effects of Enfuvirtide?
Injection site rxns
Hypersensitivity rxns
Increased risk of bacterial pneumonia
