6. Antiretroviral agents. Flashcards
What is the MOA of Nucleotide Reverse Transcription Inhibitors (NRTIs).
Nucleotide Reverse Transcriptase Inhibitors (NRTIs) also known as HAART (highly active antiretroviral therapy) are nucleotides + nucleosides that lack an OH group necessary for 3’ → 5’ phosphodiester bond formation → chain termination. Nucleoside NRTIs need P-ation by cellular enzymes to be active. Generally, analogs of the same purine/pyrimidine bases (i.e. two cytosine analogs) are not given together.
List the 1st line NNRTIs.
- Efavirenz
- Nevirapine
- Delaviridine
List the 2nd line NNRTIs.
- Ertavirine
- Rilpivirine
List the NRTIs.
- Lamivudine
- Tenofovir
- Zidovudine - AKA azidothymidine, ZDV or AZT
- Stavudine
- Didanosine
- Abacavir
- Emitricitabine
- Zalcitabine - cytosine analog, withdrawn in Europe
List the protease inhibitors.
- Indinavir
- Ritonavir
- Saquinavir
- Atazanavir (newer, least metabolic effects)
- Others: Darunavir, Lopinavir, Tipranavir, Indinavir, Nelfinavir, Fosamprenavir.
Most have the “-avir” suffix (remember “guinevere”-based Sketchy scene)
List the integrase inhibitors.
- Raltegravir
- Elvitegravir
- Dolutegravir
List the fusion inhibitors.
- Enfuviritide
List the entry inhibitors.
- Maraviroc
What are the side effects of NRTIs?
- Mitochondrial toxicity - all
- Lactic Acidosis - all
- Lipodystrophy - zidovudine and stavudine
- Peripheral Neuropathy - lamivudine, stavudine, didanosine
- Headache, Fatigue, GI issues, Liver dysfunction - all
What are the indications for Lamivudine?
Lamivudine is a cytosine analog used for Hepatitis B treatment.
What are the side effect of Lamivudine?
This is the least toxic, but also least effective NRTI.
- Peripheral Neuropathy
What are the indications for Tenofovir?
Tenofovir is the only nucleotide NRTI (no P-ation required) and is used for Hepatitis B.
What are the indications of Zidovudine?
Zidovudine is used for HIV in pregnancy + breastfeeding to prevent vertical transmission as well as infant prophylaxis.
What are the side effects of Stavudine?
- Peripheral Neuropathy
- Also myelosuppression, but not as bad as AZT.
What are the side effects of Didanosine?
- Pancreatitis - dose-dependent.
- Peripheral Neuropathy - especially ↑ risk if with stavudine.
- also hyperuricemia and liver dysfunction.
What are the side effects of Abacavir?
- Hypersensitivity - type IV → delayed rash; HLA-B57:01 assoc.
What are the side effects of Emtricitabine?
- Palmoplantar Hyperpigmentation
What is the MOA of Non-Nucleotide Reverse Transcriptase Inhibitors (NNRTIs)?
NNRTIs directly bind HIV reverse transcriptase → allosteric inhibition of DNA polymerase activity.
What are the side effects of NNRTI’s?
common in NNRTIs:
- Flu-like Symptoms: abrupt onset
- Hepatic failure: abdominal pain, fever, jaundice (within 6 wks of start)
- Skin Rash: sometimes more severe, as Stevens-Johnson syn.
- Drug Interactions: CYP450 induction + inhibition
- Teratogenicity: both delavirdine and efavirenz
What is the mechanism behind NNRTIs resistance?
Resistance is only active for HIV-1; resistance to 1st gen NNRTIs by point mutation in some strains.
What are the side effects of Efavirenz?
- CNS effects: dizziness, drowsiness, headache, psychosis, insomnia, nightmares
- Teratogenicity
- CYP450 induction and inhibition
What is the MOA of Protease inhibitors?
Protease Inhibitors inhibit HIV aspartate proteases (encoded by POL gene) necessary for cleavage of HIV polyprotein gene products (no similar protease in humans → selectivity).
What is the MOA of Entry Inhibitors?
Entry Inhibitors binds to T-cell surface protein CCR5 → blocks HIV env-encoded gp120 from co-binding CD4/CCR5 during viral entry into cell (does not work for HIV strains with CXCR4 instead of CCR5).
What is the MOA of Fusion inhibitors?
Fusion Inhibitors block env-encoded viral gp41, which normally facilitates HIV fusion to T cells.
What is the MOA of Integrase Inhibitors?
Integrase Inhibitors block pol-encoded viral integrases, which normally allow integration of viral DNA into host genome.
What are the indications for Integrase inhibitors?
known as cART (combined anti-retroviral therapy)
- HIV-related symptoms - of HIV opportunistic infections / HBV coinfection
- CD4+ count <200 - definite indication, but <350 also recommended
- Viral load > 5000 - 10,000 / ml
- Pregnancy - all except efavirenz (teratogen)
- Prophylaxis in exposed medical staff
- Children - more aggressive tx bc of faster progression
- Sexual Partners
What are the side effects of Zidovudine?
- Myelosuppression - causing anemia and neutropenia
- Lipodystrophy - redistribution of fat from limbs to trunk
- Headaches
- Asthenia
- Myalgia and myopathy
- Peripheral neuropathy
What are the indications for Emtricitabine?
Emtricitabine a cytosine analog (a newer form of lamivudine) which is also effective against hepatitis B.
What is the mechanism behind integrase inhibitor resitance?
Resistance happens via pol mutation (affects efficacy of NRTIs, NNRTIs, PIs and integrase inhibitors).
What are the side effects of integrase inhibitors?
- Rhabdomyolysis - rare; seen as ↑ creatine kinase
NNRTIs is also part of which therapy?
Also part of “HAART” therapy.
HAART = highly active antiretroviral therapy.
What are the side effects of Delavirdine?
- Teratogenicity
- CYP450 induction and inhibition
What are the indications for Nevirapine?
Single dose intrapartum ↓ vertical transmission 50%.
What are the kinetics like for Nevirapine?
Penetrates CNS well (others do not) → worse CNS effects!
What are the side effects of Nevirapine?
Moderate CYP450 induction
What are the side effects of Maraviroc?
- HA, dizziness
- Orthostatic hypotension
- Airway infections
- Allergic
- Liver disorders
- Increased malignancy
What is the mechanism behind protease inhibitors resistance?
POL gene mutation → resistant proteases
What is the mechanism behind Entry inhibitors resistance?
via env mutation
What are the side effects of protease inhibitors?
- Hyperglycemia - via insulin resistance; can → diabetes
- Dyslipidemias - TAGs and LDL ↑
- Lipodystrophy - ↑ fat on back/abdomen, ↓ on face/limbs
- CYP450 Inhibition - worst with ritonovir
- Interactions: rifampin CYP induction will ↓ protease inhibitor levels; use rifabutin instead!
What is the mechanism behind fusion inhibitors resistance?
via env mutation
How is maraviroc metabolized?
Metabolized by CYP3A4
What are the side effects of Enfuviritide?
Enfuvirtide is a polypeptide, administered subcutaneously. It is well tolerated, but may cause local reactions, HA, nausea, bacterial pneumonia?
What are the indications for Enfurviritide?
They are used for multidrug-resistant cases.
What are the side effects of Indinavir?
- Nephrolithiasis - within days of starting; ↓ by hydration
What are the side effects of Ritonavir?
Worst CYP inhibition among protease inhibitors. Can be used to ↑ levels of other CYP-metabolized protease inhibitors!
What are some important remarks about Saquinavir?
Saquinavir is the oldest, least toxic and has↓ oral availability.
What are the kinetic parameters of Raltegravir?
- Raltegravir is given orally
- Metabolized by glucuronide conjugation
What are the side effects of Raltegravir?
Chelates bivalent cations, generally well tolerated, but GI, HA, dizziness, rashes may occur.
What are the side effects to Elvitegravir?
Elvitegravir has similar sfx to raltegravir; given with CYP inhibiting “booster” (ritonavir or cobicstat).
What are the side effects of Dolutegravir?
- Severe HS rxns
- Insomnia
- Headache
What are the indications of Dolutegravir?
Known as cART (combined anti-retroviral therapy)
- HIV-related symptoms - of HIV opportunistic infections / HBV coinfection
- CD4+ count <200 - definite indication, but <350 also recommended
- Viral load > 5000 - 10,000 / ml
- Pregnancy - all except efavirenz (teratogen)
- Prophylaxis in exposed medical staff
- Children - more aggressive tx bc of faster progression
- Sexual Partners
