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32 Cards in this Set
- Front
- Back
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What are the classes of anti-retroviral drugs for treatment of HIV?
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Nucleoside reverse transcriptase inhibitors (NRTIs)
Non-nucleoside reverse transcriptase inhib. (NNRTIs) Protease inhibitors (PIs) Integrase strand transfer inhibitor (INSTI) Entry / fusion inhibitors (E/F-I) |
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What are the commonly used regimens, in general, for initial HIV treatment?
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2 NRTIs and 1 NNRTI
2 NRTIs and PI 2 NRTIs and INSTI *Subgrouped into preferred, alternative, and acceptable |
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What drugs belong to the class NRTIs?
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Abacavir
Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine |
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What is the MOA of the NRTIs?
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Inhibition of viral reverse transcriptase
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Which drugs in the NRTI class are modified versions of guanosine? Adenosine? Cytosine? Thymidine?
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Guanosine: Abacavir
Adenosine: Didanosine, Tenofovir Cytosine: Lamivudine, Emtricitabine Thymidine: Zidovudine, Stavudine |
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When using NRTIs, ___________ same types and ____________ different types.
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Substitute
Combine |
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T or F: NRTIs are pro drugs and require host cell purine and pyrimidine kinase enzymes to convert them to nucleotides
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True
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What happens to the nucleotide triphosphate form of an NRTI inside CD4 cells harboring replicating HIV?
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The NRTI triphosphate gets blended into pools of natural nucleotides for DNA synthesis.
It is perceived as natural by viral DNA polymerase and used for viral DNA synthesis. Incorporation of NRTI triphosphate into viral DNA terminates the strand elongation. |
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How do NRTI-TPs terminate viral DNA synthesis?
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They lack a 3' hydroxyl group
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T or F: 3 NRTIs is a common regimen used to treat HIV infection
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FALSE
Should never use 3 NRTI in combination |
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What are the advantages and disadvantages of using dual NRTI pairs in initial HIV therapy?
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Advantages: Established backbone of treatment, minimal drug-drug interactions
Disadvantages: Lactic acidosis and hepatic steatosis |
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What is the difference between preferred, alternative, and acceptable dual NRTI initial HIV therapy?
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Preferred: randomized controlled trials show optimal efficacy and durability, favorable tolerability and toxicity
Alternative: Effective, but have potential disadvantages, may be preferred regimen for certain patients Acceptable: Less efficacy, lack of data, or greater toxicity |
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Which two NRTIs are the preferred nucleoside analog coformulation in combo for the treatment naive patient? Why?
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Tenofovir and emtricitabine
Overall potency, favorable toxicity profile, and convenient dosing |
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What NRTI pair is favored in pregnancy?
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Zidovudine and Lamivudine
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What is the hallmark toxicity of NRTIs as a class?
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Mitochondrial toxicity
Corresponds with their inhibition of mitochondrial DNA formation by mitochondrial DNA polymerase gamma ----> leads to impaired oxidative phosphorylation ----> leads to lactate acidosis |
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What is the rank of the NRTI drugs in terms of their inhibition of mitochondrial DNA polymerase gamma (toxicity)?
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Worst: didanosine > stavudine > zidovudine >>>>
Less worse: tenofovir = lamivudine = emtricitabine = abacavir |
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How does NRTI mitochondrial toxicity manifest, and what is the black box warning for the NRTIs?
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May manifest as peripheral neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis
Black box warning: possibility of lactic acidosis syndrome, which is potentially fatal |
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Neuropathy is most closely associated with ___________ and pancreatitis with __________.
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Stavudine
Didanosine |
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When should NRTI treatment be suspended?
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Rapidly rising aminotransferase levels
Progressive hepatomegaly Metabolic acidosis of unknown origin |
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Which NRTI is often used in resource limited settings and why?
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Stavudine
Lower cost and ease of administration as a co-formulated medicine |
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What is abacavir hypersensitivity?
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Idiosyncratic, multisystem inflammatory reaction occurring in 5-8% of white patients
Symptoms appear in >90% of cases within 6 weeks: fever, rash, GI, respiratory symptoms, lethargy, malaise **HLA-B 5701 genotype favors hypersensitivity** |
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What is unique about tenofovir and how is it eliminated from the body?
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The parent molecule has a phosphate
Eliminated via glomerular filtration and active tubular secretion. Risk of nephrotoxicity in patients with renal insufficiency. Use abacavir instead |
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T or F: As a class, NRTIs have lots of clinically significant drug-drug interactions.
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False
Have few interactions because they don't affect CYP 450 at all |
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What drugs belong to the class NNRTIs?
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Delavirdine
Efavirenz Etravirine Nevirapine Rilpivirine |
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What is the MOA of the NNRTIs?
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Bind and distort reverse transcriptase enzyme
Inhibited reverse transcriptase can't make viral DNA |
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What are the advantages of NNRTIs in initial HIV therapy?
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Advantages: Long half life, less metabolic toxicity than PIs, PIs and integrase inhibitors reserved for future use
Disadvantages: prone to resistance, rash, hepatotoxicity, potential drug interactions (CYP450) |
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Which of the NNRTIs is the preferred agent?
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Efavirenz
Overal demonstrated potency, convenience, toxicity profile |
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T or F: Efavirenz is safe to use during pregnancy?
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False
Should NOT be used during first trimester of pregnancy |
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T or F: All NNRTIs have been associated with hypersensitivity and rash, including Stevens Johnson syndrome.
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True
Worst is nevirapine* |
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What is the big downfall of the NNRTIs?
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Low genetic barrier to resistance
Require only a single mutation in reverse transcriptase to confer drug resistance |
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What is the signature mutation in reverse transcriptase to confer resistance to NNRTIs?
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K103N
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Which NNRTI has activity against HIV strains that are resistant to other NNRTIs?
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Etravirine
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