Microbiology Case 2: HIV Drugs - Regal Flashcards
What are some general concepts to keep in mind with HIV treatment?
- Goal is fully undetectable levels of virus
- The lower the viral RNA can be driven, the lower the rate of accumulation of drug resistant mutants will be & the longer the therapeutic effect will last
- Maximally inhibit viral replication
- To achieve maximal and durable suppression of viral RNA, drug combinations and patient compliance are required
- Resistance testing recommended before starting therapy
- Monitor HIV RNA levels (viral load) and CD4+ cell count
- increased viral load may indicate development of drug resistance
- Use drug combinations
- but avoid contraindicated drug combinations (lists available)
- Think about drug interactions
- Encourage compliance
What is the MOA of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)?
- Competitively inhibit reverse transcriptase
- in cytosol
- Can be incorporated into viral DNA chain
- the inhibitor binds to the DNA chain and terminates the production of DNA
What do NRTIs require to become active?
Phosphorylation by cellular enzymes to the triphosphate form
What are the four NRTI drugs that we need to know?
- Zidovudine (Azidothymidine or AZT)
- Lamivudine
- Emtricitabine
- Abacavir
What are the general adverse effects of NRTIs?
- Potentially fatal syndrome of lactic acidosis with hepatic steatosis
- probably due to mitochondrial toxicity
- Associated with fat redistribution and hyperlipidemia
- skinny arms and a fat trunk
What is unique about Zidovudine compared to the other NRTI drugs?
- granulocytopenia and anemia in up to 45% of treated patients
- hematological monitoring at 2 week intervals
- CNS disturbances:
- severe headache
- nausea
- insomnia
- malaise
What is unique about Lamivudine & Emtricitabine compared to the other NRTI drugs?
- Probably best tolerated of the NRTIs
- Also active against Hepatitis B
What is unique about Abacavir compared to the other NRTI drugs?
- hypersensitivity reactions can be a problem
What is the MOA of Nucleotide Reverse Transcriptase Inhibitors (NRTI)?
- Same as Nucleoside Reverse Transcriptase Inhibitors:
- Competitively inhibit reverse transcriptase
- in cytosol
- Can be incorporated into viral DNA chain
- the inhibitor binds to the DNA chain and terminates the production of DNA
- Competitively inhibit reverse transcriptase
What is the difference between a nucleotide and a nucleoside?
Nucleotides are phosphorylated nucleosides.
What is the one Nucleotide Reverse Transcriptase Inhibitor drug that we need to know?
Tenofovir
What are adverse side effects of Tenofovir?
- Most common:
- N/V
- Diarrhea
- potential for renal failure
- Potentially fatal syndrome of lactic acidosis with hepatic steatosis
- probably due to mitochondrila toxicity
What is the MOA of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)?
- Bind directly to the reverse transcriptase at a site distinct from that of the NRTI
- enzyme cannot produce viral DNA
- Does not require phosphorylation for activity
What are the two Non-Nucleoside Reverse Transcriptase Inhibitor drugs that we need to know?
- Efavirenz
- Etravirine
Is there cross resistance with NNRTIs and NRTIs and protease inhibitors?
NO
What are adverse side effects of NNRTIs?
- Varying levels of GI intolerance
- Skin rash
- Drug interactions
- metabolized by and can affect hepatic cyp450
can be inducers, inhibitors, or mixed inducers/inhibitors of enzyme
What is unique about Efavirenz compared to the other NNRTIs?
- Once daily dosing
- CNS effects
- vivid dreams
- nightmares
- hallucinations
What is unique about Etravirine compared to the other NNRTIs?
- Rash
- Nausea
- Peripheral neuropathy
What is the MOA of Protease Inhibitors?
- Prevent protease action required for maturation of the fully assembled virus
- prevent post-translational cleavage of the Gag-Pol polyprotein
- prevent the processing of viral proteins into functional conformations
- without cleavage, virus is not infectious
- inhibit HIV protease activity and prevent HIV replication in vitro
- prevent post-translational cleavage of the Gag-Pol polyprotein
- Active against viral strains resistant to reverse transcriptase inhibitors
What are the three Protease Inhibitor drugs that we need to know?
- Atazanavir
- Ritonavir
- Darunavir
What are the potential adverse side effects of Protease Inhibitors?
- GI disturbances
- Hepatotoxicity
- Hyperglycemia and insulin resistance
- Dyslipidemia
- Cardiac conduction abnormalities
- Peripheral lipoatrophy and central fat accumulation
- Metabolized by and inhibit hepatic CYP3A4
What is Ritonavir boosting?
- Giving low doses of Ritonavir (a protease inhibitor) in addition to other PIs
- Why?
- it is a potent inhibitor of CYP3A4
- with CYP3A4 inhibited by Ritonavir, it increases the serum concentrations of other protease inhibitors
- decreases the dosage and frequency of other PIs
What is the name of the pharmacokinetic enhancer that inhibits CYP3A4 as well as certain intestinal transport proteins and can also act as a booster of protease inhibitors (but is not a protease inhibitor itself)?
Cobicistat
What is the MOA of Fusion Inhibitors?
- binds to gp41 and prevents the conformational change required to facilitate fusion of the viral and host cell membranes
