HIV drugs Flashcards
o resistance - change in AA of gp41
o binds gp41 to prevent conformational change needed for binding to CCR5 or CXCR4 - virus can no longer enter
o injection administration - not a first line drug for this reason
Fusion inhibitors
o inhibits CCR5 R → virus can’t bind and can’t enter cell
o If virus uses CXCR4 the drug will not function - can be a form of resistance
o would need to do tropism testing in order to determine if the virus is using CXCR4 rather than CCR5
Chemokine receptor inhibitors
o pro-drug → phosphorylated into active form → inhibit RT or incorporate into viral DNA as it is being made →inhibit production of the dsDNA
o host cellular enzyme does the phosphorylating - the enzyme converting nucleoside to nucleotides
o competitive inhibitor
o Occurring in cytosol (where reverse transcriptase is)
NucleoSide reverse transcriptase inhibitors
o Nucleotide has been phosphorylated
o Skip first step of nucleoside reverse transcriptase inhibitors
o Need to do some more phosphorylating (drug is a monophosphate)
NucleoTide reverse transcriptase inhibitors
o Bind directly to reverse transcriptase but at different site than NRTI
o Don’t need to be phosphorylated to be active
o Allosteric inhibitor - binds and stops the reverse transcriptase
o If HIV becomes resistant to NRTI, it might not have resistance to these because they function in different places
non-nucleoside reverse transcriptase inhibitors
o works in the cytosol (maybe the nucleus)
o blocks integrase to prevent forming the pro-virus
integrase inhibitors
o Inhibits cleaving of polyprotein - needed for survival
o bind the active site of the protease
o cannot splice gag-pol-env polyprotein → proteins cannot be used → virus cannot be infectious
o does nothing for the cell that is infected already - does not inhibit the provirus
cell can cause apoptosis of other CD4+ T cells, but no virus particle production occurs
protease inhibitors
o prevents metabolism of other protease inhibitors to promote their concentration in the blood
called a “booster”
used in conjugation with other protease inhibitors
Ritonavir
Why are drugs used in combination?
o Reverse transcriptase makes a lot of mistakes - high mutation rate
o Typically use triple cocktail of different classes of drugs
o AZT used in combination now because of this high rate of mutation - want to prevent resistance
reason AZT is no longer used alone
Toxicities of NRTIs:
- mitochondrial toxicity and lactic acidosis
Toxicities of Non-NRTIs/
- rash, GI, drug interactions
Toxicities of protease inhibitors?
o Drug interactions
o Peripheral lipoatrophy and central fat accumulation = fat distribution
skinny arms and a fat gut
Whats the difference between nucleosides and nucleotides?
nucleotides have one or more phosphate groups
nucleoSide = Smaller (no phosphates)
4 nucleoside reverse transcriptase inhibitors:
Zidovudine (Azidothymidine or AZT)
Lamivudine
Emtricitabine
Abacavir
Side fx:
- granulocytopenia and anemia in up to 45% of treated patients (hematological monitoring at 2 week intervals).
- CNS disturbances: severe headache, nausea, insomnia, malaise
Zidovudine (Azidothymidine or AZT)
- Probably best tolerated of the NRTIs
- Also active against Hepatitis B
Lamivudine
Emtricitabine
NRTI associated with hypersensitivity rxn:
Abacivir
nucleoTide RTI
nausea, vomiting, diarrhea
renal failure
lactic acidosis with hepatic steatosis, probably due to mitochondrial toxicity
Tenofovir
2 NNRTIs:
Efavirenz
Etravirine
NNRTI
Once daily dosing
CNS effects (vivid dreams, nightmares and hallucinations)
Efavirenz
NNRTI
Rash, nausea, peripheral neuropathy
Etravirine
3 protease inhibitors:
Atazanavir
Ritonavir
Darunavir
General AE 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
used at lower doses to increase the serum concentrations of other protease inhibitors
decrease the dosage frequency of other PIs
potent inhibitor of CYP3A4 which is the cytochrome that metabolizes a number of the other PIs and decreases their effectiveness.
Ritonavir
