Antiretrovirals for final Flashcards
Zidovudine (Azidothymidine or AZT)
Class NRTI
MOA: termination. The inhibitor binds to the DNA chain and terminates the production of DNA. Require phosphorylation by cellular enzymes to the triphosphate to be active.
Resistance - Resistance to one may may result in resistance to another within the class.
General adverse events - Potentially fatal syndrome of lactic acidosis with hepatic steatosis, probably due to mitochondrial toxicity. Associated with fat redistribution and hyperlipidemia.
Specific adverse events - Granulocytopenia and anemia in up to 45% of treated patients (monitor at 2 week intervals), CNS disturbances (severe headache, nausea, insomnia, and malaise)
Lamivudine
Class - NRTI
MOA: termination. The inhibitor binds to the DNA chain and terminates the production of DNA. Require phosphorylation by cellular enzymes to the triphosphate to be active.
Resistance - Resistance to one may may result in resistance to another within the class.
General adverse events - Potentially fatal syndrome of lactic acidosis with hepatic steatosis, probably due to mitochondrial toxicity. Associated with fat redistribution and hyperlipidemia.
Probably the best tolerated of NRTIs. Also active vs. Hep. B.
Abacavir
Class - NRTI
MOA: termination. The inhibitor binds to the DNA chain and terminates the production of DNA. Require phosphorylation by cellular enzymes to the triphosphate to be active.
Resistance - Resistance to one may may result in resistance to another within the class.
General adverse events - Potentially fatal syndrome of lactic acidosis with hepatic steatosis, probably due to mitochondrial toxicity. Associated with fat redistribution and hyperlipidemia.
Specific Adverse Events: Hypersensitivity reactions.
Emtricitabine
Class - NRTI
MOA: termination. The inhibitor binds to the DNA chain and terminates the production of DNA. Require phosphorylation by cellular enzymes to the triphosphate to be active.
Resistance - Resistance to one may may result in resistance to another within the class.
General adverse events - Potentially fatal syndrome of lactic acidosis with hepatic steatosis, probably due to mitochondrial toxicity. Associated with fat redistribution and hyperlipidemia.
Probably the best tolerated of NRTIs. Also active against Hep. B.
Tenofovir
Class - NRTI
MOA: termination. The inhibitor binds to the DNA chain and terminates the production of DNA. Require phosphorylation by cellular enzymes to the triphosphate to be active.
Adverse Events: Most common is nausea, vomiting, diarrhea and potential for renal failure. Potentially fatal syndrome of lactic acidosis with hepatic steatosis, probably due to mitochondrial toxicity
Specific A.E. - Renal toxicity.
Etravirine
Class - NNRTI
MOA - NNRTIs bind directly to the reverse transcriptase at a site distinct from that of the NRTI. The enzyme cannot then produce viral DNA. Do not require phosphorylation for activity and are primarily effective against HIV-1.
Resistance - No cross resistance with NNRTIs and NRTIs and protease inhibitors.
General Adverse Events - Varying levels of GI intolerance and skin rash.
Specific Adverse Events - Rash, nausea, peripheral neuropathy
PK: CYP 450 - Drug interactions. They can be inducers, inhibitors, or mixed inducers/inhibitors.
Efavirenz
Class - NNRTI
Class - NNRTI
MOA - NNRTIs bind directly to the reverse transcriptase at a site distinct from that of the NRTI. The enzyme cannot then produce viral DNA. Do not require phosphorylation for activity and are primarily effective against HIV-1.
Resistance - No cross resistance with NNRTIs and NRTIs and protease inhibitors.
General Adverse Events - Varying levels of GI intolerance and skin rash.
Specific Adverse Events - CNS effects (vivid dreams, nightmares, and hallucinations)
PK: CYP 450 - Drug interactions. They can be inducers, inhibitors, or mixed inducers/inhibitors.
Once a day administration.
Atazanavir
Class - Protease Inhibitor
MOA: These drugs prevent protease action required for maturation of the fully assembled virus. As the virus is budding, proteolytic cleavage occurs. Without this cleavage, the virus is not infectious.
General Adverse Events:
- GI disturbances
- Hepatotoxicity
- Hyperglycemia and insulin resistance
- Dyslipidemia
- Cardiac conduction abnormalities
- Peripheral lipoatrophy and central fat accumulation
PK - Metabolized by and inhibit hepatic CYP3A4
Given with Ritonavir booster
Darunavir
Class - Protease Inhibitor
MOA: These drugs prevent protease action required for maturation of the fully assembled virus. As the virus is budding, proteolytic cleavage occurs. Without this cleavage, the virus is not infectious.
General Adverse Events:
- GI disturbances
- Hepatotoxicity
- Hyperglycemia and insulin resistance
- Dyslipidemia
- Cardiac conduction abnormalities
- Peripheral lipoatrophy and central fat accumulation
PK - Metabolized by and inhibit hepatic CYP3A4
Given w/ Ritonavir booster
Ritonavir
Class - Protease Inhibitor
MOA: These drugs prevent protease action required for maturation of the fully assembled virus. As the virus is budding, proteolytic cleavage occurs. Without this cleavage, the virus is not infectious.
General Adverse Events:
- GI disturbances
- Hepatotoxicity
- Hyperglycemia and insulin resistance
- Dyslipidemia
- Cardiac conduction abnormalities
- Peripheral lipoatrophy and central fat accumulation
PK -Metabolized by and inhibit hepatic CYP3A4
High doses of the protease inhibitor ritonavir are poorly tolerated. However, it is used at lower doses to increase the serum concentrations of other protease inhibitors, and decrease the dosage frequency of other PIs. Ritonavir is a potent inhibitor of CYP3A4 which is the cytochrome that metabolizes a number of the other PIs and decreases their effectiveness.
Enfuviritide
Class - Fusion Inhibitor
MOA -Binds to gp41 and prevents the conformational change needed for fusion.
PK - Subcutaneous administration twice daily.
Adverse effects - High incidence of local reactions with pain erythema, induration, nodules, and cysts. Rare systemic hypersensitivity. Higher incidence of bacterial pneumonia.
Active against HIV resistant to other classes of antiretrovirals (last resort drug)
Raltegravir
Class - Integrase Inhibitor (or Integrase Strand Transfer Inhibitors, INSTI)
MOA - . By binding integrase, it inhibits strand transfer, the final step of provirus integration.
PK: Fewer drug drug interactions than PI or NNRTI based regimens.
Maroviroc
Class - CCR5 Antagonist
MOA: Specifically and selectively blocks host CCR5
Cobicistat
Pharmacokinetic enhancer that inhibits CYP3A4 as well as certain intestinal transport proteins and can also act as a booster of protease inhibitors. It is not a protease inhibitor itself.
HAART
Highly Active Antiretroviral Therapy
Generally reference to therapy with RTIs in combination with PI. Long term use of combination anti-retroviral therapy is associated with secondary effects, the most prevalent being HAART lipodystrophy.
HAART Lipodystrophy:
- Estimated to affect 25-50%
- Wasting of subcutaneous fat
- Central adiposity
- Hyperlipidemia, insulin resistance, and DM
- Most often seen with use of NRTIs + PI, but also seen with single NRTI treatment.
