Antiviral Agents- 2 Flashcards
List a nucleoside Reverse Transcriptase Inhibitor
Emtricitabine, FTC
List a NONnucleoside reverse transcriptase inhibitor (NNRTI)
Efavirenz, EFV
List a protease inhibitor
Atazanavir, ATV
T/F: A general principal of antiretroviral therapy is drug resistance with monotherapy.
True- must give multiple drugs simutaneously
HAART stands for:
Highly active antiretroviral therapy
General MOA for NRTIs (Emtricitabine)
1) Incorporated into DNA and terminate chain elongation.
2) Also inhibit cellular DNA polymerases, particularly mitochondrial polymerases.
What antiviral drug is this: Analogue of cytidine; can be taken orally or given IV.
Emtricitabine
Adverse Symptoms of Emtricitabine
Adverse: Diarrhea, headache, nausea, rash.
- Toxic effects uncommon
- Severe: Hepatotoxicity, lactic acidosis, relatively rare but high fatality
Resistance to NRTIs (Emtricitabine)
- Results mainly from mutations in the reverse transcriptase gene.
- Mutations accumulate gradually and after one year about 1/3 of patients are resistant.
Metabolism of NRTIs (Emtricitabine)
Primarily by the KIDNEY, rather than CYP system.
Mitochondrial toxicities related to NRTIs (7)
- Neuropathy
- Myopathy
- Myocarditis
- Pancreatitis
- Hepatic Steatosis
- Lipodystrophy
- Lactic acidosis
Drug interactions of NRTIs (Emtricitabine) (3)
- Bone marrow toxic drugs
- Rifampin
- Fluconazole and TMP-SMX
What drug has these effects:
- Vivid dreams, poor concentration
- Hepatitis, rash uncommon
- False positive cannabis test
- Non human primate teratogenicity so do not use in pregnancy
Efavirenz (NNRTI)
What drug can lower Efavirenz (NNRTI) levels?
Rifampin
MOA for Efavirenz (NNRTI) (3)
- Act in noncompetitive manner and do not compete with naturally occurring dNTPs.
- Bind directly to the RT at the site adjacent to the active site and cause conformational change and disrupt the enzyme’s catalytic site (allosteric inhibition).
- Do not require dephosphorylation to be active and no incorporated into viral DNA.
Resistance to Efavirenz (NNRTI)
- Results form mutations in the RT.
- Develops rapidly if used alone or with one nucleoside
- Cross resistance to all NNRTIs
- HIV isolates resistant to NRTIs and PIs remain sensitive to NNRTIs
1) How is Efavirenz (NNRTI) taken?
2) How is Efavirenz (NNRTI) metabolized?
3) Does Efavirenz (NNRTI) have a long or short half life?
1) Excellent oral absorption.
2) Metabolized by hepatic cytochrome P450 (primarily 3A4).
3) Long half lives
Toxicity of Efavirenz (NNRTI)
- Skin rashes most common. Usually mild to moderate but can progress to Steven-Johnson syndrome.
- Liver enzyme elevation and hepatitis
- Fever, nausea, headache, somnolence
Efavirenz (NNRTI) drug interactions
Can occur with PIs and many other drugs. They are metabolized by CYP enzymes and are both inhibitors and inducers of these enzymes.
What antiretroviral drug is considered the most effective and act in the later stages of the replication cycle?
Protease Inhibitors -Atazanavir
Protease inhibitors bind 1) (irreversible/reversibly) to the active site of the HIV protease to inhibit the HIV protease preventing post-2)_____________ processing of the viral polyproteins and thus blocking subsequent viral maturation.
1) Reversibly
2) Translational
How does resistance to protease inhibitors occur?
By stepwise mutation in the protease gene. Cross resistance among PI inhibitors occurs.
True False: PIs (Atazanavir) are:
1) Poor oral availability.
2) Metabolized through the kidney.
3) Substrates for p-glycoprotein.
1) True
2) False: All metabolized by hepatic cytochrome P450 enzymes (CYP 3A4). - Little drug is excreted by the kidney.
3) True
Dual protease inhibitor combinations can increase potency, reduce dose, and reduce pill burdens. What drug is given as a “boost”?
Ritonavir (XXX/r)
What is the most common toxicity seen with PIs (Atazanavir). What are other toxicities?
Most common: GI intolerance (Diarrhea, nausea, discomfort).
-Long term metabolic effects include peripheral fat wasting, abnormal fat redistribution, hyperlipidemia, hyperglycemia, new onset or worsening diabetes and insulin resistance.
T/F: Protease Inhibitors (Atazanavir) has a lot of drug interactions.
True. EX: Amiodarone should not be used with Ritonavir. PIs increase AUC statins. Etc…
Antiretroviral therapy (ART) is recommended for all HIV-infected individuals. What does ART do? (2)
- Reduce disease progression.
- Prevent transmission.
- Emphasize need to need to commit to treatment, adherence is key.
Patients naive to antiretroviral therapy should be started on what combination?
2 NRTIs plus:
- NNRTI
- PI (preferably boosted with ritonavir)
- INSTI
Pregnancy: PI/r + 2NRTIs (Special recommendations)
Metabolic disorders associated with PIs:
Insulin resistance/glucose intolerance/diabetes
What mycobacterial drug should be avoided in HIV/TB therapy?
Rifampin- check CDC guidelines for HIV/TB therapy.
