Pharmacology: Anti-retroviral Agents Flashcards
What are 4 goals of chronic disease management for HIV patients?
- Achieve durable virologic suppression
- Stabilize or restore immune function
- Maintain or improve the patient’s quality of life
- Reduce HIV related mortality and morbidity
What leads to increases in the CD4 cell counts of over 100-200 cells/mm/year?
HAART therapy
Regimens of how many agents are used in HAART therapy?
3 or more
What are 4 examples of FDA approved agents for Drug Therapy for HIV?
- Nuceloside reverse transcriptase inhibitors (NRTIs)
- Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
- Protease Inhibitors (PIs)
- Fusion Inhibitors (FIs)
What is the key viral enzyme that converts viral RNA to DNA?
Reverse transcriptase (catalyzes viral RNA to viral DNA)
What does reverse transcriptase allow for?
Selective toxicity
What does reverse trascriptase have to do before HIV can be inserted into the host cell’s genetic material?
Convert viral RNA into proviral DNA
What kind of cells do NRTIs protect?
Only newly infected cells
What is the MOA of NRTIs?
They target the early/essential step in HIV replication by acting as substrates for reverse transcriptase…
THEY INHIBIT REVERSE TRANSCRIPTASE BY INCORPORATING FALSE NUCLEIC ACIDS INTO THE NEWLY PRODUCED PROVIRAL DNA
-These agents lack a 3’ hydroxyl group, thus incorporation into DNA terminates chain elongation
How do NNRTIs work?
They inhibit reverse transcriptase activity by binding adjacent to the enzyme’s active site and inducing conformational changes
What kind of cells do NNRTIs protect?
Newly infecting cells
What strain of HIV are NNRTIs effective against?
Only HIV-1
What kind of metabolism do NNRTIs have?
Hepatic…many potential drug interactions
True or False: There is no need for phosphorylation in NNRTIs
TRUE
What stage of infection do NRTIs and NNRTIs work?
They only protect NEWLY INFECTED CELLS
What is an essential enzyme for viral survival and infectivity?
HIV PROTEASE
What does HIV protease do?
Cleaves viral polyprotein into active viral enzymes (reverse transcriptase, protease, and integrase)
Where do protease inhibitors bind?
Reversibly to the active site of the HIV protease
What happens to the viral particles with a protease inhibitor?
They become immature and non-infectious
What cells do protease inhibitors inhibit viral replication in?
Any infected cells
What is a unique indication for enfuvirtide (fusion inhibitor)?
Advanced HIV-1 infection patients
They have ongoing viral replication despite antiretroviral therapy
What types of drugs are given in a PI-based HAART regimen?
Protease inhibitor and 2 NRTIs
Example: Iopinavir/ritonavir + (sidovudine or stavudine) + Lamivudine
What are 3 advantages of PI-based HAART Regimen?
- Standard of care
- Longest data record including data on survival benefit
- Effective and durable
What are 3 disadvantages of PI-based HAART Regimen?
- Metabolic complications
- CYP3A4 metabolizes all the PIs and PIs inhibit it
- Complex regimens
What are 3 advantages of NNRTI-based regimens over PI-based regimens as HAART?
- Simple regimens
- Less fat maldisritbution dyslipidemia than PI-based regiments (well tolerated)
- Save PI options for future use
What are 2 significant tests to be done to determine the severity of HIV infection?
- Plasma HIV RNA levels
2. CD4 T-cell counts
What do Plasma HIV RNA levels show?
Indicates the magnitude of HIV replication and its associate rate of CD4 T-cell destruction
What do CD4 T-cell counts show?
Indicated the extent of HIV-induced immune damage already suffered
When do HIV RNA levels stabilize after diagnosis?
6-9 months
True or False: HIV RNA level changes are predictable?
FALSE… they are unpredictable
What is the best measure of the activity of antiretroviral therapy in HIV-infected persons?
HIV RNA levels
What is the goal with antiretroviral therapy in HIV-infected persons?
To decrease HIV RNA levels to undetectable (this may take up to 16-24
What is the most prominent AE to Zidovudine (AZT)?
BM suppression (myelosuppression)
What is the most prominent AE to Stavudine (d4T)?
Peripheral neuropathy (20-30%)
What is the most prominent AE to Didanosine (ddl)?
Pancreatitis, peripheral neuropathy
What are 2 indications that drug failure has occurred with anti-retroviral agents?
- Inadequate viral suppression
2. Unsatisfactory increase in CD4 count
What enzyme metabolizes all PIs?
CYP3A4- Metabolizes all PIs and PIs inhibit it
What population shouldn’t receive efavirenz?
PREGGERS
Which 2 NRTIs are preferred for treatment of HIV?
- Emtricitabine
2. Tenofovir
What are 4 disadvantages of NNRTI-based regimens over PI-based regimens as HAART?
- Not all NNRTI are equipotent to PI
- Low genetic barrier to resistance
- Cross-resistance among NNRTIs
- Skin rash
What can increase HIV RNA levels?
Immunizations or infections
What AE are common to Zidovudine, Stavudine, and Didanosine?
Cause lactic acidosis with hepatic steatosis
What AE can Abacavir cause?
HS (can be fatal, so stop drug), nausea, HA
What AE can Zalcitabine cause?
Peripheral neuropathy or pancreatitis
What is a major AE to anti-retrovirals (especially NNRTIs and PIs)?
Hepatotoxicity
How do you monitor and define hepatotoxicity from anti-retrovirals?
Serum transaminases- The hepatotox is defined as a 3-5 fold increase
