Lecture 21: HIV Pharmacology (Exam 2) Flashcards
What are 4 common drugs used as NTRIs? (E, L, A, T)
emtricitabine, lamivudine, abacavir, tenofovir
What are 3 common drugs used as INSTIs? (R, D, B)
raltegravir, doltegravir, bictelgravir
- all end with “-gravir”
What are 2 common drugs used as Protease Inhibitors? (A and D)
azatanavir /c and darunavir /c
What are 5 common drugs used as NNRTIs? (N, E, E, R, D)
nevirapine, efavirenz, etravirine, rilpivirine, doravirine
What is the normal drug combination for achieving viral suppression via ART?
- generally 3 active drugs are given from 2+ drug classes (usually 2 NRTIs as therapy BACKBONE)
- viral load reduction below limits of assay detection usually occurs in first 12-24 weeks of therapy
What are 5 predictors of virologic ART success?
- low baseline viremia, high potency of ARV regime, tolerability, convenience, and excellent adherence to regime
What is the MOA of NRTIs? (Nucleoside Reverse Transcriptase Inhibitors)
What can NTRIs potentially inhibit in human cells that is NOT viral related?
- binds to the viral DNA chain being synthesized, competes for base pair addition, and causes termination of the product
- terminate elongation because they LACK 3’-OH group (must be PHOSPHORYLATED to work)
- some mitochondrial DNA polymerases are inhibited by NTRIs, but most human ones have low affinity
What nucleotide does each NRTI mimic? (6)
Thymidine
Cytidine
Guanosine
Adenosine
T: Zidovudine (AZT) –> first NRTI used
- and stavudine
C - emtricitabine/lamivudine
G - abacavir
A - tenofovir
What are 3 toxicities commonly associated with NRTIs? (LAS, PN, P)
Lactic Acidosis Syndrome, Peripheral Neuropathy, Pancreatitis
- all due to mitochondrial toxicity
Zidovudine and Stavudine:
Clinical Applications and Toxicities
- NRTIs (S-PHASE specific; thymidine mimic)
T: inhibits HIV-1/2 and HTLV-1/2 (only IV NRTI avail.)
- bone supp, skeletal muscle myopathy, heap. steat
S: inhibits HIV-1/2
- Peripheral neuropathy, fat wasting (why we no use)
- also lactic acidosis/hepatic steatosis
Emtricitabine and Lamivudine:
What are they, what are their clinical applications, and what are their toxicities?
What other drug are they normally given with?
- NRTIs (cytidine mimic) that are coformulated with Tenofovir; low barriers to resistance if monotherapy and long half-lives; excreted unchanged in urine
CA: used to treat HIV-1/2 and HBV
T: not very toxic, though prolonged Emtricitabine use causes hyperpigmentation in the palms and soles of African Americans
- lamivudine and doltegravir are given to treat naive pts.
Abacavir:
What is it, what is its clinical application, and what are its toxicities?
Who should it NOT be given to? (2)
- NTRI (guanosine mimic) that should NOT given to HLA-B*5701 genotype pts. or pts with coronary artery disease
CA: treats HIV but does NOT treat HBV
T: potentially fatal hypersensitivity syndrome (HLA) and causes hyperlipidemia/cardiovascular events (CAD)
Tenofovir Disoproxil Fumarate and Alafenamide:
What are they, what are their clinical applications, and what are their toxicities?
NRTI (adenosine mimic) with POOR bioavailability; long half-lives and excreted unchanged in urine
CA: HIV and HBV
T: TDF has higher chance of nephrotoxicity w/acute tubular necrosis (Fanconi Syndrome) and dec. bone mineral density than TAF (due to lower plasma conc.)
What is the MOA of INSTIs? (Integrase Strand Transfer Inhibitors)
How are they incorporated into the ARV regime?
- prevent formation of covalent bonds between viral and host DNA (“Strand Transfer” blockage)
- are primary “+1” active agent recommended for treatment of NAIVE HIV patients
Raltegravir
What is it, what is its clinical application, and what are its toxicities?
INSTI that blocks strand transfer; eliminated in urine unchanged
CA: HIV and Naive pt. treatments
- resistance due to integrase mutations
T: little clinical toxicity but can cause Immune Reconstitution Syndrome
Dolutegravir and Bictegravir:
What are they, what are their clinical applications, and what are their toxicities?
INSTIs that block strand transfer and viral DNA integration into human DNA
CA: HIV and Naive pt. treatments
- resistance due to integrase mutations
- has HIGH GENETIC BARRIER to resistance though
T: D - (immune reconstitution syndrome; avoid in pregnancy) and B - generally well tolerated but only available as fixed-dose single tablet regimen
Which INSTI is metabolized by CYP3A4 and needs to be boosted if given? What is it normally given with?
ELVITEGRAVIR
- given with cobicistat, emtiricitabine, and TDF/TAF
What is the MOA of Protease Inhibitors?
- frequently second-line “+1” active agents
- peptide-like chemicals that competitively inhibit activity of viral ASPARTYL PROTEASE by cleaving N-terminal side of Pro residues
- prevents proteolytic cleavage of HIV gag and pol precursor peptides needed to generate reverse transcriptase, protease, and integrase
How are Protease Inhibitors cleared by body and how do they interact with other drugs metabolism?
- highly protein bound in plasma and mainly cleared by hepatic clearance
- metabolized by CYP3A4 –> all inhibit metabolism of other drugs (RITONAVIR is most potent inhibitor with a low dose able to BOOST other agents)
- all are substances for P-glycoproteins (MDR1)
Saquinavir and Indinavir:
What are they, what are their clinical applications, and what are their toxicities?
Saquinavir (first protease inhibitor) and Indinavir are protease inhibitors with poor bioavailability
CA: inhibits HIV-1/2 (Saquinavir - not widely used anymore due to pill burden)
T: S (lipodystrophy - long term) and I (crystaluria and renal stones)
Darunavir:
What is it, what are its clinical applications, and what are its toxicities?
- non-peptide protease inhibitor (first choice PI when boosted)
CA: inhibits HIV-1/2 (mainly HIV-1 treatment)
T: rash and hypersensitivity (its a sulfa drug), immune reconstitution syndrome, fat redistribution syndrome
Atazanavir:
What is it, what are its clinical applications, and what are its toxicities?
- protease inhibitors (first choice PI when boosted)
CA: inhibits HIV-1/2 (also for naive patients)
T: unconjugated hyperbilirubinemia NOT associated with hepatitis, immune reconstitution syndrome, fat redistribution, hypersensitivity
Iopinavir:
What is it, what are its clinical applications, and what are its toxicities?
- protease inhibitor only available in form boosted with ritonavir
CA: inhibits HIV-1/2 (often works when other PI regimes fail, also for naive patients)
T: increases triglycerides and cholesterol
Ritonavir and Cobicistat:
What are they, what are their clinical applications, and what are their toxicities?
both are used to BLOCK CYP3A4 (Ritonavir is a protease inhibitor though) used to boost levels of protease inhibitors
CA: boost plasma drug levels (cobicistat for Azatanavir and Darunavir)
T: flushing, rash, GI, CYP3A4 effects on other drugs
