HIV Pharmacology Flashcards
In general, how is viral suppression achieved?
By using a combo of ARV regiments that includes three active drugs from at least two drug classes
What does ART begin with for the backbone of therapy typically?
2 NRTI’s
How do NRTI’s work?
Inhibit incorporation of native nucleotides and terminate elongation of proviral DNA, they do NOT eradicate the virus
What human DNA polymerase is inhibited by some NRTI’s and what four NRTI’s have lower affinity for it?
Mitochondrial DNA polymerase (y)
- Emtricitabine
- Lamivudine.
- Abacavir
- Tenofovir
what are the AE’s associated with NRTI?
- Lactic acidosis syndrome due to mitochondrial toxicity
- Peripheral neuropathy due to mitochondrial toxicity
- Pancreatitis due to mito toxicity
- Anemia
- Myopathy
Zidovudine (AZT):
- MOA:
- Use:
- Toxicities:
NRTI
- Interferes with thymidine incorporation, it was the first ARV discovered
- Used in resource poor settings
- bone marrow suppression, skeletal mm myopathy, hepatic steatosis
Stavudine (d4T)
- MOA:
- Use:
- Toxicities:
NRTI
- Interferes with thymidine incorporation
- Inhibits HIV 1 and 2
- Most common serious AE is peripheral neuropathy
- associated most strongly with lipodystrophy
- assoc. with lactic acidosis and hepatic steatosis
Rarely used bc of toxicities now
Emtricitabine (FTC)
- MOA:
- Use:
- Toxicities:
- Pharmacokinetics
NRTI
- Interferes with cytosine incorporation and terminates elongation of provrial DNA
- Tx for HIV1 and 2
- low barrier to resistance if a monotherapy
- active agaisnt HepB and if discontinued resistance can occur and rebound of HepB so should not be used for HepB unless TAF pr TDF also given
- Co formulated with Tenofovir
- Least toxic agens but still HA, N/V, rash, cough infection
- long use leads to hyperpigmentation palms and soles
- Long intracellualr half life, excreted unchanged in the urine
Lamivudine (3TC)
- MOA
- Use
- Pharmokinetics
- Toxicities
NRTI
- intereferes with cytidine incorporation inhibiting native nucleotides and terminating elongation
- HIV1/2 tx, with a low barrier to monotherapy
- active against HBV and stopping causes rebound and resistance
- Dual combo with lamivudine and dolutegravir is approved for tx naive patients
- long intracellular half life, sorbitol interferes with absorption
- unchanged excretion in the urine
- Least toxic ARV no significant AE’s
Abacavir (ABC)
- MOA
- Use:
- Pharmacokintics:
- Toxicities:
NRTI
- Guanosine analog
- NOT given to patient with HLA-B 5701 genotype and NOT effective against HBV
- NOT a CYP substrate, 21 hr half life
- Unique fatal hypersensitivity syndrome:
- fevr abdominal pain, maculopapular rash, fatiguge around 6 days to 6 weeks, but does not resolve and worsens
- avoide in patients with CAD and hyperlipidemia and absolutely HLA-B5701 genotype
Tenofovir disoproxil fumarate (TDF):
- MOA:
- Use:
- Pharmacokinetics:
- Toxicities:
NRTI
- Nucleotide reverse transcriptase, it is the only nucleotide used and has poor bioavailabiltiy and that is where the D and F come in
- broad spectrum activity against viral DNA pol and low affinity for human DNA pol
- HBV active against, resistance is due to single sub in K65R but rarely cause of tx failure
- 10-50 hr half life, unchanged excretion in urinve
- well tolerated few AE besides upset GI
- nephrotoxicity with acute tublar necrosis leading to fanconi syndrome, avoid if GFR less than 60
- Decreased bone mineral density but stablizes over time
Tenofovir alaenamide
- MOA:
- Use:
- Pharmacokinetics:
- Toxicities:
NRTI
- Nucleotide adenosine analog parent compound has poor bioavailabilty so used with allafenamide prodrug, broad activity against viral DNA pol not human
- causes weight gain the most among NRTI, but less than INSTI, less renal and bone toxicities than TDF
Use and pharmacokinetics same as TDF
What combo of NRTI is “superior” to other combos?
Emtricitabine and tenofovir
What two drugs are recommended for treatment naive patients, unless their viral load is high?
- Lamivudine (NRTI) by itself in combo with the INSTI dolutegravir
What drugs end with “_gravir”?
INSTI
Raltegravir?
MOA:
Use:
Pharmacokinetics:
Toxicities:
INSTI
- prevents formation of covalent bonds btw viral and host DNA (strand transfer)
- lowers plasma viral RNA faster than NNRTI efavirenz
- ART combos in HIV adults preferred for tx naive patients, resistance can develop due to mutations in integrase
- eliminated in urine and feces as unchanged and undergoes glucuronidation
- first drug in this class, not availabe in single tablet
- Well tolerated but can see hypersensitivity rxn, immune reconstitution syndrome, myopathy, excellent target since human DNA doesn’t undergot excision/reintergration
Dolutegravir?
MOA:
Use:
Pharmacokinetics:
Toxicities:
INSTI
- prevents strand transfer process, blocks chromosomal integration of viral DNA
- Resistance develops with mutations to inetegrase but has high genetic brarier to resistance
- half life 14 hrs, metabolizedby UGR1A1 glucuronidation before renal excretion
- DTG/3TC is first choice for tx naive patients
- Well tolerated but significant weight gain and avoid in pregnancy
Bictegravir?
MOA:
Use:
Pharmacokinetics:
Toxicities:
INSTI
- prevent strand transfer, blocks chromoslam integration of viral DNA
- approved for HIV adults and tx naive patients, resistance develops with intergrase mutation, but has haigh barrier to resistance
- more soluble and readily absorbed than other INSTI’s
- metabolized by CYP3A4 few drug drug interactions
- well tolerated causes weight gain
How do protease inhibitors work?
- competitively inhibit virus aspartly protease, cleaves the N terminal side of pro residues
- prevents proteolytic cleavage of hiv gag and pol precursor peptides
How are protease inhibitors cleared?
Hepatic clearance and metabolized by CYP3A4
Saquinavir?
MOA:
Use:
Pharmacokinetics:
Toxicities:
Protease Inhibitor
- first one discovered
- no longer used due to pill burden
- GI distress N/V diarrhea Lipodystrophy
Indinavir significance?
- Protease inhibitor that has a unique AE of crystalluria and renal stones
Darunavir (DRV)
MOA
Use
Toxicities
- non peptidic protease inhibitor that prevents maturation of capsid and other proteins that budd off
- First choice PI when boosted
- Sulfa drug so rash and hypersensitivity rxn possible
*
Atazanavir (ATV)
MOA
Use
Pharmacokinetics
Toxicities
protease inhibitor
- prevents maturation of capsid and other proteins that budd off
- Inbibits HIV1 and 2 used in tx naive patients and experienced
- higher barrier to resistance thtan NNRTI and INSTI
- Jaundice unconjugated hyperbilirubinemia
Lopinavir?
- prevents maturation of HIV particle that budds off
- Often works after failure of other PI containnig regiments
What are the two CYP3A4 inhibitors?
- Ritonavir and Cobicistat
- both are used to boost levels of protease inhibitors
What form of HIV is intrinsically resistant to NNRTI’s?
HIV2
Nevirapine?
MOA
Use
Pharmacokinetics
Toxicities
NNRTI
- prevents generation of DNA from viral RNA in host cells
- reduces level of oral contraceptives
- rash and itching common AE’s
Efavvirenz (EFV)?
NNRTI
- prevents DNA from viral RNA entry in host cells
- Should not be added to failing regimen
- First NNRTI approved for once daily
- CNS toxicity/ psychiatric side effects
- was considered teratogenic
Etravirine?
- NNRTI
- used for tx experienced HIV1
- still works after mutations that disrupt activity of other NNRTI
Rilpivirine use and how to take?
- NNRTI
- Tx naive patient, not susceptible to common mutation that renders efavirenz and nevirapine innefective but affected by other mutations
- Nees to be taken with a meal
Doravirine?
- novel resistance mutations
- can be taken with or withoyt food
- metabolzied by CYP3A4 but no drug drug interactions
- low incidence of CV, CNS, GI skin AEs, better than other NNRTI’s
What is a very expensive last resort entry blocker drug that has a 36 aa peptide from the gp41 component?
Enfuviritide (T-20)
- unique MOA retains its activity agaisnt viruses resistat to other classes
What is Maraviroc?
- CCR5 entry blocker
- binds GP120 to CCR5 co receptor
- resistance develops y shifting from CCR5 to CXCR4 troposim
Essential and expensive tropism test required before use
