6. HIV Pharm Flashcards
what are the clinical applications, pharmacokinetics and toxicities of efavirenz
application: HIV-1 infxn in adults & children;
co-formulate w/ emtricitabine & tenofovir to help maintain early NNRTI selected in class
pharmacokinetics: half life = 40-50; 1st NNRTI approved for 1x/day; induce CYP34 (reduce oral contraceptive levels - change pt’s form of BC)
toxicities: most significant = CNA toxicity/psychiatric side effects; rash is common; was considerd a teratogenic
how does HIV virion mature
- HIV viron bind (CD4 & chemokine receptor) to host, fuse and enter cell
- uncoat –> ssHIV RNA –> DNA by reverse transcriptase
- DNA insert into host genome–> take control of transcription –> make viral proteins and immature noninfectious virons
- mature into fully infectious mature HIV after proteolytic cleavage
what are the MOA, effects of raltegravir and dolutegravir
& bictegravir
MOA: prevent formation of covalent bonds btn viral & host DNA (=strand transfer)
effects: block strand transfer (characteristic of retrovirus) viral DNA remain in host for prolonged period of inactivity
What is the general function of ART
decrease inflam and immune activation
(so prevent contribution higher rates of CV and other end organ damage)
what are the pharmacokinetics & toxicities of bictegravir?
pharmacokinetics:
- half-life = 16-23 hrs (1x/day dose);
- more soluble and readily abs-ed compared to INSTI
- glucuronidated by UGT1A1 & metabolized by CYP3A4 - BUT affected by potent dual inhibitors only==> few drug-drug interactions
- eliminated 1/3 via urine and 2/3 via feces
- only available as fixed-dose single tablet regimen
toxicity: well tolerated - maybe HA, diarrhea, insomnia
what are the predictors of virologic success
low baseline viremia
high potency of ARV regimen
tolerability
convenience
excellent adherence to regimen
compare and contrast zidovudine (AZT) to stavudine (d4T)
similar: MOA, effects, application (HIV-1,2), pharmacokinetic (abs well but…1/2-life = 3.5
toxicity = both= hepatic steatosis
& difference =
d4T = SEVERE toxiciy is peripheral neuropathy , lactic acidosis
NRTI associated w/ lipodystrophy/fat wasting (seen in AZT)
(rmr AZT used for prophylaxis, prevent vertical transmission & toxiciity = bone marrow suppression, sk. m myopathy)
What are common side effects seen with protease inhibitors
how do they build resistance?
nausea, vomit, diarrhea (better in several wks)
Speed of resistance btn NNRTI (fast) & NRTI (slow) - took 3-4 months in early trials & require mutation in 4-5 codons
short/long term toxicities including insulin resistance & lipdystrophy
What are the general pharmacokinetics for NNRTI
how can you build resistance?
eliminated by hepatic metabolism
single AA subsitution can cause resistance
*single exposure to Nevirapine in absence of other drugs –> resistance in 1/3 HIV-infected pts*
what are the MOA and pharmacokinetics of emtricitabine (FTC)
MOA: NRTI interfere w/ cytosine addition
rapid, extensive abs & long intracell half-life = 39 hr, excreted unchanged primarily in urine
how do NRTIs have selective toxicity
inhibit HIV RT w/o inhibiting host cell DNA polymerase ( DNA pol-alpha & beta have low affinity to these drugs)
BUT- mitochondrial DNA pol (gamma) are inhibited by some NRTI (emtricitabine, lamivudine, abacavir, tenofovir)
what are integrase strand transfer inhibitors
= primary (+1) active agents now recommended for treatment naive HIV pt
-end w/ “-gravir”
What are the clincal applications, pharmacokinetics and toxicities of nevirapine
application: HIV-1 infxn in adults & children
pharmacokinetics: half life = 25-30, induce CYP3A4 reduces level of oral contraceptive (change pts BC)
toxicities: rash/itching
Compare the pharmocokinetics of raltegravir and dolutegravir
Raltegravir: terminal half-life 9 hrs; eliminated in urine and feces as unchanged drug
Dolutegravir: terminal half life - 14 hrs ; 1x/day; metabolized by UGR1A1 glucuronidation before renal excretion
What are CCR5-blockers (ex. maraviroc)
MOA: chemokine receptor antagonist; block binding of gp120 to CCR5 (co-receptor)
block entry of CCR5-trophic HIV into cells
resistance developed by shift from CCR5 to CXCR4 tropism or mutation in V3 loop of GP120
what are the MOA and pharmacokinetics of atazanavir
MOA: protease inhibitor *1st choice PI when boosted*
pharmacokinetics: similar to darunavir (metabolized as CYP3A4 & excreted mostly in feces)
half life = 7-9 hrs
what is the mechanism of NRTIs
enter cell –> become phosphorylated –> bind DNA chain (inhibit incorporation of new NT) and terminate elongation (lack 3’OH group)
*these prevent infxn of susceptible cells but DO NOT eradicate the virus*
What are 3 considerations to keep in mind for ART
use combo therapy to prevent emergent resistant virus
tolerance and convience in addition to efficacy
realization that therapy must be life long
What are clinical applications and toxicities of saquinavir?
application : (-) HIV-1,2
no longer widely used in developed world due to pill burden
toxicities = GI distress, nausea, vomiting, diarrhea & long term = lipodystrophy
what are the clinical applications and toxicites of tenofovir disoproxil fumarate (TDF)
Applications; HIV w/ combo of drugs; HBV
resistance due to single substitution in RT (K65R) - but rare cause of tx failure
Toxicity:
generally well tolerate BUT possible nephrotoxicity w/ acute tubular necorsis –> Fanconi syndrome (so avoid is eGFR < 60ml/min/1.75 (m^2))
decreased bone mineral density but stabilizes w/ continued use
what are the MOA and pharmacokinetics of tenofovir disoproxil fumarate (TDF)
MOA: NRTI but nucleoTIDE- , ad__enosine analog ; poor bioavailability so use disoproxil fumarate prodrug formula
intracell half life = 10-50 hrs, 1x/day dose, excreted unchanged in urine
What are HIV fusion inhibitors (ex:enfuvirtide aka T20)
prvent the confirmation change and prevent the hairpin structure –> prevent fusion
MOA = 36 AA peptide derived from viral gp41 that fuses w/ cell mem
–> inhibit formation of 6-helix bundle critical for membrane fusion, inhibit infxn CD4 by free virus particles, also inhibit cell-to-cell transmission in vitro
(resistance developed by mutation in gp41)
What are the clinical application, pharmacokinetics and toxicites of doravirine
application: HIV-1 naive pt; for switching pt on stable regimen, novel resistance mutations
half-life = 15 hrs, metabolized by CYP3A4; available individually or co-formulated w/ lamivudine and tenofovir
toxicity: low incidence of CV, CNA, GI and skin adverse effects; potential immune reconstituion syndrome
What are protease inhibitors & what is its mechanism
=freq 2nd line (+1) active agent
inhibit protease –> prevent cleavage of polypeptide & maturation of virion
=peptide-like chemical- competitively inhibit activity of virus aspartyl protease
=prevent proteolytic cleavage of HIV gag & pol precursor peptides (which are needed to generate reverse transcriptase, proteast, integrase and more)
what are the consequences of treatment interruption
rebound virema
worsening of immune fxn
and increase morbidity/mortality
what are the 6 targets for HIV therapy
- nuceloside reverse transcriptase (RT) inhibitor (NRTI)
- protease inhibitor
- non-NT RT inhibitor
- HIV fusion inhibitor
- CCR5 blocker (co-receptor to enter cell)
- integrase stand transfer inhibitor
what are clinical applications and toxicities of lopinavir
application : (-) HIV-1,2; often works after failure of other PI containing regimen
toxicities: GI distress, nausea, vomiting, diarrhea, increase triglycerides & cholesterol
What is the MOA, effects and clincal application of bictegravir
how does it build resistance
MOA and effect = ISTI - block strand transfer (same as dolutegravir & raltegravir)
application -niave HIV pt (same as dolutegravir)
resistance: mutation of integrase BUT high genetic barrier resistance (same as dolutegravir)
what are the clinical applications and toxities for raltegravir and dolutegravir
application: HIV- naive pt
resistance due to mutations in integrase (dolutegravir has high genetic barrier to resistance)
toxicities:
- rarely potentially severe skin/hypersensitivity rxn
- see “immune reconstitution syndrome”
raltegravir : myopathy/rhadomyolysis
dolutegravir: avoid in pregnancy
what are toxicities that present in darunavir
GI distress, nausea, vomit, diarrhea (like other PI) & immune reconstitution syndrome (like INSTI)
increased triglycerides & cholesterol & fat redistribution syndrome
sulfa drug - hypersensitivity (some rash)
What are the clinical applications and toxicities for zidovudine (AZT)
application: (-) HIV-1, 2 & HTLV-1,2
adults and children, prevent mom-child transmission & post exposure prophyaxis in health care workers
toxicity:
- loss of limb fat,
- bone marrow suppression,
- skeletal M. myopathy &
- hepathic steatosis
what are the cllinical applications, pharmacokinetics and toxicities for rilpivirine
application: HIV-1 naive pt; not susceptible to common mutation BUT affected by other mutations so less resistant than etravirine
pharmacokinetics: half life - 50 hrs, metabolized by CYP3A4; 85% excreted in feces and 25% uncharged drug
toxicites: MOST COMMON IN KIDS & TEENS- CNS, decreased cortisol, nausea, fat restribution, immune reconsitution syndrome
what are the clinical application and toxicities of atazanavir
application: (-) HIV 1, 2; Tx naive pts; use in tx-experienced pts guided by PI resistance substitutions
toxicities =
- GI distress, nausea, vomiting, diarrhea, cough and fever (like other PI)
- increase serum cholesterol
- elevated bilirubin - unconjugated hyperbilirubinemia not assocaited w/ hepatitis
- fat redistribution, hypersensitivity rxn
- immune reconstitution syndrome
What are the steps taken to achieve treatment goals
- baseline pt characteristic & drug resistance guide regimen
- give initial treatment to suppress HIV
- if not achieved/maintained –> new regimen w/ >= 2 active drugs (increase in drugs make viral suppression below detectable limits)
- after effective ART achieved, viral load reduction to below limits of assay detection occurs w/i first 12-24 wks
compare and contrast TDF and TAF (tenofovir alafenamide)
similar: MOA, effects, clinical application
pharmacokinetics: like TDF but TAF transported differently - lower doses administed –> low [plasma] but higher intracel [tenofovir-diphosphate]
toxicities: TAF fewer side effects than TDF (= bloating, diarrhea, flatulence)
what is didanosine
adenosine analog against HIV 1, 2,and HTLV-1
replaced by less toxic drugs (causes peripheral nephropaty, pancreatitis &/or hepatic steatosis)
what is the MOA and pharmacokinetics of darunavir
MOA - non-peptidic protease inhibitor
pharmacokinetics - same as atazanavir (metabolized by CYP3A4 and mostly excreted in feces)
half life = 15 hrs
What is cobicistat?
MOA: CYP3A4 inhibitor
effect/application: Boost level of other PIs (azatanavir & darunavir)
half life - 3-5 hr; excreted in feces
toxicity= misc.
what are clincal applications, pharmacokinetics and toxicities of maraviroc?
application: combo for HIV caused by CCR5 trophic virus; not active agaisnt CXCR4 or mixed trophic viruses
retain activity against virus that become resistant
half-life 10.6 hr, CYP3A4 substrate; renal elimination
toxicities: generally well tolerated - cold like symptoms, dizziness, GI upset
Compare and contrast
pharmacokinetics, MOA, effects, application and toxicities of
lamivudine (3TC) and emticitabine (FTC)
3TC - interfere w/ cytodine & FTC - interfere w/ cytosine
clincial application of 3TC all that FTC is used for PLUS dual agent combination of 3TC and doltegravir for naive pt w/ low HIV copy
Toxicities: same BUT ONLY FTC cause hyperpigmentation in AA pts
effects, pharmacokinetics are the same (long intracell half life & excreted unchanged in urine)
what are the clinical applications and toxicities for abacavir (ABC)
applications:
- HIV in combo w/ other drugs;
- should NOT be used in pt w/ HLA-B*5701 genotype (bc toxicity- potentially fatal hypersensitivity) ;
- NOT effective against HBV
toxicities:
- potentially fatal hypersensitivity bc of HLA-B*5701 locus - fever, abd pain/GI distress, maculopapular rash, etc 6 day-6 wks –> death if continued use w/ adverse rxn
- AVOID in pt w/ coronary A disease bc may cause hyperlipidemia and CV events
what is the protocol to prevent sexual tranmission
maintain plasma HIV RNA <200
use other form of prevention (condoms, pre-exposure prophylaxis for HIV (-) partner, abstinence) for >= 6 months of treatment
maintian high levels of adherence (esp is relying on ART for prevention)
What are the toxicities associated w/ NRTIs
black box warning b/c possibility of lactic acidosis syndrome
peripheral neuropathy
pancreatitis
anemia
myopathy
what is the MOA and pharmacokinetics of zidovudine (AZT)
(first anti-retroviral drug discovered)
NRTI - interfere w/ thymidine incorporation
most potent in active cells bc thymidine kinase is S-phase specific
well-abs, extensive first pass; 1/2-life = 3-4
excrete in urine as metabolite (some unchanged)
what is the purpose of initiating ART immediately after HIV diagnosis
to increase uptake of ART & linkage to care
decrease time to viral supression
improve rate of virologic suppression
*imp to educate pt about benefits and strategies to optomize care*
what is action of virus aspartyl protease
enzyme = homodimer w/ Asp essential for catalysis
cleaves N-terminal side of Pro-residues
human aspartyl proteases (renin, pepsin, etc) = MONOMERS so NOT inhibited by protease inhibitors
What is the MOA and pharmacokinetics of saquinavir
MOA = 1st protease inhibitor
poor bioavailability (half-life 1-2 hr)
rmr- pill burden!
how are protease inhibitors cleared from body
mainly by hepatic clearance (oxidation)
metabolized by CYP3A4, all inhibit metabolism of other drugs
all = substrates for P-glycoprotein (MDR1) so infleunce(d) by other drug transport
what is imp to consider for child-bearing potential or pregnant pts
consider: pharmacokinetic interaxn w/ hormonal contraceptives –> change contraceptive method/switch ART
*pregnancy test before initiating ART*
-increased risk of n_eural tube defect_ if mother was taking dolutegravir
during pregnancy - goal of ART = maintain viral load below limit of detection thru-out pregnancy to decrease risk of transmission to fetus/newborn
what is ritonavir
MOA: PI only to block CYP3A4
effects/application: boosts levels of other more potent PI
half life = 3-5 hr , potent CYP3A4 inhibitor
toxicities: flush rash, GI upset
what are the MOA and pharmacokinetics of abacavir (ABC)
MOA: NRTI for guanosine analog (only one!)
rapid/extensive abs; intra cell half life = 21 hrs, not a CYP substrate (but metabolized by dehydrogenase and conjugated fro renal elimination)
what should you include when reasoning why virologic failure occured
adherence
drug-drug and drug-food interaxn
tolerability
HIV RNA level & CD4 cell count trends
ART history
drug-resistance
*new regimen should include atleast 2, preferably 3, fully active agents*
which NRTI/drug combinations are superior to other combos?
& which should not be combined?
FTC and tenofovir- commonly used & better than other combos
3TC w/ INSTI (dolutegravir) recommended in naive HIV pts
DONT combine -
emtricitabine & lamivudine (bc bot cytosine analogs)
TDF and TAF (bc both prodrug formulations of same active agent
what is elvitegravir combined with to form a 1x/day dose
cobicistat, emtricitabine & either TAF or TDF
(INSTIs metabolized by CYP3A4 & needs to be boosted)
Indinavir is a early protease inhibitor that inhibits HIV 1 & 2, what is it’s pharmacokinetics & toxicity
short half life - 1.8 hrs –> 3x/day
Toxicity ****** unique crystaluria/renal stones *****
once you initiate ART, you should continue therapy.. with what treatment goals to keep in mind?
- maximally and durably suppress plasma HIV RNA
- restore & preserve (CD4 count) immune fxn
- decrease HIV-assocaited morbidity
- increase survival
- prevent transmision
What are the clinical application and toxicities for emtricitabine (FTC)
applications - HIV-1, 2 in adults, HBV
low barrier to resistance if monotherapy
& co-formulated w/ tenofovir
toxicities:
*one of least toxic antiretrovirals - cause HA, nausea, diarrhea, rash, cough, infxn, fever in >10%
prolonged use –> hyperpigmentation of skin (ESP palm & soles) > in African Amercians
What are Non-nucleoside reverse transcriptase inhibitors (NNRTI)
inhibitor binds to RT and denature it; enzyme cant produce viral DNA from viral RNA
-bind to hydrophobic pocket in p66 subunit of HIV RT –> induce confirmational change (non-competitive antagonist)
ONLY active against HIV-1 (2 is intrinsically resistant)
what are the clinical applications, pharmacokinetics and toxicities of enfuvirtide (T20)
application: Tx-experienced adults w/ viral replication despite therapy; not active against HIV-2; retain activity against viruses resistant to other drug classes
MUST administered paraentrally (2x/day)
toxicity: injection site rxn
(not used often)
What are clinical applications, pharmacokinetics and toxicities of etravirine
application: HIV-1 adult & childen; unique bc still works after mutation that disrupts other NNRTIs
pharmacokinetics - half life = 41 hrs (1x/day), induce CYP3A4
toxicities: fat redistribution, immune reconstitution syndrome, rash, Steven-Johnson syndrome possible
what are the MOA and pharmakinetics in lopinavir
MOA: PI (only available in form boosted w/ ritonavir)
half life = 5-6
