Antiretroviral Agents MT2 Flashcards
this is a retrovirus of the lentivirus group; it uses host machinery to replicate, therefore it can’t survive outside the host cell for very long. Replication of this virus is constant in the host cell
human immunodeficiency virus (HIV)
is HIV a DNA or RNA virus
RNA
what cells do HIV target
CD4 lymphocytes
Abacavir, Emtricitabine, Lamivudine and Zidovudine all belong to this first-line class for HIV treatment
nucleoSIDE RT inhibitors (NRTI)
Tenofovir disoproxil fumarate and Tenofovir alafenamide belong to this first-line class for HIV treatment
nucleoTIDE RT inhibitors (NtRTI)
Doravirine, Efavirenz, Nevirapine, Etravirine and Rilpivirine all belong to this first-line class for HIV treatment
non-nucleoside RT inhibitors (nnRTI)
Bictegravir, Cabotegravir, Dolutegravir, Elvitegravir/cobi and Raltegravir all belong to this first-line class for HIV treatment
Integrase inhibitors (INSTI)
Atazanavir, Darunavir, Lopinavir/ritovanir and Ritovanir all belong to this first-line class for HIV treatment
Protease Inhibitors (PI)
Most PI’s and elvitegravir (INSTI) are used clinically in their “boosted” form; that is in combination with a CYP inhibitor (PK booster). this results in elevated drug concentrations of the PI or INSTI, which results in enhanced efficacy, reduced dosing frequency or both. which are the two PK boosters used?
Ritovanir and Cobistat (cobi)
does resistance occur within or between antiretroviral drug classes?
within not between
what are the two main drug interactions with antiretroviral agents
- antacids, H2 receptor antagonists and PPIs can reduce acidic environment needs for absorption of some ARVs (e.g. rilprivirine - nnRTI and atazanavir - PI)
- cytochrome P450 interactions are common, as well as interactions affecting other drug transport systems (e.g. P-glycoprotein, OAT and OCT systems)
true or false: ARVs may be inhibitors of CYP enzymes
false - may be substrates, inhibitors or inducers of CYP enzymes
Fostemasavir is in this second-line class for HIV treatment
attachments inhibitor (gp120 inhibitor)
Lenacapavir is in this second line class for HIV treatment
Capsid inhibitor
Maravrioc is in this second line class for HIV treatment
entry inhibitors (CCR5 co-receptor antagonist)
Enfuviritide is in this second line class for HIV treatment
Fusion inhibitors
what is the timeframe for the onset of CYP induction drug reactions?
enzymes are being produced thus days to weeks
what is the timeframe for the onset of CYP inhibition drug interactions
inactivating an enzyme that is already there thus a day or two
what is the mechanism of action of nucleoside/nucleotide RT inhibitors?
NRTI or NtRTI’s bind competitively to viral RT in place of natural nucleotide and act as chain terminators
NRTI or NtRTI?
these are synthetic nucleoside analogue prodrugs, therefore they must undergo triphosphorylation by intracellular enzymes to active form
NRTI
NRTI or NtRTI?
these are essentially a nucleotide monophosphate
NtRTI
Tenofovir disoproxil fumarate (TDF - old version) or Tenofovir alafenamide (TAF - new version)?
attachment of lipophilic groups allow passive drug diffusion across cell membranes - not stable in plasma and bloodstream, therefore most of TFV gets taken up into renal cells instead of CD4 target cells which can cause renal toxicity
TDF
Tenofovir disoproxil fumarate (TDF - old version) or Tenofovir alafenamide (TAF - new version)?
phosphonoamidate prodrug designed to be more stable in plasma vs other drug, therefore less plasma exposure to tenofovir, resulting in less uptake in renal tubular cells and less Renal and bone toxicity
TAF
these NRTI/NtRTI agents need dosing adjustment in renal impairment
- emtricitabine
- lamivudine
- tenofovir
- zidovudine
true or false: NRTI/NtRTI have no metabolism or effect on cytochrome P450 system
true
intracellular concentrations and half-life are of _________ (less/greater) clinical significance than plasma levels
greater
what is the route of administration for NRTIs (abacavir, emitricitabine, lamivudine) and NtRTI’s (TDF and TAF)?
PO/oral
this NRTI requires HLA-B*5701 screening prior to treatment.
adverse effects of this medication include a hypersensitivity syndrome: presents as a flu-like illness (fever, rash, GI, fatigue, cough, respiratory symptoms) that occurs usually within first 6 weeks of tx -> MUST D/C DRUG AND NEVER RECHALLENGE - FATAL
may also be associated with increased risk of MI
abacavir
what are the adverse effects of emtricitabine and lamivudine
headaches and nausea - but usually well tolerated
adverse effects of this NtRTI include renal dysfunction, headaches, nausea, diarrhea, flatulence, increased risk of osteoporosis
TDF
adverse effects of this NtRTI include increased cholesterol
TAF
what is the mechanism of action of non-nucleoside RT inhibitors (e.g. doravirine, efavirenz and rilpivirine)
noncompetitive inhibitor of reverse transcriptase (RT) -> nnRTI’s bind to an inactive site on the RT to induce a conformational change in the 3D structure of there RT that greatly reduces its activity
active against HIV-1 strains only
should efavirenz be taken with food or on an empty stomach in order to reduce intolerable side effects
fatty foods increases CNS penetration of efavirenz therefore should be taken on an empty stomach to reduce intolerable side effects
what are some points to keep in mind for administration of oral rilpivarine regarding its absorption
- should be taken with a high calorie meal (at least 550 kcal)
- absorption is significantly reduced when co-administered with antacids. if H2RA is necessary, can administer rilpivarine 4 hours before or 12 hours after H2RA
do nnRTIs have any effect on the cytochrome P450 system
yes - all are metabolized primarily by CYP 3A4 therefore nnRTI levels are reduced with coadministration of CYP 3A4 inducers and increased with CYP 3A4 inhibitors
efavirenz is an inducer of CYP 3A4
doravirine does not inhibit or induce CYP enzymes
rilpivarine is a moderate inducer of some CYP enzymes - it does not produce clinically sig. interactions at usual doses
are nnRTIs administered PO or IV
doravirine and efavirenz are PO
rilpivirine is PO and IM
this nnRTI is generally well tolerated. may cause nausea, drowsiness/dizziness, headache, insomnia/nightmares
doravirine
this nnRTI may cause QT prolongation or depressed mood. chance of elevated cholesterol, hepatotoxicity and rash… if severe d/c
rilpivirine
this nnRTI may cause CNS toxicity, dizziness, difficulty concentrating, insomnia. tolerance usually develops to all except abnormal dreams. may cause altered mood. chance of elevated cholesterol, hepatotoxitiy and rash… if severe d/c
efavirenz
what is the mechanism of action of integrase inhibitors (bictegravir, cabotegravir, dolutegravir, elvitegravir/cobi)
inhibits the catalytic activity of HIV intergrase, preventing the integration of the HIV genome into the host genome in the early stages of HIV replication
should integrase inhibitors be taken with or without food for optimal absorption
elvitegravir should be taken with food; the others may be taken with or without
this integrase inhibitor is primarily metabolized by UGT1A1 with a minor UGT1A9 component
cabotegravir
these integrase inhibitors are substrates of UGT 1A1 and CYP 3A4; not an inhibitor or inducer of CYP, UGT or any major transport systems
bictegravir and dolutegravir
this integrase inhibitor is a substrate of both UGT 1A1 and CYP 3A4
- requires CYP inhibitor (cobistat) to permit once daily dosing
- may not be recommended in those with reduced renal fxn
elvitegravir
what is the route of administration of integrase inhibitors
bictegravir, dolutegravir and elvitegravir are PO
cabotegravir can be PO or IM
this integrase inhibitor must be taken with rilprivarine
cabotegravir
what are some AE of integrase inhibitors
pretty well tolerated
- may get some nausea, diarrhea, headache
what is the MOA of protease inhibitors
bind to HIV aspartyl protease to prevent proteolytic cleavage of HIV “gag” and “pol” poly proteins, which include essential structural and enzymatic components of the virus, thus producing immature, non-infectious virions
should protease inhibitors be taken with food or on an empty stomach for optimal absorption
with food
which protease inhibitors absorption is reduced if co-administered with antacids, H2RA’s, PPIs
atazanavir
all protease inhibitors are metabolized by which enzyme
CYP 3A4
all protease inhibitors are substrates of what type of transporters
p-glycoprotein drug transporters
all protease inhibitors are inhibitors of what enzyme
CYP 3A4
* ritonavir is the most potent 3A4 inhibitor
what is an important drug-drug interaction of protease inhibitors
ritovanir boosted PI’s and oral contraceptives -> alternative form of birth control should be used in this situation
are protease inhibitors PO or IM
PO
what are some AE for all protease inhibitors
- GI (N/V/D)
- increased cholesterol levels
- metabolic side effects
which protease inhibitor should caution be taken with regarding a sulfa allergy
darunavir (has sulfa moeity)
this specific protease inhibitor has side effects such as: prolonged QT and renal impairment
atazanavir
what is the MOA of fostemsavir, which is an attachment inhibitor (gp120 inhibitor)
fostemsavir is a prodrug of temsavir. temsavir bind to the viral envelope gp120 and interferes with viral attachment and entry of the virus
is fostemsavir PO or IM
PO
what is the MOA of lenacapvir which is a capsid inhibitor
directly binds to the interface between capsid protein subunits - multi-stage, selective inhibitor of HIV-1 capsid function therefore inhibits HIV-1 replication
is lenacapavir PO or SC injection
SC injection following an oral lead in
what is the MOA of maraviroc which is an entry inhibitor
binds to human chemokine receptor CCR5 in order to inhibit the interaction between the envelope glycoprotein (gp120) from CCR5-tropic HIV-1 strains
is maraviroc PO or SC injection
PO
what is the MOA of enfuvirtide which is a fusion inhibitor
binds to the gp41 glycoprotein to prevent conformation changes necessary for HIV to fuse to the CD4 cell membrane
* only active against HIV-1 strains
is enfuviritide PO or SC injection
SC injection
