Exam 4 lecture 4 Flashcards
What drug blocks attachment and entry of virus into cell
Enfuviritide
Maravoric
What drug targets reverse transcription of HIV
Nucleoside RT inhibitors
non- nucleoside RT inhibitors
What Anti HIV drug targets Integrase
Raltegavir
What drugs target the maturation of HIV drugs
Protease inhibitors
What is the use of integrase
inserts the HIV DNA into the hosts chromosome
What are the 3 activities of RT
RNA dependent DNA polymerase (uses RNA to make DNA)
Ribonuclease H activity (chops up RNA)
DNA depndent DNA polymerase activity (makes complementary strand from synthesized DNA)
- copies plus strand RNA to produce minus strand DNA
- Degrades RNA template from RNA-DNA hybrid
- synthesizes plus strand DNA from minus strand DNA template
What are NRTIs? What are their2 effects?
NRTIs are nucleoside analogs that lack the 3’ OH
Two effects
- competitive inhibitor of reverse transcriptase
-DNA chain terminator - inhibit elongation
What do we use NRTIs in combo with
2 NRTIs plus NNRTI or PI or integrase inhibitor
what are NRTI combos that work best
Tenofovir and emtricitabine
Abacavir and lamivudine
what is a characteristic shared by all NRTIs?
all must be activated by cellular kinase to triphosphate form
name NRTIs
abacavir
tenofovir
emtricitabine
lamivudine
what enzymes activate NRTIs
use cellular enzymes
How is tenofovir different from tenofovir alafenamide
Activated by different pathway than previous tenofovir drugs
Increased accumulation in lymphocytes, fewer side effects
What can be a negative about tenofovir alafenamide (TAF)? positive?
negative- TAF is associated with higher lipid levels compared to other tenofovir drugs.
Positive- Better accumulation in lymph nodes and higher intracellular concentration (reduced renal damage)
different activation pathway to TAF allows for 10x lower dose compared to other Tenofovir
Tenofovir alafenamide activation
It is stable in the plasma, TAF turns into tenofovir diphosphate in HIV cells or infected cells.
What are NRTIs competing with
dATP, d CTP, d GTP and dTTP
Do NRTIs have higher affinity to GIV RT or cellular DNA polymerase
HIV RT
What must happen to TAF before phosphorylation?
TAF must be processed to TFV by cellular enzymes
how many phosphorylations does tenofovir require?
2
Why do resistance mutations arise so quickly for HIV
-HIV polymerase is error prone
-RT inhibitors unable to suppress viral replication
- large amounts of virus present
What are the two types of resistance mutations seen with resistance to NRTIs
- discriminatory mutations
- mutations that selectively impair the ability of reverse transcriptase to incorporate analogues into DNA - Excision mutations
- ATP molecule mediates the removal of a nuceoside analogue after it has been incorporated
Where do most mutations to NRTIs occur
near RT active site
What can mutations against NRTIs do?
Help RT to distinguish between normal dNTPs and NRTIs
Promote removal of NRTIs after they have been incorporated into the growing chain
Do NRTIs have high or low barrier of resistance? WHat does that mean?
NRTIs have a low barrier of resistance.
High risk of mutations
adverse effects of NRTIs
Mitochondrial toxicity
- Anemia, granulocytopenia, myopathy, neuropathy and pancreatitis
abacavir black box warning? What genes are linked with them?
Abacavir HS rxn, Highly associated with HLA B 5701 in needed before initiating tx
Where do NNRTIs bind (Nonnucleoside RT inhibitors)? Competitive or noncompetitive inhibitors?
Directly to site on RT?
Do not compete with nucleotides for binding (non competitive)
do NNRTIs have to be phosphorylated?
no
WHat do NNRTIs block?
block RNA and DNA dependent DNA polymerase activity (blocks polymerization)
Name 1st gen NNRTIs? Side effects
Nevirapine
Efavirenz
Delaviridine
CNS side effects
Potentially teratogenic
Name second gen NNRTIs
Etravirine
Rilpivirine
Why is there less chance at resistance with second gen NNRTIs
Designed to be inherently flexible.
Can bind in multiple orientations
adverse effects of NNRTIs
Rash
Drug-drug interactions (CYP 450)
nevapirine- hepatotoxicity or SJS
Efavirenz- teratogenic and neuropsychiatric
DO NNRTIs bind to cellular DNA polymerases? How many mutations can confer NNRTI resistance? Do NNRTIs and NRTIs share common resistance mutations?
Do, NNRTIs do not bind to cellular DNA polymerase
Resistance to NNRTIs can be acquired through single mutation
Mutations that confer resistance to NNRTIs do not cause resistance to NRTIs
What do integrase inhibitors (INI) do??
Inhibit insertion of HIV DNA into the human genome
Common side effects with INI
N/V/D
compatible with other antiretroviral drugs due to favorable interaction profile
INI drug drug interactions
SOme interact with CYP450
What are the 2 steps to INI
3’ processing
string transfer- incorporation of HIV strand into host chromosome
name integrase inhibitors
Raltegavir
Elvitegravir
Dolutegravir
Bictegravir
what is integrase inhibitor resistance caused by
Caused by primary mutations that reduce INI susceptability
WHat is special in the way elvitegravir is formulated
Co formulated with cobicistat (COBI)
this is because it is metabolized by CYP3A4
What is the use of cobicistat
Formulated with elvitegravir to boost its concentrations by inhibiting metabolism by CYP3A4
What are things about dolutegavir that we should know (interactions, boosting and barrier for resistance)
No boosting required and no interactions with CYP3A4.
Higher barrier for resistance
things to know about bictegravir (resistance, drug interactions)
low risk of resistance and few drug interactions.
Can not be used with rifampin
Raises Scr levels 0.1
Which drug can be started without HLA B 5701 testing testing
Bictegravir
What type of protease is HIV protease. How is it activated
aspartic acid in active site
Dimer- active site formed at interface
How do HIV protease inhibitors act
HIV protease inhibitors are transition state mimetics (peptidomimetic)
amide bond is replaced by non-cleavable linkages
Which drug is the only protease inhibitor that is not a peptidomimetic
Tipranavir
what happens when HIV protease inhibitors bind to protease
Protease flaps to closed conformation
What is notable about protease inhibitor and interactions
ALL are substrates and some are inhibitors of CYP3A4
What are things we can do to boost protease inhibitors (PK enhancement)
Low doses of rotinavir inhibit CYP3A4
blocks metabolism of other PIs
How does low doses of ritonavir affect PIs? Advantage vs disadvantage
advantage- increases serum concentrations and blocks metabolism of PIs by inhibiting CYP3A4.
disadvantages- Drug-drug interctions with ritonavir and increased risk of hyperlipidemia
Name protease inhibitors? most potent of all?
Atazanavir (most potent after darunavir)
Darunavir (preferred PI for initial antiretroviral)
Tipranavir
What two drugs reduce atazanavir levels
Efavirenz and tenofovir
What are two unique features of darunavir
makes extensive hydrogen bonds with protease backbone
Inhibits HIV protease dimerization
What is important to note about darunavir
Peptide backbones of wildtype and mutant HIV protease have similar structures so darunavir can inhibit both wildtype and mutants
What is special about tipranavir
Retains activity against protease in highly treated patients including resistant to DRV
Nonpeptidic PI
tipranavir drug ia
CYP3A4
Describe the resistance to protease inhibitors
Highest genetic barrier of antiretrovirals
what two drugs retain activity against most PI resistant mutant proteases
darunavir and tipranavir
adverse effects of PI
hyperlipidemia
drug dfrug i/a (cyp3A4)
Name two long acting injectable therapies for HIV
Cabotegavir (INI) and rilpivirine (NNRTI)
Where are HSV1 common? Where are HSV2 common?
HSV 1 is common in oral mucosa
HSV 2 is common in genital mucosa
describe HSV1 and HSV2
HSV 1- cold sore, transferred viral oral secretions. first episodes can systemic side effects (fever, body aches etc)
Re occurance can start with tingling or burning sensation where sore will form prodrome)
HSV 2- genital/anus transferred via infected secretions. Prodrome is there for this one as well.
which HSV mostly causes HSV encephalitis
HSV 1
Name drugs that are used for HSV
Acyclovir
Valacyclovir
famciclovir
MOA of acyclovir? elimination?
Prodrug actively converted to acyclovir triphosphate.
Acyclovir TP competitively inhibits viral DNA polymerase to inhibit viral replication. Also incorporated into viral DNA to cuase premature chain termination
renally eliminated
adverse effects of acyclovir
N/V/D
nephro (important)
Dose for acyclovir for HSV encephalitis
10 mg/kg IV q8hr for 14-21 days (adjusted body weight)
MOA of valacyclovir
Prodrug of acyclovir. (Same MOA, adverse effects and spectrum)
MOA of famciclovir
Prodrug of penciclovir, converted to active form via triphosphorylation. Linear kinetics
What is the drug of choice for variclla zoster
Acyclovir or valacyclovir
Drug of choice for cytomegalovirus (CMV)
ganciclovir
MOA of ganciclovir
The drug is a pro drug trned into the active form by thymidine kinase
Describe how resistance can develop in ganciclovir
Resistance can develop via a UL97 gene mutation, leading to viral kinase deficiency
Ganciclovir adverse effects
Bone marrow suppression (reversible)
How to treat CMV retinitis, esophagitis, colitis, pneumonitis and prevention of CMV in bone marrow
Ganciclovir
Describe valganciclovir? Toxicity and MOA? Elimination?
Pro drug of ganciclovir, more bioavailable
Adverse effects same as ganciclovir (hematologic toxicity)
Counsel to take with food
use of valganciclovir
CMV retinitis and prevention of CMV disease in transplant patients at high risk
letermovir MOA
inhibits the pUL56 subunit of CMV, prevents cleavage ofDNA, resulting in inhibition of CMV replication and prevention of CMV infection
letermovir use
Prophylaxis of CMV infection in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
What are some letermovir drug interactions
CYP 3A4 substrate (A LOT of interactions)
Azole, statin, warfarin
Foscarnet MOA
Does not require phosphorylation (is not a pro drug) and it directly inhibits viral DNA polymerase
Use of foscarnet
last line against drug resistant HSV, VZV and CMV
Foscarnet adverse effects
Nephrotoxicity
Name neuraminidase inhibitors used in influenza (flu)
Zanamivir (dry powder inhallation)
Oseltamivir
Peramivir (IV)
Oseltamivir MOA, excretion and adverse effects
Prodrug
Renally dose adjusted
N/V/D
Who do we give oseltamivir to
symptomatic for no more than 2 days. (same with zanamivir)
Prophylaxis of influenza inpts >1
zanamivir adverse effects
Brochospasms
use of baloxavir marboxil
Used for flu in 12 and older, not used if symptomatic for more than 48 hrs
Drug of choice in CMV
ganciclovir and vanganciclovir
Drug of choice in VZV
Acyclovir and valacyclovir
Drug of choice in HSV 1/2
acyclovir/valacyclovir
WHat drug is used for flu B
Zanamivir
