Pharm - HIV pharmacotherap Flashcards
what does HIV stand for
human immunodeficiency virus
what does AIDS stand for
acquired immuno deficiency syndrome
HIV is a retrovirus
what does this mean
has reverse transcriptase
converts vRNA to ssDNA and then to dsDNA – and then integrase enzyme integrates the dsDNA into the human genome
(both steps through reverse transcriptase)
is HIV an RNA or DNA virus
RNA
is HIV1 or HIV2 more common in europe/america
HIV1
true or false
HIV is a ssRNA virus
true
which 2 glycoproteins on the HIV virus are important for attachment to the membrane of host cells?
gp120 (docking glycoprotein)
gp41 (transmembrane glycoprotein)
name of the enzyme that allows viral dsDNA to integrate into the human genome to make NEW viral RNA?
INTEGRASE
Explain the structure of a retrovirus (HIV is one)
contains an RNA genome in a capsid, surrounded by a lipid envelope
this envelope contains receptors that mediate entry and infection into the host cell
true or false
we do not have drugs that kill the HIV virus
TRUE
only that inhibit their growth. thus, patients with HIV have to be on the meds forever
explain the lifecycle of the HIV virus
gp41 and gp140 allow for binding to CD4 receptors and CCR5 receptors (chemokine receptors) on the host cell membrane
fusion and uncoating occurs, and the viral RNA is released
reverse transcriptase converts this viral RNA into DNA, when then goes into the nucleus and is incorporated into the host genome through INTEGRASE.
then, transcription and translation of new viral proteins occurs.
the proteins assemble together into virions and mature. protease breaks down this polyprotein into smaller proteins which can assemble into a whole new virus that can then leave the host cell and infect more cells with the HIV virus
which receptors on the host cell are important for HIV virus to enter?
3:
CD4
CCR5
CXCR4
CCR5 and CXCR4 are coreceptors
what is the portal of entry for the HIV virus to get into the body?
blood, colon-rectum, and vagina — can get into bloodstream
HIV causes ___ and ___ infection of CD4 cells and persistent infection of cells of the ______ family, AND can disrupt _____
what is the result of these actions?
lytic and latent infection
monocyte macrophage family
can disrupt neurons
AIDS – also potential dementia bc affects neurons
which 2 cells can HIV infect
CD4 cells and macrophages
explain and differentiate between the lytic and latent phase of the HIV virus
latent:
HIV infects CD4 cells + macrophages. these serve as a reservoir for the virus. these cells can move to other areas of the body and cause lot of issues and cytokine release
lytic:
increased viral load in the blood causes CD4 cell to LYSE. the virus itself is released and can go to the brain – cause AIDS and dementia, and immuodeficiency,
total loss of cd4 cell functions – which causes SEVERE systemic opportunistic infections and lymphomas are common
once the CD4 count reaches below _____, severe immunodeficiency begins
below 200 cells/cubic mm
explain the progression of:
-viral load
-CD4 cells
-Anti-HIV antibody
throughout infection with HIV
at first, anti-HIV antibodies rise, CD4 numbers fall, and viral load increases substantially
after around 4 years, CD4 count continually decreases untill less than 200 (AIDS), but viral load is at zero bc of the antibodies still being produced
HOWEVER, past that mark of less than 200 T cells, viral load increases substantially and less antibodies produced
how do CD4 cells have a critical role in regulating human immune response?
they mediate the release of cytokines and the delayed-type hypersensitivity toward intracellular pathogens
loss of CD4 cells due to HIV has many negative results.
name them
loss of macrophage activation and thus (thru t cell release of IFN Y) delayed type hypersensitivity reactions – and thus loss of control of bacterial, fungal, and viral infections
also, no more growth and control of B cells, CD8 cells, and NK cells (CD8 cells and NK cells - IL2) - resulting in tumors and tumor progression
as mentioned, the receptor for HIV virus is CD4
tropism (early) is primarily for which coreceptor? how does this change into the advanced stages)
early - CCR5
advanced - switch to CXCR5 concurrently with CD4 cell loss
an issue with HIV pharmacotherapy is the rapid emergence of..
DRUG RESISTANCE (if the agents aren’t used properly)
true or false
discontinuing HIV drugs could be fatal
TRUE
have to be on forever
method to decrease HIV antiretroviral resistance
use combination therapy for which the virus is more susceptible
when administering HIV therapy, when should we get to an undetectable viral load? what is considered an undetectable viral load?
in 6 months
less than 50 copies of the viral RNA/plasma mL
standard HIV therapy consists of how many drugs
2+
all current HIV drugs do not affect what viral stage?
latent viral stage
(when viral DNA is already integrated with the host)
name 5 toxicities from HIV drugs
-HIV lipodystrophy syndrome (fat redistribution, hyperlipidemia, insulin resistance)
-CV toxicities (ie -QT prolongation)
-alltergies (sulfa)
-effect on CYPS
-accelerated inflammatory reactions (immune reconstitution inflammatory syndrome - IRIS)
name 5 NRTIs
abacavir
emtricitabine
lamivudine
tenofovir
zidovudine
what does NRTI stand for
nucleoside/nucleotide reverse transcriptase inhibitors
what is cobicistat
NOT an nrti/nnrti
its a pharmacokinetic enhancer - used in combination to inhibit CYPs and increase the half life of the antiviral drug
of the 5 NRTIs listed, (abacavir, lamivudine, emtricitabine, tenofovir, and zidovudine)
which is the ONLY nucleotide? (all the others are nucleosides)
TENOFOVIR
remember - FO - has phosphate
of the 5 NRTIs, name which resemble guanine/adenine/thymine/
cytosine
thymine - zidovudine
adenine - tenofovir
cytosine - emtricitabine, lamivudine
guanine - abacavir
true or false
ALL the NRTIs are prodrugs
TRUE
name the 2 enzymes that are part of HIV reverse trancriptase
polymerase and nuclease (breaks nucleotide bonds in DNA/RNA)
explain the MOA of NRTIs
1st, the NRTI has to be metabolized to become a TRIPHOSPHATE. competes with native nucelotides to incorporate into DNA strand
this then incorporates into the DNA strand and causes CHAIN TERMINATION in HIV reverse transcriptase enzyme
true or false
NRTIs are noncompetitive inhibitors
FALSE - competitive inhibitors
compete with native nucleotides for incorporation into the DNA strand
what is the backbone of HIV therapy
NRTIs
given with other drugs as well as other NRTIs
what is the most potent NRTI
abacavir
do NRTIs have side effects?
why or why not?
yes bc they also have affinity for human polymerase y in the mitochondria
this gives side effects like anemia, LACTIC ACIDOSIS (rare but serious), granulocytopneia, myopathy, peripheral neuropathy, and pancreatitis
between all of the NRTIs, which has the worst oral bioavailability
tenofovir (it’s the only nucleotide!)
all the others have good oral bioavailability
which 2 NRTIs have very little renal excretion of the parent drug
abacavir and zidovudine
abacavir is a synthetic ____ analog
how is it administered?
guanosine
orally
very important counseling point for abacavir
NO ALCOHOL!!!
ALCOHOL WILL INCREASE THE SERUM LEVELS OF ABACAVIR
how is abacavir metabolized
hepatic - glucuronidation and carboxylation
resistance mechanism to abacavir
mutations in reverse transcriptase
important consideration before starting abacavir
there is hypersensitivity in 8% of patients
before starting, do HLAB5701 testing to identify hypersensitivity potential
**some patient on abacavir have higher risk of…
myocardial infarction!
emtricitabine is a ____ analog of ____
fluorinated analog of cytosine
when is emtricitabine CONTRAINDICATED
in renal or hepatic failure
ALSO — do NOT use with lamivudine
can emtricitabine be used for prophylaxis?
why or why not??
YES
can be used in combo for prophylaxis - has very long half life
true or false
emtricitabine is active against both HIV and HBV
TRUE
some rare AE of emtricitabine
lactic acidosis/severe hepatomegaly wiht steatosis
fat redistribution, IRIS (immune reconstitution inflammatory syndrome)
lamivudine is a ____ analog
cytosine
true or false
lamivudine, like emtricitabine, is also active against both HIV and HBV
true
true or false
lamivudine cannot be given to pregnant women
FALSE
it can!!! recommended for pregnant women
what happens with lamivudine is administered with chlorpropamide
increase glucose levels (use alternative!)
which 2 NRTIS are recommended for use in pregnancy
what 3 are alternates?
lamivudine and zidovudine
alternates - abacavir, emtricitabine, tenofovir
which NNRTI is recommended for use in pregnancy
nevirapine
are protease inhibitors okay to give during pregnancy?
YES
recommended ones are lopinavir, ritonavir, and atazanavir
alternate is saquinavir
tenofovir is an acyclic ______
nucleotide
which base does tenofovir structurally mimic
adenosine
how many steps of phosphorylation are needed for tenofovir
2
can tenofovir be given for prophylaxis
YES
has long t 1/2
4 major side effects of tenofovir
loss of renal function (fanconi syndrome)
bone mineral density decrease
lactic acidosis
liver damage
zidovudine is a ______ analog
deoxythymidine
what was the first HIV drug approved by the FDA
zidovudine
AE of zidovudine
myelosuppression
lactic acidosis and severe hepatomegaly
lipoatrophy
name 5 NNRTIS
efavirenz
etravirine
nevirapine
rilpivirine
doravirine
‘VIR”
true or false
NNRTIS are NOT prodrugs
TRUE
explain the MOA of NNRTIS
they DO NOT BIND THE ENZYMATIC/CATALYTIC SITE OF RT LIKE NRTIS!!!!!
they bind a distant, allosteric site on the enzyme which affects the enzyme’s structural transformation, and it’s activity decreases
true or false
NNRTIS are reversible, competitive antagonists
FALSE
reversible, NON competitve
bind the ALLOSTERIC SITE
true or false
NNRTIs do NOT need intracellular phosphorylation
TRUE - THEY ARE NOT PRODRUGS!!!!!!!!!!!!!!
true or false
NNRTIs are active against both HIV1 and HIV2
FALSE
only HIV1
true or false
NNRTIs do NOT target host DNA polymerase
TRUE
this is good bc less side effects
very important DDI consideration with NNRTIS
they have HIGH hepatic metabolism by CYP3A4!!! therefore, considerable drug drug interactions
explain NNRTI resistance and is there any cross resistance with NRTIS
NNRTIs are susceptible to resistance by a SINGLE mutation
however, there is no cross resistance with NRTIs
since these agents are highly suceptible to resistance, they are combined with AT LEAST 2 OTHER ACTIVE AGENTS to avoid resistance. they are still highly potent and effective
