Pharm - HIV pharmacotherap Flashcards by amanda kastel

what does HIV stand for

human immunodeficiency virus

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what does AIDS stand for

acquired immuno deficiency syndrome

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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)

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is HIV an RNA or DNA virus

RNA

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is HIV1 or HIV2 more common in europe/america

HIV1

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true or false

HIV is a ssRNA virus

true

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which 2 glycoproteins on the HIV virus are important for attachment to the membrane of host cells?

gp120 (docking glycoprotein)

gp41 (transmembrane glycoprotein)

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name of the enzyme that allows viral dsDNA to integrate into the human genome to make NEW viral RNA?

INTEGRASE

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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

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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

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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

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which receptors on the host cell are important for HIV virus to enter?

CD4
CCR5
CXCR4

CCR5 and CXCR4 are coreceptors

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what is the portal of entry for the HIV virus to get into the body?

blood, colon-rectum, and vagina — can get into bloodstream

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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

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which 2 cells can HIV infect

CD4 cells and macrophages

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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

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once the CD4 count reaches below _____, severe immunodeficiency begins

below 200 cells/cubic mm

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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

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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

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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

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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

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an issue with HIV pharmacotherapy is the rapid emergence of..

DRUG RESISTANCE (if the agents aren’t used properly)

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true or false

discontinuing HIV drugs could be fatal

TRUE

have to be on forever

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method to decrease HIV antiretroviral resistance

use combination therapy for which the virus is more susceptible

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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

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

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