CMBM exam 3 > Antivirals > Flashcards

Antivirals Flashcards

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0
Q

Goals of ART?

A

reduce HIv infection-related morbidity and prolong duration and quality of survival
resotre and preserve immunologic function
maximally and durably suppress viral load
prevent vertical HIV transmission
Key - achieve and maintain durable viral suppression

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1
Q

HAART

A

highly active antiretroviral therapy

increase survivability

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2
Q

how would you determine which drugs to choose?

A

-Pre ART - determine CD4 count, measure HIV RNA and perform resistance testing
-determine viral tropism - prior to initiation of CCr5 antagonist
HLAB*5701 testing - prior to initiation of abacavir (ABC) due to risk of hypersensitivity reaction

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3
Q

What shows success of ART treatment?

A

high potency of ARV regimen
excellent adherence to treatment regimen
low baseline viremia
higher baseline CD4 count - >200 cells/mm3
rapid reduction of viremia in response to treatment

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4
Q

Classes of Antiretrovirals

A

Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease Inhibitors
Integrase inhibitor
Fusion inhibitors
Chemokine receptor antagonists - CCR5 antagonists

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5
Q

What can Antiretrovirals NOT do?

A

do not cure HIV infection or AIDS
do not eliminate risk of passing HIV to other
HIV medicines must be taken in combination with other HIV medicines
not all medicines are right for all ppl and treatments may be different for each person

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6
Q

Mechanism of Nucleoside reverse transcriptase inhibitors

A
  • competitively inhibit RT effectively blocking ability of virus to make a provirus copy
  • the NRTIs gets added to the growing proviral chain by RT leading to chain termination
  • bind at the RT active site
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7
Q

Zidovudine

A

ZDV (was AZT)

Thymidine analogue

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8
Q

When ZDV was used as monotherapy

A

HIV quickly became resistant

so currently used in combination drug regimens

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9
Q

Side effects of ZDV

A

anemia and granulocytopenia

avoid using with other myelosuppressive drugs

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10
Q

Examples of Nucleoside reverse transcriptase inhibitors

A 
Zidovudine - AZT,ZDV
Lamivudine 
Abacavir (this is the one associated with hypersens. reaction) 
Didanosine 
Emtricitabine 
Stavudine 
Tenofovir
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11
Q

Non nucleoside Reverse transcriptase inhibitors mechanism?

A

bind to and alter reverse transcriptase
bind directly to RT
can be used synergistically with NRTIs due to differences in binding location

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12
Q

what is a concern with NNRTI?

A

whether the virus will be susceptible or resistant

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13
Q

Examples of NNRTIs

A 
Efavirenz*
Delavirdine
Nevirapine
Rilpivirine
Etravirine - has anti HIV-2 activity as well
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14
Q

Mechanism of Protease Inhibitors

A

binds to HIV protease (which essential for proteolytic processing of nascentt polypeptides into individual proteins during maturation)

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15
Q

Activity of PIs

A

against HIV-1 and HIV-2

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16
Q

Mechanism of resistance to PIs

A

due to mutations inside and outside the active protease domain

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17
Q

Examples of Protease Inhibitors

A 
Ritonavir*
Darunavir 
Atazanavir
Fosamprenavir 
Indinavir 
Nelfinavir 
Saquinavir 
Tipranavir
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18
Q

Potency of NRTI

A

less potent than NNRTIs and PIs

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19
Q

Mechanism of ZDV/AZT resistance?

A

mutations remove ZDV from DNA chain
a conformational change allowed Thymine to continue to bind but disabled
ZDVs ability to bind RT
also able to remove ZDV from the proviral DNA

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20
Q

NRTI is active against?

A

HIV-1 and HIV-2

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21
Q

Efavirenz

A

preferred drug for combination therapy in treatment naive individuals

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22
Q

Etravirine

A

has anti-HIV-2 activity as well

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23
Q

Ritonavir side effects?

A

inhibits host protein cytochrome P450 3A4 which results in failure to metabolize other drugs, including other PIs, this leads to higher serum levels and sometime an increase in toxicity

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24
Lipodystrophy
Fat wasting - fat is lost from arms, legs, face and buttocks fat redistribution due to PIs (&NNRTIs) disturbs the way the body produces, uses, and stores fat
25
Hyperadiposity
fat accumulation | fat builds up in belly, breasts and back of the neck
26
Clinical signs of Lipodystrophy
back of neck and upper shoulders - buffalo hump abdomen - protease paunch or crixivan potbelly breasts - both men and women Lipomas - fatty growths in different parts of the body
27
Proviral integration
Proviral integration is 2 step process - 3'-processing in host cell cytoplasm to prepare proviral strands for attachment - strand transfer where proviral DNA is covalently linked to cellular DNA
28
Mechanism of Integrase Inhibitors (INSTI)
competitively inhibits Mg+2 or Mn+2 both essential cofactors for integrase binding to proviral DNA
29
Examples of INSTIs
Raltegravir Elvitegravir Dolutegravir
30
INSTI resistance
mutations in integrase gene associated with resistance to raltegravir and elvitegravir
31
which step of proviral integration do INSTIs block?
step 1 - 3' processing in host-cell cytoplasm
32
1 pill with 4 drugs
Raltegravir Elvitegravir both have same mechanism - blocks Mg binding (only told two of them)
33
Mechanism of Fusion Inhibitors
prevent HIV from entering binds gp41 and prevents fusion to host cell and viral entry ONLY for HIV-1 used in combo with other ART drugs
34
Enfuvirtide (T-20)
36 AA peptide derived from EC domain of gp41 of HIV-1 envelop given when other drugs have failed
35
Mechanism of chemokine receptor antagonists
blocks binding of virus to target cell | directly competes with gp120 for site
36
Maraviroc
its a CRA blocks gp120 from binding CCR5 only works for CCR5 tropic viruses
37
What viruses are there antivirals available for?
``` Influenza viruses Herpes viruses - HSV-1, and 2 VZV, CMV Respiratory syncytial virus (RSV) Hep B virus Hep C virus Papillomaviruses HIV ```
38
Inhibiting Antiviral drugs can target
attachment/adsorption penetration/entry nucleic acid synthesis release
39
A drug that affects viral inhibition of cellular processes could do so by
prevent viral inhibition by interferon production
40
How could anti virals support the immune system to combat viral infections?
by affecting antibodies and immune modulators - polyclonal antisera - monoclonal antibodies - Imiquimod
41
Anti-Influenza drugs
Permavir Oseltamivir (Tamiflu) Zanamivir (Relenza) -these inhibit cleavage of HA-SA bonds by NA - thus no viral release Amantadine Rimantadine -these block M2 ion channel - no viral coating
42
Neuraminidase inhibitors for Inf A and B
inhibits viral release and virion clumping promoted must be started reduces severity and shortens duration of symptoms - Peramivir - IV adults only - Oseltamivir - Zanamivir
43
H+ ion channel (M2) inhibitors for Influenza A
not currently rec. due to high levels of resistance to circulating strains of Influenza A interfers with H+ transport, necessary component for uncoating to occur thus RNA transcription cannot happen - Adamantes - Rimantadine
44
M2
required by Influenza to uncoat and release its genome
45
Activation of Nucleoside Analogues for HSV,VZV
converted to active drug by 3 phosphorylation steps in viral-infected cells 1-first phosphorylation step by viral thymidine kinase 2-Next 2 phosphorylation steps by host cell enzymes 3-Acyclovir tri phosphate added to growing chain of herpes virus DNA - results in chain termination
46
Mechanism of Nucleoside Analogues for HSV
Acyclovir - prodrug | Added to growing chain of virus DNA
47
Acyclovir related compounds
Valacyclovir - better bioavaible than oral acyclovir Famciclovir - higher intracellular levels Penciclovir - higher intracellular levels
48
CMV is opportunisitc in IC pts, clinical manifestations of infection
``` AIDS pts tend to be infected, pts may be on myelosuppressive (AZT) or nephrotoxic drugs Retinitis Esophagitis Coliis Encephalitis Pneumonia ```
49
HIV+ patients are resistance to
Acyclovir
50
CMV doesnt encode
Thymidine Kinase
51
Nucleoside Analogues for CMV
Acyclovir and related not active because uses different enzymes to initiate phosphorylation Ganciclovir - bone marrow toxicity - leads to neutropenia, CMV retinitis Valganciclovir Cidofovir - cytosine analog
52
Foscarnet
...
53
Fomivirsen
...
54
Palivizumab
monoclonal antibody to RSV F protein
55
Ribavirin mechanism
Broad spectrum antiviral synthetic nucleoside analog - GTP analog interferes with viral RNA-dep RNA polymerase (RdRP)
56
Side effects of Ribavirin
dose dep hemolytic anemia dry cough, dyspnea Teratogenic
57
Indications for Ribavirin
RSV - hospitalized infants Hep C Vaccinia, Monkeypox
58
Nucleoside analogues for HBV -RT inhibitor
Lamivudine, telbivudine | blocks HBV DNA synthesis by incorporating into the growing DNA chain, causing premature chain termination
59
NA -RT AND DNA poly inhibitor - HBV
Adefovir - rare cases Renal toxic Tenofovir - rare cases Hepatotoxic Entecavir
60
what does cellular release of Type 1 IFN
induces antiviral state in uninfected cells - induces enzymes that block viral replication Increases expression of MHC I on infected cells to accelerate killing by CTLs
61
Type 1 IFN for HCV
IFN given to up general cellular responses to viral infection Immunomodulatory - increases MHC I expression on infected cells to enhance killing
63
Hep C antivirals Protease Inhibitors
Boceprevir Telaprevir block production of structural proteins

CMBM exam 3 (24 decks)

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