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CMBM exam 3 > Antivirals > Flashcards

Antivirals Flashcards

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
Q

Lipodystrophy

A

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

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25
Q

Hyperadiposity

A

fat accumulation

fat builds up in belly, breasts and back of the neck

26
Q

Clinical signs of Lipodystrophy

A

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
Q

Proviral integration

A

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
Q

Mechanism of Integrase Inhibitors (INSTI)

A

competitively inhibits Mg+2 or Mn+2 both essential cofactors for integrase binding to proviral DNA

29
Q

Examples of INSTIs

A

Raltegravir
Elvitegravir
Dolutegravir

30
Q

INSTI resistance

A

mutations in integrase gene associated with resistance to raltegravir and elvitegravir

31
Q

which step of proviral integration do INSTIs block?

A

step 1 - 3’ processing in host-cell cytoplasm

32
Q

1 pill with 4 drugs

A

Raltegravir
Elvitegravir
both have same mechanism - blocks Mg binding

(only told two of them)

33
Q

Mechanism of Fusion Inhibitors

A

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
Q

Enfuvirtide (T-20)

A

36 AA peptide derived from EC domain of gp41 of HIV-1 envelop
given when other drugs have failed

35
Q

Mechanism of chemokine receptor antagonists

A

blocks binding of virus to target cell

directly competes with gp120 for site

36
Q

Maraviroc

A

its a CRA
blocks gp120 from binding CCR5
only works for CCR5 tropic viruses

37
Q

What viruses are there antivirals available for?

A 
Influenza viruses 
Herpes viruses - HSV-1, and 2 VZV, CMV 
Respiratory syncytial virus (RSV) 
Hep B virus 
Hep C virus 
Papillomaviruses 
HIV
38
Q

Inhibiting Antiviral drugs can target

A

attachment/adsorption
penetration/entry
nucleic acid synthesis
release

39
Q

A drug that affects viral inhibition of cellular processes could do so by

A

prevent viral inhibition by interferon production

40
Q

How could anti virals support the immune system to combat viral infections?

A

by affecting antibodies and immune modulators

  • polyclonal antisera
  • monoclonal antibodies
  • Imiquimod
41
Q

Anti-Influenza drugs

A

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
Q

Neuraminidase inhibitors for Inf A and B

A

inhibits viral release and virion clumping promoted
must be started
reduces severity and shortens duration of symptoms

  • Peramivir - IV adults only
  • Oseltamivir
  • Zanamivir
43
Q

H+ ion channel (M2) inhibitors for Influenza A

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
Q

M2

A

required by Influenza to uncoat and release its genome

45
Q

Activation of Nucleoside Analogues for HSV,VZV

A

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
Q

Mechanism of Nucleoside Analogues for HSV

A

Acyclovir - prodrug

Added to growing chain of virus DNA

47
Q

Acyclovir related compounds

A

Valacyclovir - better bioavaible than oral acyclovir
Famciclovir - higher intracellular levels
Penciclovir - higher intracellular levels

48
Q

CMV is opportunisitc in IC pts, clinical manifestations of infection

A 
AIDS pts tend to be infected, pts may be on myelosuppressive (AZT) or nephrotoxic drugs 
Retinitis 
Esophagitis 
Coliis 
Encephalitis 
Pneumonia
49
Q

HIV+ patients are resistance to

A

Acyclovir

50
Q

CMV doesnt encode

A

Thymidine Kinase

51
Q

Nucleoside Analogues for CMV

A

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
Q

Foscarnet

A

…

53
Q

Fomivirsen

A

…

54
Q

Palivizumab

A

monoclonal antibody to RSV F protein

55
Q

Ribavirin mechanism

A

Broad spectrum antiviral
synthetic nucleoside analog - GTP analog
interferes with viral RNA-dep RNA polymerase (RdRP)

56
Q

Side effects of Ribavirin

A

dose dep hemolytic anemia
dry cough, dyspnea
Teratogenic

57
Q

Indications for Ribavirin

A

RSV - hospitalized infants
Hep C
Vaccinia, Monkeypox

58
Q

Nucleoside analogues for HBV -RT inhibitor

A

Lamivudine, telbivudine

blocks HBV DNA synthesis by incorporating into the growing DNA chain, causing premature chain termination

59
Q

NA -RT AND DNA poly inhibitor - HBV

A

Adefovir - rare cases Renal toxic
Tenofovir - rare cases Hepatotoxic
Entecavir

60
Q

what does cellular release of Type 1 IFN

A

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
Q

Type 1 IFN for HCV

A

IFN given to up general cellular responses to viral infection
Immunomodulatory - increases MHC I expression on infected cells to enhance killing

63
Q

Hep C antivirals Protease Inhibitors

A

Boceprevir
Telaprevir
block production of structural proteins

CMBM exam 3 (24 decks)

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