Exam 4 - Antivirals (Medchem-Stahelin) Flashcards Preview

Therapeutics V Spring 2019 (P3 Spring) > Exam 4 - Antivirals (Medchem-Stahelin) > Flashcards

Flashcards in Exam 4 - Antivirals (Medchem-Stahelin) Deck (151):
1

There are ___#___ classes of viruses

6

2

what are the 6 different classes of viruses?

double stranded DNA
single stranded DNA
single stranded RNA -- negative sense
single stranded RNA -- positive sense
retroviruses

3

Viruses Facts:
Obligate _________

intracellular parasites

4

Viruses Facts:
small or large genomes

small

5

Viruses Facts:
Must use ________ to replicate

host cell machinery

6

Viruses Facts:
Inhibit cellular pathways to promote replication ---
what are 3 common pathways that are inhibited??

cell death (apoptosis)
interferon
tumor suppression (p53)

7

Some viruses are surrounded by lipids?
If covered by lipids they are called _____
if no lipid layer they are called _____

enveloped

non enveloped....

8

what are some examples of enveloped viruses

HIV
influenza
herpes

9

what are some examples of non-enveloped viruses

picornavirus
adenovirus

10

General Virus Life cycle steps?
(steps 1 - 8)

1. viral attachment/entry
2. penetration
3. uncoating
4. nucleic acid synthesis
5. integration / transcription
6. viral protein synthesis
7. packaging/assembly
8. viral release

11

what drug class will block viral release from the cell?

neuraminidase

12

HIV Fusion/Entry:
HIV _______ binds to _____ on target cell

gp120 (on HIV cell) binds to CD4 (on target cell)

13

HIV Fusion/Entry:
A conformational change will occur where a region of GP120 is exposed... the exposed region binds to the __________ receptor

cytokine

14

HIV Fusion/Entry:
The exposed region binds to a cytokine receptor will be ______ or ____ depending on the strain of HIV

CCR5 or CXCR4

15

_________ and ________ are HIV entry and fusion inhibitors

Enfuviritide
Maraviroc

16

Enfuviritide MOA?

binds to GP41 ON HIV and blocks the GP41 conformation
(HIV fusion/entry inhibitor)

17

Maraviroc MOA

binds to HUMAN CCR5 and blocks GP120 binding

18

Enfuviritide binds to ________ cells
Maraviroc binds to ________ cells

Enfuv: binds to HIV cells
Mara: binds to human cells

19

Maraviroc:
can only be used in patients with HIV strains that _______

utilize CCR5

20

Enfuvirtide is only active against HIV ______

1

21

what are the 3 jobs of Reverse Transcriptase (RT)?

RNA dependent DNA Pol
Ribonuclease H
DNA-Dependent DNA Pol

22

Reverse transcriptase copies the ______ strand of RNA to make the _____ strand of DNA

plus strand RNA to minus strand DNA

23

NRTIs interfere with ____________ synthesis

1st and 2nd strand DNA synthesis

24

NRTIs MOA

they are nucloeside analogs that lack the 3' OH =
- competitive inhibitor of reverse transcriptase
- DNA chain terminator (inhibits elongation)

25

T or F:
All NRTIs need to be activated/they are prodrugs

TRUE!
(need to be activated by kinases)

26

What activation step do NRTIs need?

need activated by kinases / need to get to a triphosphate (PO4- need to be added)

27

what NRTI has the longest half life

Tenofovir DISOPROXIL FUMURATE aka a prodrug...

28

problems with tenofovir disoproxil fumarate (TDF)?

TFV is eliminated by the kidney = if kidney issues, acute renal failure is more likely

and overall there is a larger reduction in bone mineral density compared to other NRTIs

29

what is a different prodrug option for TFV?

TAF
(tenofovir alafenamide)
activated by a diff pathways/ fewer side effects

30

what enzyme is used to activate TAF

CatA (cathepsin A)

31

T or F:
The same kinase is used to add the 3 phosphates

FALSE! different kinases for each addition!1

32

activated NRTIs compete with what 4 things to be incorporated into the growing DNA chain made by RT

4 things: dATP, dCTP, dGTP, and dTTP

33

NRTIs have a higher affinity for______ than __________

higher affinity for HIV RT than cellular DNA pol

34

Tenofovir requires __#___ phosphorylation steps

2

35

Resistance to HIV Drugs:
why do mutations happen so quickly?

HIV pol is error prone
RT inhibitors are unable to suppress viral replication
Large amount of viruses are present

36

Resistance to HIV Drugs:
Rate at which mutations appear is _______ related to the serum ______

inversely related

serum drug concentration

37

If there a drug has a ______ genetic barrier it is easy for a virus to become resistant

low

38

if there a drug has a ____ genetic barrier it is hard for a virus to become resistant

high

39

what are the 2 kinds of resistance to NRTIs

Discriminatory mutations
or
Excision mutations

40

Explain discriminatory mutations towards NRTIs

helps the RT distinguish between normal dNTPs and NRTIs

41

Explain excision mutations against NRTIs

promote removal of NRTIs after thye have been incorporated into the growing chain

42

Single NRTI therapy has a ______ genetic barrier

low

43

ADEs of NRTIs?

Mitochondrial toxicity
Lipoatrophy
Abacavir Hypersensitivity (black box)

44

Why does mitochondrial toxicity happen with NRTIs

NRTIs are selective for HIV RT over DNA pol alpha and beta but NOT gamma
(aka some NRTIs will inhibit DNA pol-gamma)

45

what effects are seen with mitochondrial toxicity

!![anemia
granulocytopenia
myopathy
peripheral neuropathy
pancreatitis]!!
lactic acidosis
hepatic steatosis

46

what is lipoatrophy

loss of body fat

47

what does Abacavir hypersensitivity look like?

Malaise
dizziness
headache
GI disturbances --- STOP IMMEDIATELY if any of these

48

what allele should be tested for with Abacavir use

HLA-B 5701

49

What are two of the recommended combo NRTI therapies

Tenofovir/Emtracitabine
or
Abacavir/Lamivudine
(emtracitabine and lamivudine are interchangable)

50

what NRTI therapies are not recommended

monotherapy
dual NRTI therapy (if no other antivirals)
3 NRTI (because too much toxicity)

51

MOA of NNRTIs
bind to what?
block what?

bind directly to the site of RT
block polymerization

52

NRTIs or NNRTIs compete with nucleotides for binding (aka noncompetitive inhibitors)

NRTIs do compete

53

T or F:
NNRTIs need to be phosphorylated

false!!
NNRTIs do NOT need to be phosphorylated
(NRTIs doooo)

54

2nd Gen NNRTIs
are designed to be inherently ________ which allows them to ________

inherently FLEXIBLE

allows them to bind in multiple orientations(can bind to mutants)

55

ADEs of NNRTIs

rash
drug drug interactions
Nevirapine -- hepatotoxicity (SJS rash)
Efavirenz -- neuropsychiatric, teratogenic in primates

56

Specific ADEs of Nevirapine

it is a NNRTI
and it causes hepatotoxicity and SJS rash

57

Specific ADE of Efavirenz

it is a NNRTI
neuropsychiatric
teratogenic in primates

58

Metabolism of NNRTIs
All metabolized by ________

CYP3A4

59

NNRTI Facts:
They do or do not require activation

do not

60

NNRTI Facts:
Do or not compete with dNTPs

do not

61

NNRTI Facts:
Do or do not get incorporated into DNA

do not

62

NNRTI Facts:
Do or do not bind to cellular DNA pol

do not

63

NNRTI Facts:
A NNRTI mutation does or does not cause NRTI resistance

does not

64

Integrase Enzyme works to do what?

insert HIV DNA into host cell DNA

65

Integrase inserts HIV DNA into host cell DNA in what 2 steps?

3' processing
Strand Transfer

66

MOA of Integrase Inhibitors:
works by blocking what?

binds to what?

blocks the strand transfer step

binds to/chelates to metal ions and stabilizes enzyme-DNA complex

67

Integrase uses ______ to catalyze insertion

divalent metal ions

68

which INI has the highest genetic barrier (compared to other INIs)

Dolutegravir

69

what drug is used with Elvitegravir to boost its concentrations

Cobicistat

70

why is cobicistat given with Elvitegravir?

Cobi inhibits CYP3A4 = inhibits metabolism of Elvitegravir = higher elvitegravir levels

71

Does dolutegravir have higher or lower barrier of resistance

higher barrier

72

HIV Protease is an ______ protease
(aka has a _____ in the active site)

aspartic protease
(has aspartic acid in active site)

73

HIV protease inhibitors are _______mimetics
and can of what 2 types?

transition state mimetics

could be peptidomimetic or nonpeptide compounds

74

HIV Proteases job is what?

-cut itself free and the cuts 4 other enzymes free from the long precursor
-peptide bond cleavage via hydrolysis reaction reaction

75

how do Protease inhibitors work?

-they have a replaced amide bond with a non cleavable linkage
-causes a conformation change/closes it

76

All protease inhibitors except for _____ are consider peptidomimetics

tipranavir

77

Metabolism of Protease Inhibitors:
Are they affected by CYP?

yes!
all are substrates and some are inhibitors

78

what protease inhibitor is the most potent inhibitor of CYP enzymes

Ritonavir

79

_______ is a protease inhibitor if given at low doses is used to increase serum concentrations of other antivirals

Ritonavir

80

What are the two unique features of darunavir?

makes extensive hydrogen bonds with protease backbone

inhibits HIV protease dimerization

81

Protease inhibitors:
have the lowest or highest genetic barrier compared to other antivirals

highest

82

ADEs of Protease inhibitors?

Hyperlipidemia
Insulin resistance/diabetes
lipodystrophy(changes in body fat)
Elevated liver function tests
possible increase bleeding risk in hemophiliacs
drug-drug interactions

83

Herpes Virus:
(small or large)
(single or double) stranded
(RNA or DNA) virus

LARGE
DOUBLE
DNA

84

Herpes Virus infections can be in what 2 forms of infection?

lytic (producing new virions)
latent (dormant)

85

HSV-1 or HSV-2:
which one normally causes oral herpes

1

86

HSV-1 or HSV-2:
which one normally causes genital herpes

2

87

CMV (cytomegalovirus) usually not a problem unless what....

unless infection happens during fetal development
or
if immunocompromised pt

88

what are some anti-herpesvirus agents

acyclovir
valacyclovir
cidofovir
foscarnet
penciclvir
ganciclovir
valganciclovir...

89

Acyclovir MOA?
competitive inhibitor of _______
competes with ____
is an (reversible or irreversible) inhibitor

competitive inhibitor of viral DNA pol (lower concentration needed for VIRAL DNA pol than host DNA pol)
competes with dGTP
is an irreversible inhibitor

90

Acyclovir:
requires phosphorylation?

yes!! 3 phosphorylation events

91

Acyclovir:
is incorporated into _______ and is a _____ terminator

DNA;
chain

92

two main resistance mechanisms to acyclovir?

mutations in viral thymidine kinase
or
mutations viral DNA pol

93

relation of valacyclovir to acyclovir?

valacyclovir is L-valyl ester of acycylovir...

converted to acyclovir by esterases in the intestines/liver

94

Famciclovir and Penciclovir relation?

famciclovir is a prodrug of penciclovir
(activated by 1st pass metab of intestine and liver)

95

MOA of famiciclovir/penciclovir (how is it different than acyclovir)

Fam and pen are competitive inhibitors of viral DNA pol BUT they do NOT cause immediate chain termination (they allow for short chain elongation)

96

Penciclovir or Acyclovir:
which one has higher affinity for HSV TK (thymydine kinase)

penciclovir

97

Penciclovir or Acyclovir:
which has higher affinity for HSV DNA pol

acycolovir

98

Penciclovir or Acyclovir:
which one is more stable in HSV infected cells

penciclovir

99

T or F: Topical penciclovir and famciclovir are great for topical herpes infections

FALSE: pencic is good but famcic needs 1st pass metab -- aka famcic not used topically)

100

Ganciclovir is structurally similar and same MOA as ________
but Ganciclovir is a better substrate for ______ than others

same MOA as penciclovir

better substrate for cytomegalovirus kinase

101

Is toxicity in ganciclovir or acyclovir worse?

ganciclovir toxicity is worse

102

Ganciclovir or Valganciclovir:
which one has good bioavailability?
which one has bad bioavailability?

Gancic: BAD bioavail
Valgan: GOOD bioavail

103

Foscarnet Facts:
Needs or does not need phosphorylation for activity

does NOT need

104

Foscarnet Facts:
what kind of compound is it

inorganic pyrophosphate compound

105

MOA of Foscarnet:
It blocks ________ binding site of the viral ______
and inhibits cleavage of ________ from _______

blocks pyrophosphate binding site
of viral DNA pol;

cleavage of pyrophosphate from dNTPs

106

Foscarnet Facts:
What is it used for?

CMV (like ganciclovir)

107

Foscarnet Toxicities?

renal insufficiency (RENAL ADJUST)
phosphate levels (hypo or hyper)
calcium levels (hypo or hyper)
headaches

108

Foscarnet MOA:
inhibits what enzymes?

viral DNA pol
RNA pol
HIV RT

109

Cidofovir:
acyclic nucleoside phosphonate analog of ______

cytosine

110

MOA of Letermovir mechanism

inhibits terminase complex
(normally herpes virus DNA replicates through rolling circle mechanism and individual genomes need to be cut out by the terminase complex)

111

influenza virus
(positive or negative) strand (DNA or RNA) virus

negative RNA virus

112

3 types of influenza virus?

A,B,C

113

Influenza Viruses: A, B or C
___ will infect humans and many different animals

A

114

Influenza Viruses: A, B or C
___ widely circulates in ONLY humans

B

115

Influenza Viruses: A, B or C
___ causes a very mild disease

C

116

Influenza Viruses: A, B or C
____ and ____ cause epidemics nearly every winter

A and B

117

Influenza A Subtypes are divided into two gene types: what are the two gene types?

H and N
H - hemagglutinin
N - Neuraminidase

118

what are the two ways influenza viruses change?

Antigenic drift
or
Antigenic shift

119

Antigenic Drift or Shift:
small changes to the virus

drift

120

Antigenic Drift or Shift:
major abrupt change to the virus

shift

121

Amantadine and Rimantandine:
inhibits __________ by targeting the ___ protein of influenza ____

inhibits penetration into host cells
by targeting M2 protein of influenza A

122

ADEs of Amantadine?

GI intolerance
CNS effects
(worse in older people -- over 60 years of age)

123

influenza virus neuraminidase:
essential for virus _______
is located in the virus _______

replication
membrane

124

influenza virus neuraminidase:
works to cleave the glycolytic bonds b/w terminal _____ and adjacent sugars

sialic acids

125

influenza virus neuraminidase:
facilitates virus ________
______ binds to terminal sialic acid residues and _____ releases the virus

dissemination
HA (hemaglutinin)
NA (neuraminadase)

126

what drugs are neuraminidase inhibitors

zanamavir
oseltamivir

127

Oseltamivir:
Needs activated by liver -- yes or no?

yes -- it is a prodrug

128

Oseltamivir:
it is an effective inhibitor of _____

NA (neuraminidase)

129

Oseltamivir:
Effect depends on how soon therapy is started -- need to initiate within _____ of first symptoms

48 hours

130

Dosage form for Oseltamivir and Zanamivir?

Oseltam: oral
Zanamivir: oral inhaler...

131

what is the newest neuraminidase inhibitor?
how is it administered?
it is a transition state analog of _____

Peramivir;
IV
sialic acid

132

HCV stands for?

Hepatic C Virus

133

Hepatic C Virus:
transmission via __________
Can cause what 3 things?

transmission via contaminated blood

can cause chronic hepatitis; liver cirrhosis, hepatocellular carcinoma

134

what does SVR stand for and what is its definition?

sustained virological response

HCV RNA is undetectable for 6 months after treatment

135

what is a common/nonspecific defense against viral infections

interferon

136

what are the HCV NS3 protease inhibitors

Telaprevir
Boceprevir
Paritaprevir
Simeprevir
Grazoprevir
Voxilaprevir
Glecaprevir

137

HCV Protease Inhibitors:
target the HCV protease _____

NS3

138

HCV Protease Inhibitors:
block the cleavage of the _____

HCV polyprotein

139

HCV Protease Inhibitors:
what drugs are the 2nd gen/P1-P3 substrate analogs

Simeprevir
Paritaprevir

140

HCV Protease Inhibitors:
what drugs are the 2nd gen/P2-P4 substrate analogs

Voxilaprevir
Glecaprevir
Grazoprevir

141

HCV RNA Polymerase inhibitors:
_____ is known as the HCV RNA pol

NS5B

142

what drug is a HCV RNA Polymerase inhibitor?

Sofosbuvir

143

Sofosbuvir:
does it need phosphorylated?

yes

144

Sofosbuvir Mechanism:
gets incorporate into _______ and causes ______

viral RNA chain (makes sense bc it is a RNA pol inhibitor..)

causes chain termination

145

what drugs are HCV NS5A inhibitors

Ombitasvir
Ledipasvir
Daclatasvir
Velpatasvir (2nd gen)
Pibrentasvir (2nd gen)
(-ASVIR)

146

MOA of HCV NS5A inhibitors:
Inhibits both _______ and _______

viral RNA replication
and
assembly of release of infectious viral particles

147

what drugs are HCV NS5B inhibitors?

Sofosbuvir
Dasabuvir
(-BUVIR)

148

Blackbox warning for HCV direct acting antivirals (DAA)?

cases of fulminant hepatitis, hepatic failure, and death because of HBV (hepatic B virus) reactivation!!

149

The blackbox warning for HCV agents happens when the DAAs are _______

alone/NOT used with an interferon

150

Ways to decrease the HBV reactivation with HCV DAAs?

screen ALL pts for current or prior HBV infection
Monitor for HBV reactivation
talk to Drs who specialize in Hep B infections

-- counsel patients to report side effects

151

What are signs of serious liver injury?

Yellow eyes or skin
light colored stools
fatigue/weakness
loss of appetite
N/V