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Therapeutics P3 Semester 2 > Exam 4 - Stahelin antivirals 1 > Flashcards

Exam 4 - Stahelin antivirals 1 Flashcards

1
Q

describe the herpes virus type

A

large, double stranded DNA viruses
can cause latent infections
enveloped

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2
Q

differences between HSV-1 and HSV-2

A

-2 is less common
-2 reactivates in genital area
-1 reactivates on face or lips
-1 commonly causes oral herpes but can cause genital

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3
Q

VZV (varicella zoster virus)

A

-shingles tx with small molecules
-chickenpox can reactivate later in life as shingles
-biggest complication=postherpetic neuralgia (PHN)
-shingles cannot transmit as shingles to other people, but can cause chicken pox in other people
-prevention=vaccination

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4
Q

CMV (cytomegalovirus)

A

-up to 80% of adults are infected
-most show no or mild symptoms
-severe disease can occur if:
–infection occurs during fetal development or immunocompromised people

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5
Q

anti-herpesvirus agents

A

acyclovir
valacyclovir
cidofovir
foscarnet
penciclovir
ganciclovir
valganciclovir

all sound similar to nucleotide analogs that block viral DNA or RNA polymerase as competitive inhibitors

all are prodrugs, and must be phosphorylated to the triphosphorylated form (active form)

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6
Q

acyclovir info
-acyclic, does not have full ribose ring
-OH group must be phosphorylated to become active

A

selectively accumulates in infected cells
-higher conc. in infected cells
-high ratio of therapeutic value to toxicity (virus produces products that activate the drug)

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7
Q

acyclovir requires how many phosphorylation events?
describe these events

A

3 events
1. virally encoded enzyme (thymidine kinase) performs the first step of phosphorylation
2. and 3. happen by the host kinases

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8
Q

acyclovir MOA

A

chain terminator that incorporates into DNA

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9
Q

acyclovir best against which types?

A

HSV-1, HSV-2, and VZV
-not great against CMV

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10
Q

explain mechanisms of resistance to acyclovir

A

mutations in viral thymidine kinase is most common at 95%
mutations in viral DNA polymerase, less common

in immunocompromised people, resistance is more common

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11
Q

valacyclovir

A

-has hydrophobic modifications compared to acyclovir that increase its absorption
-L-valyl ester of acyclovir
-no OH group, protects this region from reactivity, increasing oral bioavailability (48-54%)
-improved efficacy compared to acyclovir

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12
Q

valacyclovir is transported by ______ amino acid transporters

A

intestinal

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13
Q

for valacyclovir to work it needs to be converted to _______ and then ________

A

acyclovir, phosphorylated

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14
Q

famciclovir and penciclovir

A

famciclovir is a prodrug of penciclovir converted by first pass metabolism in intestine and liver, lacks intrinsic antiviral activity
-need phosphorylation on the OH group to become activated and bind viral DNA polymerase

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15
Q

famciclovir and penciclovir MOA

A

-activated by viral and cellular kinases
-competitive inhibitor of viral DNA polymerase
-does NOT cause immediate chain termination

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16
Q

famciclovir and penciclovir resistance

A

viral kinase mutants confer cross-resistance to penciclovir and acyclovir

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17
Q

which has higher affinity for HSV TK: acyclovir or penciclovir?

A

penciclovir
reasoning: levels of penciclovir triphosphate in infected cells are much higher than the levels of acyclovir triphosphate

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18
Q

which has a longer half life in HSV-infected cells: acyclovir or penciclovir?

A

penciclovir triphosphate
reasoning: half life is 10-20x longer

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19
Q

based on 2 above, this would mean penciclovir is a better drug right? not exactly, the efficacy is about equal and the reason for this is:

A

HSV DNA polyerases have a higher affinity for acyclovir triphosphate than for penciclovir triphosphate, making them about equal in antiviral potency
penciclovir is also not as well tolerated because it can be more actively phosphorylated in healthy host cells compared to infected cells

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20
Q

famciclovir and penciclovir routes of admin and tolerability

A

oral fam: genital herpes, acute herpes zoster
topical pen: recurrent herpes zoster

generally well tolerated

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21
Q

ganciclovir info

A

similar in structure and action to penciclovir
better substrate for cytomegalovirus kinase than acyclovir because its intracellular half life is 12h (and is able to be phosphorylated easier), where acyclovir is 1-2h. this makes it about 100x more active against CMV

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22
Q

ganciclovir oral bioavailability

A

6-9%
mostly used IV
can be used oral and in intraocular implants to treat CMV retinitis

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23
Q

ganciclovir toxicity

A

more severe than acyclovir
-myelosuppression
–neutropenia
–thrombocytopenia

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24
Q

ganciclovir resistance

A

-due to mutations in CMV kinase (UL97 gene) or CMV DNA polymerase (UL54)
-mutations are NOT cross-resistant with cidofovir or foscarnet, so we use these next if pt fails ganciclovir
-mutations in DNA polymerase may confer resistance to cidofovir or foscarnet

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25
valganciclovir created to:
increase oral bioavailability of ganciclovir to about 60%
26
foscarnet info
-inorganic pyrophosphate compound -inhibits viral DNA polymerase, RNA polymerase, and HIV RT -does NOT require phosphorylation for activity -blocks pyrophosphate binding site of the viral DNA polymerase -inhibits cleavage of pyrophosphate from dNTPs
27
foscarnet MOA
-traps polymerase in closed formation -DNA is unable to translocate
28
foscarnet PK
-poor oral bioavailability -only administered IV -30% deposited in bone -renal clearance in proportion to CrCl
29
foscarnet clinical use
-CMV retinitis (equivalent to ganciclovir) -adjust dose based on CrCl -synergistic with ganciclovir against CMV -may see changes in Ca and phos levels
30
foscarnet resistance
-mutations in DNA polymerase or HIV reverse transcriptase -resistant CMV isolates are cross-resistant to ganciclovir -foscarnet usually still effective against cidofovir resistant CMV
31
cidofovir info
-acyclic nucleoside phosphate analog of cytosine -phosphate cannot be cleaved by cellular esterases -phosphorylated by cellular kinases -intracellular half life is 17-65 h -poor substrate for cellular (human) enzymes - less tox. ?
32
cidofovir SOA
hits most viruses but mostly used for CMV -selective for viral DNA polymerase, good selective tox. seen -does not require phosphorylation by viral kinases, cellular kinases can activate in 2 steps -competitive inhibitor AND chain terminator: chain termination by CMV polymerase requires 2 consecutive incorporations
33
cidofovir AE
dose dependent nephrotoxicity
34
clinical use of cidofovir
CMV retinitis (IV)
35
letermovir use -newest antiviral drug (approved 2017)
good prophylaxis against CMV infection
36
letermovir class
new class: non-nucleoside -means dif. MOA
37
letermovir info
-high specificity for CMV over human cells (15,000x) -no activity against other herpes viruses -low nanomolar EC50: at low concentrations, can still inhibit virus -very well tolerated because of selectivity for CMV
38
letermovir MOA
-herpes virus DNA replication is through rolling circle mechanism -letermovir inhibits terminase complex (binds to pUL56) and prevents cleavage and packaging -no cross resistance to other CMV drugs
39
influenza virus info
-Negative strand RNA virus -enveloped -can infect humans, pigs, birds, horses -animal influenza viruses can infect humans that can be more deadly because humans aren't used to defending against them
40
3 types of flu
A: affects humans and many animals B: widely circulates only in humans C: mild disease A and B epidemics occur every winter, vaccines protect against A and B
41
flu A subtypes based on two genes:
hemagglutinin (H) neuraminidase (N) -each virus only has one H and one N
42
influenza virus neuraminidase importance
-essential for virus replication -target for drugs
43
neuraminidase inhibtors
mimic structure of sialic acid -zanamavir (inhaled route) -oseltamivir (Tamiflu) --due to groups, better oral bioavailability and binding
44
oseltamivir info
-prodrug converted to active form by liver -metabolite is inhibitor of NA -pentoxyl group increases affinity to bind NA -work best when viral load is low, reason for using when symptoms first arise
45
resistance to oseltamivir
-associated with mutations in the active site off neuraminidase -occurs in 3% of pts -resistance develops more easily against oseltamivir than zanamavir
46
zanamavir and oseltamivir used for same thing and by same mechanism, what about them is different?
route -oseltamivir: oral -zanamivir: inhaled
47
zanamivir should be avoided in what pts?
those with airway disease like asthma and COPD
48
peramivir info
-newest NA inhibitor -IV -drug of last resort -transition state analog of sialic acid
49
baloxavir marboxil info
-mechanism: inhibits 'cap-snatching' (blocks transcription, virus cannot make proteins) -used for flu (within 48hrs of onset of sx) -AE: diarrhea, bronchitis
50
Hep C (HCV) info
-small, positive stranded RNA virus -causes chronic liver infections -transmission occur through contaminated blood (IV drug users at increased risk) -major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC)
51
Hep C, unlike what we've seen so far, makes what?
a large polyprotein that is cleaved by a protease into smaller pieces to do their viral function
52
tx options for HCV
-previous standard of care: ribavirin plus pegylated interferon alpha -goal of tx: sustained virological response to achieve undetectable RNA for 6 months
53
interferon alpha as an antiviral drug
-recombinant protein produced in e. coli and purified -PK: not absorbed after oral admin, given IM or SC -pegylated: much higher efficacy seen, increased half life and reduced dosing freq.
54
interferon alpha tox.
-flu sx in first 6h -neuro, autoimmune, ischemic and infectious disorders
55
ribavirin info
-guanosine analog -needs to be phosphorylated byt cellular kinases -broad spectrum
56
ribavirin MOA
-inhibits the inosine monophosphate dehydrogenase (a host, not virus, enzyme) - reduces GTP levels -direct inhibition of viral RNA polymerase -incorporates into viral RNA leading to error catastrophe
57
ribavirin uses
Hep C RSV
58
HCV protease inhibitors info
-1st gen approved in 2011, not used much anymore because 2nd gen (2015) work better -target the HCV protease NS3 -block cleavage of HCV polyprotein
59
HCV protease inhibitors 2nd gen P1-P3
simeprevir paritaprevir both are substrates and weak inhibitors of CYP3A4 both non-covalent inhibitors
60
HCV protease inhibitors 2nd gen P2-P4
grazoprevir voxilaprevir glecaprevir all 3 can form covalent bonds
61
HCV protease inhibitors resistance mechanisms
mutations in NS3 active site
62
drug name hints by class
HCV NS3 protease inhibitors -previr HCV NS5(A) inhibitors -(a)svir HCV NS5(B) inhibitors -(b)uvir
63
black box warning for direct acting antivirals (DAAs)
reactivation of Hep B (HBV) in pts co-infected with HCV while undergoing tx with DAA for HCV infection
64
nirmatrelvir use
SARS-CoV2
65
nirmatrelvir given with what drug to increase nirmatrelvir levels?
ritonavir (inhibits CYP3A4)

Therapeutics P3 Semester 2 (33 decks)

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