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Therapeutics P3 Spring > Exam 4 lecture 3 > Flashcards

Exam 4 lecture 3 Flashcards

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1
Q

What are the two types of herpes simplex viruses?

A

HSV-1
- causes oral herpes, can cause genital herpes
60% of adults in US are seropositive
Reactivates on face or lips

HSV-2
common cause of genital herpes, but can cause oral herpes
16% of adults in US (more common in women and african americans)
reactivates in genital areas

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2
Q

Varicella zoster virus (VZV) causes what diseases

A

Caused shingles and chicken pox. reactivates later in life

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3
Q

How is shingles caused? WHat complication can it cause? Transmission?

A

Virus migrates to ganglia in area of infection. Rash and blisters scab over.

Causes postherpetic neuralgia (PHN)

Shingles is not transmitted, but virus can cause chicken pox

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4
Q

How is shingles prevented

A

CDC recommends 2 doses of shingrix separated by 2-6 months forall immunocompetent adults 50 and older

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5
Q

What is CMV? When is it an issue?

A

cytomegalovirus affects 80% of adults, most have no sx. Infection occurs in immunocompromised people (AIDS)

If infection occurs during fetal development, may cause congenital abdormalities, most infants are not affected.

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6
Q

name anti herpesvirus agents

A

Acyclovir
Valacyclovir
cidofovir
Foscarnet
Penciclovir
Ganciclovir
Valganciclovir

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7
Q

What type of drugs are valacyclovir and acyclovir

A

prodrugs

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8
Q

MOA of acyclovir?

A

selectively accumulates in infected cells.

Results in higher concentration in infected cells

Is incorporated in DNA chain as a chain terminator

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9
Q

How is acyclovir activated?

A

requires 3 phosphorylations to form active acyclovir triphosphate

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10
Q

what type of inhibitor is acyclovir? How?

A

Competitive inhibitor of viral DNA polymerase

Competes with dGTP

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11
Q

summary of acyclovir

A

Acyclovir is incorporated into DNA

Acts as a chain terminator

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12
Q

acyclovir spectrum of activity

A

active against HSV-1, 2 and VZV

reduced activity against cytomegalovirus

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13
Q

How can resistance occur with acyclovir

A
  • mutations in viral thymidine kinase (phosphorylation does not occur)
  • mutations in viral DNA polymerase

Resistant common in immuocompromised pts

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14
Q

DIfference between valacyclovir and acyclovir structurally

A

Allows for oral bioavailability higher that acyclovir. Rapidly converted to acyclovir in liver.

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15
Q

How is valacyclovir transpoorted

A

by intestinal amino acid transporters

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16
Q

Relationship of famciclovir and penciclovir

A

Famciclovir is a prodrug of penciclovir.

Famciclovir converted to penciclovir by 1st pass metabolism

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17
Q

How are famciclovir and penciclovir activated? MOA?

A

Activated by viral and cellular kinases

Competitive inhibitor of viral DNA polymerase

short chain terminator (allows limited DNA chain elongation)

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18
Q

Do famciclovir and penciclovir cause immediate chaintermination?

A

NO, allow for short chain elongation

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19
Q

How does resistance occur in famciclovir and penciclovir

A

Viral kinase mutants confer cross resistance to penciclovir and acyclovir

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20
Q

compare penciclovir and acyclovir in terms of affinity and efficacy for HSV TK (Thymidine kinase)? Why?

A

Penciclovir has higher affinity for HSV TK than acyclovir

Levels of penciclovir triphosphate in infected cells are much higher than levels of acyclovir triphosphate

Penciclovir triphosphate is more stable than acyclovir triphosphate in HSV infected cells

HSV DNA polymerase have higher affinity for acycyclovir triphosphate than for penciclovir triphosphate

Net effect- both drugs equal antiviral properties

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21
Q

clinical use of famciclovir and penciclovir

A

oral- Herpes (acute, or genital or primary)

Topical- herpes

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22
Q

MOA of ganciclovir

A

MOA same as penciclovir

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23
Q

Compare ganciclovir to acyclovir

A

ganciclovir better substrate for cytomegalovirus kinase than acyclovir

100X better

Toxicity of ganciclovir more severe than acyclovir

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24
Q

clinical use of ganciclovir

A

IV, PO and IO implants can be used to treat CMV retinitis

Oral ganciclovir can be used for CMV prophylaxis

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25
toxicity of ganciclovir
myelosuppression - neutropenia - thrombocytopenia
26
What is the resistance mechanism for ganciclovir
Due to mutations in CMV kinase
27
for ganciclovir, are mutations cross resistant with cidofovir? Foscarnet?
Mutations in kinase are not cross resistant to cidofovir or foscarnet Mutations in DNA polymerase may confer resistance to cidofovir or foscarnet (less frequent)
28
Compare valganciclovir and ganciclovir? use?
Valganciclovir is more orally bioavailable. Rapidly hydrolyzed to ganciclovir in intestine/liver. used to treat CMV retinitis in AIDS pts
29
MOA of foscarnet? Does it require phosphyrylation? (exam)
Inhibits viral DNA polymerase by blocking pyrophosphate binding site of the viral DNA polymerase (remember), (traps DNA polymerase in closed formation) Does not require phosphorylation for activity (1st drug so far)
30
What does the foscarnet ability to block pyrophosphate binding site of DNA polymerase lead to
Inhibits cleavage of pyrophosphate from dNTPs
31
How is foscarnet administered? main use?
only administered IV CMV retinitis (equivalent to ganciclovir)
32
toxicity of foscarnet
Renal insufficiency Hypo/hyper phosphatemia/calcemia
33
Resistance MOA of foscarnet? cross resistance?
Mutations in DNA pol or HIV reverse transcriptase Resistant are cross resistant to ganciclovir
34
is foscarnet still effective against cidofovir resistant CMV
yes
35
What type of analog is cidofovir? How is it phosphorylated (EXAM)
cytosine Phosphorylated by cellular kinases Phosphonate cannot be cleaved by cellular esterases- catabolically stable
36
SOA of cidofovir?
CMV, HSV-1, 2, VZV, adenovirus, poxvirus, polyomavirus and HPV
37
MOA of cidofovir? Does it require activation by viral kinases
Competitive inhibitor by CMV pol and chain terminator. Does not require activation by viral kinases
38
adverse effect and clinical use of cidofovir
dose dependent nephrotoxicity CMV retinitis
39
What is letermovir used for?
Prophylaxis of CMV infection and disease in adult allogenic hematiopoietic stem cell transplant (HSCT) pts who have CMV
40
what is unique about letermovir
non nucleoside Highly specific for CMV (no activity against herpes virus members)
41
What type of virus in influenza
Negative stranded RNA virus, enveloped can infect humans, birds, pigs, horses
42
What are the three types of influenza? Describe them
3 types, A< B, C A infects humans and many different animals (ducks, chickens, pigs, whales, horses and seals) B widely circulates in humans C causes mild disease A and b cause epidemics nearly every winter
43
What are the two influenza A subtypes? How many of each exist?
Hemagglutin (H) Neuraminidase (N) Both exposed proteins (N is enzyme) if N is inhibited, we stop ability to of virus to leave infected cell and spread 16H genes and 9 N genes
44
how do neuraminidase inhibitors work?
Inhibitors block neuraminidase activity and blocks viral enzyme activity, reduces spread
45
What is the influenza neuraminidase used for?
Essential for virus replication - cleaves glycolytic bonds between terminal sialic acids and adjacent sugars Facilitates virus dissemination
46
Name neuraminidase inhibitors
Sialic acid Zanamavir DANA Oseltamivir
47
MOA of oseltamivir
prodrug, converted to active form by liver esterase metabolite inhibits neuraminidase. Less effective against B
48
therapeutic use of ostltamivir
need to initiate within 48 h of first symptoms of influenza to see effect
49
describe mechanism of resistance of oseltamivir
Resistance is associated with mutations in the active site of neuraminidase resistance develops easier with oseltamivir than zanamivir
50
MOA od zanamivir
Same as oseltamivir, binds and inhibits neuraminidase activity, inflenza a and b, but more for A ot is an oral inhaler
51
Excretion of zanamavir
Excreted unchanged by kidneys (not a prodrug like oseltamivir)
52
Toxicity of zanamivir
bronchospasms have been seen, not recommended in pts with COPD or asthma
53
MOA of paeramivir
Transition state analog of sialic acid, IV drug
54
baloxavir marboxil MOA, indication and adverse effects
MOA- inhibits viral cap- snatching (blocks transcription) Clinical indication- influenza within 48 hrs of sx adverse effects- diarrhea, bronchitis
55
What type of virus is Hep C? Transmission?
small, positive stranded RNA virus, causes chronic liver infection Contaminated blood/needle sharing
56
What can Hep C lead to?
Chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC)
57
what is a part of the Hep C life cycle that can be targeted by meds
Hep C forms a large poly protein that is cleaved by viral proteases.
58
What does virus form after viral protease cleaves protein
forms replication complex where polymerase resides to replicate RNA genome.
59
why do interferons work against HCV
interferons induce synthesis of cellular proteins, have antiviral effects
60
What analog is ribavirin? How is it activated?
Guanosine analog phosphorylated by cellular kinases to triphosphate form
61
SOA of ribavirin
Influenza A and B Hep A, B, C Herpes Measles Hantavirus Lassa fever virus
62
MOA of ribavirin
Inhibits inosine monophosphate dehydrogenase (IMPDH)- reduces GTP levels. direct inhibition of viral RNA polymerase and incorporation into viral RNA leading to error and catastrophe
63
clinical use of ribavirin
Combo therapy for hep C
64
HCV protease inhibitors MOA
Target the HCV protease NS3, block cleavage of the HCV polyprotein form reversible covalent bonds
65
what are the 2 second gen HCV protease inhibitors
P1-P3 substarate analogs- Simeprevir and paritaprevir (non covalent inhibitors) P2-P4 sibstarate analogs- Grazoprevir, voxilaprevir and glecaprevir (covalent)
66
How does resistance occur in HCV protease inhibitors
Mutations in NS3 active site
67
What is the RNA polymerase in hep c called? What targets it
NS5B sofosbuvir targets it
68
sofosbuvir MOA
Incorporated in viral RNA chain. Causes chain termination.
69
name a non nucleoside RNA polymerase inhibitor for Hep C
Dasabuvir
70
how many binding sites does NS5B hav?
5 known binding sites (1 catalytic and 4 allosteric sites). Dasasbuvir can bind allosteric sites
71
MOA of dasabuvir
Binds to palm I site of HCV RNA polymerase. prevents conformational changes. blocks neucleotide incorporation into viral RNA
72
nameNS5A inhibitors
Ledipasvir (1st gen) Elbasvir (1st gen) Daclatasvir (2nd gen) Velpatasvir (2nd gen) Pibrentasvir (2nd gen)
73
NS5A inhibitors MOA
Bind tightly to NS5A, inhibits both viral RNA replication and assembly or release of infectious viral particles
74
how does resistance to HCV NS5A inhibitors occur
Mutations occur in 1st 100 amino acids
75
how to remember NS3 protease inhibitors? NS5A inhibitors? NS5B inhibitors
NS3- -previr NS5A inhibitors- -asvir NS5B inhibitors-buvir
76
blackbox warning for HCV direct acting antivirals (DAA)
Hep B reactivation has occured in pts co infected with Hep C while undergoing tx with DAAs for HCV DAAs used without interferon have resulted in fulminant hepatitis, hepatic failure and death
77
what can Hep B lead to
Can cause chronic liver infections that lead to cirrhosis and hepatocellular carcinoma
78
name anti HBV drugs
Tenofovir Entecavir lamivudine all pro drugs
79
name drugs for SARS COV 2
remdisivir Nirmatrelvir Molnupiravir
80
Remdesivir SOA, MOA and ROA
broad spec antivral Prodrug that is biotransformed to ribonucleotide anakog that inhibit viral RNA polymerase IV
81
nirmatrelvir MOA
protease inhibitor.
82
molnupiravir MOA
prodrug that serves as polymerase inhibitor and chain terminator

Therapeutics P3 Spring (33 decks)

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