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Flashcards in hepatitis Drugs Deck (27):
1

Biological agents used for treatment of Chronic HBV infection?

Nucleos-(t)ide reverse transcriptase inhibitors?

- ALL caps the nucleoTIDE

-interferon a . . . and Pegylated versions

-Entecavir
-TENOFOVIR
-Lamivudine
-Telbivudine

2

Interferon-a formulations, especially PEG-interferons are primarily used for treatment of what patients

those with well compensated Liver disease who do not wish to be on long term treatment or are planning to be pregnant within next 2 to 3 years

3

Side effects of interferon therapy

-flu like syndrome
-DANGEROUS in decompensated cirrhosis

4

difference in pharmacokinetics b/t interferon and PEG-interferon

PEG increases half life and only have to take once a week . . non pegylated interferon is 3x/week

5

IFN actions on UNINFECTED hepatocytes step by step

-IFN binding activates Jak1 and Tyk2
-Jak1 and Tyk2 phosphorylate IFN receptor
-Phospho-IFN receptor recruits STATs
-Jak1 and Tyk2 phosphorylate STATs
-Phospho-STATs "undock" from IFN receptor and dimerize
-they relocalize to nucleus
-upregulates DNA transcription of interferon stiumlated genes (ISG)

6

What are the 2 ISGs that are synthesized after interferon binding

-2,5 oligoadenylate synthetase (2'5' OAS)
-Protein Kinase R (PKR)

7

the ISG 2'5' OAS does what

-activates Ribonuclease L --> degrades viral RNA

8

The ISG PKR does what

phosphorylate Elongation initiation factor (EiF) which then inhibits protein synthesis

9

What is the immunomodulary effect of IFN therapy?

what is the consequence?

favors cell mediated immunity TH1 phenotypes to eradicate HBV

increase in inflammation and fibrosis (explains the contraindications)

10

IFN therapy is contraindicated in what patients

those with one or more complication of chronic liver disease such as:
-ASCITES
-encephalopathy
-variceal bleeding
-COAGULOPATHY
-HEPATOCELLULAR CARCINOMA

11

Adverse effects of IFN therapy

-Flu like syndrome
-fatigue and mental depression
-Dose limiting toxicity (Bone marrow suppression and neurotoxicity)

12

explain the mechanism of why tenofovir is used with resistant cells

It is already phosphorylated so it can be harbored in cells that have low purine/pyrimidine kinase activity

13

First line oral Anti-HBV agents

Second line?

-Tenofovir
-Entecavir

-Lamivudine
-Telbivudine

14

explain the adverse effect of tenofovir and it's relationship with HIV infected individuals

Nephrotoxicity
-more often with HIV because higher doses are used but still encountered without this

15

What part of the renal tubule is susceptible to Tenofovir toxicity

-proximal tubule

16

Explain Resistance profile to Entecavir

-Resistance is rare among Nucleoside-naive patients but resistance occurs in 50% of lamivudine-resistant patients after 5 years of treatment

17

When might Entecavir be a better option than adefovir or tenofovir

patents with renal insufficiency and in those who are at risk for renal insufficiency

18

Long-term efficacy of lamivudine is limited by frequent emergence of drug resistant HBN by a mutation in what

CATALYTIC DOMAIN OF HBV POLYMERASE

19

Ribavirin is what analog

nucleoSide . . . guanosine analog

20

mechanism of action of Ribavirin

-MONO-phosphate form inhibits IMP dehydrogenase --> decrease GTP
-TRI-phosphate form inhibits RNA-dependent RNA polymerase --> no RNA replication
-induces mutation into viral RNA

21

What does Ribavirin do to IFN action

potentiates it . .altering the balance between proinflammatory Th1 and Th2 cytokines

22

Explain half life of Ribavirin

-through renal clearance it's only 1 day
-BUT .. a lot of it is stored in erythrocytes and 60x concentrated so half life depends on the life span of the erythrocytes . . . . 40 days!!

23

Contraindications for Ribavirin

-hemolytic anemia
-Pregnancy . . even until 6 months post therapy

24

New Direct acting antiviral agents used for HCV infection

-Simeprevir
-Ledipsavir
-Sofobuvir

25

Simeprevir inhibits what

-protease

26

Ledipsavir inhibits what

NS5A

27

Sofosbuvir inhibits what

Polymerase