hepatitis Drugs Flashcards
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
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
Side effects of interferon therapy
- flu like syndrome
- DANGEROUS in decompensated cirrhosis
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
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)
What are the 2 ISGs that are synthesized after interferon binding
- 2,5 oligoadenylate synthetase (2’5’ OAS)
- Protein Kinase R (PKR)
the ISG 2’5’ OAS does what
-activates Ribonuclease L –> degrades viral RNA
The ISG PKR does what
phosphorylate Elongation initiation factor (EiF) which then inhibits protein synthesis
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)
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
Adverse effects of IFN therapy
- Flu like syndrome
- fatigue and mental depression
- Dose limiting toxicity (Bone marrow suppression and neurotoxicity)
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
First line oral Anti-HBV agents
Second line?
- Tenofovir
- Entecavir
- Lamivudine
- Telbivudine
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
What part of the renal tubule is susceptible to Tenofovir toxicity
-proximal tubule
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
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
Long-term efficacy of lamivudine is limited by frequent emergence of drug resistant HBN by a mutation in what
CATALYTIC DOMAIN OF HBV POLYMERASE
Ribavirin is what analog
nucleoSide . . . guanosine analog
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
What does Ribavirin do to IFN action
potentiates it . .altering the balance between proinflammatory Th1 and Th2 cytokines
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!!
Contraindications for Ribavirin
- hemolytic anemia
- Pregnancy . . even until 6 months post therapy
New Direct acting antiviral agents used for HCV infection
- Simeprevir
- Ledipsavir
- Sofobuvir
