Anti-Hepatitis Agents

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  1. Define the following acronyms:
    • NRTI: nucleoside reverse transcriptase inhibitor
    • PI: protease inhibitor
  2. What are the goals for effective HBV/HCV therapy?
    • HBV:
    • rapid and potent HBV DNA viral suppression
    • Histological improvement (necroinflammatory score and fibrosis score)
    • High rate HBeAg seroconversion
    • Effective normalization of serum ALT (alanine aminotransferase) levels
    • Safe in long-term use
    • Low resistance potential
    • Oral administration

    • HCV:
    • Undetectable HCV RNA in plasma (>6mo)
  3. List the NRTIs used to treat chronic Hepatitis B
    • (Generic name, brand name)
    • Telbivudine, Tyzeka
    • Entecavir, Baraclude
    • Adefovir dipivoxil, Hepsira
    • Tenofovir, Viread
    • Lamivudine, 3TC, Heptovir
  4. List some of the common features of NRTIs used for HBV treatment
    • Phosphroylated intracellularly by cellular kinases
    • MOA: competitively inhibit HBV DNA polymerase +/- incorporate into viral DNA causing chain termination
    • Associated with mitochondrial DNA toxicity- by inhibiting DNA polymerase gamma
  5. Lamivudine (3TC): tell me all about it
    • A cytosine analogue
    • Has a prolonged intracellular half-life in HBV (more than in HIV)
    • Rapid oral absorption; eliminated unchanged
    • Used at lower doses for hepatitis than for AIDS
    • Safe for patients with decompensated liver disease
    • Increased pancreatitis in HIV?HBV patients
    • Energence of resistance (from mutations of DNA polymerase)
  6. Adefovir dipivoxil: tell me all about it
    • A prodrug of adefovir (adenosine analogue)
    • Lipophilic (pivoxil) moiety enhances oral bioavailability
    • Slow suppression of HBV DNA; lease seroconversion
    • Effective for lamivudine-resistant HBV
    • Adverse reactions: nephrotoxicity (high doses); potential mitochondial DNA toxicity
  7. Tenofovir
    • Adenosine analogue
    • Structurally similar to adefovir, but higher rate of complete response and less resistance
  8. Entecavir: tell me about it
    • Guanosine analogue
    • Inhibits all 3 functions of HBV RNA dependant DNA polymerase: base priming, reverse transcription of the (-) strand, synthesis of the (+) strand of HBV DNA
    • The most potent anti-HBV agent
    • Clinical resistance is rare
    • Oral bioavailability is decreased by food (taken with an empty stomach)
    • Renal elimination (serum conc increased with altered renal activity)
    • Side effects: headache, fatigue nausea
    • POtential mitochondial DNA tox (lactic acidosis and hepatic stenosis)
  9. Telbivudine: tell me about it
    • Thymidine analog
    • Oral bioavailability not effeted by food
    • No known drug interaction
    • Effective suppression of HBV DNA, normalization of ALT and reducing HBeAg
    • Emergence of resistance in long term use
    • Potential mitochondial DNA tox (lactic acidosis and hepatic stenosis)
    • GI side effects, myalgia, potential peripheral neuropathy
  10. Define the following:
    • Interferon
    • Polyethylene glycol
  11. Are the following natural or synthetic? How are they administered?
    • IFN-alpha-2a: natural, SC or IM
    • IFN-alpha-2b: natural, SC or IM
    • IFN-alphacon-1: synthetic, SC
  12. How are pegylated IFN-alpha-2a and -2b different from their non pegylated counterparts?
    • Slower clearance (less frequent dosing)
    • Dosage adjustment is needed in renal dysfunction
  13. What are the side effects and contraindications for interferons?
    • Side effects: flu-like symptoms, neurotox, myelosuppression, fatigue, transient hepatic enzyme elevation
    • Contraindications: hepatic decompensation, autoimmune disease, cardiac arrhythmia, pregnancy
  14. Explain the MOA od interferon
    Seriously. I dont get it.
  15. Which drugs are approved for pediatric use?
    IFN-alpha, lamivudine
  16. Tell me about the life cycle of HCV: what is so special about NS3
    HCV NS3 encodes a serine protease essential for viral replication and immune evasion. NS3 cleaves viral polyproteins to generate functional protein products for viral maturation and subsequnt replication
  17. Ribavirin
    • Generally given in combo with Peg IFN-a-2b
    • A prodrug (guanosine nucleoside analogue)
    • MOA: phosphorylated by host cell enzymes; inhibits viral RNA-dependant polymerases
    • Oral bioavailability increased with high-fat meal, decreased with antacid
    • Adverse reactions: dose dependant hemolytic anemia; depression, fatigue, irritability, nausea, insomnia
    • COntraindications: patients with uncorrented anemia, end stage renal failure, pregnancy
    • Teratogenic: avoid pregnancy for > 6 months thereafter
  18. Boceprevir, Telaprevir
    • Serine protease inhibitors
    • MOAL Bind to inhibit HCV non-structural protein NS3
    • Combine with IFN/ribavirin to improve therapeutic response in HCV genotype 1
    • Oral- 3 times daily
    • p450 substrated
    • Adverse reactions: anemia, neutropenia, dysgeusia (altered sense of taste), skin rash, increased QT intervals
Card Set:
Anti-Hepatitis Agents
2012-02-06 04:45:49
Block Lin

How to fight hepatitis
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