Drugs for HCV & HBV Flashcards Preview

GI Liver Pharmacology > Drugs for HCV & HBV > Flashcards

Flashcards in Drugs for HCV & HBV Deck (35):
1

Treatment of Chronic HBV

The 5 orally active antivirals are front-line therapy:
–Tenofovir (preferred)
–Entecavir (preferred)
–Telbivudine
–Adefovir
–Lamivudine
*Emtricitabine In HIV/HBV co-infected patients*

2

The orally active antivirals for HBV Better:

– Better tolerated (than interferons)
– Better suppression of the virus

3

Nucleoside/tide Structural Analogs
L-nucleosides

Lamivudine (3TC)
Telbivudine (LdT)

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Nucleoside/tide Structural Analogs
Acyclic Phosphonates

Adefovir (ADV)
Tenofovir (TDF)

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Nucleoside/tide Structural Analogs
d-cyclopentane

Entecavir (ETV)

6

Antiviral drug resistance tends to be

structure (sugar residue) specific
Arises from mutations in HBV polymerase

7

Tenofovir
Mechanism of Action

Pro-drug for tenofovir, a nucleotide analog
of adenosine-5-monophosphate
Diphosphate form inhibits HBV polymerase & produces chain termination

8

Entecavir
Mechanism of Action

Guanosine nucleoside analog
Triphosphate form inhibits HBV polymerase

9

Telbivudine
Mechanism of Action

L-isomer of thymidine
Triphosphate form inhibits HBV polymerase & produces chain termination

10

Adefovir
Mechanism of Action

Adenosine-5-monophosphate
Diphosphate form incorporated into viral DNA producing chain termination

11

Lamivudine
Mechanism of Action

L-isomers of cytosine with similar activity, potency, side effects & patterns of resistance
Triphosphate form inhibits HBV polymerase

12

Emtricitabine
Mechanism of Action

L-isomers of cytosine with similar activity, potency, side effects & patterns of resistance
Triphosphate form inhibits HBV polymerase

13

HBV antivirals ADME

NO CYP interactions of note, BUT competitive renal secretory mechanisms may be opportunity for drug-drug interactions (GFR + RTS)

14

Tenofovir Bioavailability

Taken with high fat meal increases bioavailability

15

Entecavir Bioavailability

Food delays absorption; coordinate meals &
dosing

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Telbivudine, Adefovir, Lamivudine, & Emtricitabine Bioavailability

Food has no substantial effect upon bioavailability

17

Tenofovir Adverse Effects:

Rare Renal Toxicity: Avoide Systemic/renal disease or concurrent nephrotoxic drugs NSAIDs. Serum creatinine/BUN & phosphate testing recommended.
Osteoporosis: shown to produce decrease bone
mineral density & increase markers of bone turnover.

18

Serum creatinine/BUN tests also recommended for

lamivudine, adefovir, & entecavir

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Interferons

Pleiotropic biological effects including antiviral,
antiproliferative and immunomodulatory actions

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Interferon Highpoints

• IM or SC administration
• Cellular effect, exceed persistence of drug in body
• The 2 PEG products differ in the structure of the PEG; straight chain vs. branched chain
• Acute influenza-like syndrome following injection
• Use antipyretics
• Pegylated products usually better tolerated – lower rates of discontinuance

21

Interferon Dose-Limiting Toxicity

• Neuropsychiatric issues – Depression
• Higher in HCV infected patients than in HBV infections – Somnolence, confusion, behavioral changes, & rarely, seizures
• Effect on serotonin and/or corticotropin?
• Myelosuppression with granulocytopenia &
thrombocytopenia
• Increase hepatic enzymes & triglycerides– Monitor thyroid function & LFTs during IFN therapy
• Infrequent development of serum neutralizing antibodies– Loss of clinical responsiveness

22

Treatment of Chronic HCV
Genotype 1

• Peginterferon-alfa
• + Ribavirin for 24 – 48 weeks
• + Telaprevir or Boceprevir – HCV NS3/4A protease inhibitors

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Treatment of Chronic HCV
Genotype 2 & 3

• Peginterferon-alfa
• + Ribavirin for 24 – 48 weeks

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Ribavirin:
Mechanisms of action include:

– enhanced host T-cell immune clearance of HCV
– inhibition of the host inosine monophosphate dehydrogenase (IMPDH), with depletion of pools of guanosine triphosphate, an essential substrate for viral RNA synthesis
– direct inhibition of HCV replication (RNA-dependent RNA polymerase)

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Ribavirin:
ADME

• Bioavailability: Increase by high fat meal
• Extensive uptake into cells, including erythrocytes
• No CYP action - renal elimin -> accumulation possible

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Ribavirin:
Toxicity

• The primary toxicity of oral ribavirin therapy is
hemolytic anemia
• Fatal & non-fatal MI & difficulty breathing reported, 2° to ribavirin-induced anemia

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Male-Mediated Teratogenicity

Ribavirin, Boceprevir, & Telaprevir
Contraindicated in:
– Women in pregnancy
– Women who could become pregnant
– Men whose partners are pregnant

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Telaprevir & Boceprevir
Mechanisms of action:

The NS3/4A serine protease cleaves several key sites in the polyprotein precursor. The inhibitors prevent formation of several of the critical nonstructural proteins.

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Telaprevir & Boceprevir Somewhat less effective in

African Americans

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Telaprevir & Boceprevir
Side Effects:

Both drugs produce fatigue, anemia* and nausea
– *Additive anemia over and above the combination drug effects

31

Telaprevir & Boceprevir
SERIOUS SIDE EFFECT:

Telaprevir but NOT boceprevir associated with pruritis, rash; sometimes serious rash
– DRESS (Drug Rash w/ Eosinophilia & Systemic Symptoms
– Stevens-Johnson syndrome (SJS)
– Toxic epidermal necrolysis (TEN)
– Erythema multiforme (EM

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Telaprevir & Boceprevir
ADME

• Take BOTH with food – increases bioavailability
– High fat for telaprevir; no preference w/ boceprevir
• Boceprevir & telaprevir extensively bind plasma proteins
• BOTH undergo hepatic metabolism w/ elimination primarily in stool

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Telaprevir & Boceprevir
Contraindicated:

Co-administration with strong CYP3A4 inducers (rifampin) or with drugs reliant on CYP3A4 or P-gp contraindicated.

34

Vidarabine
Mechanism:

Vidarabine works by interfering with the synthesis of viral DNA. It is a nucleoside analog & therefore has to be phosphorylated to be active (X3). Both an inhibitor & a substrate of viral DNA polymerase.

35

Vidarabine:

Excreted kidneys.