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Pharmacology Test 3 > Anti-Viral Hepatitis Agents > Flashcards

Anti-Viral Hepatitis Agents Flashcards

1
Q

Hep C

A

Only curable one

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2
Q

Hep C Infection Cure does not prevent against

A

reinfection

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3
Q

Why can Hep C be cured?

A

Virus does no integrate into human genome

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4
Q

Epclusa

A

SOF + Velpatasvir

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5
Q

Mavyret

A

Glecaprevir (GLE) + Pibrentasvir (PIB)

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6
Q

Vosevi

A

SOF + VEL+ Voxilaprevir (VOX)

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7
Q

NS3/4A protease

A

-PREVIR

Targeting HCV Protein Processing

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8
Q

NS3/4A protease

Names

A
  • Glecaprevir
  • Grazoprevir
  • Paritaprevir
  • Simeprevir
  • Voxilaprevir
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9
Q

NS5B Polymerase

A

-BUVIR

Targeting HCV Replication

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10
Q

NS5B Polymerase

Names

A
  • Sofosbuvir

- Dasabuvir

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11
Q

NS5A

A

-ASVIR

Targeting HCV Replication

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12
Q

NS5A

Names

A
  • Pibrentasvir

- Velpatasvir

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13
Q

HCV NS3/4A Protease

A
  • NS4A critical for activity of NS3 serine protease (HCV protease)
  • early work to identify inhibitors focused on optimizing SUBSTRATE-BASED INHIBITORS
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14
Q

Modern NS3/4A Protease Inhibitors

A
  • Voxilaprevir (VOX)
  • Glecaprevir (GLE)
  • both active against NS3/4A IN ALL HCV GENOTYPES

only 2 FDA approved for HCV

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15
Q

Voxilprevir

VOX

A

NS3/4A Protease Inhibitor

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16
Q

Glecaprevir

GLE

A

NS3/4A Protease Inhibitor

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17
Q

HCV NS5A Inhibitors

A
  • bind to DIMERIZED DOMAIN I and prevent RNA from binding, disrupting replication
  • ** 1st gen LOW BARRIER TO DEVOLOPMENT OF RESISTANT VARIANTS ***
18
Q

NS5A

A
  • protein with virus induced MEMBRANE VESICLES
  • DIMER
  • plays important role in VIRAL RNA REPLICATION
19
Q

2nd Gen NS5A Inhibitors

A
  • Velpatasvir
  • Pibrentasvir
  • PANGENOTYPIC
  • IMPROVED RESISTANCE BARRIER
20
Q

Velpatasvir

A

2nd Gen NS5A Inhibitors

21
Q

Pibrentasvir

A

2nd Gen NS5A Inhibitors

22
Q

NS5B RNA-Dependent RNA Polymerase (RdRp) Nucelos(t)ide Inhibitors

A
  • Sofosbuvir
  • – TROJAN HORSE
  • add first P to overcome rate limiting step (which is adding the first P)
  • mask/protect drug with other groups in order to promote entry with P
23
Q

NS5B RdRp

A
  • catalyzes RNA synthesis
  • nucleotide binding site conserved across all genotypes
  • Challenge
  • – identificying inhibitors
  • – NEED 3P INORDER TO BE ACTIVE; can’t get into cell with 3P
24
Q

Sofosbuvir

A

NS5B RNA-Dependent RNA Polymerase (RdRp) Nucelos(t)ide Inhibitors

  • – TROJAN HORSE
  • add first P to overcome rate limiting step (which is adding the first P)
  • mask/protect drug with other groups in order to promote entry with P
25
Q

Allosteric Inhibitors of NS5B Polymerase

A
  • Dasabuvir (not as effective as Sofosbuvir)
26
Q

Recommended Regimens for HCV Therapy

A
  • Sofosbuvir/velpatasvir 12 week
  • Sofobuvir/velpatasvir/voxilaprevir RESCUE THERAPY
  • Glecaprevir/pibrentasvir 8 week

** DONT NEED TO TEST FOR GENOTYPE **

27
Q

HCV cures are associated with a _____ reduction in HCC risk

A

79%

28
Q

HBV

A
  • DNA virus
  • integrates into human genome
  • 7 known viral genotypes
  • – relaxed circular dsDNA
  • no cure yet
29
Q

Key HBV Markers

A
  • NTCP: membrane receptor

- cccDNA: main template for RNA

30
Q

First-line Agents for Treating HBV

A
  • Entecavir
  • TAF
  • TDF
31
Q

TDF

A
  • Tenofovir disproxil fumarate
32
Q

TAF

A
  • Tenofovir Alafenamide
33
Q

Entecavir

A
  • nucleoside reverse transcriptase inhibitor (NRTI)
  • COMPETITIVELY inhibits all 3 functions of HBV DNA polymerase:
  • – BASE PRIMING
  • – REVERSE TRANSCRIPTION
  • – SYNTHESIS OF + STRAND
  • ** HIGH BARRIER TO RESISTANCE ***
34
Q

Entecavir

Pharmacokinetics

A
  • orally active
  • t1/2 > 5 days
  • renal elimination
35
Q

Entecavir
Common Side Effects
Severe Side Effects

A

Common
- headache, fatigue, dizziness, nausea, high blood sugar, decreased kidney function

Severe

  • LACTIC ACIDOSIS
  • liver issues
36
Q

Tenofovir (TFV)

A
  • ADENOSINE NUCLEOTIDE ANALOG
  • phosphorylated in situ to active TENOFOVIR DISPHOSPHATE (TFV-DP)
  • – triphosphate analog
  • inhibits HIV and HBV RNA-dependent DNA polymerases (RT)
  • LOW BIOAVAILABILITY
37
Q

TFV Prodrugs

TDF & TAF

A
  • prodrug increases cell permeability and oral bioavailability
  • nucleotide analog RT inhibitor for both HIV and HBV
  • ** TAF REDUCES OFF-TARGET EXPOSURE OF TDF, particularly to the kidney and bone ***
38
Q

TAF Mechanism of Action

A
  • passively enters cell
  • CARBOXYPEPTIDASE CATHEPSIN A (CatA) hydrolyzes TAF
  • – TAF -> TFV
  • key intermediate formed (alanine)
  • alanine releases TFV
  • TFV phosphorylated into pharmacologically active metabolite TFV-DP
39
Q

TAF novel prodrug

A
  • goes right into liver cell
  • no need to adjust for bioavailability (you do with TDF)

TAF > TDF

40
Q

Important things to note with HBV

A
  • when to START treatment
  • when to STOP treatment
  • lifelong therapy?
41
Q

Bulevirtide

Myrcludex B

A
  • HepD
  • ENTRY INHIBITOR
  • active against both HBV and HDV
  • block infection in cell via entry

Pharmacology Test 3 (9 decks)

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