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Flashcards in Viral Drugs Deck (15)
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1

General Features of Antivirals?

  • Viral Replication depends no host cell machinery 
  • To work, antivirals must block:
    • viral entry
    • intracellular viral activity (replication)
    • Viral exit
  • The more selective the better
  • Antivirals drugs are virustatic

2

General Features for Herpes virus infection Drugs:

-major us4e

-MOA

-Adverse effects

-DDI 

-Resistance

  • Major Use:
    • HSV-1, HSV-2, VZV, CMV
  • MOA:
    • After entry into host cell, drug is selectively phosphorylated by virus-specific enzymes
      • ex thymidine kinase
    • The kinases the convert to a triphosphate that blocks viral DNA synthesis by:
      • inhibiting viral DNA polymerase
      • Incorporating into viral DNA, causing early chain termination
  • Adverse Effects:
    • Nephrotoxicity is dose limiting
    • Headache and GI upset
  • DDI:
    • Avoid other nephrotic drugs
      • aminoglycosides, B-lactams
    • Avoid other drugs that compete for tubular secretion
      • Increase blood levels of antiviral=Increase adverse effects
  • Resistance:
    • caused by mutations in viral thymidine kinase or DNA polymerase
    • Cross-resistance common due to same/similar MOA

3

Herpes virus infection: Drug spectrum for each virus

-HSV

-VZV

-CMV

HSV/VZV

  • Acyclovir
  • Valacyclovir
  • Famciclovir
  • Penciclovir
  • Docosanol
  • Trifluridine

HSV/VZV/CMV

  • Foscarnet
  • Ganciclovir

CMV

  • Valgancyclovir
  • Cidofovir

4

Acyclovir:

-clinical use

-MOA

-PK

-Side effects

-DDIs

-Resistance

Systemic drug for HSV and VZV infections

  • Clinical Use:
    • 1st line agent for HSV-1 and HSV-2 
    • Some activity against VZV
      • 10x more potent against HSV than VZV
    • Preferred choice for VZV in immunocompromised patients
      • HIV + HSV
    • Drug of choice for ocular herpetic infections including VZV
  • MOA:
    • Nucleoside analog is phosphorylated by virus-specific thymidine kinase and incorportated into viral DNA
    • Phosphorylated to the di- and tri-phosphates by host cell
    • Competively inhibits DNA polymerase
  • PK
    • Poor bioavailabilty (15%)
    • Renal elimination (decrease dose in renal impaired)
    • PO, IV, Topical
  • Side effects:
    • Well tolerated
    • Some GI Upset and headache with PO
    • Renal toxicity and neurological effects w/IV
  • DDIs
    • Avoid combining with drugs that compete for tubular secretion
      • ex: Probenecid, cimetidine 
    • Avoid combining with nephrotic drugs
      • vancomycin, aminoglycoside=Increase risk of renal toxicity
  • Resistance:
    • Changes in thymidine kinase or DNA polymerase cause resistance
    • Cross-resistance to valacyclovir, famciclovir, and ganciclovir

5

Valacyclovir:

-Clinical Use

-MOA

-PK

-Side effects

systemic drug for HSV and VZV infections:

  • Clinical Use:
    • 1st line agent for HSV-1, HSV-2, VZV infection (herpes3)
    • Especially useful for first or recurrent genital herpes and VZV
    • Once a day dosing for suppression of recurrent genital herpes=decreased transmission
  • MOA:
    • same as acyclovir 
  • PK:
    • Prodrug of acyclovir
      • undergoes 1st pass metabolism to form acyclovir
    • Increase Bioavilability (50-70%)
    • Increase Plasma levels (3-5 x higher than acyclovir
    • Orally (especially for genital herpes)
  • Side effects:
    • acyclovir like
      • plus: confusion, delerium, seizures at high dose
      • especially in immunocompromised

6

Famciclovir

-clinical use

MOA

-PK

Systemic drug for HSV and VZV

  • Clinical Use:
    • 1st line agent for VZV infeciton
    • Also useful for:
      • tx of 1st and recurrent genital and orolabial herpes
        • chronic daily suppression
  • MOA:
    • Nucleoside analog that inhibits viral DNA polymerase to block DNA synthesis
  • PK:
    • Prodrug for penciclovir (undergoes 1st pass metabolism)
    • Increase bioavailability (70%) and plasma levels compared to penciclovir 
    • Orally

7

Penciclovir:

-Clinical Use

-MOA

-PK

Topical Drug for HSV and VZV

  • Clinical Use:
    • tx of herpes labialis and genitalis
  • MOA: 
    • same
  • PK
    • active metabolite of famciclovir
    • Poor Bioavailability--> 1% topical cream

8

Docosanol:

-MOA

-PK

Topical Drug for HSV and VZV

  • MOA:
    • inhibits fusion of plasma membrane to HSV envelope (block viral entry)
  • PK
    • 10% cream available OTC (Abreva)

9

Trifluridine:

-Clinical Use

-MOA

-PK

-Side effects

HSV & VZV: Topical drug for Herpetic Infection of the EYE

  • Clinical Use:
    • keratojunctivitis and epithelial keratitis due to HSV-1 and HSV-2
  • MOA:
    • same
  • PK:
    • topical emulsion--> undetectable in plasma
  • Side effects:
    • eye irritation, eyelid edema(rare), blurred vision
    • no systemic effects when used topically

 

10

Ganciclovir

-clinical use

-MOA

-PK

-side effects

-DDIs

-Resistance

Systemic drug for CMV

  • Clinical use:
    • CMV retinitis 
    • often combined with foscarnet to delay progression in AIDs patients
  • MOA
    • nucleosid analog phosphorylated by virus-specific UL97 kinase  enzyme to inhibit polymerase and cause early chain termiation
  • PK
    • poor bioavailability (<10%)
    • Renal Elimination
    • IV 
  • Side effects: 
    • leukopenia, thrombocytopenia, liver damage, seizuires 
    • Pregancy category C
      • Caused by teratogenicity and infertility in animal studies
    • councel men and women to use birth control 90 days post treatment
  • DDIs:
    • Severe neutropenia with myelosuppressive agents 
      • lamivudine
    • Probenecid, Trimethoprim increase plasma levels of ganciclovir
      • other renal secreted drugs
  • Resistance:
    • increases with druation of use
    • UL97 mutations decrease triphosphorylation to the active form 
      • lower efficacy

11

Valganciclovir

-clinical use

-MOA

-PK

-DDIs

-Side effects

 

Systemic drug for CMV

  • Clinical use:
    • CMV retinitis treatment and prophylaxis 
  • PK:
    • prodrug of ganciclovir 
      • replaced need for IV
    • Greater bioavailability (60%)
    • Oral
  • MOA, Side effects, DDIs=same as ganciclovir

 

12

Foscarnet

-Clinical use

-MOA

-PK

-Side effects

-DDIs

-Resistance

Systemic drug for CMV:

  • Clinical use:
    • CMV retinitis treatment
    • Synergism when combined with ganciclovir, but toxicity increases
      • greater effect combined than seperate
  • MOA:
    • inhibits viral DNA and RNA polymerase & HIV transcripatse directly (does not require phosphorylation)
    • Covers full HHV spectrum
  • PK:
    • Poorly water soluble (requires dose in large fluid volume)
    • Deposited into bone (10-30%) 
      • Prolongs half life for months
    • IV only due to poor bioavailability and GI intolerance
  • Side effects:
    • Nephrotoxicity, fever, rash, elevated liver enzymes (AST, LST)
    • CNS effects exacerbated by use with imipenem (B-lactam antibioitic)
    • abnormal state in calcium, phosphate, and magnesium levels
    • Infusion pump that controls rate must be used to avoid toxicity
    • Saline preloading helps avoid renal toxicity
  • DDIs
    • avoid other nephrotoxic drugs
  • Resistance:
    • Develops with prolonged or repeated exposure due to mutations in DNA polymerase gene

13

Cidofovir:

-Clinical Use

-MOA

-PK

-Side effects

 

Systemic drug for HSV/VZV/CMV

  • Clinical use:
    • CMV retinitis treatment
  • MOA:
    • converted to cidofovir disphospahte by the host cell kinase 
    • Cidovir disphosphate inhibits viral DNA polymerase
    • Retais activity against acyclovir and ganciclovir resistant viral strains bc activity is not dependent on viral kinase 
  • PK:
    • Cidoffovir disphosphate (active metabolite) has a longer intracellular half life: 17-65 hours
    • IV
  • Side effects:
    • Neutropenia
    • Proteinuria (15-25%)
    • Metabolic acidosis
    • Nephrotoxicity: can be moderated if patient is given PO probenecid + IV saline 2-3 hours prior to administration
      • probencid blocks active tubular secretion (delating cidofovir clearance via the renal tubules)
      • Decrease Nephrotoxicity

14

Probenecid

Blocks active tubular secretions

Decreases nephrotoxicity 

15

Chrnoic Hepatitis B and C:

-Therapeutic goals:

Standard of care

Hep B:

  • Therapeutic goals
    • Suppression of HBV DNA to undetectable levels
    • Seroconversion of HBeAg from + to -
    • Reduction in liver transaminase levels
  • Standard of care
    • HBIG vacine or Hepislav-B
    • Nucleoside/tide Analogs (PO) and/or Peginterferons (SQ)

Hepatitis C:

  • Therapeutic goals:
    • eradicate virus