Acyclovir (Famciclovir, Valacyclovir)

Summary

Acyclovir, and the closely related drugs, famciclovir and valacyclovir, are guanosine analogs that are used as antiviral drugs. They work by inhibiting viral DNA polymerase, preventing the synthesis of viral DNA. Importantly, acyclovir must be activated by phosphorylation performed by viral kinases. These drugs are used to treat herpes simplex viruses, or HSV, as well as varicella-zoster virus, or VZV. The major side effect to look out for is kidney toxicity.

Key Points

• Acyclovir (famciclovir, valacyclovir)
  • Valacyclovir has better oral availability
    • Prodrug of acyclovir
  • Mechanism
    • Guanosine analog inhibits viral DNA polymerase
      • Causes DNA chain termination, preventing viral DNA replication
      • Requires phosphorylation by HSV/VZV thymidine kinase
        • Phosphorylation produces an active triphosphate form
        • Not phosphorylated in uninfected cells → limits side effects
  • Clinical Use
    • HSV
      • Used for mucocutaneous and genital lesions, meningoencephalitis
      • Cannot eliminate latent forms
    • VZV
      • Cannot eliminate latent forms
    • Negligible activity against EBV and CMV
      • EBV and CMV produce different thymidine kinases with lower affinity for acyclovir, reducing phosphorylation and activation
  • Adverse Effects
    • Nephrotoxicity
      • Can precipitate into crystalline form, which can obstruct and damage tubules, leading to acute renal failure
      • Ample hydration can prevent nephrotoxicity
  • Resistance
    • Mutated viral thymidine kinase