Acyclovir: Mechanism of Action
  • Acyclic guanosine derivative: clinical activity --herpes simplex virus -1,-2, Varicella-zoster virus.
  • In vitro activity against Epstein-Barr virus, cytomegalovirus, human herpes virus-6
  • requires three phosphorylation steps:
    • first to the monophosphate (requires viral kinase); Viral kinase requirement provides selectivity for infected cells.
    • selected activation results in triphosphate accumulation only in infected cells.
    • Acyclovir triphosphate accumulates in infected cells and inhibits viral DNA synthesis by: competitive inhibition of dGTP for the viral DNA polymerase and by binding to the DNA template and resulting in chain termination after incorporation into viral DNA
Acyclovir Resistance
  • in HSV (Human Simplex Virus) or VZV (Varicella-zoster virus):
    • alteration in viral thymidine kinase or viral DNA polymerase
    • deficiency in thymidine kinase activity (cross resistance with valacyclovir, famcyclovir, and ganciclovir)
  • Other antiviral agents that do not depend on viral kinases and which would not the exhibit cross resistance: foscarnet, cidofovir, or trifluridine.
  • Acyclovir: oral, IV, topical; cleared primarily by glomerular filtration and tubular secretion. Half life varies enormously dependent on renal function. Drug tissue levels are from 50 percent to 100 percent of serum levels
Clinical Uses and Consideration
  • Most widespread use: treatment of primary infection and recurrence of genital and labial herpes; shortens symptom duration; viral shedding time; time to lesion resolution.
  • Failure of treatment to reduce the frequency of recurrences suggests that acyclovir does not eliminate latent infection.
  • IV acyclovir: treatment of choice for herpes simplex encephalitis and neonatal HSV infection
  • VZV -- less susceptible to acyclovir therapy then HSV
  • IV acyclovir in immunocompromised patients reduces likelihood of cutaneous and visceral dissemination.
  • Adverse Reactions: generally few side effects, and occasional nausea, diarrhea, headache; no evidence of terratogenicity; most frequently encountered toxicity -- renal dysfunction; occasional CNS affects (tremors, lethargy).