Zylovir Mechanism of Action

Pharmacology: Pharmacokinetics: Aciclovir is excreted through the kidney by both glomerular filtration and tubular secretion. The terminal or beta-phase half-life is reported to be about 2 to 3 hours for adults without renal impairment. In chronic renal failure, this value is increased and may be up to 19.5 hours in anuric patients. During haemodialysis the half-life has been reported to be reduced to 5.7 hours, with 60% of a dose of aciclovir being removed. Faecal excretion may account for about 2% of a dose. There is wide distribution, including into the CSF where concentrations achieved are about 50% of those achieved in plasma. Protein binding is reported to range from 9 to 33%. Probenecid increases the half-life and the area under the plasma concentration-time curve of aciclovir. About 15 to 30% of an oral dose of aciclovir is considered to be absorbed from the gastrointestinal tract. Orally active prodrugs such as valaciclovir have been developed to overcome this poor absorption. Aciclovir crosses the placenta and is distributed into breast milk in concentrations about 3 times higher than those in maternal serum.
Microbiology: Antiviral Action: Aciclovir is active against herpes simplex virus type 1 and type 2 and against varicella-zoster virus. This activity is due to intracellular conversion of Aciclovir by viral thymidine kinase to the monophosphate with subsequent conversion by cellular enzymes to the diphosphate and the active triphosphate. This active form inhibits viral DNA synthesis and replication by inhibiting the herpes virus DNA polymerase enzyme as well as being incorporated into viral DNA. This process is highly selective for infected cells. Studies in animals and in vitro have found various sensitivities but show that these viruses are inhibited by concentrations of Aciclovir that are readily achieved clinically. Herpes simplex virus type I appears to be the most susceptible, then type 2, followed by varicella-zoster virus. The Epstein-Barr virus and CMV are also susceptible to Aciclovir to a lesser extent. However, for CMV it does not appear to be activated by thymidine kinase and may act via a different mechanism. Epstein-Barr virus may have reduced thymidine kinase activity but its DNA polymerase is very sensitive to inhibition by Aciclovir triphosphate, which may account for the partial activity. Aciclovir has no activity against latent viruses, but there is some evidence that it inhibits latent herpes simplex virus at an early stage of reactivation.
Resistance: Herpes simplex virus develops resistance to Aciclovir in vitro and in vivo by selection of mutants deficient in thymidine kinase. Other mechanisms of resistance include altered substrate specificity of thymidine kinase and reduced sensitivity of viral DNA polymerase. Resistance has also been reported with varicella-zoster virus, probably by similar mechanisms. Although occasional treatment failures have been reported, resistance has not yet emerged as a major problem in treating herpes simplex infections. However, resistant viruses are more likely to be a problem in patients with a suppressed immune response; AIDS patients may be particularly prone to Aciclovir-resistant mucocutaneous herpes simplex virus infections. Viruses resistant to Aciclovir because of absence of thymidine kinase may be cross-resistant to other antivirals phosphorylated by this enzyme, such as Brivudine, Idoxuridine, and Ganciclovir. Viruses resistant because of altered substrate specificity of thymidine kinase may display cross-resistance to brivudine; those with altered DNA polymerase sensitivity may be resistant to Brivudine and Vidarabine. However, those viruses with altered enzyme specificity or sensitivity tend to have variable cross-resistance patterns and may be relatively susceptible to the aforementioned antivirals.