Overdosage of intravenous aciclovir has resulted in elevations of serum creatinine, blood urea nitrogen and subsequent renal failure. Neurological effects including confusion, hallucinations, agitation, seizures and coma have been described in association with intravenous overdosage.

Management: patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.

5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Direct acting antivirals, Nucleosides and nucleotides excl. reverse transcriptase inhibitors

ATC code: J05AB01.

Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) types I and II and varicella zoster virus (VZV). The inhibitory activity of Aciclovir for HSV I and HSV II and VZV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected cells does not use Aciclovir effectively as a substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV and VZV converts Aciclovir to Aciclovir monophosphate, a nucleoside analogue which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Aciclovir triphosphate interferes with the viral DNA polymerase and inhibits viral DNA replication with resultant chain termination following its incorporation into the viral DNA.

Prolonged or repeated courses of Aciclovir in severely immuno-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued Aciclovir treatment. Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK, however, strains with altered viral TK or viral DNA polymerase have also been reported. In vitro exposure of HSV isolates to Aciclovir can also lead to the emergence of less sensitive strains. The relationship between the in vitro-determined sensitivity of HSV isolates and clinical response to Aciclovir therapy is not clear.

5.2 Pharmacokinetic properties
Aciclovir is only partially absorbed from the gut. Mean steady state peak plasma concentrations (Cssmax) following doses of 800 mg Aciclovir administered four-hourly were 8 microMol (1.8 micrograms/ml) and equivalent trough plasma levels were 4 microMol (0.9 micrograms/ml).

In adults the terminal plasma half-life after administration of intravenous Aciclovir is about 2.9 hours. Most of the drug is excreted unchanged by the kidney. Renal clearance of Aciclovir is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration, contributes to the renal elimination of the drug. 9-carboxymethoxymethyl-guanine is the only significant metabolite of Aciclovir, and accounts for 10-15% of the dose excreted in the urine. When Aciclovir is given one hour after 1 gram of probenecid the terminal half-life and the area under the plasma concentration time curve is extended by 18% and 40% respectively.

In adults, mean steady state peak plasma concentrations (Cssmax) following a one hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/kg were 22.7 microMol (5.1 microg