A Textbook of Clinical Pharmacology and Therapeutics

ANTIVIRALDRUGTHERAPY(EXCLUDINGANTI-HIV DRUGS) 345

NUCLEOSIDE ANALOGUES

ACICLOVIR

Uses

Acicloviris effective against herpes (simplex and zoster), but is
much less active against cytomegalovirus (also a herpes virus).
Aciclovirand its analogues have replaced idoxuridine.

1. Aciclovirointment (3%) accelerates healing in herpetic
   keratitis. The efficacy of topical aciclovirin genital and
   labial herpes simplex has been unimpressive.

2.Aciclovirgiven orally accelerates healing in genital
herpes. It is much less effective in secondary than in
primary infection. It does not eliminate vaginal carriage,
so Caesarean section is indicated to avoid neonatal herpes.

3.Treatment of shingles (herpes zoster) should be started
within 72 hours of the onset and is useful for patients with
severe pain, although it shortens the illness only modestly.

4.In generalized herpes simplex or herpetic
meningoencephalitis,acicloviris given intravenously.

Mechanism of action

Aciclovirundergoes intracellular metabolic activation to its
monophosphate, selectively in infected cells, by a specific
thymidine kinase that is coded for by the virus but not by the
host genome. Aciclovirmonophosphate is subsequently con-
verted to the corresponding di- and triphosphate (ACIC-TP).

Absorption

Penetration

Uncoating

Early transcription

Late transcription

Early translation

Late translation

Assembly

Oseltamivir

Zanamivir

Amantadine

Interferons

Nucleoside

analogues

(Adefovir

Lamivudine)

Oseltamivir

Zanamivir

Release

Replication

Figure 45.2:Sites of action of antiviral drugs.

(Adapted and updated from de Clercq E.

Biochemical Journal1982; 205: 1–13.)

The viral DNA polymerase is inhibited competitively by

ACIC-TP from synthesizing nascent viral DNA.

Adverse effects

These include:

1. a reversible rise in plasma urea and creatinine;
   2.neurological disturbance;
   3.rash;
   4.nausea and vomiting;
   5.hepatitis.

Contraindications

Acicloviris relatively contraindicated in pregnancy as it is an

analogue of guanosine and so potentially teratogenic in the

first trimester.

Pharmacokinetics

Aciclovirbioavailability is approximately 20% after adminis-

tration of a standard (200 mg) dose orally, and may be dose

dependent. The mean elimination t1/2ofacicloviris three hours

and it crosses the blood–brain barrier producing a CSF concen-

tration that is approximately 50% of that in plasma. Clearance is

largely renal and includes an element of tubular secretion; renal

impairment requires dose/schedule adjustment.

Drug interactions

Probenecid prolongs the half-life of aciclovirby 20% by

inhibiting renal tubular secretion.