A Textbook of Clinical Pharmacology and Therapeutics

ANTIVIRALDRUGTHERAPY(EXCLUDINGANTI-HIV DRUGS) 347

ganciclovir, yielding a ganciclovirbioavailability of 60%.
Ganciclovirhas a mean elimination t1/2of between two and
five hours and is virtually totally excreted by the kidney. Dose
reduction is needed in renal failure.

Drug interactions

Probenecid reduces renal clearance of ganciclovir.
Antineoplastic drugs, co-trimoxazoleandamphotericin B
increase its toxic effects on rapidly dividing tissues including
bone marrow, skin and gut epithelium. Zidovudine(AZT)
should not be given concomitantly with ganciclovirbecause of
the potentiation of bone marrow suppression.
The pharmacology and therapeutics of other available
nucleoside analogue anti-herpes drugs are shown in Table 45.3.

RIBAVIRIN (TRIBAVIRIN)

Uses

Ribavirinis active against a number of RNA and DNA (HSV-1
and HSV-2, influenza) viruses. It is used to treat hepatitis C
(combined with interferon) or bronchiolitis secondary to
respiratory syncytial virus infection in infants and children.
Administration for bronchiolitis is via aerosol inhalation.

Mechanism of action

Ribavirinis taken up into cells and phosphorylated to trib-
avirin 5-monophosphate by adenosine kinase and is then

phosphorylated to its di- and triphosphates by other cellular

kinases. Ribavirin-triphosphate inhibits the guanylation reac-

tion in the formation of the 5cap of mRNA and inhibits viral

RNA methyltransferase. It has little or no effect on mam-

malian RNA methyltransferase.

Adverse effects

Systemic administration can cause:

• dose-related haemolytic anaemia and haematopoietic
  suppression;


• rigors (during infusion);


• rash, pruritus;


• teratogenesis.
  No systemic adverse effects of ribavirinhave been reported
  following administration by aerosol or nebulizer.
  General adverse effects include:


• worsening respiration and bacterial pneumonia
  (super-infection);


• pneumothorax;


• teratogenesis (a concern even with aerosol exposure of
  healthcare workers).

Pharmacokinetics

Following nebulized administration, only small amounts of

ribavirinare absorbed systemically.

Table 45.3:Summary of available aciclovir-like antiviral agents

Druga Use Side effects Pharmacokinetics Other specific comments

Famciclovir Herpes simplex virus See aciclovir Prodrug of penciclovir. High bioavailability

(HSV) and recurrent Bioavailability of penciclovir is prodrug of penciclovir.

genital HSV varicella 77% from famciclovir. t1/2is 2.5 h. Aciclovir-resistant isolates

zoster (VZV) Renal excretion are cross-resistant

Penciclovir Systemic therapy, for See aciclovir. Bioavailability is very good. t1/2 High bioavailability. Viral

HSV and VZV and Same as placebo for is 2.5 h. Renal excretion (in renal DNA polymerase

hepatitis B. Topical topical use failure t1/218 h). Intracellular not as sensitive to

therapy for HSV triphosphate is longer lasting Pen-Triphosphate.

(7–20 h) than aciclovir Aciclovir-resistant isolates

are cross-resistant.

Valaciclovir HSV infection but L-Valyl ester of aciclovir. Rapid absorption bioavailability High bioavailability.

uncertainty about Haemolytic–uraemic / is 54%. Converted to aciclovir Aciclovir-resistant isolates

VZV and CMV TTP syndrome in before phosphorylation are cross-resistant

in future immunosuppressed

individuals

Cidofovir Intravenous therapy See ganciclovir, but has Plasma t1/2of cidofovir is 2.6 h CMV isolates resistant to

for HSV and CMV been noted to cause and of cidofovir diphosphate ganciclovir are sensitive.

renal failure (active) is 17–30 h. Cidofovir is Not to be used in patients

renally eliminated with renal failure

aOther drugs in the antiviral arena with recent availability or undergoing further clinical development include sorivudine (nucleoside analogue for VZV)

n-Docosanol (topical cream for recurrent herpes labialis) and Fomiversen (an antisense phosphorothioate oligonucleotide complementary to human CMV

immediate–early mRNA, used in AIDS patients).