A Textbook of Clinical Pharmacology and Therapeutics

348 FUNGAL AND NON-HIVVIRAL INFECTIONS

ANTI-INFLUENZA AGENTS

AMANTADINE (OR RIMANTADINE)

Amantadineis effective in preventing the spread of influenza A
and has an unrelated action in Parkinson’s disease (Chapter 21).
Its usefulness as an antiviral agent is limited to influenza A. Its
mode of action is unknown. Prophylaxis with amantadinehas
an advantage over immunization in that the latter can be inef-
fective when a new antigenic variant arises in the community
and spreads too rapidly for a killed virus vaccine to be prepared
and administered. Prophylaxis with amantadineduring an epi-
demic should be considered for people at special risk (e.g.
patients with severe cardiac or lung disease, or healthcare per-
sonnel).Amantadineis less effective during periods of anti-
genic variation than during periods of relative antigenic
stability. Treating established influenza with amantadine
within the first 48 hours may ameliorate symptoms. The mean
eliminationt1/2is 12 hours and elimination is via renal excre-
tion. Thus, dose reductions are needed when amantadineis
given to patients with renal failure.

Adverse effects

These include:

• dizziness, nervousness and headaches;


• livedo reticularis.

OSELTAMIVIR PHOSPHATE

Oseltamivir phosphateis an ethyl ester prodrug of oseltamivir
carboxylate. It is used to prevent and treat influenza A and B
infections, when given orally twice a day for five days.
Oseltamivir carboxylateis an analogue of sialic acid and is a
competitive inhibitor of the influenza virus neuraminidase that
cleaves the terminal sialic acid residues and destroys the
receptors recognized by viral haemagglutinin present on the cell
surface of progeny virions and in respiratory secretions.
Neuraminidase activity is needed for release of new virions
from infected cells. When oseltamivir carboxylatebinds to the
neuraminidase it causes a conformational change at the active
site, thereby inhibiting sialic acid cleavage. This leads to viral
aggregation at the cell surface and reduced viral spread in the
respiratory tract. Adverse effects include headache, nausea,
vomiting and abdominal discomfort (noted more frequently in
patients with active influenza than if the agent is used for
prophylaxis). Adverse effects are reduced by taking the drug
with food. Oral oseltamivir phosphateis absorbed orally and
de-esterified by gastro-intestinal and hepatic esterases to the
active carboxylate. The bioavailability of the carboxylate
approaches 80% and its mean elimination t1/2is between six and
ten hours. Both parent and metabolite are eliminated by renal
tubular secretion. No clinically significant drug interactions
have been defined, but probenaciddoubles the half-life of the
active carboxylate. Resistant influenza isolates have mutations
in the N1 and N2 neuraminidases, but these variants have
reduced virulence in animal models. Activity against the
dreaded H5N1 avian flu strain is not proven.

ZANAMIVIR

This is another inhibitor of influenza virus neuraminidase

enzymes. If given early during influenza A or B infection via

intranasal route it is effective in reducing symptoms.

Key points

Antiviral therapy

• Selective toxicity for viruses is more difficult to achieve
  than for fungi or bacteria.


• Viruses survive and proliferate inside human cells and
  often use human cellular enzymes and processes to
  carry out their replicative process.


• Certain viruses encode virus-specific enzymes that can
  be targeted (e.g. herpes virus and aciclovir; CMV virus
  and its DNA polymerase which is a target for
  ganciclovir).

INTERFERONS AND ANTIVIRAL HEPATITIS

THERAPY

Interferons are cytokines (mediators of cell growth and func-

tion). They are glycoproteins secreted by cells infected with

viruses or foreign double-stranded DNA. They are non-

antigenic and are active against a wide range of viruses, but

unfortunately they are relatively species specific. Thus, it is

necessary to produce human interferon to act on human cells.

Interferon production is triggered not only by viruses but also

by tumour cells or previously encountered foreign antigens.

Interferons are important in immune regulation.

Four main types of interferon are recognized:

1. Interferon-α– known previously as leukocyte or
   lymphoblastoid interferon. Subspecies of the human
   αgene produce variants designated by the addition of a
   number, e.g. interferon-α 2 , or in the case of a mixture of
   proteins, by Nl, N2, etc. Two methods of commercial
   production have been developed and these are indicated
   byrbe(produced from bacteria – typically Escherichia coli–
   genetically modified by recombinant DNA technology)
   andlns(produced from cultured lymphoblasts stimulated
   by Sendai virus). Interferon-α 2 may also differ in the
   amino acids at positions 23 and 24 and these are shown by
   the addition of a letter. Thus, α-2a has Lys–His at these
   sites, while α-2b has Arg–His. It is not yet clear whether
   these different molecules have different therapeutic
   properties;
   2.interferon-βfrom fibroblasts;
   3.interferon-ωhas 60% homology with interferon-α;
   4.interferon-γformerly called ‘immune’ interferon because
   it is produced by lymphocytes in response to antigens and
   mitogens.
   Commercial production of interferon by cloning of human
   interferon genes into bacterial and yeast plasmids is now
   available, facilitating large-scale production.