A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

348 FUNGAL AND NON-HIV VIRAL INFECTIONS
ANTI-INFLUENZA AGENTS
AMANTADINE (OR RIMANTADINE)
Amantadine is 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 amantadine has
an advantage over immunization in that the latter can be ineffective
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 amantadine during an epidemic
should be considered for people at special risk (e.g.
patients with severe cardiac or lung disease, or healthcare personnel).
Amantadine is less effective during periods of antigenic
variation than during periods of relative antigenic
stability. Treating established influenza with amantadine
within the first 48 hours may ameliorate symptoms. The mean
elimination t 1/2 is 12 hours and elimination is via renal excretion.
Thus, dose reductions are needed when amantadine is
given to patients with renal failure.
Adverse effects
These include:
• dizziness, nervousness and headaches;
• livedo reticularis.
OSELTAMIVIR PHOSPHATE
Oseltamivir phosphate is 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 carboxylate is 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 carboxylate binds 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 phosphate is 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 t 1/2 is between six and
ten hours. Both parent and metabolite are eliminated by renal
tubular secretion. No clinically significant drug interactions
have been defined, but probenacid doubles 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 function).
They are glycoproteins secreted by cells infected with
viruses or foreign double-stranded DNA. They are nonantigenic
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
α gene 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
by rbe (produced from bacteria – typically Escherichia coli –
genetically modified by recombinant DNA technology)
and lns (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-β from fibroblasts;
3. interferon-ω has 60% homology with interferon-α;
4. interferon-γ formerly 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.