A Textbook of Clinical Pharmacology and Therapeutics

344 FUNGAL AND NON-HIV VIRAL INFECTIONS
Key points
Echinocandin antifungal drugs
• Fungicidal activity against candida and aspergillus.
• They are administered by intravenous infusion.
• They inhibit 1,3-beta D glucan synthase involved in the
formation of glucan polysaccharide in certain fungal
cell walls.
• They are generally well tolerated, but cause infusion
phlebitis, fever and histamine release effects with rapid
infusions, gastro-intestinal upsets, hepatitis and
leukopenia.
• Few drug interactions: ciclosporin increases caspofungin
AUC and micafungin increases the AUC of sirolimus and
nifedipine.
OTHER ANTIFUNGAL AGENTS
GRISEOFULVIN
Uses
Griseofulvin is orally active, but its spectrum is limited to dermatophytes.
It is concentrated in keratinized cells. It is given
orally with meals and treatment is recommended for six weeks
for skin infections and up to 12 months for nail infections.
Mechanism of action
Griseofulvin is concentrated in fungi and binds to tubulin,
blocking polymerization of the microtubule, disrupting the
mitotic spindle.
Adverse effects
These include:
• headaches and mental dullness or inattention;
• diarrhoea or nausea;
• rashes and photosensitivity;
Pharmacokinetics
Griseofulvin is metabolized by the liver to inactive 6demethylgriseofulvin,
which is excreted in the urine. Less than
1% of the parent drug is excreted in the urine. Griseofulvin
induces hepatic CYP450s and consequently can interact with
many drugs.
FLUCYTOSINE (5-FLUOROCYTOSINE)
Flucytosine is used to treat systemic candidiasis and cryptococcosis,
provided that the strain is sensitive. Its spectrum is
relatively restricted and acquired resistance is a major problem.
Consequently, it is only used in combination therapy (e.g.
with amphotericin B). It is deaminated to 5-fluorouracil in the
fungus and converted to an antimetabolite 5-FdUMP. This
inhibits thymidylate synthetase, impairing fungal DNA synthesis.
Adverse effects include gastro-intestinal upset, leukopenia
and hepatitis. Flucytosine is well absorbed after oral
administration and penetrates the CSF well (thus it is usefully
combined with amphotericin B to treat cryptococcal meningitis).
It is excreted unchanged by glomerular filtration (�10% of a
dose is metabolized). The normal t 1/2 is six hours and this is
prolonged in renal failure.
ANTIVIRAL DRUG THERAPY (EXCLUDING
ANTI-HIV DRUGS)
INTRODUCTION
Many viral illnesses are mild and/or self-limiting, but some
are deadly (e.g. the now extinct smallpox, some strains of
influenza, the global HIV-1 epidemic and various exotic diseases,
including Marburg disease, and various encephalitides).
Some produce chronic disease (e.g. hepatitis B and C). Even the
mild common cold is economically significant, as is its deadly
relative SARS (severe acute respiratory syndrome). Patients
who are immunocompromised, especially by HIV-1 infection,
are at risk of serious illness from viruses that are seldom serious
in healthy individuals. Antiviral drug therapy is therefore
increasingly important. Antiviral therapy is more difficult than
antibacterial therapy because viruses are intimately incorporated
in host cells and the therapeutic targets are often similar
to the equivalent enzymes/structures in human cells. To
summarize these problems:
• Viral replication is intracellular, so drugs must penetrate
cells in order to be effective.
• Viral replication usurps the metabolic processes of host
cells.
• Although viral replication begins almost immediately
after the host cell has been penetrated, the clinical signs
and symptoms of infection often appear after peak viral
replication is over.
Several events in the viral life cycle may prove susceptible
as drug targets:
• when the virus is outside cells it is susceptible to antibody
attack; however, finding drugs that are non-toxic but
which can destroy viruses in this situation remains a
challenge;
• viral coat attachment to the cell surface probably involves
interaction between the virus coat and the cell membrane
surface;
• penetration of the cell membrane can be prevented (e.g. for
influenza A by amantadine or neuraminidase inhibitors);
• uncoating of the virus with release of viral nucleic acid
intracellularly;
• viral nucleic acid acts as a template for new strands of
nucleic acid that in turn direct the production of new viral
components utilizing the host cell’s synthetic mechanisms.
Most non-HIV antiviral drugs act at this stage of viral
replication;
• extracellular release of new viral particles.
Figure 45.2 summarizes the sites of action of antiviral
drugs.