A Textbook of Clinical Pharmacology and Therapeutics

344 FUNGAL AND NON-HIVVIRAL INFECTIONS

It is excreted unchanged by glomerular filtration ( 10% of a

dose is metabolized). The normal t1/2is 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 dis-

eases, 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 ser-

ious in healthy individuals. Antiviral drug therapy is therefore

increasingly important. Antiviral therapy is more difficult than

antibacterial therapy because viruses are intimately incorpo-

rated 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 amantadineor 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.

OTHER ANTIFUNGAL AGENTS

GRISEOFULVIN

Uses

Griseofulvinis orally active, but its spectrum is limited to der-
matophytes. 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

Griseofulvinis 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 6-
demethylgriseofulvin, 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)

Flucytosineis used to treat systemic candidiasis and crypto-
coccosis, provided that the strain is sensitive. Its spectrum is
relatively restricted and acquired resistance is a major prob-
lem. Consequently, it is only used in combination therapy (e.g.
withamphotericin B). It is deaminated to 5-fluorouracil in the
fungus and converted to an antimetabolite 5-FdUMP. This
inhibits thymidylate synthetase, impairing fungal DNA syn-
thesis. Adverse effects include gastro-intestinal upset, leuko-
penia and hepatitis. Flucytosineis well absorbed after oral
administration and penetrates the CSF well (thus it is usefully
combined with amphotericin Bto treat cryptococcal meningitis).

Key points

Echinocandin antifungal drugs

• Fungicidal activity against candida and aspergillus.


• They are administered by intravenous infusion.


• They inhibit 1,3-beta Dglucan 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.